Rev of Pat and Gen 7 TH Edi

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Review of Pathology
and Genetics
Seventh Edition
Gobind Rai Garg MBBS MD

(Gold Medalist)
Ex-Assistant Professor (Pharmacology)
MAMC, Delhi, India
Director
Ayush Institute of Medical Sciences
Delhi, India
Sparsh Gupta MBBS MD

(Gold Medalist)
Assistant Professor (Pharmacology)
VMMC and Safdarjung Hospital, Delhi, India
The Health Sciences Publisher

New Delhi | London | Panama | Philadelphia
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2015, Gobind Rai Garg, Sparsh Gupta
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is not associated with any product or vendor mentioned in this book.
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Assistant Editors: Mrs Praveen Kumari, Mrs Krishna Gupta
Review of Pathology and Genetics

First Edition: 2009
Second Edition: 2010
Third Edition: 2011
Fourth Edition: 2012
Fifth Edition: 2013
Sixth Edition 2014
Seventh Edition 2015
ISBN: 978-93-5152-867-8
Printed at
Dedicated to
My parents, wife Praveen,

son Ayush and other family members
Gobind Rai Garg
My family members and

my teachers (Shri SK Suri and Mrs V Gopalan)
Sparsh Gupta
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Preface to the Seventh Edition
We acknowledge the support shown by each of our esteemed readers (present and past) for placing the book at the numero uno
position amongst the pathology books for PGMEE. To meet the expectations of students, we have tried to further improve this
seventh edition.
The book has been fully colored to increase its appeal to the esteemed readers. We have intentionally chosen the topic of
Immunology because apart from being very important, it is considered as one of the most difficult chapters of Pathology.
Dear friends, the apprehension regarding the National Eligibility Cum Entrance Test (NEET) has now been taken care of
as the examination pattern has not been modified drastically. Cracking the NEET exam and other important PG examinations
require a thorough knowledge and understanding of the subject. Readers of this book have got an edge over others because
of the strong theory and conceptual questions. This along with the key points given under the heading of various boxes in the
chapters has helped many of you to get extremely good ranks in NEET 2013, 14 and 2015.
It is a humble request from our side that all the chapters (and not only general pathology) of this book has to be read by
the student so as to maximise the benefit. This is because many additional concepts and questions asked frequently in the exam
have been explained in systemic pathology chapters. This is one important point which came as a gist differentiating the people
getting a good rank in NEET versus those who did not.
In our constant endeavour to improvise the book, there has been incorporation of important additions in almost all chapters
along with the new section of Most recent questions. The question bank of the every chapter has been subdivided into smaller
portions. It will help students to solve MCQs after reading the theory of a particular topic of a chapter.
For getting a grasp on the NEET questions in a better way, a new section in the end comprising of Image Based Questions
has also been added.
In this seventh edition, we have added a lot of diagrams and flow charts to make learning interesting and easier. Another
salient feature of this edition is the updating of appropriate authentic references from standard textbooks particularly in regard
to the controversial questions so that reader gets all the relevant information under one roof. Other salient features of the
current edition are:
All references have been updated from Robbins 9th edition

The question bank has been expanded and includes the most recent questions
More color plates for image based questions have been added
A summary of important information added in Robbins 9th edition has been mentioned separately at the end of each chapter.
We have fully revised the book and corrected the typographical and some other errors present in the previous editions.
We have also added plenty of vital information under the heading of Concept, Info and Subject Links at multiple places in
almost all the chapters in the book. Further, we have also expanded some of the old topics.
Questions from latest entrance examinations of AIIMS have been added. Several other questions have been incorporated
from PGI, DNB and other state PG entrance examinations. In some topics, there are contradictions between different books. In
such a situation, we have quoted the text from Harrisons Principles of Internal Medicine, 18th edition.
To help the students to understand the subject better, Dr Gobind has started Ayush Institute of Medical Sciences. Any
query regarding the admission in the same maybe addressed to Dr Gobind at the under mentioned e-mail ID.
We must admit hereby that despite keeping an eagles eye for any inaccuracy regarding factual information or typographical
errors, some mistakes must have crept in inadvertently. You are requested to communicate these errors and send your valuable
suggestions for the improvement of this book. Your suggestions, appreciation and criticism are most welcome.
April 2015 Gobind Rai Garg

Sparsh Gupta
E-mail: gobind_garg@yahoo.co.in
healing_sparsh@yahoo.co.in
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Preface to the First Edition
Pathology is one of the most difficult and at the same time most important subject in various postgraduate entrance examinations.
As we experienced it ourselves, most of the students preparing for postgraduate entrance examinations are in a dilemma,
whether to study antegrade or retrograde. Antegrade study takes a lot of time and due to bulky textbooks, some important
questions are likely to be missed. In a retrograde study, the students are likely to answer the frequently asked MCQs but new
questions are not covered. We have tried to overcome the shortcomings of both of the methods while keeping the advantages
intact.
In this book, we have given a concise and enriched text in each chapter followed by MCQs from various postgraduate
entrance examinations and other important questions likely to come. The text provides the advantage of antegrade study in a
short span of time.
After going through the book, it will be easier for the student to solve the questions of most recent examinations, which are
given at the end of the book.
Eighth edition of Robbins is just to strike the Indian market. We have arranged this edition directly from US and added the
references from its text. Further, important differences between 7th and 8th edition of Robbins have been mentioned with the
relevant questions.
It is very difficult and at times very confusing to remember large number of pathological features. To make learning easy,
several easy to grasp MNEMONICS have been given throughout the text.
Despite our best efforts, some mistakes might have crept in, which we request all our readers to kindly bring to our notice.
Your suggestions, appreciation and criticism are most welcome.
Gobind Rai Garg

Sparsh Gupta
E-mail: gobind_garg@yahoo.co.in
healing_sparsh@yahoo.co.in
Acknowledgments
When emotions are profound, words sometimes are not sufficient to express our thanks and gratitude. With these few words,
we would like to thank our teachers at University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, for the
foundation they helped to lay in shaping our careers.
We are especially thankful to Dr KK Sharma, Ex-Professor and Head, Department of Pharmacology, UCMS, Delhi who
has been a father-figure to whole of the department. Prof CD Tripathi, (Director-Professor and Head, VMMC and Safdarjung
Hospital).
We would also like to acknowledge the encouragement and guidance of Prof CD Tripathi, (Director Professor and Head,
Pharmacology, VMMC and Safdarjung Hospital), Dr SK Bhattacharya (Professor and Head, Hindu Rao Hospital), Dr Uma
Tekur (Director Professor, MAMC), Col (Dr) AG Mathur (Professor, ACMS), Dr Vandana Roy (MAMC) and Dr Shalini Chawla
(MAMC), all professors in the department of Pharmacology, in the completion of this book.
We feel immense pleasure in conveying our sincere thanks to all the residents of department of Pharmacology at VMMC,
MAMC and ACMS for their indispensable help and support.
No words can describe the immense contribution of our parents, Ms Praveen Garg, Ms Ruhee, Mr Nitin Misra,
Ms Dhwani Gupta, Mr Rohit Singla and Mrs Komal Singla, without whose support this book could not have seen the light of
the day.
We want to extend our special thanks to Dr Sonal Aggarwal (ESI Hospital, Delhi) and Dr Raina SG (AIIMS, Delhi) for their
unconditional support in the making of this edition.
We would also like to extend our special thanks to Dr Sonal Pruthi (UCMS, Delhi), Dr Smiley M Gupta (Kerala), Dr Saurabh
Jain (TSMA, Tver, Russia), Dr Amrita Talwar (ACMS, Delhi), Dr Avinash A, Dr Nikita Mary Baby, Dr Mamta Nikhurpa,
Dr Rihas Mohammed, Dr Anuradha Tiwari (ACMS, Delhi) and Dr Sandeep Goel (MD Radiodiagnosis, AIIMS).
Although it is impossible to acknowledge the contribution of all individually, we extend our heartfelt thanks to:

Dr Bhupinder Singh Kalra, Assistant Professor (Pharmacology), MAMC, Delhi

Lt Col (Dr) Dick BS Brashier, Associate Professor (Pharmacology), AFMC, Pune

Lt Col (Dr) Sushil Sharma, Associate Professor (Pharmacology), AFMC, Pune

Lt Col (Dr) Dahiya, Associate Professor (Pharmacology), AFMC, Pune

Dr Nitin Jain, DCH, DNB (Pediatrics, Std), Delhi

Dr Sushant Verma, MS (General Surgery), MAMC, Delhi

Dr Kapil Dev Mehta, MD (Pharmacology), UCMS, Delhi

Dr Saurabh Arya, MD (Pharmacology), UCMS, Delhi

Dr Deepak Marwah, MD (Pediatrics), MAMC, Delhi

Dr Shubh Vatsya, MD (Medicine), MAMC, Delhi

Mr Rajesh Sharma, MBA

Dr Puneet Dwivedi DA (Std), Hindu Rao Hospital, Delhi

Dr Sandeep Agnihotri, DVD, Safdarjung Hospital, Delhi

Dr Harsh Vardhan Gupta MD, Pediatrics (Std), Patiala

Mr Tarsem Garg, LLB, DM, SBOP

Dr Pardeep Bansal, MD (Radiodiagnosis), UCMS, Delhi

Dr Pankaj Bansal, MS (Orthopedics), RML Hospital, Delhi

Dr Pradeep Goyal, MD (Radiodiagnosis), LHMC, Delhi

Dr Rakesh Mittal, MS (Surgery), Safdarjung Hospital, Delhi

Dr Amit Miglani, DM (Gastroenterology), PGI, Chandigarh

Dr Sachin Gupta DA, DMC (Ludhiana)

Dr Reenu Gupta DGO BMC (Bangalore)

Dr Shiv Narayan Goel, MCh (Urology), KEM, Mumbai
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Review of Pathology

Dr Kamal Jindal, Assistant Professor (Physiology), LHMC, Delhi

Dr Gaurav Jindal, MD, Radiodiagnosis Resident, Boston, USA

Dr Saket Kant, MD (Medicine UCMS), DM (Endocrinology, BHU)

Dr Mukesh Kr Joon, DM (Cardiology), Udaipur, Rajasthan

Dr Amit Garg, Assistant Professor (Psychiatry), IHBAS, Delhi

Dr Garima Mahajan, MD (Pathology), UCMS, Delhi

Dr Ravi Gupta, MD (Psychiatry), Jolly Grants Medical College, Dehradun, Uttarakhand

Dr Shashank Mohanty, MD (Medicine), Udaipur, Rajasthan

Dr Amit Shersia, MS (Orthopedics), MAMC, Delhi

Dr Mohit Gupta, DCP, DNB (Pathology), Delhi

Dr Mayank Dhamija, DCH, DNB (Pediatrics), DNB (Hemato-oncology), Delhi
Last but not the least, we would like to thank Shri Jitendar P Vij (Group Chairman), M/s Jaypee Brothers Medical
Publishers (P) Ltd, New Delhi, India, publishers of this book and the entire PGMEE team, for their keen interest,
innovative suggestions and hardwork in bringing out this edition.

April 2015 Gobind Rai Garg
Sparsh Gupta
From the Publishers Desk

We request all the readers to provide us their
valuable suggestions/errors (if any)
at: jppgmee@gmail.com
so as to help us in further improvement of this book in the subsequent edition
viii
References
Robbins Pathological Basis of Diseases, 9th edition

Harsh Mohans Textbook of Pathology, 7th edition
Harrisons Principles of Internal Medicine, 18th edition
Current Medical Diagnosis and Treatment 2015
Wintrobes Clinical Hematology, 12th edition
Ackermans Surgical Pathology, 10th edition
Sternbergs Diagnostic Surgical Pathology, 5th edition
SYMBOLS USED IN BOXES ON HIGH YIELD POINTS

Key points
Definition
Mnemonic
Concept Concept
Questions asked in most recent exam
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Contents
Important Notes of New Chapter Added in Robbins 9th Edition xiii-xvi

1. Cell Injury 1
Chapter Review 1
Multiple Choice Questions 10
Explanations 18
2. Inflammation 31
Chapter Review 31
Explanations 55
3. Hemodynamics 71
Chapter Review 71
Explanations 82
4. Genetics 89
Chapter Review 89
Explanations 114
5. Neoplasia 133
Chapter Review 133
Explanations 161
6. Immunity 183
Chapter Review 183
Explanations 217
7. Anemia and Red Blood Cells 239
Chapter Review 239
Explanations 272
8. White Blood Cells and Platelets 297
Chapter Review 297
Explanations 332
9. Cardiovascular System 361
Chapter Review 361
Explanations 388
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10. Respiratory System 405

Chapter Review 405
Explanations 426
11. Kidney and Urinary Bladder 439
Chapter Review 439
Explanations 466
12. Gastrointestinal Tract 487
Chapter Review 487
Explanations 509
13. Liver 521
Chapter Review 521
Explanations 538
14. Genital System and Breast 551
Chapter Review 551
Explanations 575
15. Central Nervous System 583
Chapter Review 583
Explanations 596
16. Endocrine System 605
Chapter Review 605
Explanations 625
17. Musculoskeletal System 633
Chapter Review 633
Explanations 642
18. Miscellaneous 649
Chapter Review 649
Explanations 659
19. Recent Papers 669
AIIMS November 2014 669
AIIMS May 2014 674
20. Important Stains and Bodies 679 679
Image Based Questions 685
xii
Important Notes of New Chapter Added IN Robbins 9th Edition
CELL AS A UNIT OF HEALTH AND DISEASE
Virchow coined the term cellular pathology

The human genome contains roughly 3.2 billion DNA base pairs and only about 2% is used for coding of proteins.
80% of the human genome either binds proteins, implying it is involved in regulating gene expression, or can be
assigned some functional activity, mostly related to the regulation of gene expression, often in a cell-type specific
fashion.
The two most common forms of DNA variation in the huxivxiiiman genome are single-nucleotide polymorphisms
(SNPs) and copy number variations (CNVs).
SNPs are variants at single nucleotide positions and are almost always biallelic (i.e., only two choices exist at a given
site within the population, such as A or T).
CNVs are a more recently identified form of genetic variation consisting of different numbers of large contiguous
stretches of DNA from 1000 base pairs to millions of base pairs.
Epigenetics is defined as heritable changes in gene expression that are not caused by alterations in DNA sequence.
Nuclear chromatin exists in two basic forms:
1. Cytochemically dense and transcriptionally inactive heterochromatin and

2. Cytochemically dispersed and transcriptionally active euchromatin
Different histone modifications are generically called as marks. The modifications include methylation, acetylation, or
phosphorylation of specific amino acid residues on the histones.
Gene regulation can also be done through noncoding RNAs which can be of the following subtypes:

a. MicroRNAs (miRNA): The miRNAs are small RNA molecules 22 nucleotides in length which do not encode proteins.
They function primarily to modulate the translation of target mRNAs into their corresponding proteins.

b. Long noncoding RNAs (lncRNA): RNAs are >200 nucleotides in length. Its example includes XIST, which is tran-
scribed from the X chromosome and plays an essential role in physiologic X chromosome inactivation.
MiRNA associated with cancers are called oncomiRs. They act by increasing the number of cancer causing genes and suppress
the tumor suppressor genes.
The non coding RNAs fall into several classes:
Piwi-interacting RNAs (piRNAs), the most common type of small noncoding RNA, which (like miRs) are believed to
have a role in post-transcriptional gene silencing;
Sno RNAs, which are important in maturation of rRNA and the assembly of ribosomes; and
Long intervening noncoding RNAs (lincRNAs), some of which regulate the activity of chromatin writers, the fac-
tors that modify histones and thereby control gene expression
CELLULAR HOUSEKEEPING (as per 9th edition of Robbins)
Organelles Key points

Mitochondria Oxidative phosphorylation
Intermediates for heme synthesis
Intrinsic pathway of Apoptosis (programmed cell death)
Smooth endoplasmic reticulum Abundant in gonads and liver
(SER) Used for lipoprotein and steroid hormone synthesis,
Required for converting the hydrophobic compounds like drugs into water-soluble molecules
Sequestration of calcium
Proteasomes Required for selectively chewing of denatured proteins using ubiquitin.
Also needed for presentation of peptides in context of the class I major histocompatibility molecules
Peroxisomes Breakdown of fatty acids
Contd...
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Contd...
Organelles Key points
Plasma membrane proteins Phosphatidylinositol serves as scaffold for intracellular proteins as well as for the generation of intracellular
second signals like diacylglycerol and inositol trisphosphate.
Phosphatidylserine is required for apoptosis (programmed cell death) and on platelets, it serves as a
cofactor in the clotting of blood.
Glycolipids are important in cell-cell and cell-matrix interactions, including inflammatory cell recruitment and
sperm-egg interactions.
Lysosomes Most cytosolic enzymes prefer to work at pH 7.4 whereas lysosomal enzymes function best at pH 5 or less.
Golgi apparatus Mannose 6 phosphateQ is the marker
Channel proteins create hydrophilic pores, which, when open, permit rapid movement of solutes (usually restricted
by size and charge)
Carrier proteins bind their specific solute and undergo a series of conformational changes to transfer the ligand
across the membrane; their transport is relatively slow.
Exocytosis is the process by which large molecules are exported from cells. In this process, proteins synthesized and
Important Notes of New Chapter Added in Robbins 9th Edition
packaged within the RER and Golgi apparatus are concentrated in secretory vesicles, which then fuse with the plasma
membrane and expel their contents.
Transcytosis is the movement of endocytosed vesicles between the apical and basolateral compartments of cells. It is
a mechanism for transferring large amounts of intact proteins across epithelial barriers.
Potocytosis is literally cellular sipping. whereas pinocytosis is cellular drinking
Endocytosis is the uptake of fluids or macromolecules by the cell. It could be of the following types:
1. Caveolae-mediated endocytosis: CaveolinQ is the major structural protein of caveole. Internalization of caveolae with any
bound molecules and associated extracellular fluid is sometimes called potocytosisliterally cellular sipping.
2. Pinocytosis and receptor mediated endocytosis: Pinocytosis (cellular drinking) describes a fluid-phase process during
which the plasma membrane invaginates and is pinched off to form a cytoplasmic vesicle. Receptor-mediated
endocytosis is the major uptake mechanism for certain macromolecules like transferrin and low-density lipoprotein
(LDL).
Most cytosolic enzymes prefer to work at pH 7.4 whereas lysosomal enzymes function best at pH 5 or less.
Cytoskeleton
The ability of cells to adopt a particular shape, maintain polarity, organize the relationship of intracellular organelles, and
move about depends on the intracellular scaffolding of proteins called the cytoskeleton. The three major classes of cytoskeletal
proteins are:
i. Actin microfilaments are 5- to 9-nm diameter fibrils formed from the globular protein actin (G-actin), the most
abundant cytosolic protein in cells.
ii. Intermediate filaments are 10-nm diameter fibrils that impart tensile strength and allow cells to bear mechanical
stress. The examples include:
Lamin A, B, and C: nuclear lamina of all cells
Vimentin: mesenchymal cells (fibroblasts, endothelium)
Desmin: muscle cells, forming the scaffold on which actin and myosin contract
Neurofilaments: axons of neurons, imparting strength and rigidity
Glial fibrillary acidic protein: glial cells around neurons
Cytokeratins: 30 different types are present, hence can be used as cell markers
Clinical significance!
Since they have characteristic tissue-specific patterns of expression, they are useful for assigning a cell of origin for poorly
differentiated tumors.

iii. Microtubules: these are 25-nm-thick fibrils composed of non-covalently polymerized dimers of - and -tubulin
arrayed in constantly elongating or shrinking hollow tubes with a defined polarity. Within cells, microtubules are
required to move vesicles, organelles, or other molecules around cells along microtubules. There are two varieties of
these motor proteins: kinesins (for anterograde transport) and dyneins (for retrograde transport).
xiv
Mitochondrial function: key points
Intermembrane space in the mitochondria is the chief site of ATP synthesis.

Thermogenin is an inner membrane protein which is used to generate heat by uncoupling electron transport chain
with ATP generation. It is present in high concentration in brown fat and is useful to generate heat by non-shivering
thermogenesis.
Warburg effect: it is the phenomenon in which rapidly growing cells (both benign and malignant) upregulate
glucose and glutamine uptake and decrease their production of ATP per glucose molecule. This is responsible for
providing metabolic intermediates which are useful for cellular growth and maintenance.
Receptors
Cell-surface receptors are generally transmembrane proteins with extra cellular domains that bind soluble secreted ligands. They
can be of the following types:
1. Ion channels (typically at the synapse between electrically excitable cells)

2. G protein coupled receptors: activate an associated GTP-binding regulatory protein
3. Enzymatic receptors: activate an associated enzyme usually tyrosine kinase

4. Receptors which trigger a proteolytic event or a change in protein binding or stability that activates a latent
transcription factor. Examples include Notch, Wnt, and Hedgehog receptors which regulate normal development.
Transcription factors
MYC and JUN are the transcription factors that regulate the expression of genes that are needed for growth.
p53 is a transcription factor that triggers the expression of genes that lead to growth arrest.
Summary of growth factors and the receptors

The major role of growth factors is to stimulate the activity of genes that are required for cell growth and cell division. They
are also involved in the non-growth activities, including migration, differentiation, and synthetic capacity. Some important
examples include:
a. Epidermal Growth Factor and Transforming Growth Factor-.
The EGF receptor family includes four membrane receptors with intrinsic tyrosine kinase activity. The examples in-
clude EGFR1 involved in lung cancer, head and neck, breast etc. and the ERBB2 receptor (also known as HER2) involved
in breast cancer
b. Hepatocyte Growth Factor (also known as scatter factor)
HGF acts as a morphogen in embryonic development, promotes cell migration and enhances hepatocyte survival. MET
is the receptor for HGF, it has intrinsic tyrosine kinase activity and is frequently over-expressed or mutated in tumors,
particularly renal and thyroid papillary carcinomas.
Platelet-Derived Growth Factor
c.
PDGF is stored in platelet granules and is released on platelet activation.
d. Vascular Endothelial Growth Factor
VEGF-A is the major angiogenic factor (inducing blood vessel development) after injury and in tumors.
VEGF-B and PlGF (placental growth factor) are involved in embryonic vessel development, and VEGF-C and -D
stimulate both angiogenesis and lymphatic development (lymphangiogenesis).
In adults, VEGFs are also involved in the maintenance of normal adult endothelium and not involved in angiogenesis.
Hypoxia is the most important inducer of VEGF production.
VEGFR-2 is highly expressed in endothelium and is the most important for angiogenesis.
Anti-VEGF antibodies are being used for a number of ophthalmic diseases including wet age-related macular
degeneration, the angiogenesis associated with retinopathy of prematurity; and diabetic macular edema.
e. Fibroblast Growth Factor (FGF-7)
FGF-7 is also referred to as keratinocyte growth factor (KGF).
f. Transforming Growth Factor-
xv
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TGF- has multiple and often opposing effects depending on the tissue and concurrent signals. Agents with such multiplicity
of effects are called pleiotropic.
TGF- is involved in scar formation after injury. It also drives fibrosis in lung, liver, and kidneys in conditions of
chronic inflammation.
TGF- is an anti-inflammatory cytokine that serves to limit and terminate inflammatory responses.
Extracellular matrix
Laminin is the most abundant glycoprotein in basement membrane
The major constituents of basement membrane are amorphous nonfibrillar type IV collagen and laminin.
Collagens are typically composed of three separate polypeptide chains braided into a ropelike triple helixQ.
xvi
CHAPTER 1
Pathology is a science dealing with the study of diseases. Four important components of
Cell Injury
pathology are etiology (causative factors), pathogenesis (mechanism or process by which
disease develops), morphology (appearance of cells, tissues or organs) and clinical features.
CELL INJURY
Disease occurs due to alteration of the functions of tissues or cells at the microscopic level.
The various causes of cell injury include:

1. Hypoxia: It is the most common cause of cell injury. It results due to decrease in
Hypoxia is the most common
oxygen supply to the cells. Hypoxia may be caused by
cause of cell injury.
a. Ischemia: Results due to decrease in blood supply. It is the most common cause of
hypoxiaQ
b. Anemia: Results due to decrease in oxygen carrying capacity of blood
c. Cardio-respiratory disease: Results from decreased oxygenation of blood due to
cardiac or respiratory disease.
2. Physical Agents: Cell injury may occur due to radiation exposure, pressure, burns, Ischemia is the most common
cause of hypoxia.
frost bite etc.
3. Chemical Agents: Many drugs, poisons and chemicals can result in cell injury.
4. Infections: Various infectious agents like bacteria, virus, fungus and parasites etc
can cause cell injury.
5. Immunological reactions: These include hypersensitivity reactions and autoimmune
diseases.
6. Genetic causes: Cell injury can also result due to derangement of the genes. Neurons are the most sensitive
7. Nutritional imbalance: Cell injury can result due to deficiency of vitamins, minerals cells in the body. They are most
etc. commonly damaged due to
global hypoxia.
Clinical Importance
At a the cellular level, the protective effect in mammalian cells against hypoxic injury is induction of a
transcription factor called as hypoxia inducible factor 1 which promotes blood vessel formation, stimu-
lates cell survival pathways and enhances anaerobic glycolysis. The only reliable clinical strategy to
decrease ischemic brain and spinal cord injury is transient reduction of core body temperature to 92F.
In response to injury, a cell/tissue can have following consequences:

Adaptation: The cell changes its physiological functions in response to an injurious
Concept
stimulus. The only reliable clinical

Reversible cell injury strategy to decrease ischemic

Irreversible cell injury. brain and spinal cord injury is
transient reduction of core body
1. ri n r
Reve s ble Cell I ju y: As already discussed, hypoxia is the most common temperature to 92F.
cause of cell injury. Oxygen is an important requirement of mitochondria for
the formation of ATP; therefore, hypoxia will result in earliest involvement of
mitochondriaQ resulting in decreased formation of ATP. All cellular processes
requiring ATP for normal functioning will be affected. Important organelles affected
are cell membranes (require ATP for functioning of Na+ - K+ pump), endoplasmic
reticulum (require ATP for protein synthesis) and nucleus.
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Mitochondria is the earliest

organelle affected in cell injury.
Cell Injury
Swelling of organelles like endoplasmic reticulum results in decreased protein synthesis

Bleb formation results due to outpouching from the cell membrane to accommodate
more water.
Hydropic change or swelling of Loss of microvilli
the cell due to increased water Formation of myelin figures due to breakdown of membranes of cellular organelles like
entry is the earliest change seen endoplasmic reticulum. These are composed of phospholipidsQ. Myelin figures are in-
in reversible cell injury. tracellular whorls of laminated lipid material (resembling myelin of nerves). When these
are present in membrane bound structures containing lysosomal enzymes, these are
known as myeloid bodies or myelinoid bodies.
All the features discussed above are of reversible cell injury because if the injurious
agent is removed at this point, cell can recover back to its normal state of functioning.
However, if the stimulus continues, then irreversible cell injury ensues.
2. Irreversible Cell Injury: Features of irreversible cell injury include
Damage to cell membrane: It results due to continued influx of water, loss
of membrane phospholipids and loss of protective amino acids (like glycine).
Damage to cell membranes result in massive influx of calcium.
Pyknosis is nuclear condensation Calcium influx: Massive influx of Ca2+ results in the formation of large flocculent
Karyorrhexis is fragmentation mitochondrial densities and activation of enzymes.
of the nucleus. Nuclear changes: These are the most specific microscopic features of irreversible
Karyolysis is nuclear dissolution cell injury. These include: *Pyknosis, *Karyorrhexis and *Karyolysis.
2
Cell Injury
Inability to reverse mitochon-

drial dysfunction and develop-
ment of profound disturbances
in the membrane function
characterize irreversibility.
Cell Injury
Inability to reverse mitochondrial dysfunctionQ and development of profound disturbances in the mem-
brane function characterize irreversibilityQ.
Irreversible cell injury may be necrosis or apoptosis (Programmed cell death)

Necrosis Apoptosis
Always pathological May be physiological or pathological
Increased calcium, reactive
Associated with disruption of cellular homeostasis Important for development, homeostasis oxygen species and oxygen
(e.g. ischemia, hypoxia & poisoning) & elimination of pathogens & tumor cells deprivation causes damage of
Affects contiguous (adjacent) group of cells Affect single cells mitochondria.
Cell size is increased Cell size is shrunken
Passive Active
Causes inflammatory reaction No inflammatory reaction
Plasma membrane is disrupted Plasma membrane is intact
Smear pattern on electrophoresis Step ladder pattern is seen
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Mnemonic: Apoptosis can be considered as suicide whereas necrosis as murder. Like

Murder is always done by someone else (i.e. pathological) whereas suicide can be committed by
oneself (physiological) or due to undue pressure (pathological).
A person can murder many people (affects group of cells) whereas suicide can be committed only
by oneself (affect single cells).
The person who is being killed doesnt need to plan or do anything (passive) whereas for suicide,
Concept lot of planning and effort has to be made (active process).
When a person is being killed, he will make a lot of efforts to save himself and thus may lead
Liquefactive necrosis is seen to accumulation of other people or police (equivalent to inflammatory mediators coming there)
in CNS specifically because whereas in suicide no help is called for (no-inflammation).
there is lack of extracellular
architecture in brain and the Type of neorosis
brain is rich in liquefactive
hydrolytic enzymes.
Coagulative Liquefactive Caseous Fat necrosis Fibrinoid Gangrenous

necrosis necrosis necrosis necrosis necrosis

Most com-
monQ type of

Enzymatic
destruction of

Combnination
of coagulative

Action of
lipases on

Complexes of
antigens and
(Surgically used
term; necrosis of
necrosis cells and liquefac- fatty tissue antibodies are tissue with super-

Loss of nu-
cleus with

Abscess for-
mation tive necrosis
Characteristic
Seen in
breast,
deposited in
vessel wall
added
tion)
putrefac-
Coagulative necrosis is associated

the cellular
outline being

Pancreatitis
Seen in brain of TBQ
Cheese like
omentum
and pan-
with leakage
of fibrinogen

Dry gangrene is
similar to coag-
with tomb stone appearance preserved appearance creatitisQ out of vessels ulative necrosis
of affected tissue
Associated
with ischemia
of the necrotic
material.
Seen in PANQ
Aschoff

Wet gangrene
is similar to liq-
Seen in or- bodiesQ (in uefactive necro-
gans (heart, rheumatic sis and is due
liver, kidney heart disease) to secondary
etc.) except and malignant infection
BRAINQ. hypertensionQ.
Noma is gan-
grenous lesion
Cell Injury
of vulva or
mouth (cancrum
Concept oris)
Fourniers gan-
grene is seen in
Caseous necrosis is seen in scrotum
tuberculosis and systemic
fungal infections (like histo-
plasmosis) because of the pres- APOPTOSIS
ence of high lipid content in the
cell wall in these organisms. So, Apoptosis or programmed cell death can be induced by intrinsic or extrinsic pathway.
there is cheese like appearance Normally, growth factors bind to their receptors in the cells and prevent the release of
of the necrotic material. cytochrome C and SMAC. So, withdrawal or absence of growth factors can result in release of
these mediators and initiate the intrinsic pathway.
Intrinsic pathway: It is initiated by the release of cytochrome C and SMAC (second
mitochondrial activator of caspases) from the mitochondrial inter-membrane space. Upon
release into the cytoplasm, cytochrome C associates with dATP, procaspase-9 and APAF-
Concept 1 (apoptosis activating factor -1) leading to sequential activation of caspase-9 and effector
caspases {Caspases- 3 and -7}. On the other hand, upon release, SMAC binds and blocks
In fibrinoid necrosis, there the function of IAPs (Inhibitor of Apoptosis Proteins). Normally, IAPs are responsible for
is no deposition of fibrin. causing the blocking the activation of caspases and keep cells alive and so, neutralization of
Fibrinoid means the appearance IAPs permits the initiation of a caspase cascade.
of the necrotic material in this
case is similar to fibrin. Due
E
xtrinsic pathway: It is activated by binding of Fas ligand to CD95 (Fas; member of
to inflammation seen in these TNF receptor family) or binding of TRAIL (TNF related apoptosis inducing ligand) to death
conditions, there is increased receptors DR4 and DR5. This induces the association of FADD (Fas- associated death domain)
vessel permeability which and procaspase-8 to death domain motifs of the receptors resulting in activation of caspase 8 (in
causes plasma proteins to be humans caspase 10) which finally activates caspases- 3 and 7 that are final effector caspases.
deposited in the vessel wall. The Cellular proteins particularly a caspase antagonist called FLIP, binds to procaspase-8 but
microscopic appearance is like
fibrin but the actual composition
can not activate it. This is important because some viruses produce homologues of FLIP and
is plasma proteins. protect themselves from Fas mediated apoptosis.
4
Cell Injury
Mitochondrion must be
recognized not only as an
organelle with vital roles in
intermediary metabolism and
oxidative phosphorylation, but
also as a central regulatory
structure of apoptosis.
Caspase 3 is the most important

executioner caspase.
Condensation of nuclear chro-

matin is the most characteris-
tic feature of apoptosis
Mnemonic: Short Story to understand the pathogenesis of apoptosis.
Cell Injury
Suppose, a person is working in some institution. If he leaves his job, this will be equivalent to apop-
tosis. There are two reasons due to which that person can leave the work. 1. This person is fired from
work (equivalent to extrinsic pathway through death receptors). 2. Person is not given pay for long
time, so that the person himself gives resignation (equivalent to intrinsic pathway, due to absence of
growth factors). In latter case, before giving resignation, the person will talk to his colleagues, whether Glucocorticoids induce apop-
he should leave or not. Some of them will suggest him to leave (equivalent to pro-apoptotic gene prod- tosis while sex steroids inhibit
ucts like bak, bid etc.) and some of them will stop him and suggest to wait (equivalent to anti-apoptotic apoptosis
factors like bcl-2, bcl-xL etc.) This regulation has been discussed below.
e ulation of Apoptosis
R g
Regulation is primarily by bcl-2 family of genes located on chromosome 18. Some members
S
of this family like bak, bid, bin, bcl-x (to remember, S for stimulate apoptosis) stimulate
apoptosis whereas others like bcl-2, bcl-xL (to remember, L for lower apoptosis) etc inhibit
apoptosis.
Apoptosis affects only single

cells or small group of cells
Normal cells have bcl-2 and bcl-xL present in the mitochondrial membrane. They inhibit
apoptosis because their protein products prevent the leakage of mitochondrial cyt c into
Cells are decreased in size due
the cytoplasm. When there is absence of growth factors or hormones, bcl-2 and bcl-xL are to destruction of the structural
replaced by bax, bin etc. resulting in increased permeability of mitochondrial membrane. proteins
This result in stimulation of intrinsic pathway of apoptosis (described above in flowchart).
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a ples of Apoptosis
Ex m
Physiological conditions Pathological conditions
1. Endometrial cells (Menstruation) 1. Councilman bodies: Viral hepatitis
2. Cell removal during embryogenesis 2. Gland atrophy following duct
3. Virus infected cells and Neoplastic cells by obliteration as in cystic fibrosis
cytotoxic T cells 3. Graft versus host disease (GVHD)
Apoptotic cells express mol- Diagnosis of apoptosis

ecules facilitating their uptake
by adjacent cells/macrophages.

1. Chromatin condensation seen by hematoxylin, Feulgen and acridine orange staining.
2. Estimation of cytochrome c
This leads to absence of in-
3. Estimation of activated caspase
flammatory response in apop-
tosis.

4. Estimation of Annexin V (apoptotic cells express phosphatidylserine on the outer layer of
plasma membrane because of which these cells are recognized by the dye Annexin VQ. Some
cells also express high concentration of thrombospondin).

5. DNA breakdown at specific sites can be detected by step ladder pattern on gel electro-
phoresis or TUNEL (TdT mediated d-UTP Nick End Labelling) technique.
Clinical Significance of apoptosis in cancers

On agarose gel electrophoresis,
ladder patternQ is seen in Mutated cells are cleared normally in the body by apoptosis but in cancers, apoptosis is decreased.
apoptosis (in necrosis, smeared Commonly it could be due to mutation in p53 gene or increased expression of genes like bcl-2. The
pattern is seen). bcl-2 over expression is seen with translocation (14;18) preventing the apoptosis of abnormal B lym-
phocytes which proliferate then and result in the development of B cell follicular lymphoma.
3. ADAPTATION: Cells may show adaptation to injury by various processes like

atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia etc.
Atrophy Hypertrophy Hyperplasia
Reduced size of Increase in size and Increase in number of cells in tissues/
Cell Injury
an organ or tissue function of cells organ.

resulting from a Results due to Results due to increase in growth factors,
decrease in cell size increase in growth increased expression of growth promoting
and number. factors or trophic genes and increased DNA synthesis.
Caused by ischemia, stimuli. It persists so long as the stimulus is
ageing, malnutrition Includes puberty, present.
etc. lactating breasts and e.g. breast development at puberty, endo-
May result due to skeletal muscle fibres metrial hyperplasia, benign hyperplasia
chronic absence of (in body builders). of prostate, hyperplasia of liver cells after
stimulus (disuse atrophy). partial hepatectomy.
Metaplasia Dysplasia
Reversible change in which one differentiated Abnormal multiplication of cells characterized
cell type (epithelial or mesenchymal) is by change in size, shape and loss of cellular
Epithelial metaplasia: Barrets replaced by another cell type. organization
esophagus (squamous to intes- Results from reprogramming of stem cells The basement membrane is intactQ
tinal columnar epithelium). that are known to exist in normal tissues, Can progress to cancer
or of undifferentiated mesenchymal cells in
Connective tissue metaplasia:
connective tissue.
myositis ossificans (bone forma-
tion in muscle after trauma)
I ntracellular Accumulations
Various substances like proteins, lipids, pigments, calcium etc. can accumulate in cells.

1. Proteins: Proteins are synthesized as polypeptides on ribosomes. These are then
re-arranged into a-helix or b sheets and folded. Chaperones help in protein folding
and transportation across endoplasmic reticulum and golgi apparatus. Chaperones
thus can be induced by stress (like heat shock proteins; hsp 70 and hsp 90). They
also prevent misfolding of p roteins. However, if misfolding occurs, chaperones
facilitate degradation of damaged protein via ubiquitin-proteasome complex.
6
Cell Injury
Disorders with protein defects

Defect in transport and secretion of proteins Misfolded/unfolded proteins
Accumulation of proteins inside cells Initially increase chaperone concentration, Later,
these induce apoptosis by activating caspases
a1 Antitrypsin deficiency Q Alzheimers DiseaseQ
Cystic fibrosis Q Huntingtons Disease
Parkinsons Disease
2. Lipids:
Triglycerides: Fatty change in liver, heart and kidney (stained with Sudan IV or
Oil Red O).
Cholesterol: Atherosclerosis, xanthoma
Complex lipids: Sphingolipidosis
3. Endogenous Pigments:
Lipofuscin (wear and tear pigment) Melanin Hemosiderin
- Perinuclear, brown coloured pigment - Only naturally occurring - Golden yellow pig- Lipofuscin is an important
- Responsible for brown atrophyQ of endogenous black ment indicator of free radical injury
liver and heart pigment derived from - Seen at sites of
- It is derived through lipid peroxidation tyrosineQ hemorrhage or
of polyunsaturated lipids of subcellular - Responsible for bruiseQ
membranes and is indicative of free pigmentation of skin and - Also seen in hemo-
radical injury Q to the cell hair chromatosisQ (Iron
- Seen in aging, protein energy overload)
malnutrition and cancer cachexia.
4. Hyaline change: It is any intracellular or extracellular accumulation that has pink

homogenous appearance.
Intracellular Extracellular
Cell Injury
- Mallory alcoholic hyaline - Hyaline membrane in newborns
- Russell bodies (seen in multiple myeloma) - Hyaline arteriosclerosis
- Zenkers hyaline change - Corpora amylacea in prostate, brain, Concept
spinal cord in elderly, old lung infarct
Zenkers degeneration is a true
necrosis (coagulative necrosis)
INFO: The deposition of such hyaline like material and the associated sclerosis is important in dis- affecting skeletal muscles (more
eases affecting the kidneys (glomerulopathies). commonly) and cardiac muscles
(less commonly) during acute
5. Calcification: Pathologic calcification is the abnormal tissue deposition of calcium infections like typhoid. Rectus
and the diaphragm are the usual
salts, together with smaller amounts of iron, magnesium, and other mineral salts. It muscles affected.
can be of the following two types:
Dystrophic Metastatic
- Seen in dead tissuesQ - Seen in living tissues also
- Serum calcium is normalQ - Association with elevated serum Ca2+
- Seen at sites of necrosisQ - Does not cause clinical dysfunction
- Often causes organ dysfunction - Seen in
- Examples include: HyperparathyroidismQ

R Rheumatic heart disease (in cardiac valves) Renal failureQ

A Atheromatous plaque Vitamin D intoxicationQ
D for Dead and D for Dystrophic.

T Tubercular lymph node SarcoidosisQ
So, at sites of necrosis or death
of cells, we have dystrophic
Tumors (MOST for PG) Milk alkali syndromeQ
calcification
M Meningioma, Mesothelioma Multiple myelomaQ
O Papillary carcinoma of Ovary (serous Metastatic tumors to boneQ
ovarian cystadenoma) - Found in organs which loose acid and
S Papillary carcinoma of Salivary gland have alkaline environment inside them
Calcification begins in mito-
T Papillary carcinoma of Thyroid [like lungs (most commonly), kidneys,
chondria of all organs except
Prolactinoma stomach, systemic artery, pulmonary
kidney (begin in basement mem-
Glucagonoma veins etc] brane)
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Note: *Hypercalemia normally is responsible for metastatic calcification but it also accentuates dys-
Lungs are the commonest site trophic calcification.
for metastatic calcification
R eperfusion injurY
Reperfusion injury is char- It is seen with cerebral or myocardial injury. On re-establishment of blood flow, there is
acteristically seen in cardiac increased recruitment of white blood cells which cause inflammation as well as generation of more
cells appearing as contraction free radicals.
bands after myocardial infarc-
tion. CELLULAR A EIN G G
Features of ageing include decreased oxidative phosphorylation, decreased synthesis of
nucleic acids and proteins, deposition of lipofuscin, accumulation of glycosylation products
and abnormally folded proteins. The most effective way to prolong life is calories restriction
A defect in DNA helicase enzyme
S U S
because of a family of proteins called IRT IN . The latter have histone deacetylase activity
(required for DNA replication
and promote expression of genes whose products increase longevity.
and repair) results in premature The best-studied mammalian sirtuin is Sirt-1Q which has been shown to improve glucose tolerance
ageing (WERNER SYNDROME) and enhance cell insulin secretion. It is implicated in diabetesQ.
Ends of the chromosomes are known as telomeres. Enzyme telomerase helps in

keeping the length of telomere constant. Decreased activity of this enzyme is associated
with ageing whereas excessive activity is associated with cancers.
Decreased activity of telome-

rase is associated with ageing
whereas its excessive activity
is associated with cancers.
Cell Injury
Fenton reaction: H2O2 + Fe2+

Fe2++ OH- + OH.
Free Radical Injury
Free radical injury is caused by the following mechanisms:

1. Oxidative stress/reactive oxygen species (O2, H2O2, OH)

2. Radiation exposure

3. Drugs (carbon tetrachloride, paracetamol)

4. Metals (iron, copper):
Nitric oxide (NO), an important chemical mediator generated by endothelial cells, macrophages, neu-
Free radicals in reperfusion rons, and other cell types can act as a free radical and can also be converted to highly reactive perox-
injury are produced by ynitrite anion (ONOO-) as well as NO2 and NO3.
neutrophils
Mechanism of Free Radical Injury

It can result in lipid peroxidation, DNA breaks and fragmentation of the proteins. This is
associated with formation of more free radicals thereby making free radical induced injury as an
autocatalytic reaction.
8
Cell Injury
Antioxidants
Antioxidants may act by inhibiting the generation of free radials or scavenging the already
present free radicals. These may be divided into enzymatic and non-enzymatic.
Enzymatic Non-enzymatic
a. Superoxide dismutase a. Vitamin E
b. Catalase b. Sulfhydryl containing compounds: cysteine and glutathione
c. Glutathione peroxidase c. Serum proteins: Albumin, Ceruloplasmin and Transferrin
Concept
The intracellular ratio of oxidized
glutathione (GSSG) to reduced
glutathione (GSH) is a reflection
of the oxidative state of the cell
and is an important aspect of the
cells ability to detoxify reactive
Catalase is present in peroxisomes and decomposes H2O2 into O2 and H2O. (2 H2O2 oxygen species.
O2 + 2 H2O).
Superoxide dismutase is found in many cell types and converts superoxide ions to
H2O2. (2 O2- + 2 H H2O2 + O2).This group includes both manganese-superoxide
dismutase, which is localized in mitochondria, and copper-zinc-superoxide.
dismutase, which is found in the cytosol.
Glutathione peroxidase also protects against injury by catalyzing free radical
breakdown. (H2O2 + 2 GSH GSSG [glutathione homodimer] + 2 H2O, or 2 OH + 2
GSH GSSG + 2 H2O).
Clinical importance: Deficiency of SOD 1 gene may result in motor neuron disorder. This finding
Cell Injury
strengthens the view that SOD protects brain from free radial injury.
e ical fixatives
Ch m
The most common fixative
Chemical fixatives are used to preserve tissue from degradation, and to maintain for light microscopy is 10%
the structure of the cell and of sub-cellular components such as cell organelles (e.g., neutral buffered formalin (4%
nucleus, endoplasmic reticulum, mitochondria). formaldehyde in phosphate
The most common fixative for light microscopy is 10% neutral buffered formalin (4%
buffered saline).
formaldehyde in phosphate buffered saline).
For electron microscopy, the most commonly used fixative is glutaraldehyde, usually
as a 2.5% solution in phosphate buffered saline.
These fixatives preserve tissues or cells mainly by irreversibly cross-linking proteins.
Frozen section is a rapid way to fix and mount histology sections. It is used in surgical For electron microscopy, the
most commonly used fixative is
removal of tumors, and allow rapid determination of margin (that the tumor has glutaraldehyde.
been completely removed). It is done using a refrigeration device called a cryostat.
The frozen tissue is sliced using a microtome, and the frozen slices are mounted on
a glass slide and stained the same way as other methods.
Commonly Used Stains
Substance Stain
Glycogen Carmine (best), PAS with diastase sensitivity
Lipids Sudan black, Oil Red O
Amyloid Congo Red, Thioflavin T (for JG apparatus of kidney) and S
Calcium Von Kossa, Alzarine Red
Hemosiderin Perls stain
Trichrome CollagenQ appears blue, while smooth muscleQ appears red.
9
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Multiple Choice Questions

cell injury, Necrosis, Apoptosis 9. Fibrinoid necrosis may be observed in all of the
following, except: (AI 2005)
1. CD 95 is a marker of (AIIMS Nov 2012) (a) Malignant hypertension
(a) Intrinsic pathway of apoptosis (b) Polyarteritis nodosa
(b) Extrinsic pathway of apoptosis (c) Diabetic glomerulosclerosis
(c) Necrosis of cell (d) Aschoffs nodule
(d) Cellular adaption 10. In apoptosis, Apaf-I is activated by release of which of
2. Which of the following is the characteristic of the following substances from the mitochondria?
irreversible injury on electron microscopy? (a) Bcl-2 (AI 2005)
(a) Disruption of ribosomes (AIIMS May 2012) (b) Bax
(b) Amorphous densities in mitochondria (c) Bcl-XL
(c) Swelling of endoplasmic reticulum (d) Cytochrome C
(d) Cell swelling 11. Which of the following is an anti-apoptotic gene?
3. Caspases are associated with which of the following? (a) C-myc (AI 2004)
(a) Hydopic degeneration (AIIMS May 2010) (b) p 53
(b) Collagen hyalinization (c) bcl-2
(c) Embryogenesis (d) bax
(d) Fatty degeneration 12. Annexin V on non-permeable cell is indicative of:
4. Caspases are seen in which of the following? (a) Apoptosis (AIIMS May 2009)
(a) Cell division (AI 2010) (b) Necrosis
Cell Injury
(b) Apoptosis (c) Cell entering replication phase

(c) Necrosis (d) Cell cycle arrest
(d) Inflammation 13. Ultra-structural finding of irreversible injury
5. Light microscopic characteristic feature of apoptosis is: (a) Ribosomal detachment from endoplasmic reticulum
(a) Intact cell membrane (AI 2010) (b) Amorphous densities in mitochondria
(b) Eosinophilic cytoplasm (c) Formation of phagolysosomes (AIIMS Nov 2007)
(c) Nuclear moulding (d) Cell swelling
(d) Condensation of the nucleus 14. Caspases are involved in (AIIMS Nov 2007)
6. Coagulative necrosis is found in which infection? (a) Necrosis
(a) TB (AI 2009, AIIMS May 10) (b) Apoptosis
(b) Sarcoidosis (c) Atherosclerosis
(c) Gangrene (d) Inflammation
(d) Fungal infection 15. True about Apoptosis are all except:
7. Organelle which plays a pivotal role in apoptosis is: (a) Inflammation is present (AIIMS May 2007)
(a) Cytoplasm (AI 2011, 09, AIIMS May 2010) (b) Chromosomal breakage
(b) Golgi complex (c) Clumping of chromatin
(c) Mitochondria (d) Cell shrinkage
(d) Nucleus 16. The following is an antiapoptotic gene
8. All of the following statements are true regarding (a) Bax (AIIMS Nov 2006)
reversible cell injury, except (AI 2005) (b) Bad
(a) Formation of amorphous densities in the mitochon- (c) Bcl-X
drial matrix (d) Bim
(b) Diminished generation of adenosine triphosphate 17. Cytosolic cytochrome C plays an important function in
(ATP). (a) Apoptosis (AIIMS Nov 2006)
(c) Formation of blebs in the plasma membrane. (b) Cell necrosis
(d) Detachment of ribosomes from the granular (c) Electron transport chain
endoplasmic reticulum. (d) Cell division
10
Cell Injury
18. Most pathognomic sign of irreversible cell injury

(c) Fibrinoid necrosis
(a) Amorphous densities in mitochondria
(d) Liquefaction necrosis
(b) Swelling of the cell membrane (AIIMS Nov 2006)
(c) Ribosomes detached from endoplasmic reticulum 27. Which of the following is an inhibitor of apoptosis?
(d) Clumping of nuclear chromatin (a) Bad (Delhi PG-2006)
(b) Bax
19. Internucleosomal cleavage of DNA is characteristic of (c) Bcl-2
(a) Reversible cell injury (AIIMS Nov 2005) (d) All of the above
(b) Irreversible cell injury
(c) Necrosis 28. Inhibitor of apoptosis is: (Delhi PG-2005, DNB-2007)
(d) Apoptosis (a) p53
(b) Ras
20. Programmed cell death is known as: (c) Myc
(a) Cytolysis (AIIMS Nov 2005)
(d) Bcl-2
(b) Apoptosis
(c) Necrosis 29. Apoptosis is associated with all of the following
(d) Proptosis features except: (Karnataka 2009)
21. Ladder pattern of DNA electrophoresis in apoptosis is (a) Cell shrinkage
caused by the action of the following enzyme: (b) Intact cellular contents
(a) Endonuclease (AIIMS Nov 2004) (c) Inflammation
(b) Transglutaminase (d) Nucleosome size fragmentation of nucleus
(c) DNAse
(d) Caspase
30. Liquefactive necrosis is typically seen in
(a) Ischemic necrosis of the heart (Karnataka 2006)
22. Which finding on electron microscopy indicates (b) Ischemic necrosis of the brain
irreversible cell injury? (AIIMS Nov 2002) (c) Ischemic necrosis of the intestine
(a) Dilatation of endoplasmic reticulum (d) Tuberculosis
(b) Dissociation of ribosomes from rough endoplasmic
reticulum 31. All of the following are morphological features of
(c) Flocculent densities in the mitochondria apoptosis except (Karnataka 2004)
Cell Injury
(d) Myelin figures (a) Cell shrinkage
(b) Chromatin condensation
23. True about apoptosis is all, except: (AIIMS Nov 2001) (c) Inflammation
(a) Considerable apoptosis may occur in a tissue before
it becomes apparent in histology (d) Apoptotic bodies
(b) Apoptotic cells appear round mass of the intensely 32. Coagulative necrosis as a primary event is most often
eosinophilic cytoplasm with dense nuclear chroma- seen in all except: (AP 2002)
tin fragments (a) Kidneys

(c) Apoptosis of cells induce inflammatory reaction (b) CNS

(d) Macrophages phagocytose the apoptotic cells and
(c) Spleen
degrade them
(d) Liver
24. Morphological changes of apoptosis include 33. Liquefactive necrosis is seen in:
(a) Cytoplasmic blebs (PGI Dec 01)
(b) Inflammation (a) Heart
(c) Nuclear fragmentation (b) Brain
(d) Spindle formation (c) Lung
(e) Cell swelling (d) Spleen
25. True about apoptosis (PGI June 2003) 34. Irreversible injury in cell is (UP 2000)
(a) Migration of Leukocytes (a) Deposition of Ca++ in mitochondria
(b) End products are phagocytosed by macrophage (b) Swelling
(c) Intranuclear fragmentation of DNA (c) Mitotic figure
(d) Activation of caspases (d) Ribosomal detachment
(e) Annexin V is a marker of apoptotic cell
26. Which of the following is the hallmark of programmed 35. Apoptosis is (UP-98, 2004)
(a) Cell degeneration
cell death? (Delhi PG 2009 RP) (b) Type of cell injury
(a) Apoptosis
(c) Cell regeneration
(b) Coagulation necrosis
(d) Cell activation
11
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36. Pyogenic infection and brain infarction are associated 44. A 23-year-old lady Sweety was driving her car when
with (UP 2008) she had to apply brakes suddenly. She suffered from
(a) Coagulative necrosis steering wheel injury in the right breast. After 5 days
(b) Liquefactive necrosis of pain and tenderness at the site of trauma, she noticed
(c) Caseous necrosis the presence lump which was persistent since the
(d) Fat necrosis S
day of trauma. Dr. M. partan does an excision biopsy
and observed the presence of an amorphous basophilic
37. In apoptosis initiation: (UP 2008) material within the mass. The amorphous material is an
(a) The death receptors induce apoptosis when it example of
engaged by fas ligand system
(a) Apocrine metaplasia.
(b) Cytochrome C binds to a protein Apoptosis
(b) Dystrophic fat necrosis
Activating (Apaf-1) Factor 1
(c) Enzymatic fat necrosis
(c) Apoptosis may be initiated by caspase activation
(d) Granulomatous inflammation
(d) Apoptosis mediated through DNA damage 45. A patient Subbu is diagnosed with a cancer. It was
observed that he shows a poor response to a commonly
38. Apoptosis is alternatively called as (RJ 2005)
used anti-cancer drug which acts by increasing
(a) Ischemic cell death
programmed cell death. Inactivation of which of the
(b) Programmed cell death following molecules/genes is responsible for the
(c) Post traumtic cell death resistance shown in the tumor cells?
(d) All
(a) Granzyme and perforin
39. First cellular change in hypoxia: (Kolkata 2003)
(b) Bcl-2
(a) Decreased oxidative phosphorylation in mitochon-
(c) p53
dria

(d) Cytochrome P450
(b) Cellular swelling 46. Dr Maalu Gupta is carrying out an experiment in which
(c) Alteration in cellular membrane permeability a genetic mutation decreased the cell survival of a cell
(d) Clumping of nuclear chromatin culture line. These cells have clumping of the nuclear
chromatin and reduced size as compared to normal
40. About apoptosis, true statement is: (Bihar 2003) cells. Which of the following is the most likely involved
(a) Injury due to hypoxia gene in the above described situation?
Cell Injury
(b) Inflammatory reaction is present

(a) Fas
(c) Councilman bodies is associated with apoptosis
(b) Bax
(d) Cell membrane is damaged
(c) Bcl-2
41. Fourniers gangrene is seen in:
(d) Myc
(a) Nose (Jharkhand 2006) 4 7-49. Read the following statement for questions 49, 50
(b) Scrotal skin and 51 carefully and answer the associated questions.
(c) Oral cavity A 50-year old male Braj Singh presented to the
medicine emergency room with retrosternal chest pain
(d) All are true
of 15 minutes duration. He also had sweating and mild
42. Coagulative necrosis is seen in: (Jharkhand 2006) dyspnea. The physician immediately gave him a nitrate
(a) Brain tablet to be kept sublingually following which his chest
(b) Breast pain decreased significantly.
(c) Liver 47. Which of the following best represents the biochemical
(d) All change in the myocardial cells of this patient during the
43. A patient Fahim presents to the hospital with jaundice, transient hypoxia?
right upper quadrant pain and fatigue. He tests positive

(a) Decreased hydrogen ion concentration
for hepatitis B surface antigen. The serum bilirubin

(b) Increase in oxidative phosphorylation

(c) Loss of intracellular Na+ and water
levels is 4.8mg/dl (direct is 0.8mg/dl and indirect
bilirubin is 4.0mg/dl), AST levels is 300 U/L, ALT is 325

(d) Stimulation of anaerobic glycolysis and
U/L and alkaline phosphatase is within normal limits. glycogenolysis
The elevation in AST and ALT can be explained by 48. Which of the following if accumulated is suggestive of
reversible cell injury due to hypoperfusion of different
which of the following?
organs during this duration of myocardial ischemia?
(a) Bleb formation
(b) Cell membrane rupture

(a) Carbon dioxide
(c) Clumping of nuclear chromatin

(b) Creatinine
(d) Swelling of endoplasmic reticulum

(c) Lactic acid

(d) Troponin I
12
Cell Injury
49. If we presume that the patient has experienced several

(c) Blebs
similar episodes of pain over the last 10 hours, which
(d) Myelin figures
of the following ultra-structural changes would most
likely indicate irreversible myocardial cell injury in
52.5. Coagulative necrosis as a primary event is most often
seen in all except:
this patient?
(a) Kidneys

(a) Myofibril relaxation (b) CNS

(b) Disaggregation of polysomes (c) Spleen

(c) Mitochondrial vacuolization (d) Liver

(d) Disaggregation of nuclear granules
52.6. Liquefactive necrosis is seen in:
V
50. A 55-year-old man, ikas develops a thrombus in his (a) Heart
left anterior descending coronary artery. The area of (b) Brain
myocardium supplied by this vessel is irreversibly (c) Lung
injured. The thrombus is destroyed by the infusion (d) Spleen
of streptokinase, which is a plasminogen activator,
and the injured area is reperfused. The patient, 52.7. Organelle that plays a pivotal role in apoptosis:
however, develops an arrhythmia and dies. An electron (a) Endoplasmic reticulum
E
microscopic ( M) picture taken of the irreversibly (b) Golgi complex
injured myocardium reveals the presence of large, dark, (c) Mitochondria
irregular amorphic densities within mitochondria. (d) Nucleus
What are these abnormal structures? 52.8. Intracellular calcification begins in which of the

(a) Apoptotic bodies following organelles?

(b) Flocculent densities (a) Mitochondria

(c) Myelin figures (b) Golgi body

(d) Psammoma bodies (c) Lysososme

(e) Russell bodies (d) Endoplasmic reticulum
51. Which one of the listed statements best describes 5 2.9. Which of the following induces apoptosis in a cell?
the mechanism through which Fas(CD95) initiates (a) Oleic acid (Aiims Nov 2013)
(b) Isoprenoids
Cell Injury
apoptosis?

(a) BCL2 product blocks channels (c) Myristic acid

(b) Cytochrome activates Apaf-1 (d) Glucocorticoids

(c) FADD stimulates caspase 8 52.10. Which of the following is not seen is apoptosis?

(d) TNF inhibits Ikb (a) Chromatin condensation (Aiims Nov 2013)

(e) TRADD stimulates FAD (b) DNA fragmentation
(c) Inflammation
Most Recent Questions (d) Cell membrane shrinkage
5 2.1. In apoptosis, cytochrome C acts through:
(a) Apaf 1
52.11. Following gene when mutated protects tumor cells
from Apoptosis
(b) Bcl-2
(a) BCL 2
(c) FADD
(b) BRCA
(d) TNF
(c) RB
5 2.2. Cells most sensitive to hypoxia are: (d) TGF
(a) Myocardial cells
5 2.12. Following is seen in both apoptosis and necrosis:
(b) Neurons
(a) Both may be physiological
(c) Hepatocytes
(b) Both may be pathological
(d) Renal tubular epithelial cells
(c) Inflammation
5 2.3. In cell death, myelin figures are derived from: (d) Intact cell membrane
(a) Nucleus
(b) Cell membrane cellular adaptation, Intracellular accumulation
(c) Cytoplasm
(d) Mitochondria
53. Psammoma bodies are seen in all except:
5 2.4. Irreversible cell injury is characterised by which of the (a) Follicular carcinoma of thyroid (AI 2011,09)
following? (b) Papillary carcinoma of thyroid
(a) Mitochondrial densities (c) Serous cystadenoma of ovary
(b) Cellular swelling (d) Meningioma
13
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Review of Pathology
54. True about metastatic calcification is 63. Pigmentation in the liver is caused by all except:
(a) Calcium level is normal (AIIMS May 2009) (a) Lipofuscin (PGI Dec 01)
(b) Occur in dead and dying tissue (b) Pseudomelanin
(c) Occur in damaged heart valve (c) Wilsons disease
(d) Mitochondria involved earliest (d) Malarial pigment
55. Both hyperplasia and hypertrophy are seen in? (e) Bile pigment
(a) Breast enlargement during lactation 64. Wear and tear pigment in the body refers to
(b) Uterus during pregnancy (AIIMS May 2009)
(a) Lipochrome (Karnataka 2006)
(c) Skeletal muscle enlargement during exercise
(b) Melanin
(d) Left ventricular hypertrophy during heart failure
(c) Anthracotic pigment
56. Which of the following is not a common site for (d) Hemosiderin
metastatic calcification? (AIIMS Nov 2005)
(a) Gastric mucosa 65. Mallory hyaline bodies are seen all Except:
(b) Kidney (a) Indian childhood cirrhosis (AI 97) (UP 2004)
(c) Parathyroid (b) Wilsons disease
(d) Lung (c) Alcoholic hepatitis
(d) Crigler-Najjar syndrome
57. Calcification of soft tissues without any disturbance of
calcium metabolism is called 66. Russells body are accumulations of: (UP 2006)
(a) Inotrophic calcification (AIIMS Nov 2004) (a) Cholesterol
(b) Monotrophic calcification (b) Immunoglobulins
(c) Dystrophic calcification (c) Lipoproteins
(d) Calcium induced calcification (d) Phospholipids
58. The light brown perinuclear pigment seen on H & E 67. Dystrophic calcification is seen in: (UP 2006)
staining of the cardiac muscle fibres in the grossly
(a) Atheroma
normal appearing heart of an 83 year old man at
(b) Pagets disease
autopsy is due to deposition as: (c) Renal osteodystrophy

(a) Hemosiderin (AIIMS May 2003) (d) Milk-alkali syndrome

(b) Lipochrome
Cell Injury

(c) Cholesterol metabolite 68. Brown atrophy is due to (AP 2000)

(d) Anthracotic pigment (a) Fatty necrosis
(b) Hemosiderin
59. Dystrophic calcification is seen in: (c) Lipofuscin
(a) Rickets (AIIMS Nov 2002) (d) Ceruloplasmin
(b) Hyperparathyroidism
(c) Atheromatous plaque 69. Psammoma bodies are typically associated with all of
(d) Vitamin A intoxication the following neoplasms except (AP 2001)
(a) Medulloblastoma
60. The Fenton reaction leads to free radical generation (b) Meningioma
when: (AIIMS Nov 2002) (c) Papillary carcinoma of the thyroid
(a) Radiant energy is absorbed by water (d) Papillary serous cystadenocarcinoma of the ovary
(b) Hydrogen peroxide is formed by Myeloperoxidase
(c) Ferrous ions are converted to ferric ions
70. Transformation of one epithelium to other epithelium
is known as (AP 2001)
(d) Nitric oxide is converted to peroxynitrite anion
(a) Dysplasia
61. Mallory hyaline is seen in: (PGI Dec 2000) (b) Hyperplasia
(a) Alcoholic liver disease (c) Neoplasia
(b) Hepatocellular carcinoma (d) Metaplasia
(c) Wilsons disease 71. All are true about metaplasia except (AP 2004)
(d) I.C.C. (Indian childhood cirrhosis) (a) Slow growth (AIIMS 1996, UP 2002)
(e) Biliary cirrhosis (b) Reverse back to normal with appropriate treatment
62. Heterotopic calcification occurs in: (c) Irreversible
(a) Ankylosing spondylitis (PGI Dec 2000) (d) If persistent may induce cancer transformation
(b) Reiters syndrome 72. About hyperplasia, which of the following statement is
(c) Forrestiers disease false? (AP 2007)
(d) Rheumatoid arthritis (a) no of cells
(e) Gouty arthritis (b) size of the affected cell
14
Cell Injury

(c) Endometrial response to estrogen is an example 79. A 50-year-old male alcoholic, Rajesh presents with

(d) All symptoms of liver disease and is found to have mildly
elevated liver enzymes. A liver biopsy examined with
73. Example of hypertrophy is: (Kolkata 2004)
E
a routine hematoxylin and eosin (H & ) stain reveals
(a) Breast in puberty
abnormal clear spaces in the cytoplasm of most of the
(b) Uterus during pregnancy
hepatocytes. Which of the following materials is most
(c) Ovary after menopause
likely forming cytoplasm spaces?
(d) Liver after resection

(a) Calcium
74. Metastatic calcification occurs in all except:
(b) Cholesterol
(a) Kidney (Bihar 2005)
(c) Hemosiderin
(b) Atheroma
(d) Lipofuscin
(c) Fundus of stomach
(e) Triglyceride
(d) Pulmonary veins 80. A 36-year-old woman, Geeta presents with intermittent
75. Dystrophic calcification is: (Jharkhand 2006) pelvic pain. Physical examination reveals a 3-cm mass in
(a) Calcification in dead tissue the area of her right ovary. Histologic sections from this
(b) Calcification in living tissue ovarian mass reveal a papillary tumor with multiple,
(c) Calcification in dead man scattered small, round, laminated calcifications. Which
(d) None of the following is the basic defect producing these
abnormal structures?
76. An old man Muthoot has difficulty in urination (a) Bacterial infection
associated with increased urge and frequency. He has (b) Dystrophic calcification
to get up several times in night to relieve himself. There (c) Enzymatic necrosis
is no history of any burning micturition and lower back (d) Metastatic calcification
pain. On rectal examination, he has enlarged prostate. (e) Viral infection
Which of the following represents the most likely
change in the bladder of this patient? 81. A 28-year-old male executive presents to the doctor
(a) Hyperplasia with complaints of heartburn non responsive to
usual medicines undergoes endoscopy with biopsy of
(b) Atrophy
Cell Injury
the distal esophagus is taken. What type of mucosa is
(c) Hypertrophy
normal for the distal esophagus?
(d) Metaplasia
(a) Ciliated, columnar epithelium
77. An increase in the size of a cell in response to stress is (b) Keratinized, stratified, squamous epithelium
called as hypertrophy. Which of the following does not (c) Non-keratinized, simple, squamous epitheliu
represent the example of smooth muscle hypertrophy (d) Non-keratinized, stratified, squamous epithelium
as an adaptive response to the relevant situation?
(a) Urinary bladder in urine outflow obstruction Most Recent Questions
(b) Small intestine in intestinal obstruction 8 2.1. True about psammoma bodies are all except:
(c) Triceps in body builders (a) Seen in meningioma
(d) None of the above (b) Concentric whorled appearance
(c) Contains calcium deposits
78. A patient Ramu Kaka presented with complaints (d) Seen in teratoma
of slow progressive breathlessness, redness in the
eyes and skin lesions. His chest X ray had bilateral 8 2.2. Metastatic calcification is most often seen in:
hilar lymphadenopathy. His serum ACE levels were (a) Lymph nodes
elevated. On doing Kveim test, it came out to be positive. (b) Lungs
Final confirmation was done with a biopsy which (c) Kidney
(d) Liver
demonstrated presence of non-caseous granuloma. A
diagnosis of sarcoidosis was established. Which of 8 2.3. Russell bodies are seen in:
the following statements regarding calcification and (a) Lymphocytes
sarcoidosis is not true? (b) Neutrophils
(a) The calcification in sarcoidosis begins at a cellular (c) Macrophages
level in mitochondria (d) Plasma cells
(b) There is presence of dystrophic calcification 8 2.4. Psammoma bodies show which type of calcification:
(c) The granulomatous lesions contain macrophages (a) Metastatic
which cause activation of vitamin D precursors (b) Dystrophic
(d) None of the above (c) Secondary
(d) Any of the above
15
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Review of Pathology
82.5. Gamma Gandy bodies contain hemosiderin and: 90. Stain not used for lipid (AIIMS Nov 2007)
(a) Na+ (a) Oil red O
(b) Ca++ (b) Congo red
(c) Mg++ (c) Sudan III
(d) K+ (d) Sudan black
8 2.6. Oncocytes are modified form of which of the following: 91. Acridine orange is a fluorescent dye used to bind
(a) Lysososmes (a) DNA and RNA (AIIMS Nov 2007)
(b) Endoplasmic reticulum
(b) Protein
(c) Mitochondria
(c) Lipid
(d) None of the above
(d) Carbohydrates
Miscellaneous: Free radical injury: stains 92. PAS stains the following except (AIIMS Nov 2007)
(a) Glycogen
83. Which of the following is the most common fixative (b) Lipids
used in electron microscopy? (AIIMS Nov 2012) (c) Fungal cell wall
(a) Glutaraldehyde (d) Basement membrane of bacteria
(b) Formalin 93. All are components of basement membrane except
(c) Picric acid (a) Nidogen (AIIMS Nov 2007)
(d) Absolute Alcohol (b) Laminin
84. The fixative used in histopathology: (AIIMS May 2012) (c) Entactin
(a) 10% buffered neutral formalin (d) Rhodopsin
(b) Bouins fixative 94. Which of the following pigments are involved in free
(c) Glutaraldehyde radical injury? (AIIMS Nov 2006)
(d) Ethyl alcohol (a) Lipofuscin
85. Which is the most commonly used fixative in (b) Melanin
histopathological specimens? (AI 2011) (c) Bilirubin
(a) Glutaraldehyde (d) Hematin
Cell Injury
(b) Formaldehyde 95. True about cell ageing: (AIIMS Nov 2001)
(c) Alcohol (a) Free radicals injury
(d) Picric acid (b) Mitochondria are increased
86. Lipid in the tissue is detected by: (AIIMS Nov 2009) (c) Lipofuscin accumulation in the cell
(a) PAS (d) Size of cell increased
(b) Myeloperoxidase 96. Neutrophil secretes: (PGI Dec 2002)
(c) Oil Red O (a) Superoxide dismutase
(d) Mucicarmine (b) Myeloperoxidase
87. The most abundant glycoprotein present in basement (c) Lysosomal enzyme
membrane is: (AI 2004) (d) Catalase
(a) Laminin (e) Cathepsin G
(b) Fibronectin 97. Which of the following is a peroxisomal free radical
(c) Collagen type 4 scavenger? (Delhi PG 2006)
(d) Heparan sulphate (a) Superoxide dismutase
88. Enzyme that protects the brain from free radical injury (b) Glutathione peroxidase
is: (AI 2001) (c) Catalase
(a) Myeloperoxidase (d) All of the above
(b) Superoxide dismutase 98. Crookes hyaline body is present in: (Kolkata 2001)
(c) MAO (a) Yellow fever
(d) Hydroxylase (b) Basophil cells of the pituitary gland in Cushings
89. Increased incidence of cancer in old age is due to syndrome
(a) Telomerase reactivation (AIIMS May 2009) (c) Parkinsonism
(d) Huntingtons disease
(b) Telomerase deactivation
(c) Inactivation of protooncogene 99. An autopsy is performed on a 65-year-old man, Suresh
(d) Increase in apoptosis who died of congestive heart failure. Sections of the
16
Cell Injury
liver reveal yellow-brown granules in the cytoplasm of resembling eczema. Microscopic examination of a series
most of the hepatocytes. Which of the following stains of peripheral blood smears taken during the course of a
would be most useful to demonstrate with positive staphylococcal infection indicates that the bactericidal
staining that these yellow-brown cytoplasmic granules capacity of the boys neutrophils is impaired or absent.
are in fact composed of hemosiderin (iron)? Which of the following is the most likely cause of this

(a) Oil red O stain childs illness?

(b) Oil red O stain
(a) Defect in the enzyme NADPH oxidase

(c) Periodic acid- Schiff stain
(b) Defect in the enzyme adenosine deaminase (ADA)

(d) Prussian blue stain
(c) Defect in the IL-2 receptor

(e) Sudan black B stain
(d) Developmental defect at the pre-B stage

(f) Trichrome stain
(e) Developmental failure of pharyngeal pouches 3
and 4
100. An S
AID patient Khalil develops symptoms of
pneumonia, and Pneumocystis carinii is suspected as
B
the causative organism. ronchial lavage is performed.
M
ost Recent Questions

Which of the following stains would be most helpful 102.1. Which of the following is a negative stain?
in demonstrating the organisms cysts on slides made
(a) Fontana
from the lavage fluid?
(b) ZN stain

(a) Alcian blue
(c) Nigrosin

(b) Hematoxylin and eosin
(d) Albert stain

(c) Methenamine silver S
102.2. tain used for melanin is:

(d) Trichrome stain
(a) Oil red

101. Which process makes the bacteria tasty to the
(b) Gomori methamine silver stain
macrophages: (Kolkata 2008)
(c) Masson fontana stain

(a) Margination
(d) PAS stain

(b) Diapedesis
102.3. Which of the following statements about Telomerase is

(c) Opsonisation
true?

(d) Chemotaxis

Cell Injury
(a) Has RNA polymerase activity

102. In an evaluation of a 7-year-old boy, Ram who has
(b) Causes carcinogenesis
had recurrent infections since the first year of life,
(c) Present in somatic cells
findings include enlargement of the liver and spleen,
(d) Absent in germ cells
lymph node inflammation, and a superficial dermatitis
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Review of Pathology
E xplanations
1. Ans. (b) Extrinsic pathway of apoptosis (Ref: Robbins 8/e p29-30, 9/e p56)
In the activation of Extrinsic pathway of apoptosis, binding of Fas ligand takes place to CD95 (Fas; member of TNF receptor
family) or binding of TRAIL (TNF related apoptosis inducing ligand) attaches to death receptors DR4 and DR5. This induces
the association of FADD (Fas- associated death domain) and procaspase-8 to death domain motifs of the receptors resulting in
activation of caspase 8 (in humans caspase 10) which finally activates caspases- 3 and 7 that are final effector caspases
2. ans. (b) Amorphous densities in mitochondria (Ref: Robbins 8/e p14-19, 9/e p42,50)
Two phenomena consistently characterize irreversibility:
1. The first is the inability to reverse mitochondrial dysfunction (lack of oxidative phosphorylation and ATP generation) even
after resolution of the original injury.
2. The second is the development of profound disturbances in membrane function
So, the answer for the given question is Amorphous densities in mitochondria.
However, please remember friends that the Robbins in its 8 edition pg 14 mentions small amorphous densities to be
th
present in reversible cell injury also. Therefore, the best answer for characterizing irreversibility of an injury is profound
disturbances in membrane function.
3. Ans. (c) Embryogenesis (Ref: Robbins 8/e p25, 9/e p52)
Caspases are cysteine proteases and are critical for the process of apoptosis. Physiologically, apoptosis is required to elimi-
nate the cells no longer required and to maintain a steady number of various cell populations in tissues. The programmed
cell death (apoptosis) is required at the time of different processes in embryogenesis like implantation, organogenesis,
developmental involution and metamorphosis.
Cell Injury
4. Ans. (b) Apoptosis (Ref: Robbins 8/e p27, 9/e p53)

5. Ans. (d) Condensation of the nucleus (Ref: Robbins 8/e p14-15, 26-27, 9/e p53)
The morphologic features characteristic of apoptosis includes
Cell shrinkage: The cell is smaller in size having dense cytoplasm and the organelles are tightly packed.
Chromatin condensation: This is the most characteristic feature of apoptosis.
Formation of cytoplasmic blebs and apoptotic bodies
Regarding option aPlasma membranes are thought to remain intact till late stage of apoptosis, as well as is a normal cell.
Regarding option b, eosinophilic cytoplasm, it is a common feature of necrosis and apoptosis.
Regarding option c, nuclear moulding is defined as the The shape of one nucleus conforming around the shape of an adjacent
nucleus. It is a characteristic of malignant cells.
6. Ans. (a) TB > (c) Gangrene (Ref: Robbins 8/e p16, 9/e p43)
In the 7 edition of Robbins it was clearly stated thatCaseous necrosis, a distinctive form of coagulative necrosis, is en-
th
countered most often in foci of tuberculous infection. The term caseous is derived from the cheesy white gross appearance of the area of
necrosis.
Regarding the option gangrene, it is not specified the type of gangrene and therefore, we go with the better option as tu-
berculosis in the given question. Moreover, according to Robbins, gangrenous necrosis is not a specific pattern of necrosis
but is a term used in clinical practice.
Dry gangrene has coagulative necrosis whereas wet gangrene has liquefactive necrosis.
7. Ans. (c) Mitochondria (Ref: Robbins 8/e p28, Harrison 18/e p681, 9/e p53)
8. Ans. (a) Formation of Amorphous densities in mitochondrial matrix (Ref: Robbins 7/e p19, 9/e p42)
Formation of amorphous densities in the mitochondrial matrix is a feature of irreversible injury and not reversible injury.
Decreased formation of ATP constitutes the critical mechanism of cell injury and occurs in both reversible as well as
irreversible cell injury.
18
Cell Injury
Features of Reversible cell injury Features of irreversible cell injury

Cellular swellingQ Large flocculent, amorphous densitiesQ in swollen mitochondria due to increased
Loss of microvilli calcium influx.
Formation of cytoplasmic blebs Swelling and disruption of lysosomes and leakage of lysosomal enzymes in cytoplasm
Endoplasmic reticulum swelling Decreased basophiliaQ
Detachment of ribosomes Severe damage to plasma membranes
Myelin figuresQ Nuclear changes include
Clumping of nuclear chromatinQ *Pyknosis (Nuclear condensation)
*Karyorrhexis (Nuclear fragmentation)
*Karyolysis (Nuclear dissolution)
9. Ans. (c) Diabetic glomerulosclerosis (Ref: Robbins 7/e p214, 594, 1008, 9/e p44)
Fibrinoid necrosis is a distinctive morphological pattern of cell injury characterized by deposition of fibrin like proteinaceous
material in walls of arteries. Areas of fibrinoid necrosis appear as smudgy eosinophilic regions with obscured underlying
cellular details.
Fibrinoid necrosis is seen in
Malignant hypertension
Vasculitis like PAN
Acute Rheumatic Fever.
10. Ans. (d) Cytochrome C (Ref: Robbins 7/e p30; Harrison 17/e p506, 9/e p55)
Apoptosis or programmed cell death can be induced by intrinsic or extrinsic pathway. As can be seen in the intrinsic
pathway; cyt c gets associated with APAF-1 which activates caspase and cause cell death.For detail see text.
11. Ans. (c) bcl 2 (Ref: Robbins 7/e p29-30, Harrison 17/e p506)
12. Ans. (a) Apoptosis (Ref: Robbins 8/e p27, 9/e p56)
Apoptotic cells express phosphatidylserine in the outer layers of their plasma membranes. This phospholipid moves out
from the inner layers where it is recognized by a number of receptors on the phagocytes. These lipids are also detected by
binding of a protein called Annexin V. So, Annexin V staining is used to identify the apoptotic cells.
13. Ans. (b) Amorphous densities in mitochondria (Ref: Robbins 7/e p12, 9/e p42)
Cell Injury
See earlier explanation.
14. Ans. (b) Apoptosis (Ref: Robbins 7/e p28, 9/e p53)
Caspases are present in normal cells as inactive proenzymes and when they are activated they cleave proteins and induce apop-
tosis. These are cysteine proteases.
15. Ans. (a) Inflammation is present (Ref: Robbins 7/e p31, 27, 9/e p56)
In Apoptosis the dead cell is rapidly cleared, before its contents have leaked out, and therefore cell death by this pathway
Q
does not elicit an inflammatory reaction in the host.
16. Ans. (c) Bcl-X (Ref: Robbins 7/e p29, 9/e p55)
Cytosolic cytochrome C and Apaf-1 are involved in intrinsic pathway of apoptosis . Q
Mitochondrial cyt c and not cytosolic cytc is involved in aerobic respiration .

Q
18. Ans. (a) Amorphous densities in mitochondria (Ref: Robbins 7/e p12, 9/e p50)
Two phenomenons consistently characterize irreversible cell injury:
Large amorphous densities in the mitochondria (this indicates inability to reverse mitochondrial dysfunction)
Development of profound disturbance in membrane function
19. Ans. (d) Apoptosis (Ref: Robbins 7/e p27; Robbins 8/e p27, 9/e p52)
The inter-nucleosomal cleavage of DNA into oligonucleosomes (in multiples of 180-200 base pairs) is brought about by
Ca2+ and Mg2+ dependent endonucleases and is characteristic of apoptosis.
20. Ans. (b) Apoptosis (Ref: Robbins 7/e p26, 27, 9/e p52)
21. Ans. (a) Endonuclease (Ref: Robbins 7/e p26, 27, 28; 8/e pg28)
Endonucleases are enzymes which cause internucleosomal cleavage of DNA into oligonucleosomes, the latter being
visualized by agarose gel electrophoresis as DNA ladders.
In necrosis, smeared pattern is commonly seen
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Review of Pathology
22. Ans. (c) Flocculent densities in mitochondria (Ref: Robbinss 7/e p12, 9/e p50)
23. Ans. (c) Apoptosis of cells induce inflammatory reaction (Ref: Robbins 7/e p27, 9/e p56)
Remember important features of apoptosis
Formation of cytoplasmic blebs and apoptotic bodiesQ
Cell ShrinkageQ: The cells are smaller in size and the cytoplasm is dense.
Chromatin condensationQ: This is the most characteristic features of apoptosis.
Absence of inflammationQ
Gel Electrophoresis of DNA shows Step ladderQ Pattern.
24. Ans. (a) Cytoplasmic blebs; (c) Nuclear Fragmentation: (Ref: Robbins 7/e p26, 9/e p53)
Apoptosis is a programmed cell death.
During apoptosis, cells destined to die activate enzymes that degrade the cells own nuclear DNA and nuclear and
cytoplasmic proteins. There is no inflammatory reaction elicited by host.
Spindle formation is found in cell division in mitosis.
During necrosis, cell swelling is seen.
Differences between apoptosis and necrosis
Feature Necrosis Apoptosis
Cell size Enlarged (swollen) Reduced (shrink)
Nucleus Pyknosis/Karyorrhexis/Karyolysis Fragmentation into nucleosome-sized fragments
Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids
Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies
Adjacent inflammation Frequent No
Role in body Invariably pathologic (culmination of Often physiologic. May be pathologic after cell injury as DNA
irreversible cell injury) damage.
Cell Injury
Proapoptotic Bak; Bax; Bim; P53 gene; Caspases TNFRI; Fas [CD95]; FADD
(Fas associated death domain)
Anti-apoptotic Bcl-2/bcl-X; FLIP; Apaf-1 (Apoptosis activating factor-1)
Cytochrome C
25. Ans. (b) End products are phagocytosed by macrophage; (c) Intranuclear fragmentation of DNA; (d) Activation of
caspases; (e) Annexin V is a marker of apoptotic cell (Ref: Harsh Mohan 5th/53, Robbins 7/e p25-3l, 9/e p53)
27. Ans. (c) Bcl-2 (Ref: Robbins 7/e p31, 32)
Inhibitors of apoptosis: Promoters of apoptosis: Sensors of apoptosis:
Bcl-2 Bax Bad
Bcl-XL BAK Bim
P-53 activation Bid
Ischemic injury Noxa
Death of virus infected cells Pu ma
Neurodegenerative diseases
28. Ans. (d) Bcl-2 (Ref: Robbins 7/e p29, 31, 32, 9/e p55)
29. Ans. (c) Inflammation (Ref: Robbins 7/e p26, 9/e p53)
30. Ans. (b) Ischemic necrosis of the brain (Ref: Robbins 7/e p21-22, 9/e p43)
31. Ans. (c) Inflammation (Ref: Robbin 7/e p27, 9/e p56)
32. Ans. (b) CNS (Ref: Robbins 8/e p15, 7/e p22, 9/e p43)
33. Ans. (b) Brain (Ref: Robbins 8/e p15, 7/e p22, 9/e p43)
34. Ans. (a) Deposition of Ca in mitochondria (Ref: Robbins 8/e p13-14; 7/e p11, 9/e p47)
++
35. Ans. (b) Type of cell injury (Ref: Robbins 8/e p25; 7/e p26-28, 9/e p52)
20
Cell Injury
36. Ans. (b) Liquefactive necrosis (Ref: Robbins 7/e p22, 8/e p1300, 9/e p43)
37. Ans. (a) The death receptors induce apoptosis when it engaged by fas ligand system (Ref: Robbins 8/e p29; 7/e p30, 9/e p56)
38. Ans. (b) Programmed cell death (Ref: Robbins 8/e p25, 9/e p52)
39. Ans. (a) Decreased oxidative phosphorylation in mitochondria (Ref: Robbins 8/e p18-19, 7/e p15, 9/e p45)
40. Ans. (c) Councilman bodies is a type of apoptosis (Ref: Robbins 8/e p25; 7/e 26, 9/e p823)
41. Ans. (b) Scrotal skin
42. Ans. (c) Liver (Ref: Robbins 7/e p21, 8/e p15; 9/e p43)
43. Ans. (b) Cell membrane rupture (Ref: Robbins 8/e p23, 9/e p49-50)
The symptoms and the medical reports of the patient are suggestive of liver cell injury. Out of the options provided,
rupture of the cell membrane is the only cellular change suggestive of irreversible cell injury. All others may be seen in
reversible cell injury as well.
Infact, the enzymes normally are stored inside the cells but in irreversible injury which is usually associated with cell membrane damage,
these intracellular enzymes leak out and their serum levels are elevated. This is the basis of the commonly prescribed diagnostic tests.
44. Ans. (b) Dystrophic fat necrosis (Ref: Robbins 8/e p16-17, 9/e p65)
The situation described above is a typical description of a traumatic fat necrosis. This condition needs to be distinguished
from enzymatic fat necrosis. The hint is in the stem of the question which describes the presence of amorphous basophilic
material. This is suggestive of calcification and such pattern of calcification of previous damaged tissue is termed dystrophic
calcification.
Dystrophic calcification has normal serum calcium levels whereas metastatic classification is associated with increased calcium levels.
45. Ans. (c) p53 (Ref: Robbins 8/e p30,292, 9/e p53-55)
When anti-cancer drugs are administered, they induce the death of the tumor cells by activating p53 gene and increasing
apoptosis. Tumor cells may show resistance to these drugs if there is a mutation in the p53 gene thereby preventing
apoptosis. Bcl-2 promotes the cell growth by inhibiting apoptosis. Granzyme and perforin also increase apoptosis but in
case of cytotoxic T cells. Cytochrome P450 is not associated with apoptosis.
46. Ans. (c) Bcl-2 (Ref: Robbins 8/e p28, 9/e p55)
The process being described in the stem of the question is apoptosis. Fas and Bax are genes which promote apoptosis. Bcl-2
Cell Injury
is inhibitory for apoptosis. So, a Bcl-2 mutation is associated with an increase in apoptosis. Myc is involved in development
of cancer and not directly associated with apoptosis.
47. Ans. (d) Stimulation of anaerobic glycolysis and glycogenolysis (Ref: Robbins 8/e p18, 9/e p46)
The hypoxic cell damage results in decrease in oxidative phosphorylation followed by ATP depletion and increase in
AMP and ADP. Increased phosphofructokinase and phosphorylase activities respectively stimulate anaerobic glycolysis
and glycogenolysis. This results in decrease in intracellular pH and depletion of cellular glycogen stores. Decrease avail-
ability of ATP also results in failure of the Na+ -K+- ATPase pump, which then leads to increased cell Na+ and water and
decreased cell K+.
Mitochondrion is the earliest organelle affected in cell injury.
48. Ans. (c) Lactic acid (Ref: Robbins 8/e p18, 9/e p45)
Anaerobic glycolysis results in accumulation of cellular lactic acid in almost every organ having reduced perfusion. Lactate
accumulation also causes reduced pH. Carbon dioxide and creatinine would increase in involvement of the lung and the
kidneys respectively. But these are not common for every organ involvement.
Troponin I is increased in irreversible injury to the myocardium and is the best marker for diagnosing MI.
49. Ans. (c) Mitochondrial vacuolization (Ref: Robbins 8/e p19, 9/e p46)
The appearance of vacuoles and phospholipid-containing amorphous densities within mitochondria generally signifies
irreversible injury, and implies a permanent inability to generate further ATP via oxidative phosphorylation. When the
mitochondria are injured irreversibly, the cell cannot recover.
Myofibril relaxation is an early sign of reversible injury in cardiac myocytes. It is associated with intracellular ATP depletion and
lactate accumulation due to anaerobic glycolysis during this period.
Disaggregation of polysomes denotes the dissociation of rRNA from mRNA in reversible ischemic/hypoxic injury. ATP depletion
promotes the dissolution of polysomes into monosomes as well as the detachment of ribosomes from the rough endoplasmic
reticulum.
Disaggregation of granular and fibrillar elements of the nucleus is associated with reversible cell injury. Another common
nuclear change associated with reversible cell injury is clumping of nuclear chromatin due to a decrease in intracellular pH.
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50. Ans. (b) Flocculent densities (Ref: Robbins 7/e p15-16, 37-38, , 9/e p51)
Irreversible cellular injury is characterized by severe damage to mitochondria (vacuole formation), extensive damage
to plasma membranes and nuclei, and rupture of lysosomes.
Severe damage to mitochondria is characterized by the influx of calcium ions into the mitochondria and the subse-
quent formation of large, flocculent densities within the mitochondria. These flocculent densities are characteristi-
cally seen in irreversibly injured myocardial cells that undergo reperfusion soon after injury.
51. Ans. (c) i.e. FADD stimulates caspase 8 (Ref: Robbins 7/e p26-32, , 9/e p56)
Apoptosis has two basic phases: an initiation phase, during which caspases are activated, and an execution phase,
during which cell death occurs.
The initiation phase has two distinct pathways: the extrinsic (receptor mediated) pathway and the intrinsic (or mito-
chondrial) pathway.
The extrinsic pathway is mediated by cell surface death receptors, two example of death receptors are type I TNF
receptor (TNFR1) and Fas (CD95).
Fas ligand (FasL), which is produced by immune cells, stimulates apoptosis by binding to Fas, which activates the
cytoplasmic Fas-associated death domain protein (FADD), which in turn activates the caspase cascade via the activa-
tion of caspase 8.
In contrast to the extrinsic pathway, the intrinsic pathway does not involve death receptors and instead results from
increased permeability of mitochondria.
52.1. Ans. (a) Apaf 1 (Ref: Robbins 8/e p29, 9/e p55)
On being released in the cytosol, cytochrome c binds to a protein called Apaf-1 (apoptosis-activating factor-1 which is re-
sponsible for formation of a complex called apoptosome. This complex binds to caspase-9 which is a critical initiator caspase
of the mitochondrial pathway of apoptosis.
N EET POINTS about APOPTOSIS
Mitochondrion is the critical organelle required for apoptosis.
Chromatin condensation is the most characteristic feature.
Cell shrinkage is seen
Cell Injury
Gel electrophoresis demonstrates step ladder pattern

Annexin V is the marker for apoptosis.
CD 95 is the molecular marker for apoptosis
52.2. Ans. (b) Neurons (Ref: Robbins 8/e p11-2)

The neurons are the most sensitive cells in the body to get injured because of hypoxia.
So, Purkinje cells of the cerebellum and neurons of the hippocampus are the most susceptible cells which get af-
fected in hypoxic ischemic encephalopathy.
5 2.3. Ans. (b) Cell membrane (Ref: Robbins 8/e p23, 9/e p50-51)
Dead cells may be replaced by large, whorled phospholipid masses called myelin figures that are derived from damaged
cell membranes. These phospholipid precipitates are then either phagocytosed by other cells or further degraded into fatty
acids.
5 2.4. Ans. (a) Mitochondrial densities (Ref: Robbins 8/e p23-4, 9/e p50)
The two key features of irreversible injury are:
Inability to reverse mitochondrial dysfunction and
Q
Development of profound disturbances in the membrane function . Q
5 2.5. Ans. (b) CNS (Ref: Robbins 8/e p15, 7/e p22, 9/e p43)
As discussed in text, central nervous system is characterized by the presence of liquefactive necrosis during ischemic
Q
injury.
5 2.6. Ans. (b) Brain (Ref: Robbins 8/e p15, 7/e p22, 9/e p43)
As discussed earlier, CNS shows liquefactive necrosis.
5 2.7. Ans. (c) Mitochondria (Ref: Robbins 8/e p28, 7/e p29, 9/e p15, 53)
Mitochondrion must be recognized not only as an organelle with vital roles in intermediary metabolism and oxidative
phosphorylation, but also as a central regulatory structure of apoptosis.
5 2.8. Ans. (a) Mitochondria (Ref: Robbins 8/e p19, 9/e p65-66)
Direct quote.. Initiation of intracellular calcification occurs in the mitochondria of dead or dying cells that accumulate
calcium.
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Cell Injury
52.9 Ans. (d) Glucocorticoids (Ref: Underwoods Pathology 6/e p80)

Glucocorticoids induce apoptosis while sex steroids inhibit apoptosis. ..Underwood Pathology
Inducers of apoptosis Inhibitors of apoptosis
Withdrawal of growth factor Growth factors
Loss of matrix attachment Extracellular matrix
Glucocorticoids Sex steroids
Free radicals Some viral proteins
Some viruses
Ionising radiation
DNA damage
5 2.10. Ans. (c) Inflammation (Ref: Robbin 8/e p26-7)

Inflammation is not seen in apoptosis.
Chromatin condensation is the most characteristic feature of apoptosis. Other findings like cell membrane shrinkage and DNA
fragmentation are also associated with apoptosis.
5 2.11. Ans (a) Bcl-2 (Ref: Robbin 9th/ 8thed: pg606)
We need to identify a gene which should be able to inhibit apoptosis. The answer therefore is bcl-2. It is seen to result in
the development of follicular lymphoma.
52.12. Ans (b) Both may be pathological (Ref: Robbin 9th/40)
53. Ans. (a) Follicular carcinoma of Thyroid (Ref: Robbins 8/e p38, 9/e p65)
Tumors (MOST for PG)
M Meningioma
O Papillary carcinoma of Ovary (serous ovarian cystadenoma)
S Papillary carcinoma of Salivary gland
T Papillary carcinoma of Thyroid
Prolactinoma, Papillary type of renal cell carcinoma
Glucagonoma
Cell Injury
(Psammoma bodies are seen in papillary thyroid cancer and not follicular thyroid cancer)
54. Ans. (d) Mitochondria involved earliest (Ref: Robbins 8/e p38, Robbins 7/e p41-42, 9/e p65)
When the calcium deposition occurs locally in dying tissues despite normal serum levels of calcium, it is known as
dystrophic calcification. It is seen in atherosclerosis, tuberculous lymph node and aging or damaged heart valves.
The deposition of calcium salts in otherwise normal tissues almost always results from hypercalcemia and is known
as metastatic calcification.
Friends, Robbins 7 edn page 41-42 mentions that initiation of intracellular calcification occurs in the mitochondria of dead
th
or dying cells that accumulate calcium. Nothing is mentioned regarding the involvement of mitochondria in metastatic
calcification in either 8th or 7th edition of Robbins. However, we got an article on Medscape which states that Within the
cell it is the mitochondria that serves as the nidus for metastatic calcification.
55. Ans. (b) Uterus during pregnancy (Ref: Robbins 8/e p6-8, 9/e p36)
Hypertrophy refers to an increase in the size of cells, resulting in an increase in the size of the organ. The increased size of the
cells is due the synthesis of more structural components.
The massive physiologic growth of the uterus during pregnancy is a good example of hormone-induced increase in
the size of an organ that results from both hypertrophy and hyperplasia
Regarding the a choice, Breast enlargement during lactation; it is written in Robbins that prolactin and estrogen
cause hypertrophy of the breasts during lactation. Hormonal hyperplasia is best exemplified by the proliferation of
the glandular epithelium of the female breast at puberty and during pregnancy.
56. Ans. (c) Parathyroid (Ref: Robbins 7/e p42, 9/e p65)
Metastatic calcification may occur widely throughout the body but principally affects:
Interstitial tissues of gastric mucosa Q
Kidneys Q
Lungs Q
Systemic arteries and

Q
Pulmonary veins Q
The common feature of all these sites, which makes them prone to calcification is that can loose acid and therefore
they have an internal alkaline component favorable for metastatic calcification.
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Absence of derangement in calcium metabolism

Often a cause of organ dysfunction.
57. Ans. (c) Dystrophic calcification (Ref: Robbins 7/e p41, 8/e p38, 9/e p65)
58. Ans. (b) Lipochrome (Ref: Robbins 7/e p39, 9/e p64)
Regarding other options
Hemosiderin: It is a pigment deposited in conditions of excess iron.
Anthracotic pigment: It is pigment seen in the lung of coal
59. Ans. (c) Atheromatous plaque (Ref: Robbins 7/e p41, 9/e p65)
Atheromatous plaque would have dead cells, so, there is presence of dystrophic calcification.
Mnemonic: D for Dead and D for Dystrophic.
60. Ans. (c) Ferrous ions are converted to ferric ions (Ref: Robbins 7/e p16, 9/e p48)
Free radicals are generated through Fentons reaction which is (H O + Fe Fe + OH + OH )
2 2
2+ 3+ +
In this reaction iron is converted from its ferrous to ferric form and a radical is generated.
The other options are also examples of free radical injury but the questions specifically about Fenton reaction.
The effects of these reactive species relevant to cell injury include: Lipid peroxidation of membranes, oxidative
modification of proteins and lesions in DNA.
61. Ans. (a) Alcoholic liver disease; (b) Hepatocellular carcinoma; (c) Wilsons disease; (d) I.C.C. (Indian childhood
cirrhosis); (e) Biliary cirrhosis (Ref: Robbins 7/e p905)
Mallory bodies: Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins,
visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes. See details in chapter on Liver.
62. Ans. (a) Ankylosing spondylitis; (c) Forrestiers disease (Ref: Robbins 7/e p41-2; Harrison17/e p1952)
Pathologic calcification (Heterotopic calcification) is the abnormal tissue deposition of calcium salts together with small
amounts of iron, manganese and other mineral salts. It may be of two types: Dystrophic calcification or Metastatic
calcification
Cell Injury
*In ankylosing spondylitis - There is calcification and ossification usually most prominent in anterior spinal ligament that gives
Flowing wax appearanceQ on the anterior bodies of vertebrae.
*Diffuse idiopathic skeletal hyperostosis (Forrestiers diseaseQ, ankylosing hyperostosis) affects spine and extra-spinal locations.
It is an enthesopathy, causing bony overgrowths and ligamentous ossification and is characterized by flowing calcification over the
anterolateral aspects of vertebrae.
63. Ans. None (Ref: Harsh Mohan 5th/735; Robbins 7/e p39, 910, 914)
Pigmentation in liver is caused by:
Lipofuscin: It is an insoluble pigment known as lipochrome and wear and tear pigment. It is seen in cells undergoing
low, regressive changes and is particularly prominent in liver and heart of ageing patient or patients with severe
malnutrition and cancer cachexia.
Pseudomelanin: After death, a dark greenish or blackish discoloration of the surface of the abdominal viscera results
from the action of sulfated hydrogen upon the iron of disintegrated hemoglobin. Liver is also pigmented.
Wilsons disease: Copper is usually deposited in periportal hepatocytes in the form of reddish granules in cytoplasm
or reddish cytoplasmic coloration stained by rubeanic acid or rhodamine stain for copper or orcein stain for copper
associated protein. Copper also gets deposited in chronic obstructive cholestasis.
Malarial pigment: Liver colour varies from dark chocolate red to slate-grey even black depending upon the stage of
congestion.
In biliary cirrhosis liver is enlarged and greenish-yellow in colour due to cholestasis. So liver is pigmented due to
bile.
64. L
Ans. (a) ipochrome (Ref: Robbins 7/e p39, 9/e p64)
65. Ans. (d) Crigler-Najjar syndrome (Ref: Robbins 8/e p858; 7/e p905, Harsh Mohan 6/e p621-622)
66. Ans. (b) Immunoglobulins (Ref: Robbins 8/e p610; 7/e p680-681, 9/e p63)
67. Ans. (a) Atheroma (Ref: Robbins 8/e p38, 7/e p41-42, 9/e p65)
68. L
Ans. (c) ipofuscin (Ref: Robbins 8/e p10,532; 7/e 10, 9/e p64)
69. Ans. (a) Medulloblastoma (Ref: Robbins 8/e p38, 1122; 7/e 41,1178,1407, 9/e p65)
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Cell Injury
70. Ans. (d) Metaplasia (Ref: Robbins 8/e p10,11; 7/e 10,11, 9/e p37)
71. Ans. (c) Irreversible (Ref: Robbins 8/e p265; 7/e 10), 9/e p37-38
72. Ans. (b) Size of affected cell (Ref: Robbins 8/e p8-9, 7/e p7 , 9/e p35)
73. Ans. (b) Uterus during pregnancy (Ref: Robbins 8/e p6, 7/e p7-8 , 9/e p34-36)
Breast at Puberty Hyperplasia
Breast during lactation Hypertrophy
Uterus after resection Hyperplasia
Uterus during pregnancy Hyperplasia + Hypertrophy
74. Ans. (b) Atheroma (Ref: Robbins 8/e p38; 7/e p41, 9/e p65)
75. Ans. (a) Calcification in dead tissue (Ref: Robbins 8/e p38, 7/e p41, 9/e p65)
76. Ans. (c) Hypertrophy (Ref: Robbins 8/e p6-7, 9/e p36)
The patient is most likely suffering from benign hyperplasia of the prostate. The question however asks about the change
in bladder which would be hypertrophy. This is secondary to the obstruction in the urine outflow following the smooth
muscle in the bladder undergoes hypertrophy.
Benign prostatic hyperplasia is due to action of the hormone dihydrotestosterone and not testosterone.
77. Ans. (c) Triceps in body builders (Ref: Robbins 8/e p6-7, 9/e p34)
The enlargement of the triceps is an example of skeletal muscle hypertrophy (not smooth muscle hypertrophy).
78. Ans. (b) There is presence of dystrophic calcification (Ref: Robbins 8/e p38, 9/e p65)
In sarcoidosis, there is presence of metastatic calcification because of the presence of increased concentration of calcitriol
(most active form of vitamin D). Both the patterns of calcification begin in mitochondria.
79. Ans. (e) Triglyceride (Ref: Robbins 7/e p35-37, 41-42; Chandrasoma, 3/8-10, 9/e p62)
Substance that can form clear spaces in the cytoplasm of cells as seen with a routine H&E stain include glycogen,
lipid, and water. In the liver, clear spaces within hepatocytes are most likely to be lipid, this change being called fatty
change or steatosis.

Cell Injury
Increased formation of triglycerides can result from alcohol use, as alcohol causes excess NADH formation (high
NADH/NAD ratio), increases fatty acid synthesis, and decreases fatty acid oxidation.
In contrast to lipid, calcium appears as a dark blue-purple color with routine H&E stains, while hemosiderin, which
is formed from the breakdown of ferritin, appears as yellow-brown granules.
L ipofuscin also appears as fine, granular, golden brown intracytoplasmic pigment. It is an insoluble wear and
tear (ageing) pigment found in neurons, cardiac myocytes, or hepatocytes.
80. Ans. (b) Dystrophic calcification (Ref: Robbins 7/e p41-42; Henry/195-196, 9/e p65)
Dystrophic calcification is characterized by calcification in abnormal (dystrophic) tissue, while metastatic calcification
is characterized by calcification in normal tissue.
Examples of dystrophic calcification of damaged or abnormal heart valves, and calcification within tumors
Small (microscopic) laminated calcifications within tumors are called Psammoma bodies and are due to single- cell
necrosis. Psammoma bodies are characteristically found in papillary tumors, such as papillary carcinomas of the
thyroid and papillary tumors of the ovary (especially papillary serous cystadenocarcinoma), but they can also be
found in meningiomas or mesotheliomas.
With dystrophic calcification the serum calcium levels are normal, while with metastatic calcification the serum
calcium levels are elevated (hypercalcemia).
81. Ans. (d) i.e. Non-keratinized, stratified, squamous epithelium (Ref: Robbins 8/e p770, 9/e p37)
The esophagus is covered by non-keratinized, stratified, squamous epithelium for its entire length. Heartburn is usually a
sign of gastric regurgitation of the acidic contents in the lower esophagus (acid reflux disease).
8 2.1. Ans. (d) Seen in teratoma (Ref: Robbins 8/e p38, 9/e p65)
The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies because of
their resemblance to grains of sand. Some common cancers associated with psammoma bodies are:
M Meningioma, Mesothelioma
O Papillary carcinoma of Ovary (serous ovarian cystadenoma)
S Papillary carcinoma of Salivary gland
T Papillary carcinoma of Thyroid
Prolactinoma
Glucagonoma
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8 2.2. Ans. (b) Lungs (Ref: Dail and Hammars Pulmonary Pathology: Non-neoplastic lung disease, Springer 3/e p777)
Direct quoteLung are the most frequent involved of all organs.
Ours is the only and the first book to give you an authentic reference for this one friends. This is in sharp contrast to all our
competitors who give name and page number of books where this info is just not there. Try that yourself. You would
find many such questions and answers in other chapters of this edition. Happy reading!
8 2.3. Ans. (d) Plasma cells (Ref: Robbins 8/e p35, 7/e p37, 9/e p63)
Russell bodies are homogenous eosinophilic inclusions that result from hugely distended endoplasmic reticulum.
82.4. Ans. (b) Dystrophic (Ref: Robbins 8/e p38, 7/e p41 , 9/e p65)
Direct quote On occasion single necrotic cells may constitute seed crystals that become encrusted by the mineral
deposits. The progressive acquisition of outer layers may create lamellated configurations, called psammoma bodies.
8 2.5. Ans. (b) Ca++ (Ref: Harsh Mohan 6/e p106-107, Robbins 7/e p705)
In chronic venous congestion of spleen, some of the hemorrhages overlying fibrous tissue get deposits of hemosiderin and
calcium, these are called as Gamma Gandy bodies or siderofibrotic nodules.
8 2.6. Ans. (c) Mitochondria (Ref: Robbins 8/e p35, 7/e p37 , 9/e p53)
Oncocytes are epithelial cells stuffed with mitochondria, which impart the granular appearance to the cytoplasm.
83. Ans. (a) Glutaraldehyde (Ref: Bancroft 6/e p53, Ackerman 9th/27)
fixative used for light microscopic examination: 10% buffered neutral formalin
Commonest Commonest fixative used for electron microscopic examination: Glutaraldehyde
84. Ans. (a) 10% buffered neutral formalin (Ref: Bancroft 6/e p53, Ackerman 9th/27)
Commonest fixative used for light microscopic examination: 10% buffered neutral formalin
Commonest fixative used for electron microscopic examination: Glutaraldehyde
85. Ans. (b) Formaldehyde (Ref: Bancroft 6/e p53)
Formaldehyde is the most commonly used fixative in histopathological specimens. See text for details.
86. Ans. (c) Oil Red O (Ref: Bancroft histology 6/e p53)
Cell Injury
87. Ans. (a) Laminin (Ref: Robbins 7/e p105, Harrison 17/e p2462 , 9/e p24)
Laminin is the most abundant glycoprotein in basement membranes. Type IV collagen, laminin and nidogen are present
in basement membranes.
Tendons and ligaments consist primarily of collagen type I whereas cartilage is mainly consisted of Type II collagen.
88. Ans. (b) Superoxide dismutase (Ref: Robbins 7/e p17, Harrisons 17/e p2572 , 9/e p48)
Antioxidant enzymes include glutathione peroxidase, SOD and catalase.
Deficiency of SOD 1 gene may result in motor neuron disorder. This finding strengthens the view that SOD protects
brain from free radial injury.
89. Ans. (a) Telomerase reactivation (Ref: Robbins 8/e p296-297 , 9/e p67)
After a fixed number of divisions, normal cells become arrested in a terminally non-dividing state known as replicative senescence.
With each cell division there is some shortening of specialized structures, called telomeres, at the ends of chromosomes. Once
the telomeres are shortened beyond a certain point, the loss of telomere function leads to activation of p53-dependent cell-cycle
checkpoints, causing proliferative arrest or apoptosis. Thus, telomere shortening functions as a clock that counts cell divisions.
In germ cells, telomere shortening is prevented by the sustained function of the enzyme telomerase, thus explaining the ability
of these cells to self-replicate extensively. This enzyme is absent in most somatic cells, and hence they suffer progressive loss
of telomeres.
Cancer cells prevent telomere shortening by the reactivation of telomerase activity. Telomerase activity has been detected in more
than 90% of human tumors. Telomerase activity and maintenance of telomere length are essential for the maintenance of replicative
potential in cancer cells.
90. Ans. (b) Congo red (Ref: Bancrofts histopathology 5th/204)

Congo red is used for staining amyloid and not lipids
Stains for Lipids
Oil red O Sudan black Sudan III and IV
Filipin Schultz Nile blue sulfate
26
Cell Injury
91. Ans. (a) DNA and RNA (Ref: Bancroft 5th/236, 237, 238)
Acridine orange is a nucleic acid selective fluorescent cationic dye useful for cell cycle determination.
It is cell-permeable, and interacts with DNA and RNA by intercalation or electrostatic attractions respectively and
emits green and red right respectively.
Acridine orange can be used in conjunction with ethidium bromide to differentiate between live and apoptotic
cells.
92. Ans. (b) Lipids (Ref: Bancrofts histopathology 5th/204)
PAS (periodic acid-Schiff) stain is versatile and has been used to stain many structures including glycogen, mucin, mu-
coprotein, glycoprotein, as well as fungi. PAS is useful for outlining tissue structures, basement membranes, glomeruli,
blood vessels and glycogen in the liver.
*Lipids are stained by oil red O and Sudan stains. (See explanation above)
*PAS can also stain glycolipids but here it is used for staining carbohydrate moiety of these compounds and not lipid portion.
93. Ans. (d) Rhodopsin (Ref: Robbins 7/e p103, 9/e p24)
Basement membrane is Periodic Acid Schiff (PAS) positive amorphous structures that lie underneath epithelia of different
organs and endothelial cells. It consists of
Laminin Fibronectin Tenascin
Proteoglycans Entactin (Nidogen) Perlecan (heparin sulphate)
Collagen type IV
94. Ans. (a) Lipofuscin (Ref: Robbins 7/e p39 , 9/e p64)
Important points about Lipochrome or Lipofuscin.
*Also called wear and tear pigmentQ or pigment of ageingQ
*Perinuclear in location
*Derived through lipid peroxidationQ
*Indicative of free radical injury to the cell
*Prominent in ageingQ, severe malnutritionQ and cancer cachexiaQ
95. Ans. (c) Lipofuscin accumulation (Ref: Robbins 8/e p36, 39 41, 9/e p64)
Cell Injury
96. Ans. (b) Myeloperoxidase; (e) Cathepsin G (Ref: Robbins 7/e p73)
Granules of Neutrophils
Specific granules Azurophil granules
Lactoferrin Myeloperoxidase
Lysozyme Lysozyme
Type IV collagenase Cationic proteins
Leucocyte adhesion molecules Acid hydrolase
Plasminogen activator Elastase
Phospholipase A2 Non-specific collagenase
BPI
Defensin
Cathepsin G
Phospholipase A2
97. Ans. (d) All of the above (Ref: Robbins 7/e p17 , 9/e p48)
Catalase is present in peroxisomes and decomposes H O into O and H O.
2 2 2 2
Superoxide dismutase is found in many cell types and converts superoxide ions to H2O2. This group includes both
manganese-superoxide dismutase, which is localized in mitochondria, and copper-zinc-superoxide dismutase, which
is found in the cytosol.
Glutathione peroxidase also protects against injury by catalyzing free radical breakdown.
98. Ans. (b) Basophil cells of the pituitary gland in Cushings syndrome (Ref: Robbins 8/e p1149)
In Cushing syndrome, the normal granular, basophilic cytoplasm of the ACTH producing cells in the anterior pituitary becomes paler and
homogenous. This is due to accumulation of intermediate keratin filaments Q in the cytoplasm.
99. Ans. (c) Prussian blue stain (Ref: Robbins 7/e p39- 42, 9/e p64)
Yellow-brown granules in hepatocytes as seen with routine hematoxylin and eosin (H&E) stain can be hemosiderin,
bile, and Lipofuscin.
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The special histologic stain for hemosiderin, which contains iron, is the Prussian blue stainQ.
Oil red OQ and Sudan black BQ stain are both used to demonstrate neutral lipidsQ in tissue sections.
PAS (periodic acid Schiff) stainQ is used to demonstrate carbohydratesQ.
Trichrome stainQ is used to demonstrate collagen or smooth muscle in tissue. With this stain collagenQ appears blue, while
smooth muscleQ appears red.
100. Ans. (c) i.e. Methenamine silver (Ref: Harsh Mohan 6/e p474)
The appropriate stain is methenamine silver. The routine hematoxylin and eosin does not adequately demonstrate the
organisms. The cysts, when stained with methenamine silver, have a characteristic cup or boat shape; the trophozoites are
difficult to demonstrate without electron microscopy.

Alcian blue (choice A) is good for demonstrating mucopolysaccharidesQ.

Hematoxylin and eosin (choice B) is the routine tissue stainQ used in pathology laboratories.

Trichrome stain (choice D) is good for distinguishing fibrous tissue from nerve and muscle.
101. Ans. (c) Opsonisation (Ref: Robbins 8/e p52-53, 7/e p59 , 9/e p78)
102. Ans. (a) Defect in the enzyme NADPH oxidase (Ref: Robbins 7/e p61-62, 243-244 , 9/e p79)
Patients with chronic granulomatous disease have defective functioning of phagocytic neutrophils and monocytes.
The most common cause of chronic granulomatous disease is defective NADPH oxidase, which is an enzyme on the
membrane of lysosomes that converts O2 to superoxide and stimulates oxygen burst. This deficiency results in recur-
rent infections with catalase-positive organisms, such as S. aureus. Key findings in chronic granulomatous disease
include lymphadenitis, hepatosplenomegaly, eczematoid dermatitis, pulmonary infiltrates.
A defect in the enzyme adenosine deaminase (ADA) is seen in the autosomal recessive (Swiss) form of severe com-
bined immunodeficiency disease (SCID), while a defect in the IL-2 receptor is seen in the X-linked recessive form of
SCID.
A developmental defect at the pre-B stage is seen in X-linked agammaglobulinemia of Bruton, while developmental
failure of pharyngeal pouches 3 and 4 is characteristic of DiGeorges syndrome.
Cell Injury
102.1. Ans. (c) Nigrosin

Negative stainingis a technique in which the background is stained, leaving the actual specimen untouched,
and thus visible. In contrast, with positive staining, the actual specimen is stained.
Examples of negative stains include nigrosin and India Ink.
India ink is used to make a diagnosis of cryotococcal infection by making its capsule prominent.
102.2. Ans. (c) Masson fontana stain (Ref: Histopathology p150)

Stain Substance
Masson Fontana Melanin
Oil red O Neutral lipids and fatty acids
PAS Glycogen, mucin, mucoprotein, glycoprotein and fungi
Gomori methamine silver stain Fungi (like Cryptococcus, Coccidiodes and Pneumocystis jiroveci (carinii)
Other stains for melanin are Schmorls method and enzyme histochemical method called DOPA-oxidase (most
specific method).
102.3. Ans. (b) Causes carcinogenesis (Ref: Robbins 8/e p40, 9/e p67)
Telomerase is a specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the
ends of chromosomes.
Regulatory protein sense the telomere length and they restrict the activity of telomerase to prevent unnecessary
elongation.
Telomerase activity is highest in germ cells and present at lower levels in stem cells, but it is usually undetectable
in most somatic tissues
Decreased activity of telomerase is associated with ageing whereas its excessive activity is associated with cancers.
28
Cell Injury
Golden Points For quick revision

(Cell Injury)
Hypoxia is the most common cause of cell injury.
Neurons are the most sensitive cell to hypoxic injury in the brain.
Coagulative necrosis is associated with tombstone appearance. It is seen with ischemic injury to all tissues except
central nervous system.
Best example of coexistence of hypertrophy and hyperplasia is uterus during pregnancy (gravid uterus).
Most common metaplasia is squamous metaplasia in the lungs of smokers.
CD 95 plays a role in apoptosis.
Mitochondria plays a pivotal role on apoptosis
Marker for apoptosis (programmed cell death) is annexin V
Most important stimulatory gene for apoptosis is p53 gene and most important inhibitory gene for apoptosis is bcl
family (bcl-2) of genes.
Key words associated with apoptosis: caspases, cytochrome C and embryogenesis
Chromatin condensation is the hallmark feature of apoptosis.
Step ladder pattern on gel electrophoresis is a feature of apoptosis. Stepladder fever is seen in typhoid/enteric fever.
Lipofuscin is also known by several other names like lipochrome, wear and tear pigment, pigment of aging and
indicator of free radical injury. It gets deposited mostly in heart and liver.
The endogenous brown-black pigments include melanin (present in skin) and homogentisic acid (the black pigment
in patients with alkaptonuria)
Dystrophic calcification: normal serum calcium levels and in dead tissues (areas of necrosis).
Metastatic calcification: increased serum calcium levels and in living tissues.
Lungs are the commonest site for metastatic calcification. Other sites include stomach, pulmonary vein, systemic
artery and kidneys.
Psammoma bodies: meningioma, papillary thyroid carcinoma, prolactinoma, glucagonoma and serous cystadenoma
Cell Injury
of the ovary.
Gandy gamma body is seen in congestive splenomegaly. It contains hemosiderin and calcium.
Oncocytes are formed with modified mitochondria.
Germ cells have the capacity for self renewal because of telomerase activation.
Cancer cells have the phenomenon of telomerase reactivation.
Germ cells have the maximum telomerase activity amongst all the cells of the body.
Cell cannibalization required for self survival is called autophagy.
Necroptosis is a caspase independent process which resembles necrosis morphologically and apoptosis mechanistically
as a form of programmed cell death.
Pyroptosis is a programmed cell death is accompanied by the release of fever inducing cytokine IL-1. It also involves
caspases 1 and 11.
Commonest fixative used for light microscopic examination: 10% buffered neutral formalin
Commonest fixative used for electron microscopic examination: glutaraldehyde
Updated information from 9th edition of robbins

Necroptosis and Pyroptosis
Necroptosis resembles necrosis morphologically and apoptosis mechanistically as a form of programmed cell
death. It is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses.
Necroptosis is caspase-independent but dependent on signaling by the RIP1 and RIP3 complex.
RIP1-RIP3 signaling reduces mitochondrial ATP generation, causes production of ROS, and permeabilizes
lysosomal membranes, thereby causing cellular swelling and membrane damage as occurs in necrosis.
The release of cellular contents evokes an inflammatory reaction as in necrosis.
Pyroptosis occurs in cells infected by microbes. It involves activation of caspase-1 which cleaves the precursor form of IL-1 to generate
biologically active IL-1. Caspase-1 along with closely related caspase-11 also lead to death of the infected cell.
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Autophagy
Autophagy is an adaptive response that is enhanced during nutrient deprivation, allowing the cell to cannibalize itself
to survive. It involves sequestration of cellular organelles into cytoplasmic autophagic vacuoles (autophagosomes)
that fuse with lysosomes and digest the enclosed material. The autophagosome formation is regulated by more
than a dozen proteins that act in a coordinated and sequential manner.
Dysregulation of autophagy occurs in many disease states including cancers, inflammatory bowel diseases, and
neurodegenerative disorders. Autophagy plays a role in host defense against certain microbes.
In Alzheimer disease, formation of autophagosomes is accelerated and in Huntington disease, mutant huntingtin
impairs autophagy.
Cell Injury
30
CHAPTER 2
Response of the blood vessels and cells to an injurious stimulus is called inflammation. It can be:
Inflammation

Acute inflammation: It is of shorter duration (seconds, minutes, few hours)

Chronic inflammation: It is of longer duration (weeks, months and years)
The changes seen in inflammation can be in the blood vessels (called vascular changes) and
in the cells (called cellular changes).

I. Vascular Changes

1. Vasoconstriction: It is the firstQ change in the blood vessels which is transient
in nature. Clinically it is responsible for the blanching seen immediately after
injury.

2. Vasodilation: Second change in the blood vessels lasting for a longer duration is Increased vascular permeability
vasodilation. It results in increased blood flow leading to redness (rubor) and the is the hallmark of acute inflam-
sensation of warmth (color). mation

3. Increased permeability: It is the hallmark of acute inflammationQ caused by separation
of the endothelial cells resulting in movement of fluid, cells and proteins out of
the blood vessels (collectively called as exudate). The exudate is a protein rich
fluid which is responsible for the swelling (tumor) associated with an injury. It
is maximally seen in the venules. The various mechanisms of increased vascular
permeability are explained below:
m I
Mechanis s of ncreased Vascular Per eability m
Mechanism Caused by Affected blood Properties of
vessels response

1. Formation of Vasoactive mediators like Venules Rapid;
endothelial gaps histamine, leukotrienes, Reversible; short
(Immediate transient bradykinin and contraction of lived (15 to 30
responseQ) endothelial cell cytoskeleton minutes)

2. Direct endothelial Toxins, infections, burns, Venules, Fast and may be
injury (immediate chemicals causing endothelial capillaries and long lived
sustained cell necrosis and detachment arterioles
responseQ)

3. Cytoskeletal Due to cytokines and hypoxia Mostly venulesQ; Reversible,
reorganisation capillaries may delayed and
E
( ndothelial cell be also involved prolonged
retractionQ)

4. Delayed prolonged Thermal and radiation injury Venules and Delayed and
leakage induced endothelial cell damage capillaries long lived
5. Leukocyte mediated Activated leukocytes causing Venules (mostly); Late and long
endothelial injury endothelial injury or detachment pulmonary and lived
glomerular
capillaries

6. Increased transcytosis Formation of vesiculo-vacuolar Venules
organelles near inter cellular
junctions by histamine and VEGF

7. Leakage from new Mostly by vascular endothelial Sites of
blood vessel growth factor (VEGF) and less angiogenesis
commonly by histamine and Formation of endothelial gaps
substance P I
( mmediate transient response)
4. The loss of fluid results in concentration of red cells in small vessels and is the commonest mechanism
for increased permeability.
increased viscosity of the blood leading to slower blood flow and is called stasis.
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II. Cellular Changes
Selectins are responsible for The sequence of events in the journey of leukocytes from the vessel lumen to the
rolling of neutrophils. interstitial tissue, called extravasation, can be divided into the following steps:

1. Margination: Movement of the leukocytes which are normally moving in the
centre of the blood vessel towards the periphery of the blood vessel is called as
margination.

2. Rolling: It is the process of transient adhesion of leukocytes with the endothelial
cells. Selectins are the most important molecules responsible for it. They interact
Endothelial cell expression of with the complementary molecules resulting in transient adhesion. The selectins
E-selectin is a hallmark of acute can be either.
cytokine mediated inflammation. E selectin (CD 62E) Present on cytokine-activated endothelial cells and interacts with
sialyl lewis X receptor on the leukocyte.
L selectin (CD 62L) Present on leukocytes and interacts with glycoprotein adhesion mol-
ecules (GlyCAM-1), Mad CAM-1 and CD34 on endothelial cells.
P selectin (CD 62P) Present on platelets and endothelial cells and interacts with sialyl
lewis X receptor on leukocytes.
3. Adhesion: It is firm attachment of the leukocytes to the endothelial cells. Integrins
are the most important molecules promoting cell-cell or cell-matrix interactions
b2-Integrins are neutrophil adhe- by interacting with vascular cell adhesion molecule (VCAM) or intercellular
sion molecules. adhesion molecule (ICAM). These can be of two types:
1-containing integrins: These are also called VLA molecules and interact with
VCAM-1 on endothelial cells.
2-containing integrins: These are also called LFA-1 or Mac-1 and interact with
ICAM-1 on endothelial cells.
Concept: Clinical importance of adhesion molecules (Harrisons 18th/478)

Leukocyte adhesion deficiency type 1 (LAD1) is caused by a defect in the CD 18 molecule required
nflammation
for biosynthesis of the 2 chain shared by the LFA-1 and Mac-1 integrins. Poor adhesion is accompa-
nied by defective aggregation and chemotaxis. So, these patients have recurrent bacterial infections
involving skin, oral and genital mucosa, respiratory and intestinal tract; persistent leukocytosis because
cells dont marginate and a history of delayed separation of umbilical cord stumpQ is present.
LAD1: Integrin defects; recurrent
I infections and delayed separa-
tion of umbilical cord stump
Leukocyte adhesion deficiency type 2 (LAD2) is caused by the absence of sialyl-Lewis X, the
fucose-containing ligand for E-selectin, owing to a defect in the enzyme fucosyl transferase respon-
sible for binding fucose moieties to protein backbones. Patients have recurrent bacterial infections,
B
platelet disfunction short stature, ombay blood groupQ and mental retardation. LAD 2 is also called
as congenital disorder of glycosylation IIc.
Leukocyte adhesion deficiency type 3 ( LAD 3) is caused by the mutation in FERMT3 gene result-
ing in impaired signaling for integrin activation. Patients have petechial hemorrhage, leucocytosis and
LAD2: Selectin defects; recurrent infections.
recurrent infections, B
ombay
blood group and mental *Both LAD1 and LAD2 are autosomal recessive conditions.
retardation.
Endothelial Leukocyte adhesion molecules and their functions
Endothelial molecule WBC receptor Major role
P-selectin Sialyl- Lewis X Rolling
E-selectin Sialyl- Lewis X Rolling, adhesion to activated endothelium
ICAM-1 CD 11/CD 18 (Integrins) Adhesion, arrest, transmigration
VCAM-1 VLA 4, LPAM-1 Adhesion
Glycam-1 L-selectin Lymphocytes homing to high endothelial venules
CD 31(PECAM) CD 31 WBC migration through endothelium.
4. Transmigration: The step in the process of the migration of the leukocytesQ
through the endothelium is called transmigration or diapedesis. The most
important molecule responsible for diapedesis is called PECAM-1 (platelet
endothelial cell adhesion molecule) or CD31. Neutrophils predominate in the
32
Inflammation
inflammatory infiltrate during the first 6 to 24 hours, then are replaced by

monocytes in 24 to 48 hours (except in Pseudomonas infection in which neutrophils L eukocyte diapedesis, similar
predominate over 2 to 4 days). to increased vascular perme-
5. Chemotaxis: It is unidirectional movementQ of the leukocytes towards antigens/ ability, occurs predominantly in
the venules (except in the lungs,
bacteria in response to certain chemicals. These chemicals are called chemotactic
where it also occurs in capillaries).
stimuli. They can be:
a. Exogenous: Bacterial productsQ
b. Endogenous products: C5a, LTB 4, IL-8
All the chemotactic agents mentioned above bind to G-protein coupled receptors
(GPCRs) on the surface of leukocytes to cause actin polymerization and all movements.
Other actin-regulating proteins like filamin, gelsolin, profilin, and calmodulin also interact O
Example of psonins include
antibodies, complement proteins
with actin and myosin to produce contraction and cellular movement. The leukocytes and lectins.
degranulate to release lysosomal enzymes, cytokines and produce arachidonic acid
metabolites. The leukocyte activation takes place due to GPCRs, cytokine receptors
and Toll-like receptors (TLRs).
6. Opsonisation: Coating of the bacteria so that they are easily phagocytosed by the
Chemotaxis: It is unidirectional
white blood cells is known as opsonisation.
or targeted movement of the
*Mnemonic corollary friends I believe all of you have had waterballs or golgappe at some leukocytes towards antigens/
point of time in your life, u can have them both with and without water but in which condi- bacteria.
tion do u think they are tastier? Well majority would answer the latter option i.e. with water.
The function of water is to make the golgappa tastier. Similarly, opsonins make the bacteria
tastier for the leukocytes. Please remember that the WBCs can kill bacteria without opsonins
also but opsonised bacteria are preferentially killed.
Concept
Chemicals causing opsonisation are called opsonins. These are:
IgG is produced by activated
C3bQ
Fc fragment of antibody or IgGQ.
B cells called plasma cells.
Brutons disease is a defect
I
nflammation
Some serum proteins (like fibrinogenQ, mannose binding lectinQ and C reactive proteinQ) in maturation of the B cells
7.
Phagocytosis: It is the process by which bacteria are killed/eaten up by the white in which there is absence of
immunoglobulin. So, Brutons
blood cells. Lysosomes are important organelles required for phagocytosis. disease is characterized by
Phagocytosis: It is characterized by 3 steps defective opsonisation.

a. Recognition and attachment: The particles to be ingested by leukocytes (microbes
and dead cells) are recognized by receptors present on the surface of WBCs. These
receptors are.

i. Scavenger receptors: These bind microbes and oxidized or acetylated LDL
particles.

ii. Mac-1 integrins: These are present on the surface of macrophages.

iii. Mannose receptors: These bind to mannose and fucose residues of glycoproteins
in microbial cell wall. The presence of an additional terminal sialic acid or
N-acetyl galactosamine in human cells prevents their destruction by WBCs. Phagocytosis (cell eating) requires

b. Engulfment: There is formation of phagolysosome (due to fusion of the lysosomes polymerization of actin fila-
ments whereas in contrast, pino-
and the phagosome containing the microbe) inside the leukocytes. This is followed cytosis (cell drinking) and recep-
by degranulation of leukocytes. tor mediated endocytosis require
Concept clathrin coated pits.
The clinical significance of phagolysosome formation is appreciated in an autosomal recessive dis-

order known as Chediak-Higashi syndrome. It is characterized by reduced transfer of lysosomal en-
zymes to phagocytic vacuoles in phagocytes, defective degranulation, and delayed microbial killing
causing increased susceptibility to infections. The polymorphs also exhibit defective random move-
ments and have defective chemotaxis.
Clinical features: It includes neutropenia (decreased numbers of neutrophils), albinism (due to abnor-
malities in melanocytes), nerve defects, nystagmus and bleeding disorders (due to defect in neurons The leukocytes in C
hediak-
and platelets respectively). These patients also have reduced NK cell responsiveness. H igashi syndrome have giant
granules seen in peripheral
The secretion of granule proteins by cytotoxic T cells is also affected which also contributes to the im- blood smear which are due to
munodeficiency. The gene for lysosomal trafficking is called LYST. aberrant organelle fusion.
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c. Killing and degradation: Final step in phagocytosis is the killing of infectious

organism within the leukocytes. It can be accomplished by
O -dependent MPO system is
2
i. Oxygen dependent killing mechanism
most potent microbicidal system.
There is production of microbicidal reactive oxygen species within phagocytic
vesicles by the following mechanism:
The final step in the microbial killing is due to reactive oxygen species called as
respiratory burst.
Phagocytes (i.e., neutrophils, monocytes, and macrophages) require an enzyme
to produce reactive oxygen species to destroy bacteria after they ingest the
bacteria in a process called phagocytosis. This enzyme is termed phagocyte
NADPH oxidase is also called NADPH oxidase (PHOX). The initial step in this process involves the one-
by the name of respiratory
burst oxidase. electron reduction of molecular oxygen to produce superoxide free radical.
Superoxide then undergoes a further series of reactions to produce products
such as peroxide, hydroxyl radical and hypochlorite. The reactive oxygen
species thus produced are toxic to bacteria and help the phagocyte kill them
once they are ingested.
Chronic granulomatous disease

(CGD) is a disease caused due
to a defect in NADPH oxidase
activity and respiratory burst.
nflammation
Chronic granulomatous disease (CGD) has a defective NADPH oxidase activity with recur-
rent infection and granuloma formation affecting gastrointestinal or genitourinary tract. CGD
I can be diagnosed with the following tests:
Nitroblue-tetrazolium (NBT) test: It is negative in chronic granulomatous disease and posi-
tive in normal individuals. This test depends upon the direct reduction of NBT by superoxide
free radical to form an insoluble formazan. This test is simple to perform and gives rapid
results, but only tells whether or not there is a problem with the PHOX enzymes, not how
much they are affected.
Dihydrorhodamine (DHR) test: in this test, the whole blood is stained with DHR, incubated
and stimulated produce superoxide radicals which reduce DHR to rhodamin in cells with
normal function.
Concept C C
ytochrome reduction assay is an advanced test that tells physicians how much super-
oxide a patients phagocytes can produce.
is a disease caused due to Difference between Myeloperoxidase deficiency and Chronic Granulomatous
a defect in NADPH oxidase Disease (CGD)
activity characterised by repeated
infections by catalase positive In CGD, some phagocytosed organisms (catalase negative organisms like steptococci) can
organisms; (bacterial infections be killed because these organisms produce their own hydrogen peroxide which is used by
mostly due to Staph. aureus and neutrophilic myeloperoxidase to produce free radicals and kill them.
fungal due to Candida). In myeloperoxidase deficiency, the enzyme myeloperoxidase is absent, so both catalase
positive and catalase-negative organisms will survive within phagocytes and cause infec-
tions.
Enzymes involved in respiratory burst

NADPH oxidase is chiefly responsible for the formation of hydrogen peroxide
which plays the most important role in microbial killing.
Nitroblue-tetrazolium test is
Catalase degrades hydrogen peroxide into water and oxygen.
the most widely known test for
chronic granulomatous disease.

Superoxide dismutase (SOD) causes conversion of superoxide ion into hydrogen
peroxide.
34
Inflammation
Glutathione peroxidase causes conversion of reduced glutathione to its

homodimer.
2OH + 2GSH 2H O + GSSG
2
Note: H2O2 MPO halide system is the most efficient way of killing the bacteriaQ.

ii. Oxygen independent killing mechanism
It can be done by various enzymes and proteins like Major basic protein is present
E
Lysozyme: Cause hydrolysis of glycopeptide coat of bacteria. in osinophils and is toxic to
Lactoferrin: It is an iron binding protein. parasites.
Bacterial permeability increasing protein.
Major basic proteinQ (MBP).
Defensins: These are arginine rich peptides toxic to the microbes.
Cathelicidins: These are antimicrobial proteins in the neutrophils and other cells
They are highly effective against M. tuberculosis.
Important Chem al ic Mediators

Chemical mediators of inflammation may be present in cells (cellular) or in the plasma.
Concept
The synthesis of antimicrobial
protein cathelicidin is stimulated
by 1, 25 dihyroxyvitamin D. The
importance of this non skeletal
effect of vitamin D is that vitamin
D deficiency can increase the I
chances of tubercular infections
nflammation
Preformed Cellular Mediators
a. Histamine: It is formed from the amino acid histidine. Mast cells are the richest
source of histamine. It is also present in platelets and basophils. It causes vasodilation
(but vasoconstriction of large arteries), increased permeability (immediate transient
response) and bronchoconstriction.

b. Serotonin (5-HT): Richest source of serotonin (5- hydroxytryptamine; 5- HT) is
platelets. It has actions similar to histamine. It is also present in enterochromaffin
cells.

c. Lysosomal Enzymes: These are present in the lysosomes of neutrophils and monocytes.
Lysosomes contain two types of granules; Primary (azurophilic) and secondary
(specific) granules.
Histamine is the most important

chemical mediator of acute
inflammation.
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Two major anti-proteases present in the body are a1 antitrypsin and a2 macroglobulin
Neutrophils also have tertiary granules or C particles which contain gelatinase and
acid hydrolases.
Newly Synthesized Cellular Mediators

a. Nitric Oxide (NO): It is formed from l-arginine with the help of enzyme nitric oxide
synthase (NOS).
Nitric Oxide is synthesized from
the amino acid l-arginine. NADPH + O 2
L-Arginine L- Citrulline + NO
NOS
Three isoforms of NOS are present in the body:
i. e NOS (Present in endothelium)
ii. n NOS (Present in neurons)
IL-1Q is the most important cyto- iii. i NOS (inducible form)
kine responsible for the systemic
effects of inflammation
eNOS and nNOS are constitutively expressed whereas i NOS production is induced
by cytokines like TNF a and IFN-g.
Important actions of NO
Potent vasodilator
IL-10 Q and transforming growth Reduction of platelet aggregation
TF
factor beta ( G -bQ) possess Endogenous regulator of leucocyte recruitment
Also possess microbicidal action: NO acts as a free radical and can also be converted to highly reac-
anti- inflammatory action.
tive peroxynitrite anion (ONOO) as well as NO2 and NO3.

b. Cytokines : These are small proteinaceous molecules secreted by the inflammatory
cells. These include interleukins, interferons and tumor necrosis factor- alpha
TGF-b is the most important (TNF-a). These can produce local and systemic effects. Most important cytokine
fibrogenicQ agent responsible for systemic effects of inflammation are interleukin-1 (IL-1) and tumor
nflammation
necrosis factor- alpha (TNF-a).

IL-1, TNF-a
Acute phase reaction Endothelial and fibroblast effects WBC effects
I IL-1, IL-6, TNF-a and type I
- Fever PGI2 formation
Secretion of
interferons contribute to acute
- Increased sleep Procoagulant IL-1 and IL-6
phase response.
- Decreased appetite Fibroblast

- Neutrophilia Collagen
Important info
Pyrogenic cytokines
Exogenous : LPS
n
Endogenous : IL-1/T Fa Resolvins and protectins are anti inflammatory lipid mediators derived from polyunsaturated fatty acids
ISNa/C TF n which along with IL-10, TGF- and lipoxins help in the termination of acute inflammatory response.
IL-6
c. Arachidonic acid metabolites : Arachidonic acid (AA) is a 20-C fatty acid containing
four double bonds. It must be released/mobilized from membrane phospholipids
(PL) for oxygenation to various compounds.
i. COX pathway: Two type of COX-enzymes (also known as PGH synthase);

COX-1 and COX-2 convert AA to PGG2 first and then to PGH2 [both are called
cyclic endoperoxides]. Further fate of PGH2 depend upon the enzyme present
in a particular cell e.g. endothelium contain PGI2 synthase and thus forms PGI2
whereas platelets contain TXA2 synthase and therefore synthesize TXA2.
36
Inflammation
COX-1 is mostly constitutive

(house-keeping) whereas COX-
2 is inducible. However, in
endothelium, kidney and CNS,
even COX-2 is constitutively
present.
F
PG 2aQ is a vasoconstrictor
whereas PGD2 and PGE2 are
vasodilators.
I
PG 2 cause inhibition of platelet
I I
aggregation ( stands for nhibi-
A
tion) and TX 2 cause platelet ag-
A
gregation ( for aggregation)
FLAP- Five Lipoxygenase Activating Protein
ii. LOX-pathway: AA can be acted upon different types of LOX enzymes. I

1. 5-LOX (present in leukocytes, mast cells and dendritic cells) acts in the
nflammation
presence of FLAP [5-LOX activating protein] to convert AA to LTA4. This
product can be converted either to LTB4 or to cysteinyl Leukotrienes (LTC4,
D4 and E4).

2. 15-LOX converts AA to 15-HETE which can be converted to Lipoxins (LXA4
and LXB4) with the action of 5-LOX. Lipoxins can also be synthesized by
action of 12-LOX on LTA4.
LTB4 is a potent chemotactic molecule for T-lymphocytes, eosinophils, monocytes and

mast cells whereas LTC4, D4 and F4 are chemotactic for T-lymphocytes and eosinophils. LTC 4
Q and LTC4
Q [primary
LipoxinsQ cause activation of monocytes and macrophages and inhibition of neutro- components of slow reacting
philsQ. These also inhibit NK cell cytotoxicity and are powerful coronary vasoconstric- substance of anaphylaxis;
tors in vivo. SRS A - Q] are powerful broncho-
constrictors, increase perme-
ability and mucus secretion in

iii. Epoxygenase pathway: Cytochrome P450 may convert AA to 20-HETE or EET. airways.
Biological effects of EET are reduced by metabolism to less active DHET with
the help of epoxide hydrolases.

EET may function as endothelium derived hyperpolarizing factor
particularly in coronary circulation. It also possesses anti-inflammatory,
anti-apoptotic and pro-angiogenic action.

20-HETE cause vasoconstriction of renal arteries and has been
implicated in the pathogenesis of hypertension. In contrast, EET possess
antihypertensive properties via its vasodilating and natriuretic actions.
Inhibitors of epoxide hydrolase [results in elevated levels of EET] are being
developed as antihypertensive drugs.
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Abbreviations: DHET Dihydroxyeicosatrienoic acid, EET Epoxyeicosatrie-

noic acid, HETE Hydroxyeicosatetraenoic acid, HPETE Hydroxyperoxyeicosa-
tetraenoic acid.

iv. Isoeicosanoid pathway: Isoprostanes are prostaglandin stereoisomers. These
are formed by non-enzymatic free-radical based peroxidation of AA and related
lipid substrates. These have potent vasoconstrictor activity and modulate WBC
and platelet adhesive interactions and angiogenesis.

d. Chemokines : Chemokines are a family of small proteins that act primarily as
chemoattractants for specific types of leukocytes. They are classified into 4 major
groups according to the arrangement of conserved cysteine residue in mature
proteins. Most the chemokines have four conserved cysteine residues (expressed as
C). X means amino acid other than C. Thus, C-X-C means two conserved cysteines
are separated by one amino acid and C-X3-C means separation by three amino acids.
C-C means no separation and C-chemokines lack first and third conserved cysteine
residues.
nflammation
Note: Chemokines mediate their actions through chemokine receptors (CXCR or CCR). Certain re-
ceptors (CXCR4; CCR5) act as co-receptors for binding and entry of HIV into CD4 cells.
IL-8 is chemotactic for neutro-
phils whereas Eotaxin selec-
tively recruits eosinophils. Mediators Present in Plasma
a. Complement system
It consists of 20 complement proteins (and their breakdown products) present in the
plasma. These are numbered C1 to C9. The complement system has the following
four pathways:

Classic activation pathway activated by antigen/antibody immune complexes,

Mannose binding lectin activation pathway activated by microbes with
Critical step in the functioning terminal mannose groups
of the complement system is the
activation of C (most abundant

Alternative activation pathway activated by microbes or tumor cells
component).
3
Terminal pathway that is common to the first three pathways and leads to the
membrane attack complex that lyses cells.
38
Inflammation
Classical Pathway activation:

decreased C1, C2, C4, C3; with
normal factor B.
Alternative pathway activation:

decreased factor B, C3; with
normal C1, C2 and C4.
Concept
C1 inhibitor (C1 INH) blocks
binding of C1 to immune complex.
So its deficiency causes excessive
complement activation. This forms
the basis of development of
I
Irrespective of the initial pathway, all the three cause break down of activation of C3 and
nflammation
herediatary angioneurotic edema.
result in the formation of membrane attack complex (MAC). This complex causes antigenic
destruction.
ci f ii
Fun t ons o Important Ind v dual Complement rote ns P i
C and C
3a 5a are also called anaphylatoxins which are chemicals causing release
of histamine from mast cells. So, they cause vasodilation and increased vascular
permeability.
C3b and inactive C3 (C3i) used for opsonisation.
C5a also has important role in chemotaxis.
C5b-9 (Membrane Attack Complex; MAC) attacks and kills the antigen.
Deficiency of C2 is the
Regulatory Molecules of Complement System most common complement
deficiency and is associated with
Decay accelerating factor (DAF) increases the dissociation of C convertase. 3 Streptococcal septicemia and
Factor I proteolytically cleaves C . 3b lupus like syndrome in children.
CD59 (Membrane inhibitor of reactive lysis) inhibits formation of MAC.
Factor H, factor I and CD46 prevent exessive alternate pathway activation.
Deficiency of Disease/Syndrome
complement component
1. C1 esterase Inhibitor Hereditary angioneurotic edema (subcutaneous edema IgM and IgG (IgM > IgG) are
because of excessive complement activation) responsible for activation of
classical pathway whereas
2. Early complement SLE and collagen vascular disorders IgA is responsible for activation
proteins C1, C2, C4 alternate pathway.
3. C3b and C3b inactivator Recurrent pyogenic infections
4. C5 to C8 Bacterial infections with Neisseria and Toxoplasmosis
cont...
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cont...
5. C9 No particular disease
6. DAF and CD59 Paroxysmal nocturnal hemoglobinuria (complement
mediated increased intravascular lysis of RBCs, platelets and
neutrophils)
7. CD46, factors H and I Atypical or non epidemic hemolytic uremic syndrome (HUS)
All the clotting factors are
b. Clotting system
synthesized in the liver except
factor IV (calcium) and a factor
A brief overview is presented here and additional details of coagulation cascade are
mentioned in chapter 3.
VIII carrier protein called von
Willebrand factor.
Factors II, VII, IX and X depend

on vitamin K for their activation.
Monitoring of intrinsic pathway

is done using activated partial
thromboplastin time (aP ) TT
and extrinsic pathway using
prothrombin time (PT) or
International Sensitivity Index
(ISI)
nflammation
I
Factor XII is the only protein in
the coagulation cascade whose
deficiency does not cause
bleeding but rather results in a
prothrombotic state. The most important function of clotting system activation is formation blood clot
that helps to prevent excessive blood loss. Some of the components of the clotting
system also play other roles e.g. fibrinogen is used for opsonisation and thrombin
causes chemotaxis.
Clinical correlation: Deficiency of clotting factors VIII and IX resulting in hemophilia A and B
respectively.
Fibrin is degraded by the action
of plasmin into smaller fibrin Why a patient of hemophilia would bleed inspite of a normal extrinsic pathway?
degradation products (FDPs). Answer: The main function of the extrinsic pathway in hemostasis is to produce initial limited thrombin
activation upon tissue injury which is reinforced and amplified by a critical feedback loop whereby
thrombin activates factors XI and IX of the intrinsic pathway. In addition, high levels of thrombin are
required to activate TAFI (thrombin activatable fibrinolysis inhibitor) that augments fibrin deposition
by inhibiting fibrinolysis. Thus, both inadequate coagulation (fibrinogenesis) and inappropriate clot
removal (fibrinolysis) contribute to the bleeding manifestations in hemophilia.
40
Inflammation
c. Kinin System
It is initiated by activated factor XII (Hagemans factor)
Activated factor XII can cause

activation of kinin system,
clotting system, fibrinolytic
system and the complement
system.
Kallikrein can also activate plasminogen into plasmin and cause activation of
complement protein C5a
Functions of Bradykinin:

1. Contraction of smooth muscles
2. Pain

3. Dilation of the venules
The most important outcome of acute inflammation is clearance of the injurious stimuli
and replacement of injured cells (resolution).
Morphological patterns of inflammation
Serous inflammation Fibrinous inflammation C atarrhal Purulent
inflammation inflammation
Presence of outpouring Deposition of fibrin in Epithelial surface Purulent exudate Catarrhal inflammation is the
of thin fluid extracellular space due to inflammation causes is made of necrotic commonest type of inflammation
Effusion is fluid
accumulation in cavities
large vascular leaks
Characteristic of
increased mucus
secretion
cells, neutrophils
and edema fluid
I
nflammation
inflammation in body Seen in common cold
cavity linings (meninges,
pericardium)
C HRONIC INFLAMMATION
Chronic inflammation is characterized by infiltration with mononuclear cells (including
Abscess is localized collection
of purulent inflammatory tissue
macrophages, lymphocytes, and plasma cells), tissue destruction and healing by replacement
of damaged tissue via angiogenesis and fibrosis. Macrophage is the dominant cell in chronic
inflammation. It accumulates inside the tissue because of recruitment from circulation; local
proliferation in tissue and immobilization at the site of inflammation. Tissue destruction is the
hallmark of chronic inflammation.
Stem cell Gives rise to Monocyte Macrophage
Infection are the most common
cause of chronic inflammation.
(Bone marrow) monoblast (Present in blood) (Present in tissues)
Macrophages have a life span ranging from months to years and they are given different
names in different tissues e.g.
Liver - Kupffer cell
CNS - Microglia
Bone - Osteoclast
Lung - Alveolar macrophage or Dust cells
Connective tissue - Histiocyte
Placenta - Hoffbauer cells
Spleen - Littoral cells
Kidney - Mesangial cells
Synovium - Type A lining cells
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Subsets of activated macrophages

Monocytes and macrophages
are the primary leukocytes in
Classically activated macrophages (M1) Alternatively activated macrophages
(M2)
chronic inflammation.
Induced by microbial products and cytokines like IFN-gQ. Induced by microbial products and
cytokines like IL-4, IL-5Q
Release lysosomal enzymes, nitric oxide, IL-1and IL-12 Release IL-10Q, TGF-bQ
Involved in microbicidal activities and pathogenic Involved in anti-inflammatory actions and
inflammationQ wound repairQ
Epithelioid cells are macrophages

activated by interferon g released GRANULOMATOUS INFLAMMATION
from CD4 T cells
It is a type of chronic inflammation characterized by formation of granuloma. Granuloma is
an aggregation of macrophages surrounded by a collar of mononuclear cells principally lymphocytes.
Macrophages may get activated to form epithelioid cells (epithelium like cells). Some of the
cells may fuse together to form a bigger cell called a giant cell. The giant cells can be primarily
of the following types:

1. Langerhans giant cell: The nuclei in this giant cell are present in the periphery and in
F
Warthin- inkeldey giant cells a horse shoe pattern. It is seen is tuberculosis.
are seen in measles.
2. Foreign body giant cell: The nuclei are arranged randomly or haphazardly here. It is
seen in granuloma formed by foreign bodies like sutures, talc etc.

3. Touton giant cells are seen in xanthomas, fat necrosis, xanthogranulomatous inflammtion
and dermatofibroma. They are formed by fusion of epithelioid cells and contain a ring
Tumor giant cells like eed- R of nuclei surrounded by foamy cytoplasm.
Sternberg cells are seen in
4. Physiological giant cells are seen in osteoclasts, syncytiotrophoblasts and megakaryocytes.
Hodgkins lymphoma
Common conditions resulting in granuloma formation with important features
Tuberculosis
nflammation
Sarcoidosis (Non caseating granuloma ) Q
Brucellosis
Amongst IBD, Granuloma Cat scratch disease (Stellate shaped or round granuloma)
Q
formation is associated with Syphilis (Gumma ) Q
I only Crohns disease; it is not Lymphogranuloma inguinale

seen in ulcerative colitis Leprosy
Inflammatory bowel disease (IBD)
The formation of a granuloma is discussed later in the chapter of immunity.
Types of Cells
Depending on the regenerative capacity, cells can be divided into 3 categories.
1. Permanent cells Cells of the body which never divide e.g. neurons, skeletal muscle fibres and
cardiac myocytes.
2. Stable cells They have a low rate of multiplication and are usually present is the G0 phase.
When given a stimulus, they enter the G1 phase and multiply e.g. Cells of
proximal tubule of kidney, hepatocytes, pancreatic cells, fibroblasts etc.
3. Labile cells These cells can regenerate throughout life e.g. hematopoietic cells, cells of skin,
gastrointestinal mucosa etc.
W OUND HEALING
It is characterized by the process of regeneration of the damaged tissue by cells of the
same type and replacement of the lost tissue with connective tissue. Regeneration refers to
proliferation of cells and tissues to replace lost structures. It results in complete restitution of
lost or damaged tissue.
Repair consists of a combination of regeneration and scar formation by the deposition
of collagen. It may restore some original structures but can cause structural derangements.
42
Inflammation
Healing by Primary Intention

The healing of a clean uninfected wound is called healing by first intention or primary union. Granulation tissue is fibroblasts
It involves the following changes. + small blood vessel + chronic
inflammatory cells (macrophage
Day F eatures of wound and lymphocytes)
Day 0 (when the wound has formed) Presence of blood clot in the incision
Day 1 (within 24 hours) Neutrophilic infiltration + blood clot
Day 2 (24 to 48 hours) Neutrophils + blood clot + continuous thin epithelial layerQ
Day 3 Macrophages replace neutrophils, Appearance of granulation
tissue, type III collagen deposition begins but do not bridge the
incision
Neo vascularisation is maximum
on day 5.
Day 5 Abundant granulation tissue

- Collagen fibrils bridge the incision

- Neovascularisation is maximumQ

- Full epithelial thickness with surface keratinization
End of 2nd week Accumulation of collagen; fibroblast proliferation
1 month Replacement of collagen type III with collagen type I (has
greater tensile strength) due to action of collagenase enzyme Granulation tissue is the hall-
mark of the fibrogenic repair.
Vitamin C is required for the conversion of tropocollagen to collagen due to hydroxylation
of lysine and proline residues providing stability to collagen molecules.
Healing by Secondary Intention

During healing by secondary intention or secondary union; inflammatory reaction being The chief cell responsible for
scar contraction is myofibro-
more intense, granulation tissue is abundant and a large scar is formed. The scar decreases in
blast.
size after sometime; this is called as scar contraction.
Myofibroblasts are altered fibroblast having the presence of bundles of smooth muscle microfilaments
I
nflammation
actin and vimentin immediately beneath the cell membrane and the cytoplasm which is responsible
for the contractile properties of this cell. They arise from either tissue fibroblasts or fibrocytes in bone
marrow or epithelial cells.
Wound strength is 10% after 1 weekQ; it increases rapidly during next 4 weeksQ and
becomes 70% at the end of 3rd monthQ. The tensile strength of the wound keeps on increasing
as time progresses.
The predominant collagen in adult skin is type IQ whereas in early granulation tissue, it is type Zinc is a cofactor in collagenase
III and IQ.
The balance between extracellular matrix (ECM) synthesis and degradation results
in remodeling of the connective tissue framework which is an important feature of chronic
inflammation and wound repair. The collagen degradation is done by zinc dependent
matrix metalloproteinases (MMP). Collagen degradation is important for tissue remodeling,
angiogenesis and cancer metastasis. That is why zinc deficiency is associated with impaired
wound healing. MMPs are synthesized by several cells like fibroblasts, macrophages, Infections are the most common
neutrophils, synovial cells, and some epithelial cells. Activated collagenases (a type of cause of impaired wound healing.
MMP) are rapidly inhibited by specific tissue inhibitors of metalloproteinases (TIMPs), which
are produced by most mesenchymal cells, thus preventing uncontrolled action of these
proteases. The regulated activity is required for proper wound healing.
During wound healing, complications can arise from:

1. Delayed wound healing: Due to foreign body, ischemia, diabetes, malnutrition,
hormones (glucocorticoids), infection or scurvy. Ascorbic acid deficiency causes
reduced cross linking of tropocollagen to collagen and so, in this condition the
patient has increased bleeding tendencies and poor wound healing.

2. Deficient scar formation: May lead to wound dehiscence and ulceration. Dehiscence or
rupture of a wound is most common after abdominal surgery and is due to increased
abdominal pressure.
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3. Excessive formation of the repair components: Certain conditions may arise because of
increased granulation tissue or excessive collagen leading to keloid, hypertrophic
scar and proud flesh.
Sternum is commonest site for

keloid formation
Intralesional steroids (triamci-

nolone) are the usual drugs for
the managment of keloid.
Incisional scars or traumatic injuries may be followed by exuberant proliferation

of fibroblasts and other connective tissue elements called desmoids or aggressive
fibromatoses. These recur frequently after excision.

nflammation
4. Formation of contractures: Contractures are particularly prone to develop on the

palms, the soles, and the anterior aspect of the thorax. These are commonly seen
after serious burns.
I STEM CELLS
Definition: The most widely accepted stem cell definition is a cell with a unique capacity to
produce unaltered daughter cells (self-renewal) and to generate specialized cell types (potency).

1. Self-renewal can be achieved in two ways:
Asymmetric cell division Symmetric cell division
In human embryo in about 3rd Produces one daughter cell that is identical
Produces two identical daughter cells
week of development stem cells to the parental cell and one daughter cell
appear in yolk sac. that is different from the parental cell and is a
progenitor or differentiated cell
Asymmetric cell division does not increase the
number of stem cells.
In adults, most of the stem cells

For stem cells to proliferate in vitro, they must divide symmetrically. Self-renewal
alone cannot define stem cells, because any established cell line, e.g., HeLa cells
are found in the bone marrow,
but a subset normally circulates proliferate by symmetric cell division.
in peripheral blood. 2. Potency is used to indicate a cells ability to differentiate into specialized cell types.
This can be classified as:
Totipotent cells Multipotent cells Oligopotent cells Uni/Mono potent cells
Can form an Can form multiple Can form more than Can form a single
entire organism cell lineages but one cell lineage but are differentiated cell lineage.
Concept autonomously. cannot form all of the more restricted than
Stem cells are used in bone bodys cell lineages. multipotent cells.
marrow transplantation in Only zygoteQ HematopoieticQ NeuronQ stem cells SpermatogonialQ stem
treatment of various types of (fertilized egg) has this stem cells cells
leukemia and lymphoma. feature.
44
Inflammation
Terminally differentiated cells, such as fibroblast cells, also have a capacity to proliferate
(which may be called self-renewal) but maintain the same cell type (e.g., no potency to form
another cell type) and are not, therefore, considered unipotent cells.
Embryonic stem cells are pluripotent, that is, they are capable of forming all the tissues
of the body
Adult stem cells are usually only able to differentiate into a particular tissue.

Stem cells are located in special sites called niches.
Name of the cell Location Function
Oval cellsQ Canals of Herring of the liver Forming hepatocytes and biliary cells
Satellite cellsQ Basal lamina of myotubules Differentiate into myocytes after injury
Limbus cellsQ Canals of SchlemmQ Stem cells for the corneaQ
Ito cellsQ Subendothelial space of DisseQ Store vitamin AQ
Paneth cells Bottom of crypts Host defense against microorganisms
Other sites for stem cells are the base of the crypts of the colon and the dentate gyrus of
the hippocampus.
Other Important Concepts in Stem Cell Biology

Development naturally progresses from totipotent fertilized eggs to pluripotent
epiblast cells, to multipotent cells, and finally to terminally differentiated cells.
Nuclear reprogramming: The reversal of the terminally differentiated cells to
totipotent or pluripotent cells (called nuclear reprogramming) has been achieved using
nuclear transplantation, or nuclear transfer (NT), procedures (often called cloning),
where the nucleus of a differentiated cell is transferred into an enucleated oocyte.
Stem cell plasticity or trans-differentiation: The prevailing standard in I
developmental biology is that once cells are differentiated, their phenotypes are stable.
nflammation
However, a number of reports have shown that tissue stem cells, which are thought
to be lineage-committed multipotent cells, possess the capacity to differentiate into
cell types outside their lineage restrictions (called trans-differentiation). For example,
hematopoietic stem cells may be converted into neurons as well as germ cells.
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Acute inflammation, c
vas ular and cellular 9. Delayed prolonged bleeding is caused by:
changes (a) Histamine (AI 2008)
(b) Endothelial retraction
1. In acute inflammation endothelial retraction leads to (c) IL-1
(AIIMS Nov 2011) (d) Direct injury to endothelial cells
(a) Delayed transient increase in permeability 10. Earliest transient change following tissue injury will
(b) Immediate transient increase in permeability be: (AI 2007)
(c) Delayed prolonged increase in permeability (a) Neutropenia
(d) Immediate transient decrease in permeability
(b) Neutrophilia
2. After binding of complement and antibody on the (c) Monocytosis
surface of encapsulated bacteria, the process of (d) Lymphocytosis
phagocytosis by polymorphonuclear leukocytes
involves which of the following? (AIIMS Nov 2011) 11. All of the following vascular changes are observed in
(a) Fc and C3b acute inflammation, except: (AI 2005)
(b) Receptor-mediated endocytosis (a) Vasodilation
(c) Respiratory burst (b) Stasis of blood
(d) Pseudopod extension (c) Increased vascular permeability
3. Free radicals are generated by all except (AI 2011) (d) Decreased hydrostatic pressure
(a) Superoxide dismutase 12. The following host tissue responses can be seen in
(b) NADPH Oxidase acute infection, except: (AI 2002)
(c) Myeloperoxidase (a) Exudation
nflammation
(d) NO synthase
(b) Vasodilation
4. Which among the following is the hallmark of acute (c) Margination
inflammation? (AI 2011, AIIMS May 2010) (d) Granuloma formation
(a) Vasoconstriction
I (b) Stasis 13. Oxygen dependent killing is done through
(c) Vasodilation and increase in permeability (a) NADPH oxidase (AI 2007)
(d) Leukocyte margination (b) Superoxide dismutase
5. Main feature of chemotaxis is (AIIMS May 2010) (c) Catalase
(a) Increased random movement of neutrophils (d) Glutathione peroxidase
(b) Increase adhesiveness to intima
(c) Increased phagocytosis
14. Which of the following is not true?
(a) NADPH oxidase generate superoxide ion
(d) Unidirectional locomotion of the neutrophils
(b) MPO kills by OCl
(AIIMS May 2009)
6. Characteristic of acute inflammation is: (AI 2009) (c) Chediak-Higashi syndrome is due to defective
(a) Vasodilation and increased vascular permeability phagolysosome formation
(b) Vasoconstriction (d) In Brutons disease there is normal opsonization
(c) Platelet aggregation
(d) Infiltration by neutrophils 15. Nitroblue tetrazolium test is used for? (AIIMS Nov 2008)
7. Which of the following helps in generating reactive O (a) Phagocytes
(b) Complement
2
intermediates in the neutrophils?
(a) NADPH oxidase (AI 11, 08, AIIMS Nov 2008) (c) T cell
(b) SOD (superoxide dismutase) (d) B cell
(c) Catalase
(d) Glutathione peroxidase 16. In acute inflammation due to the contraction of
endothelial cell cytoskeleton, which of the following
8. Basement membrane degeneration is mediated by: results? (AIIMS Nov 2006)
(a) Metalloproteinases (AI 2008) (a) Delayed transient increase in permeability
(b) Oxidases (b) Early transient increase
(c) Elastases (c) Delayed permanent increase
(d) Hydroxylases (d) Early permanent increase
46
Inflammation
17. Diapedesis is: (AIIMS Nov 2001) (d) It is required for attracting the white blood cells near
(a) Immigration of leukocytes through the basement a targeted organism.
membrane
(b) Immigration of the leukocytes through the vessel
wall to the site of inflammation
(c) Aggregation of platelets at the site of bleeding
(d) Auto digestion of the cells
18. Endothelium leukocyte interaction during inflammation
is mediated by/due to (PGI, Dec 2003)
(a) Selectins
(b) Integrins
(c) Defensins
(d) Endothelin
19. In genetic deficiency of MPO the increased susceptibility
to infection is due to: (Delhi PG 09 RP)
(a) Defective production of prostaglandins
(b) Defective rolling of neutrophils
(c) Inability to produce hydroxyl-halide radicals
(d) Inability to produce hydrogen peroxide
20. After extravasation, leukocytes emigrate in the tissue
towards the site of injury. It is called as
(a) Margination (UP 2005) 26. A middle aged scientist Sudarshan is working in the
(b) Chemotaxis laboratory on the mechanisms involved in inflammation.
(c) Diapedesis He observes that the leucocytes leave the blood vessels
(d) Pavementing and move towards the site of bacteria. Which of the
following is likely to mediate this movement of the
21. The complex process of leukocyte movements through bacteria? I
the blood vessels are all except (a) Histamine
nflammation
(a) Rolling (UP 2008) (b) C3b
(b) Adhesion
(c) C3a
(c) Migration
(d) C5a
(d) Phagocytosis
22. All are true about exudate except (RJ 2000)
27. Which of the following statements in context of
endothelial cell contraction in inflammation is false?
(a) More protein
(b) Less protein (a) Endothelial cell contraction is the commonest mech-
(c) More specific gravity anism of increased permeability
(d) All (b) Endothelial cell contraction is responsible for imme-
diate transient response
23. All of the following are signs of inflammation except (c) It affects venules, capillaries and arterioles commonly.
(a) Pain (AP 2001) (d) It is associated with the release of histamine, sub-
(b) Swelling stance P and bradykinin.
(c) Redness
(d) Absence of functional loss 28. A 14 month old boy Chunnu is being evaluated for
recurrent, indolent skin infections and gingivitis. On
24. Endogenous chemoattractant is: (Bihar 2004)
taking a detailed history from the mother, she tells very
(a) C5a
valuable point that he had delayed separation of the
(b) Bacterial products
umbilical cord which occurred around 9-10 weeks after
(c) Lipopolysaccharide A
his birth. Which of the following proteins is most likely
(d) C8
under-expressed in this boy?
25. Which of the following statements in context of the (a) Late complement components
enzyme E shown in the diagram given below is (b) Transcobalamin II
correct? (c) Integrins
(a) It is a major mode of defense mechanism in eosino- (d) a -globulins
2
phils
(b) Its deficiency results in Chediak Higashi syndrome 29. A 5-year-old female Sukanya is hospitalized with fever
(c) It causes formation of a more important bactericidal and hemorrhagic skin lesions on her lower extremities.
agent than defensins and lysozyme About five months ago she was successfully treated
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with penicillin for bacterial meningitis. She likely to be 32. Which of the following is not a pyrogenic cytokine?
suffering from which of the following immune system (a) IL - 1 (AI 2012)
disorders? (b) TNF

(a) Pure T-cell dysfunction (c) IFN -

(b) Ineffective intracellular killing (d) IL - 18

(c) Insufficient IgA production 33. All of the following are true in respect of angioneurotic

(d) Inability to form the membrane-attack complex edema except? (AI 2012)
(a) It is caused by deficiency of complement proteins
30. A 3-year-old boy, Krish presents with recurrent (b) It is more common in females
bacterial and fungal infections primarily involving his (c) It manifests as pitting edema
skin and respiratory tract. Physical examination reveals (d) It is an autosomal dominant disorder
the presence of oculocutan-eous albinism. Examination
of a peripheral blood smear reveals large granules 34. Which of the following complement component can
be activated is both common as well as alternative
within neutrophils, lymphocytes, and monocytes. The
pathways? (AI 2011)
total neutrophil count is found to be decreased. Further
(a) C1
workup reveals ineffective bactericidal capabilities
(b) C2
of neutrophils due to defective fusion of phagosomes (c) C3
with lysosomes. Which of the following is the most (d) C4
likely diagnosis?

(a) Ataxia-telangiectasia 35. Which of the following is not an inflammatory
mediator? (AIIMS Nov 2010)

(b) Chediak-Higashi syndrome
(a) Tumor Necrosis Factor

(c) Chronic granulomatous disease
(b) Myeloperoxidase

(d) Ehlers-Danlos syndrome (c) Interferons
(d) Interleukin
Most Recent Questions 36. Nephrocalcinosis in a systemic granulomatous disease
3 0.1. All of the following are a family of selectin except is due to (AIIMS Nov 2010)
(a) P selectin (a) Over production of 1,25 dihydroxy vitamin D
(b) L selectin (b) Dystrophic calcification
(c) A selectin
nflammation
(c) Mutation in calcium sensing receptors

(d) E selectin (d) Increased reabsorption of calcium
3 0.2. Most important for diapedesis? 37. Bradykinin is for: (AI 2010)
(a) PECAM (a) Pain
I (b) Selectin (b) Vasodilatation
(c) Integrin (c) Vasoconstriction
(d) Mucin like glycoprotein (d) Increase vascular permeability
30.3. In acute inflammation the tissue response consists of all 38. Most important bactericidal agent is: (AI 2009)
except (a) Cationic basic protein

(a) Vasodilatation (b) Lactoferrin

(b) Exudation (c) Lysozyme

(c) Neutrophilic response (d) Reactive O species
2

(d) Granuloma formation
39. Bradykinin causes: (AI 2008)
30.4. The function common to neutrophils, monocytes, and (a) Vasoconstriction
macrophages is (b) Pain at the site of inflammation
(a) Immune response is reduced (c) Bronchodilation
(b) Phagocytosis (d) Decreased vascular permeability
(c) Liberation of histamine 40. Lewis triple response is caused due to:
(d) Destruction of old erythrocytes (a) Histamine (AI 2008)
(b) Axon reflex
Chemical mediators of inflammation (c) Injury to endothelium
(d) Increased permeability
31. The role of bradykinin in process of inflammation is: 41. Factor present in the final common terminal complement
(a) Vasoconstriction (AIIms May 2012) pathway is: (AI 2007)
(b) Bronchodilation (a) C4
(c) Pain (b) C3
(d) Increased vascular permeability (c) C5
(d) Protein B
48
Inflammation
42. To which of the following family of chemical mediators

(c) XII
of inflammation, the Lipoxins belong?
(d) X and Ca++
(a) Kinin system (AI 2004) 52. Which complement fragments are called anaphylatoxins?
(b) Cytokines (a) C3a and C3b (Delhi PG-2006)
(c) Chemokines (b) C3b and C5b
(d) Arachidonic acid metabolites (c) C5a and C3b
43. Both antibody dependent and independent complement (d) C3a and C5a
pathway converge on which complement component?
(a) C3
53. Cryoprecipitate is rich in which of the following
(AIIMS Nov 2008) (DNB 2008) clotting factors: (Delhi PG-2005)
(b) C5 (a) Factor II
(c) C1q (b) Factor V
(d) C8 (c) Factor VII
44. C-C beta chemokines includes (AIIMS Nov 2006) (d) Factor VIII
(a) IL-8 54. Most important mediator of chemotaxis is:
(b) Eotaxin (a) C3b (Delhi PG-2005)
(c) Lymphotactin (b) C5a
(d) Fractalkine (c) C5-7
(d) C2
45. All of the following are mediators of acute inflammation
except (AIIMS Nov 2005) 55. Histamine causes (Delhi PG-2004)
(a) Angiotensin (a) Hypertension
(b) Prostaglandin E2 (b) Vasoconstriction
(c) Kallikrein (c) Vasodilation
(d) C3a (d) Tachycardia
46. All of the following are mediators of inflammation 56. Which of the following is found in secondary granules
except: (AIIMS May 2005) of neutrophils? (UP 2000)
(a) Tumour necrosis factor-a (TNF-a) (a) Catalase
(b) Interleukin-1 (b) Gangliosidase I
(c) Myeloperoxidase (c) Proteolytic enzyme
nflammation
(d) Prostaglandins (d) Lactoferrin
47. Interleukin secreted by macrophages, stimulating 57. All are mediators of neutrophils except:
lymphocytes is: (AIIMS May 2001) (a) Elastase (UP 2004)
(a) IFN alpha (b) Cathepsin
(b) TNF alpha (c) Nitric oxide
(c) IL-1 (d) Leukotrienes
(d) IL-6
48. Cytokines are secreted in sepsis and Systemic 58. Ultra-structurally, endothelial cells contain
(a) Weibel Palade bodies (UP 2004)
Inflammatory Response Syndrome (SIRS) by: (b) Langerhans granules
(a) Neutrophils (PGI Dec 01) (c) Abundant glycogen
(b) Adrenal (d) Kallikrein
(c) Platelets
(d) Collecting duct 59. Partial thromboplastin time correlates with:
(e) Renal cortex (a) Intrinsic and common pathway (UP 2006)
(b) Extrinsic and common pathway
49. Febrile response in CNS is mediated by (PGI Dec 2003) (c) Vessel wall integrity and intrinsic pathway
(a) Bacterial toxin. (d) Platelet functions and common pathway
(b) IL-l
(c) IL-6 60. Bleeding time assesses: (UP 2006)
(d) Interferon (a) Extrinsic clotting pathway
(e) Tumor necrosis factor (TNF) (b) Intrinsic clotting pathway
(c) Fibrinogen level
50. Cytokines: (PGI Dec 2005)
(d) Function of platelets
(a) Includes interleukins
(b) Produced only in sepsis 61. The estimation of the prothrombin level is useful in the
(c) Are polypeptide (complex proteins) following clotting factor deficiency, except: (UP 2006)
(d) Have highly specific action (a) II
51. Conversion of prothrombin to thrombin requires: (b) V
(a) V only (Delhi PG-2008) (c) VII
(b) V and Ca++ (d) IX
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62. Which of the following is secondary mediator of the in the pathogenesis of her condition. This cell is most
anaphylaxis is: (UP 2006) similar to which of the following white blood cells?
(a) Histamine
(a) Neutrophil
(b) Proteases
(b) Monocyte
(c) Eosinophilic chemotactic factor
(c) Basophil
(d) Leukotriene B4

(d) Eosinophil
63. Birbecks granules in the cytoplasm are seen in:
(a) Langerhans cells (UP 2006)
(b) Mast cells
(c) Myelocytes
(d) Thrombocytes
64. The Eosinophils secrete all except (UP 2005)
(a) Major basic protein (UP 2007)
(b) Hydrolytic enzyme
(c) Reactive form of O2
(d) Eosinophilic chemotactic factor
65. In Lipooxygenase pathway of the arachidonic acid
metabolism, which of the following products helps to
promote the platelet aggregation and vasoconstriction?

(a) C5a (UP 2008)

(b) Thromboxane A2

(c) Leukotriene B4

(d) C1 activators
66. Chemotactic complement components are (RJ 2001) 72. Awith 72 year-old man Kishori Lal presented to surgery OPD
a history of difficulty in micturition, increased
(a) C3a
(b) C5a frequency of urine and lower backache for the past 8
(c) Both months. Digital rectal examination reveals an enlarged
(d) C3b prostate with irregular surface. The surgeon orders for
nflammation
the serum PSA levels which are found to be increased

67. In inflammatory process, the prostaglandin E1and E2 and X ray spine shows osteoblastic lesions. A diagnosis
cause (AP 2000)
of metastatic prostate cancer is made. Mr Lal also
(a) Vasodilatation
(b) Increased gastric output complaints of significant weight loss, loss of appetite
I (c) Decreased body temperature and loss of energy over the past 45 days. His current
(d) Vasoconstriction complaints can be attributed to which of the following?
(a) Fibroblast growth factor
68. Opsonins are (AP 2006) (b) Interleukin-2
(a) C3a
(c) Tumor necrosis factor-a
(b) IgM
(c) Carbohydrate binding proteins (d) Vascular endothelial growth factor
(d) Selectins 73. A 14-year-old girl Radha has high grade fever. She goes
69. Inflammatory mediator of generalized systemic to a physician Dr. Jeeva Roy who orders for some blood
inflammation is: (Kolkata 2002) investigations. A complete blood count with differential

(a) IL-1 implies the presence of a viral infection. Which of the

(b) IL-2 following best describes the cells that indicate a viral

(c) Interferon alpha etiology to her illness?

(d) TNF
(a) They are basophilic with spherical dark-stained
70. All are cytokines except: (Kolkata 2002)

nuclei
(a) Monoclonal antibody (b) They are precursors of osteoclasts and liver Kupffer
(b) Interleukin cells
(c) Chemokine
(c) They contain a peripheral hyalomere and central
(d) TNF granulomere
71. An 8 year old girl Geetu presents to the physician
(d) They have azurophilic granules and multilobed
with wheezing and difficulty in breathing. The nuclei
breathlessness increases when she went to the fields to
play with her friends. Her blood contains higher than
74. A 28-year-old woman, Vimla is being evaluated to
find the cause of her urine turning a dark brown color
normal concentration of IgE. The physician believes that after a recent upper respiratory tract infection. She has
the cell shown in the photograph below is implicated
been otherwise symptomatic, and her blood pressure
50
Inflammation

has been within normal limits. Urinalysis finds 75.5. The most important source of histamine:
moderate blood present with red cells and red cell casts.
(a) Mast cells
Immunofluorescence examination of a renal biopsy
(b) Eosinophil
reveals deposits of IgA within the mesangium. These
(c) Neutrophil
clinical findings suggest that her disorder is associated
with activation of the alternate complement system.

(d) Macrophages
Which of the following serum laboratory findings 75.6. Following injury to a blood vessel, immediate
is the most suggestive of activation of the alternate haemostasis is achieved by which of the following?
complement system rather than the classic complement
(a) Fibrin deposition
system?
(b) Vasoconstriction
Serum 2 C S
erum 3 C S
erum 4 C
(c) Platelet adhesion
(a) Decreased Normal Normal

(d) Thrombosis
(b) Normal Decreased Normal 75.7. PAF causes all except

(a) Bronchoconstriction
(c) Normal Normal Decreased
(b) Vasoconstriction
(d) Decreased Normal Decreased (c) Decreased vascular permeability
(e) Decreased Decreased Decreased (d) Vasodilation
75. An 18-year-old woman, Sheila is being evaluated for 7 5.8. Eosinophils are activated by:
recurrent facial edema, especially around her lips. She (a) IL1
also has recurrent bouts of intense abdo-minal pain (b) IL5
and cramps, sometimes associated with vomiting. (c) IL4
Laboratory examination finds decreased C4, while (d) IL6
levels of C3, decay-accelerating factor, and IgE are
within normal limits. A deficiency of which one of the 7 5.9. Both antibody dependent and independent comple-
following substances is most likely to be associated ment pathway converge on which complement compo-
with these clinical findings? nent?

(a) b2-integrins
(a) C3
I

nflammation
(b) C1 esterase inhibitor
(b) C5

(c) Decay-accelerating factor
(c) C1q

(d) Complement components C3 and C5
(d) C8
Most Recent Questions 75.10. Cryoprecipitate is rich in which of the following clot-
ting factors?
7 5.1. Fever occurs due to: (a) Factor II
(a) IL 1 (b) Factor V
(b) Endorphin (c) Factor VII
(c) Enkephalin (d) Factor VIII
(d) Histamine
75.11. Prostaglandins are synthesized from:
75.2. E cadherin gene deficiency is seen in: (a) Linoleic acid
(a) Gastric cancer (b) Linolenic acid
(b) Intestinal cancer
(c) Arachidonic acid
(c) Thyroid cancer
(d) Butyric acid
(d) Pancreatic cancer
75.12. Which chemical mediator is an arachidonic acid
7 5.3. Cell-matrix adhesions are mediated by?
(a) Cadherins metabolite produced by cyclo-oxygenase pathway?
(b) Integrins
(a) LXA4
(c) Selectins
(b) LXB4
(d) Calmodulin
(c) 5HETE
75.4. Pro inflammatory Cytokines include all of the following

(d) PGH2
except: 75.13. Procalcitonin is used as marker of

(a) Interleukin 1
(a) Cardiac dysfunction in acute coronary syndrome

(b) Interleukin-10
(b) Menstrual periodicity

(c) Interleukin 6
(c) Pituitary function

(d) TNF- Alpha
(d) Sepsis
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Review of Pathology
ic i f i
Chron n lammat on; granulomatous (c) Cat Scratch disease
if
n lammat on i (d) Leprosy
76. The epithelioid cell and multinucleated giant cells of 84. Epithelioid granulomatous lesions are found in all of
the following diseases, except:
Granulomatous inflammation are derived from:
(a) Tuberculosis (Delhi PG-2005)
(a) Basophils (AI 2002)
(b) Sarcoidosis
(b) Eosinophils
(c) Berylliosis
(c) CD4-T lymphocytes
(d) Pneumocystis carinii
(d) Monocytes-Macrophages
77. Granuloma is pathological feature of all, except
85. Caseous granuloma is seen in (UP 2004)
(a) Histoplasmosis
(a) Giant cell arteritis (AIIMS Nov 2001)
(b) Silicosis
(b) Microscopic polyangiitis
(c) Sarcoidosis
(c) Wegeners granulomatosis
(d) Foreign body
(d) Churg Strauss disease
78. Granulomatous inflammatory reaction is caused by all,
86. Non-caseating granuloma is characteristically seen in
(a) Syphilis (RJ 2003)
except: (AIIMS Nov 2001)
(b) Sarcoidosis
(a) M. tuberculosis
(c) Tuberculosis
(b) M. leprae
(d) Histoplasmosis
(c) Yersinia pestis
(d) Mycoplasma 87. All are granulomatous diseases except (RJ 2006)
(a) Syphilis
79. Non-caseating granulomas are seen in all of the (b) Sarcoidosis
following except (AIIMS May 2001)
(c) Schistosomiasis
(a) Byssinosis
(d) P. carinii
(b) Hodgkins lymphoma
(c) Metastatic carcinoma of lung 88. Which of the following is the most characteristic of
nflammation
(d) Tuberculosis granuloma: (Kolkata 2003)

(a) Epithelioid cell
80. Epithelioid granuloma is caused by: (b) Giant cell
(a) Neutrophil (PGI Dec 2002)
I (c) Fibroblasts
(b) Cytotoxic T-cells
(d) Endothelial cell
(c) Helper T-cells
(d) NK cells 89. Caseating granuloma are seen in: (Bihar 2003)
(a) Histoplasmosis
81. Caseous necrosis in granuloma are not found in (b) Sarcoidosis
(a) Tuberculosis (PGI June 2006)
(c) Coccidiodomycosis
(b) Leprosy
(d) All
(c) Histoplasmosis
(d) CMV
90. A 28 year old young man Alok Nath presents to the clinic
with a maculopapular rash on the palms and soles, oral
(e) Wegeners granulomatosis
ulcers, malaise, lymphadenopathy and weight loss. He
82. The most important function of epithelioid cells in has a history of a painless genital lesion 2 months ago
tuberculosis is: (Delhi PG 2010) after an unprotected intercourse about 10 weeks back.
(a) Phagocytosis Biopsy shows the presence of a granuloma. The figure
(b) Secretory shows a very important step in the pathogenesis of this
(c) Antigenic condition. Identify the cell marked ? in the figure.
(d) Healing (a) CD8 T cell
83. Necrotizing epithelioid cell granulomas are seen in all, (b) T 1
H
except: (Delhi PG 09 RP) (c) T 2
H
(a) Tuberculosis (d) Langhans cell
(b) Wegeners granulomatosis
52
Inflammation
(a) Toxoplaxmosis
(b) Lymphogranuloma venereum
(c) Cat scratch disease
(d) Kikuchis lymphadenitis
92.3. Which of these is not a granulomatous disease
(a) Leprosy
(b) Tuberculosis
(c) Sarcoidosis
(d) Amebiasis
Wound healing; stem cell biology
93. Which one of the following statements is not correct

regarding Stem cell? (DPG 2011)
(a) Developmental elasticity
(b) Transdifferentiation
(c) Can be harvested from embryo
(d) Knockout mice made possible because of it
94. An adult old man gets burn injury to his hands. Over
few weeks, the burned skin heals without the need for
skin grafting. The most critical factor responsible for
the rapid healing in this case is: (AIIMS May 2003)
91. A 45-year-old poor man Teja has a chronic cough, a
(a) Remnant skin appendages
cavitary lesion of the lung, and is sputum positive for
(b) Underlying connective tissues
acid-fast bacilli. Which of the following is the principle
(c) Minimal edema and erythema
form of defense by which the patients body fights
against this infection?

(d) Granulation tissue I
95. Absolute lymphocytosis is seen in
nflammation

(a) Antibody-mediated phagocytosis
(a) SLE

(b) Cell-mediated immunity
(b) T.B.

(c) IgA-mediated hypersensitivity
(c) CLL

(d) Neutrophil ingestion of bacteria
(d) Brucellosis
92. A 36-year-old man, Avnish presents with a cough, 96. Which of the following is absolutely essential for
fever, night sweats, and weight loss. A chest X-ray
reveals irregular densities in the upper lobe of his right wound healing? (Karnataka 2009)
lung. Histologic sections from this area reveal groups (a) Vitamin D
of epithelioid cells with rare acid-fast bacilli and a few (b) Carbohydrates
scattered giant cells. At the centre of these groups of (c) Vitamin C
epithelioid cells are granular areas of necrosis. What is (d) Balanced diet
the source of these epithelioid cells? 97. Chronic granulomatous disease is: (Karnataka 2009)

(a) Bronchial cells (a) Associated with formation of multiple granulomas

(b) Pneumocytes
(b) A benign neoplastic process

(c) Lymphocytes
(c) A parasitic disease

(d) Monocytes
(d) Acquired leukocyte function defect
Most Recent Questions 98. In regeneration (UP 2002)
(a) Granulation tissue
9 2.1. In a granuloma, epithelioid cells and giant cells and de- (b) Repairing by same type of tissue
rived from (c) Repairing by different type of tissue
(a) T lymphocytes (d) Cellular proliferation is largely regulated by
(b) Monocyte macrophages biochemical factors
(c) B lymphocytes
(d) Mast cells 99. Wound contraction is mediated by:
(a) Epithelial cells (Jharkhand 2005)
9 2.2. In a lymph node showing non necrotizing and (b) Myofibroblasts
noncaseating granuloma which of the following is (c) Collagen
suspected? (d) Elastin
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Review of Pathology
100. A 45-year-old man, Suveen presents with pain in the

(c) End of third week
mid portion of his chest. The pain is associated with
(d) End of 2 months
eating and swallowing food. Endoscopic examination
reveals an ulcerated area in the lower portion of his
100.5. Oval cells are seen in the stem cells of which of the
following tissues?
esophagus. Histologic sections of tissue taken from (a) Skin
this area reveal an ulceration of the esophageal mucosa (b) Cornea
that is filled with blood, fibrin, proliferating blood (c) Liver
vessels, and proliferating fibroblasts. Mitosis is easily (d) Bone
found, and most of the cells have prominent nucleoli.
100.6. First sign of wound injury is:
Which of the following statements best describes this
ulcerated area?

(a) Epithelialization

(b) Dilatation of capillaries
(a) Caseating granulomatous inflammation

(c) Leukocytic infiltration
(b) Dysplastic epithelium

(c) Granulation tissue

(d) Localized edema

(d) Squamous cell carcinoma 100.7. Which of the following is the source of hepatic stem

(e) Noncaseating granulomatous inflammation cells?
(a) Limbus cells
Most Recent Questions (b) Ito cell
(c) Oval cell
1 00.1. Which of the following adhesion molecules is involved (d) Paneth cell
in morphogenesis?
(a) Osteopontin
100.8. Vitamin used for post translational modification of
glutamic acid to gamma carboxy glutamate is
(b) Osteonectin SPARC (a) A
(c) Tenascin (b) D
(d) Thrombospondins (c) E
1 00.2. When a cell transforms itself into different lineage the (d) K
ability us know as:
nflammation
100.9. Tensile strength of wound after laparoscopic cholecys-

(a) De-differentiation
tectomy in a 30 year old woman depends upon:
(b) Re-differentiation
(c) Trans-differentiation

(a) Replacement of type 3 collagen (AIIMS Nov 2013)
(d) Sub-differentiation

(b) Extensive cross-linking of tropocollagen
I
(c) Macrophage activity
1 00.3. Prion disease is caused by:
(d) Granulation tissue
(a) Misfolding of protein
100.10. One of the following statements about hematopoietic
(b) Denaturation of proteins
stem cell is false?
(c) Reduced formation of proteins
(d) Exces formation of proteins

(a) Stem cells have self renewal property

(b) Subset of stem cells normally circulate in peripheral
100.4. Maximum collagen in wound healing is seen at which blood
stage of healing?
(c) Marrow derived stem cells can seed other tissues
(a) End of first week and develop into non hematopoietic cells as well
(b) End of second week
(d) Stem cells resemble lymphoblasts morphologically
54
Inflammation
E xplanations
1. Ans. (c) Delayed prolonged increase in permeability (Ref: Robbins 8th/45, 9/e p74)
2. Ans. (d) Pseudopod extension (Ref: Robbins 9/e p78)
Typically the phagocytosis of microbes and dead cells is initiated by recognition of the particles by receptors expressed
on the leukocyte surface. Mannose receptors and scavenger receptors are two important receptors that function to bind
and ingest microbes. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized by specific proteins
(opsonins) for which the phagocytes express high-affinity receptors. Binding of a particle to phagocytic leukocyte receptors
initiates the process of active phagocytosis of the particle. During engulfment, extensions of the cytoplasm (pseudopods)
flow around the particle to be engulfed, eventually resulting in complete enclosure of the particle within a phagosome
created by the plasma membrane of the cell
Direct concept quote from Robbins to clarify the answer;
How is phagocytosis different from pinocytosis and receptor mediated endocytosis
In contrast to phagocytosis, fluid phase pinocytosis and receptor-mediated endocytosis of small particles involve internalization into
Q
clathrin coated pits and vesicles and are not dependent on the actin cytoskeleton.
Option a Both Fc fragment of IgG and C3b are required in opsonisation. It takes place before phagocytosis.
O ption c respiratory burst occurs after the formation of the phagolysosome.
3. Ans. (a) Superoxide dismutase (Ref: Robbins 8th/21 9/e p48)
Superoxide dismutase (SOD) is an anti oxidant enzyme
Some clarification regarding option d. Nitric oxide (NO), an important chemical mediator generated by endothelial I
cells, macrophages, neurons, and other cell types can act as a free radical and can also be converted to highly reactive
nflammation
peroxynitrite anion (ONOO-) as well as NO2 and NO3-.

4. Ans. (c) Vasodilation and increase in permeability (Ref: Robbins 8th/46-47 9/e p74)
Direct quote a hallmark of acute inflammation is increased vascular permeability leading to the escape of protein-rich
exudate into the extravascular tissue, causing edema.

5. Ans. (d) Unidirectional locomotion of the neutrophils (Ref: Robbins 8th/50 9/e p77)
Chemotaxis is defined as locomotion oriented along a chemical gradient.
6. Ans. (a) Vasodilation and increased vascular permeability (Ref: Robbins 8th/45 9/e p74)
7. Ans. (a) NADPH oxidase (Ref: Robbins 8th/53, 7th/42-3 9/e p79)
Within the phagocytes, the following reaction takes place:
The initiating enzyme for this process is NADPH oxidase (also called respiratory burst oxidase).
Glutathione peroxidase, glutathione reductase and superoxide dismutase are examples of anti-oxidants. They reduce free
radical formation.

8. Ans. (a) Metalloproteinases (Ref: Robbins, 7th/103, 110, 312 9/e p105)
Extracellular Matrix (ECM) comprises of interstitial matrix and basement membrane. The degradation of collagen
and other ECM proteins is achieved by a family of matrix metalloproteinases (MMPs) which are dependent on zinc
ions for their activity.
MMP8 and MMP2 are collagenases which cleave type IV collagen of basement membranes.
MMPs also have a role in tumour cell invasion.
9. Ans. (d) Direct injury to endothelial cells... For details see text (Ref: Robbins 7th/35, 36 9/e p74)
10. Ans. (b) Neutrophilia (Ref: Robbins 7th/56; Chandrasoma Taylor 3rd/41 9/e p77)
Neutrophils predominate during the first 6 to 24 hours (Neutrophilia). These are replaced by monocytes/macrophages
in 24 to 48 hours.
11. Ans. (d) Decreased hydrostatic pressure (Ref: Robbins 7th/50-51 9/e p73-74)
With acute inflammation, hydrostatic pressure is increased (due to increased blood flow from vasodilation) and at the
same time osmotic pressure is reduced because of protein leakage (due to increased permeability)
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12. Ans. (d) Granuloma formation (Ref: Robbins 7th/56, 517 9/e p97)
Granuloma formation is characteristic of chronic granulomatous inflammation and is not seen in acute inflammation.
Vasodilation, increase in permeability, exudation, margination, rolling etc. are seen in acute inflammation.
13. Ans. (a) NADPH oxidase (Ref: Robbins 7th/60, 16, Robbins 8th/53 9/e p48)
The generation of reactive oxygen intermediates is due to the rapid activation of an enzyme; NADPH oxidase which
is involved in oxygen dependent killing.
Catalase, superoxide dismutase and glutathione peroxidase are free radical scavengers that prevent oxygen mediated injury.
14. Ans. (d) In Brutons disease there is normal opsonization (Ref: Robbins 8th/231-232,55 9/e p240-241)
Brutons agammaglobulinemia is an X-linked immunodeficiency disorder characterized by the failure of B-cell precursors (pro-B
cells and pre-B cells) to mature into B cells due to mutation of B-cell tyrosine kinase (Btk). Btk is required for the maturation of pre-B
cell to mature B cell. So, plasma cells derived from B cells are absent and therefore, production of immunoglobulins is impaired.
The disease is seen almost entirely in males. It usually does not become apparent until about 6 months, when maternal
immunoglobulins are depleted.
Opsonisation is a process by which preferential phagocytsosis of the opsonised bacteria is done by neutrophils and macrophages.
B
This process also requires antibodies. In rutons disease therefore, the opsonisation is defective. Other options have been
explained in the review of chapter 2 in detail.
15. Ans. (a) Phagocytes (Ref: Harrison 17th/384, Robbins 8/e 55 9/e p79)
The nitroblue-tetrazolium (NBT) test is the original and most widely known test for chronic granulomatous disease. It
is negative in chronic granulomatous disease and positive in normal individuals. It is used for detecting the production of
reactive oxygen species in the phagocytes. The basis of the test has been discussed in the text.
16. Ans. (b) Early transient increase (Ref: Robbins 7/e 51-52 9/e p74)
The hallmark of acute inflammation is increased vascular permeability.
Name of Mechanism Involved Mechanism
Early transient increase Endothelial cell contraction
Delayed transient increase in permeability Direct endothelial injury
nflammation
Delayed permanent increase Endothelial cell retraction, endothelial cell damage
17. Ans. (b) Immigration of the leukocytes through the vessel wall to the site of inflammation (Ref: Robbins 7/e 54, 8/e50, 9/e p76)
Diapedesis or Transmigration
Definition: Migration of the leukocytes through the endothelium.
I Most important molecule for diapedesis is CD31or PECAM-1Q (platelet endothelial cell adhesion molecule).
Occurs predominantly in the venules (except in the lungs, where it also occurs in capillaries).
18. Ans. (a) Selectins; (b) Integrins (Ref: Robbins 7th/54, 8th/49-50 9/e p76)
Endothelium and WBC interact through the molecules like Immunoglobulins (family molecules e.g. ICAM-I,
VCAM-I), Integrins, Mucin-like glycoprotein and selectins.
Molecule Function Deficiency disease
Integrin Firm adhesion LAD I
Selectin Rolling and loose adhesion LAD II
Defensins are cationic arginine rich peptides having broad antimicrobial activity found in Azurophil granules
of neutrophils.
Endothelin is a potent endothelial derived vasoconstrictor
19. Ans. (c) Inability to produce hydroxyl-halide radicals (Ref: Robbins 8th/53, 56, 9/e p79)
20. Ans. (b) Chemotaxis (Ref: Robbins 8th/51-52; 7th/53-57,9/e p77)
21. Ans. (d) Phagocytosis (Ref: Robbins 8th/48-49, 7th/53-54, 9/e p75)
22. Ans. (b) Less protein (Ref: Robbins 8th/46, 7th/49, 9/e p73)
23. Ans. (d) Absence of functional loss (Ref: Robbins 8th/44; 7th/79, 9/e p71)
24. Ans. (a) C5a (Ref: Robbins 8th/66; 7th/56, 9/e p77)
25. Ans. (c) It causes formation of a more important bactericidal agent than defensins and lysozyme (Ref: Robbins 8th/53, 9/e p79-80)
The enzyme E in the figure is NADPH oxidase. It is more important bactericidal agent than defensins and lysozyme. Its
deficiency is associated with chronic granulomatous disease.
56
Inflammation
Major basic protein is the defense mechanism present in eosinophils. It is highly effective against parasites. So, parasitic infection
is associated with eosinophilia.
C H
hediak igashi syndrome is due to defective LYST protein and is associated with defective phagolysosome formation. Patients
also have albinism, recurrent infections, neurological diseases and increased bleeding tendency.
Chemotaxis is required for attracting the white blood cells near a targeted organism.
26. Ans. (d) C5a (Ref: Robbins 8th/50, 9/e p77)

The movement of the leucocytes described in the question is known as chemotaxis. It is a unidirectional movement of the
cells along a chemical gradient. The chemotactic molecules include:
Exogenous chemotactic molecules Endogenous chemotactic molecules
Bacterial productsQ C5aQ
LTB4Q
IL-8Q
27. Ans. (c) It affects venules, capillaries and arterioles commonly. (Ref: Robbins 8th/47, 9/e p74)
Direct quote from Robbins..Endothelial cell contraction is classically seen in the venules 20 to 60 m in diameter leaving the
capillaries and the arterioles unaffected.
For more details, see text.
28. Ans. (c) Integrins (Ref: Robbins 8th/49-50, 9/e p76)
Explanation:
The clinical features and history described in the stem of the question are consistent with a diagnosis of leukocyte adhe-
sion deficiency. Clinical findings associated with this syndrome include late separation of the umbilical cord, poor wound
healing, recurrent skin infections (without formation of pus), gingivitis and periodontitis.
L
In immune deficiencies, late separation of the umbilical cord alone should raise the question of eukocyte Adhesion Deficiency type I
( LAD I
).
LAD I is an autosomal recessive condition caused by absence of the CD18 antigen that is necessary for the formation of
integrins (Choice c). Integrins are essential for the migration of leukocytes from the blood vessels to the tissues to exert I
their effect. A leukocyte circulating in the blood vessel undergoes a well-characterized multistep process of reaching the
nflammation
site of infection.
One of the initial steps is rolling mediated by selectins.
The subsequent step is firm adhesion which is mediated by integrins.
Then transmigration takes place followed by chemotaxis.
Wound healing, umbilical cord detachment, and the fighting against cutaneous infections all depend on the ability of neutrophils to exit
the intravascular space and initiate inflammation in the skin.
(Choice a) Deficiency of late complement components (i.e. C5b-9) results in an inability to form the complement mem-
brane attack complex and a greater risk of severe infections caused by Neisseria organism.
(Choice b) Transcobalamin II is a carrier protein for vitamin B12 after it is absorbed in the ileum. Its deficiency is not
associated with immunodeficiency.
(Choice d) a2-globulins are normal serum proteins (like haptoglobin, ceruloplasmin and a2-macroglobulin) produced
by the liver and kidneys.
29. Ans. (d) Inability to form the membrane-attack complex. (Ref: Robbins 8th/64, also read explanation below)
Patients having deficiency of the complement factors that form the membrane attack complex (MAC i.e. C5b-9 complex)
experience recurrent infections by Neisseria species (Choice d). The Neisseria disease in these patients is mild because the
remainder of the immune system is intact. MAC is the final end-product of complement activation and it forms a pore in
the bacterial cell membrane leading to cell lysis.
(Choice A) Pure T-cell dysfunction is thymic hypoplasia seen in Di George syndrome. In this condition, there is congenital absence of
the thymus and parathyroid glands caused by maldevelopment of the 3rd and 4th pharyngeal pouches. So, patients have pure T-cell
lymphopenia (causing recurrent viral and fungal infections) and hypocalcemia. (Choice B) Chronic granulomatous disease (CGD) is an
example of deficient intracellular killing due to absent NADPH oxidase.
(Choice C) Young adults infected with Neisseria meningitidis may be at increased risk for disseminated infection if they produce too
much serum IgA antibody. In these patients IgA attaches to the bacteria and blocks attachment of the IgM and lgG antibodies that induce
complement-mediated bacterial lysis. Normally, IgM and lgG activity helps protect against bacterial dissemination.
30. Ans. (b) Chediak-Higashi syndrome (Ref: Robbins 7th/61-62, 155-156)

Chediak-Higashi syndrome is an autosomal recessive disorder characterized by the abnormal fusion of phagosomes
with lysosomes, which results in ineffective bactericidal capabilities of neutrophils and monocytes. These abnormal
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leukocytes develop giant intracytoplasmic lysosomes. Abnormal formation of melanosomes in these individuals results
in oculocutaneous albinism. Most of these patients eventually develop an accelerated phase in which an aggressive
lymphoproliferative disease, possibly the result of an Epstein-Barr viral infection, results in pancytopenia and death.
3 0.1. Ans. (c) A selectin (Ref: Robbins 8/e p49, 9/e p76)
Selectins are a family of proteins that are involved in the cellular process of rolling interactions. The following are the three
types of selectins:
E selectin (CD 62E) Present on cytokine-activated endothelial cells and interacts with sialyl lewis X receptor on the
leukocyte.
L selectin (CD 62L) Present on leukocytes and interacts with glycoprotein adhesion molecules (GlyCAM-1), Mad
CAM-1 and CD34 on endothelial cells.
P selectin (CD 62P) Present on platelets and endothelial cells and interacts with sialyl lewis X receptor on leukocytes.
3 0.2. Ans. (a) PECAM (Ref: Robbins 8/e p50, 9/e p77)
The process of leukocyte recruitment is migration of the leukocytes through the endothelium, called transmigration or
diapedesis.
Transmigration of leukocytes occurs mainly in post-capillary venules.
Several adhesion molecules present in the intercellular junctions between endothelial cells are involved in the migra-
tion of leukocytes. These molecules include a member of the immunoglobulin superfamily called PECAM-1 (platelet
endothelial cell adhesion molecule) or CD31 and several junctional adhesion molecules.
30.3. Ans. (d) Granuloma formation (Ref: Robbins 9/e p97)
Granuloma formation is associated with chronic inflammation and not with acute inflammation.
3 0.4. Ans. (b) Phagocytosis
Friends, the first option actually confused lot of people when the question was asked because of the word immune. Read
the complete option carefully before answering the questions in the exam.
31. Ans. (d) Increased vascular permeability > (c) Pain (Ref: Robbins 8th/65-6, 9/e p89)
Functions of Bradykinin:
1. Increases vascular permeability
2. Contraction of smooth muscles
nflammation
3. Dilation of the blood vessels

4. Pain when injected into the skin
Out of these actions of bradykinin, the increase in vessel permeability is a better answer as it is the hallmark of acute
inflammation.
I 32. Ans. (d) IL - 18 (Ref: Robbins 8th/74, Harrison 18th/144 , 9/e p99)
Pyrogens are substances which cause fever. These can be either exogenous or endogenous. The endogenous pyrogens
(also called as the pyrogenic cytokines) include:
IL-1Q
IL-6 Q
Tumor necrosis factor Q (TNF)
Ciliary neurotopic factor Q (CNTF)
IFN-Q (alpha)
Harrison clearly mentions that the IL-18Q which is a member of IL-1 family does not appear to be a pyrogenic cytokine.
Important points about regulation of body temperature
PGE is the final mediator responsible for causing elevation of the thermoregulatory set point by increasing the concentration of cAMP.
Q
Exogenous pyrogens include microbial products and toxins; classical example is endotoxin produced by gram negative bacteria.
2
Q
Body temperature is regulated at the level of the hypothalamus. Most individuals with hypothalamic damage have subnormal and
not supranormal body temperature.
33. Ans. (c) It manifests as pitting edema (Ref: Harrison 17th/2066, 18th/2711-3)
Angioneurotic edema is a localised non pitting edema involving deeper layers of the skin and subcutaneous tissue.
Q
It is an autosomal dominantQ clinical condition caused by deficiency of C1 inhibitor protein (a complement regula-
tory protein) and associated with elevated levels of bradykinin. It is more common in femalesQ.
Diagnosis of hereditary angioedema is suggested by the presence of lack of pruritus and urticarial lesions, promi-
nence of recurrent gastrointestinal attacks of colic and episodes of laryngeal edema. The levels of complement pro-
teins C1is normal but levels of C2 and C4 are depleted.
DanazolQ is the drug which can be used for hereditary angioedema.
58
Inflammation
34. Ans. (c) C3 (Ref: Robbins 8th/63-64 , 9/e p88)

The complement proteins can be activated by 3 pathways; classical, lectin and alternate pathways. Terminal pathway
is common to the first three pathways and is present at the level of post activation stage of C3. It eventually leads to the
membrane attack complex that lyses cells.
As can be seen in the text, C3 is the first common complement protein to be activated in both classical and alternate path-
way.
35. Ans. (b) Myeloperoxidase (Ref: Robbins 8th/57, 63 , 9/e p83)
Myeloperoxidase (MPO) is an enzyme present in primary (or azurophilic) granules of the neutrophils. In the presence of a
halide such as Cl-, MPO converts H O to HOCl (hypochlorous radical) during the process of respiratory burst.
2 2
36. Ans. (a) Over production of 1, 25 dihydroxy vitamin D (Ref: Robbins 8th/433-6, Heptinstalls pathology of the kidney,
LWW, Volume 1; 6th/1051, Interstitial Lung Disease by Schwarz 5th/458-9)
Nephrocalcinosis is defined as calcification of the renal interstitium and tubules. It is associated with hypercalcemia. In
chronic granulomatous inflammation, the important cells involved are macrophages and lymphocytes.
Direct quote Heptinstalls Sarcoidosis and other granulomatous diseases can be cause of hypercalcemia and
hypercalciuria owing to exces vitamin D from extra renal conversion of 1,25 (OH)2D3. Nephrocalcinosis was found to
be associated with 22% patients with chronic sarcoidosis.
In other granulomatous conditions (like Sarcoidosis), there is presence of metastatic calcification due to activation of
vitamin D precursor by macrophages.Robbins
Interstitial Lung Disease 5th .. Hypercalciuria is seen in almost a third of patients with sarcoidosis. Serum calcium
levels in sarcoidosis rise with serum vitamin D levels. This dysregulation of calcium metabolism appears to be modulated
through abnormal synthesis of vitamin D by activated pulmonary macrophages and granulomatous tissue that leads
to excessive hydroxylation of 25- monohydroxylated vitamin D precursors. This could be an adaptive response to the
antigen in sarcoidosis.
37. Ans. (a, b, d) (Ref: Robbins 8th/65, 7th/45, 9/e p89)
Friends, in our opinion the question should have been asked with an except because bradykinin has the following
effects:
Increases vascular permeability
I
nflammation
Arteriolar dilation
Bronchial smooth muscle contraction
Pain at the site of injections/inflammation
Since increased vascular permeability is the most characteristic feature of acute inflammation, some people were of the
opinion that this could be single best option to be marked presuming the stem of question was correct.
38. Ans. (d) Reactive oxygen species (Ref: Robbins 8th/53, 9/e p79)
H O - MPO- halide system is the most efficient bactericidal system of neutrophils.
2 2
39. Ans. (b) Pain at the site of inflammation (Ref: Robbin 7th/e 45, 9/e p89)
40. Ans. (a) Histamine (Ref: Goodman & Gilman 10th/650)
Histamine is a vasoactive amine that is located in most body tissues but is highly concentrated in the lungs, skin, and gas-
trointestinal tract. It is stored in mast cells and basophils.
When it is injected intradermally it causes the triple response consisting of:
Red spot: Due to capillary dilatation
Wheal: Due to exudation of fluid from capillaries and venules
Flare: Redness in the surrounding area due to arteriolar dilation mediated by axon reflex.
41. Ans. (c) C5 (Ref: Harrison 17th/2030-2032, Robbins 8th/63-64, 9/e p88)
The terminal pathway that is common to all pathways of the complement system leads to the membrane attack
complex and consists of factors C5, C6, C7, C8 and C9 (C5b6789 ).
42. Ans. (d) Arachidonic acid metabolites (Ref: Robbins 7th/69; Katzung 11th/314-323, 9/e p85)
Lipoxins are a recent addition to the family of bioactive products generated from arachidonic acid. They have anti-
inflammatory activity (explained in text).
43. Ans. (a) C3 (Ref: Harrison 17th/2030, 9/e p88)
44. Ans. (b) Eotaxin (Ref: Robbins 8th/62-63; 7th/71, 9/e p87)
45. Ans. (a) Angiotensin (Ref: Robbins 7th/g 63, 74, 75, 9/e p83)
Kallikreins like bradykinin, PGs and complement components are mediators of acute inflammation.
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46. Ans. (c) Myeloperoxidase (Ref: Robbins 7th/74, 75, 9/e p83)
47. Ans. (c) IL 1 > (d) IL-6 (Ref: Javetz, 22nd/1291, Walter Israel 7th/227)
Macrophages release IL 1 which stimulates the T helper cells.
The T cells in response proliferate and release IL 2 which in turn further stimulates T cell proliferation and B cell
proliferation and differentiation into plasma cells.
Please note that even IL-6 (produced by macrophages) acts on late stages of B cell differentiation enhancing antibody
formation. Still, IL-1 being the most important cytokine having systemic effects of inflammation has been chosen as
the answer here in preference to IL-6.
48. Ans. (a) Neutrophils; (c) Platelets (Ref: Harrison 18th/2223-5, Robbins 7th/202)
Cytokines are peptide mediators or intercellular messengers which regulate immunological, inflammatory and reparative
host responses. They are produced by widely distributed cells like macrophage, monocytes, lymphocytes, platelets, fibro-
blast, endothelium, stromal cells etc.
Criteria for SIRS (2 or more of the following conditions)
FeverQ (oral temperature >38oC) or hypothermiaQ (<36oC)
TachypneaQ (>24 breaths/minute)
Tachycardia Q (>90 beats/minute)
LeukocytosisQ (>12,000/l), leucopeniaQ (<4,000/l), or >10%Q bands
49. Ans. (a) Bacterial toxin; (b) IL-1; (d) Interferon; (e) TNF (Ref: Harrison 18th/143-5)
Fever is produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the vascular
and perivascular cells of hypothalamus. They can be classified as:
Exogenous pyrogens - endotoxin of gram - bacteria, superantigens (gram + bacteria)
Endogenous pyrogens - IL-1, TNF-a, IL-6, Ciliary neurotropic factor and IFN-a.
PGE is the most important chemical responsible for elevation of hypothalamic set point in the body. So, NSAIDs reduce fever by
2
inhibiting cyclooxygenase and reducing prostaglandin concentration.
50. Ans. (a) Includes interleukins; (c) Are polypeptide (complex protein): (Ref: Ananthanarayan 7th/143; Harrison 16th/1915,
nflammation
Robbins 7th/202)
Cytokines are peptide mediators or intracellular messengers produced by wide variety of haemopoietic and non- hae-
mopoietic type of cells in response to immuno, inflammatory or infectious disease states. Most of the lymphokines exhibit
multiple biological effects and same effect may be caused by different lymphokines.
I Classification of cytokines
1. Cytokines that mediate innate immunity - IL-1, TNF, IFN, IL-6. IL-12
Are involved in both innate and adaptive immunity.
2. Cytokines regulating lymphocyte growth, activation and differentiation (IL-2, IL-4, IL-12, IL-15, TGF-b)
IL-2 is a growth factor for T-cells.
IL-4 stimulates differentiation to TH2 pathway.
IL-12 stimulates differentiation to T H1 pathway.
IL-15 stimulates the growth and activity of NK cells.
IL-10 and TGF-b down regulate immune responses.
3. Cytokines that activate inflammatory cells:
IL-5 activates eosinophils.
TNF induces acute inflammation by acting on neutrophils and endothelial cells.
4. Cytokines that affect movement of WBCs (chemotaxis).
5. Cytokines that stimulate hematopoiesis e.g. GM-CSF, G-CSF, stem cell factor.
Same cytokine can be produced by different cells
Same cytokine can have multiple actions (pleiotropic in nature).
51. Ans. (d) X; Ca++ (Ref: Robbins 7th/128, 8th/119, 9/e p118)
52. Ans. (d) C3a and C5a (Ref: Robbins 7th/64, 8th/64, 9/e p89)
Anaphylatoxins are chemicals which increase vascular permeability and cause vasodilation mainly by releasing
histamine from mast cells.
60
Inflammation
C3a, C5a and to a small extent C4a are called anaphylatoxins.

C5a is also a powerful chemotactic agent for neutrophils, monocytes, eosinophils and basophils.
C3b and C3bi are required for opsonisation and favor phagocytosis by neutrophils and macrophages.
53. Ans. (d) VIII (Ref: Robbins 7th/664, T. Singh 1st/258)
Cryoprecipitate is a source of Fibrinogen (factor I), Factor VIII and Von-Willebrand factor Q
Treatment of choice for Hemophilia A , von Willebrand disease and hypofibrinogenemic states .
Q Q Q
If factor VIII is unavailable, cryoprecipitate may be an alternative, since each unit contains about 80 IU of factor VIII.
54. Ans. (b) C5a (Ref: Robbins 7th/56, 9/e p77)
Role of different mediators in Inflammation
Increased vascular permeability Chemotaxis, leukocyte recruitment and activation
(a) C3a and C5a (a) C5a
(b) Vasoactive amines (b) Leukotriene B4
(c) Leukotriene C4, D4, E4 (c) Chemokines
(d) PAF (d) IL-8
(e) Substance P (e) Bacterial products
(f) Bradykinin (f) TNF
Fever Vasodilatation
(a) IL-1 (a) NO
(b) TNF (b) Histamine
(c) Prostaglandins (c) Prostaglandins
Tissue damage Pain
(a) Neutrophil/macrophage lysosomal enzymes (a) Prostaglandin
(b) NO and reactive oxygen species (b) Bradykinin
55. Ans. (c) Vasodilation (Ref: Robbins 7th/64, 9/e p73)

56. Ans. (d) Lactoferrin (Ref: Robbins 8th/54; 7th/61, 9/e p80) I
nflammation
57. Ans. None (Ref: Robbins 8th/53-54; 7th/69, 9/e p80)
Cathepsin G is a serine protease secreted by activated neutrophils that play a role in the inflammatory response.
58. Ans. (a) Weibel-Palade bodies (Ref: Robbins 8th/490; 7th/54,513, 9/e p76)
59. Ans. (a) Intrinsic and common pathway (Ref: Robbins 8th/120,666; 7th/469, 9/e p118)
60. Ans. (d) Function of platelets (Ref: Robbins 8th/666; 7th/469)
61. Ans. (d) IX (Ref: Harsh Mohan 6th/330, Robbins 8th/119, 7th/128, 9/e p119)
62. Ans. (d) Leukotriene B (Ref: Robbins 8th/200; 7th/208, 9/e p203)
4
63. Ans. (a) Langerhans cells (Ref: Robbins 8th/1166; 7th/701 , 9/e p622)
Birbeck granules are rod shaped/Tennis-racket shaped cytoplasmic organelles with a central linear density and a striated appearance.
They are diagnostic microscopic feature in Langerhans cell histiocytosis (Histiocytosis X)
64. Ans. (b) Hydrolytic enzyme (Ref: Robbins 8th/54; 7th/82,209)

65. Ans. (b) Thromboxane A (Ref: Robbins 8th/58, 7th/125-127, 9/e p84)
2
66. Ans. (b) C5a (Ref: Robbins 8th/64, 7th/56, 9/e p77)
67. Ans. (a) Vasodilatation (Ref: Robbins 8th/66; 7th/69, 9/e p85)
68. Ans. (c) Carbohydrate binding proteins (Ref: Robbins 8th/51-53; 7th/59, 9/e p78)
69. Ans. (a) IL-1 (Ref: Robbins 8th/57, 61, 7th/71, 9/e p86)
70. Ans. (a) Monoclonal antibody (Ref: Robbins 8th/61-63, 7th/71, 9/e p86)
71. Ans. (c) Basophil (Ref: Robbins 8th/200, 9/e p203)
The girl is most likely suffering from an acute attack of bronchial asthma. The figure shows the presence of an activated
mast cell. These cells are similar to the basophils.
72. Ans. (c) Tumor necrosis factor-a (Ref: Robbins 8th/61,320, 9/e p330)
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Cachexia, or wasting due to cancer, manifests with weakness, weight loss, anorexia, anemia, and infection. The principal
cytokine responsible for such manifestations is tumor necrosis-a (TNF-a). Fibroblast growth factor is involved in wound
healing. Interleukin-2 (IL-2) is an immune-stimulant produced by activated T cells. Vascular endothelial growth factor is
important in the proliferation of blood vessels in a growing tumor.
73. Ans. (a) They are basophilic with spherical dark-stained nuclei (Ref: Robbins 8th/72, 9/e p96)
Lymphocytosis is associated with viral infection. These cells are generally small and are basophilic with spherical dark-
stained nuclei normally constituting nearly 30% of leukocytes. There are two types of lymphocytes: T cells (involved in
cell-mediated immunity) and B cells (involved in humoral immunity).
Monocytes are precursors of osteoclasts and liver Kupffer cells (option b) and also give rise to tissue macrophages and alveolar
macrophages.
Platelets contain a peripheral hyalomere and central granulomere (option c).
Neutrophils have azurophilic granules and multilobed nuclei (option d). They increase in number in response to bacterial infection.
74. Ans. (b) Serum C2 normal, C3 decreased, C4 normal (Ref: Robbins 7th/64-67, 9/e p88)
Activation of the complement cascade can produce local deposition of C3, which can be seen with special histologic
techniques. If a patient has widespread activation of the complement system, then serum assays of C3 levels might
be decreased.
In particular, activation of the classic complement pathway decreases levels of the early complement components,
namely, C1, C4, and C2. In contrast, activation of the alternate complement pathway, decreases levels of C3, but the
levels of the early factors (C2 and C4) are normal.
An example of a disorder associated with the activation of the alternate complement system is IgA nephropathy
(Bergers disease), which is characterized by the deposition of IgA in the mesangium of the glomeruli.
75. Ans. (b) C1 esterase inhibitor (Ref: Robbins 7th/66-67, 9/e p89)
Deficiencies of C1 esterase inhibitor result in recurrent angioedema, which refers to episodic non-pitting edema
of soft tissue, such as the face. Severe abdominal pain and cramps, occasionally accompanied by vomiting, may be
caused by edema of the gastrointestinal tract (GI). C1 inhibitor not only inactivates C1, but also inhibits other path-
ways, such as the conversion of prekallikrein to kallikrein. It also leads to excess production of C2, and bradykinin. It
is the uncontrolled activation of bradykinin that produces the angioedema,

nflammation
A deficiency of decay accelerating factor (DAF), which breaks down the C3 convertase complex, is seen in paroxysmal
nocturnal hemoglobinuria (PNH).
75.1. Ans. (a) IL 1 (Ref: Robbins 8/e p61,66 , 9/e p83, 90)
Role in Inflammation Mediators
I Vasodilation Prostaglandins
Nitric oxide
Histamine
Increased vascular permeability Histamine and serotonin
C3a and C5a (by liberating vasoactive amines from mast cells, other cells)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis, leukocyte recruitment and activation TNF, IL-1
Chemokines
C3a, C5a
Leukotriene B4
(Bacterial products, e.g., N-formyl methyl peptides)
Fever IL-1Q, TNF
Prostaglandins
Pain Prostaglandins
Bradykinin
Tissue damage Lysosomal enzymes of leukocytes
Reactive oxygen species
Nitric oxide
62
Inflammation
75.2. Ans. (a) Gastric cancer (Ref: Robbins 8/e p96, 9/e p297)
Cadherin is derived from the calcium-dependent adherence protein. It participates in interactions between cells of the
same type. The linkage of cadherins with the cytoskeleton occurs through the catenins. The cell -to-cell interactions medi-
ated by cadherin and catenins play a major role in regulating cell motility, proliferation, and differentiation and account
for the inhibition of cell proliferation that occurs when cultured normal cells contact each other (contact inhibition).
Reduced function of E-cadherin is associated with certain types of breast and gastric cancer.
Mutation and altered expression of the Wnt/-catenin pathway is implicated in in gastrointestinal and liver cancer
development.
75.3. Ans. (b) Integrins (Ref: Robbins 8/e p96, 9/e p24)
The cell adhesion molecules (CAMs) are classified into four main families:
Immunoglobulin family CAMs
Cadherins
Integrins: bind to extracellular matrix (ECM) proteins such as fibronectin, laminin, and osteopontin providing a con-
nection between cells and extracellular matrix (ECM)
Selectins
Cadherins and integrins link the cell surface with the cytoskeleton through binding to actin and intermediate filaments.
Laminin is the most abundant glycoprotein in the basement membrane and has binding domains for both ECM
and cell surface receptors.
75.4. Ans. (b) Interleukin-10 (Ref: Robbins 8/e p56;Cytokines and Pain/pg 3, 9/e p86)
The following are the anti inflammatory cytokines:
IL-10
TGF-
IL-4
I
nflammation
IL-13
7 5.5. Ans. (a) Mast cells (Ref: Robbins 8/e p57, 9/e p83)
The richest sources of histamine are the mast cells that are normally present in the connective tissue adjacent to blood ves-
sels. It is also found in blood basophils and platelets.
7 5.6. Ans. (b) Vasoconstriction (Ref: Robbins 8/e p115 .... Not given in 8/9 edition of robbins)
After initial injury there is a brief period of arteriolar vasoconstriction mediated by reflex neurogenic mechanisms and
augmented by the local secretion of factors such as endothelin(a potent endothelium-derived vasoconstrictor.
75.7. Ans. (c) Decreased vascular permeability (Ref: Robbins 8/e p60, 9/e p73)
PAF is another phospholipid-derived mediator having the following inflammatory effects:
Platelet aggregation
Vasoconstriction
Bronchoconstriction
At extremely low concentration, it may cause vasodilation and increased venular permeability
Increases leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding), chemotaxis,
degranulation, and the oxidative burst.
Stimulates the synthesis of other mediators, particularly eicosanoids, by leukocytes and other cells.
7 5.8. Ans. (b) IL-5 (Ref: Robbins 8/e p200)

IL-5 is required for the development and maturation of the eosinophil.
7 5.9. Ans. (a) C3 .already discussed earlier in text and AIIMS question (Ref: Robbins 9/e p88, Harison 17/e 2030)
75.10. Ans. (d) Factor VIII (Ref: Robbins 7/e p664)

Cryoprecipitate is a rich source of Factor VIII. Have a glance at the flowchart given below.
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7 5.11. Ans. (c) Arachidonic acid (Ref: Robbins 9/e p84)

Arachidonic acid is an essential fatty acid which is acted on by the enzyme cyclo-oxygenase Q
(COX) leading to the formation of the prostaglandins.

Also know:
Linoleic, linolenic and arachidonic acid are examples of polyunsaturated essential fatty acidsQ (PUFA) which
means they cannot be synthesized in the human body.
Docosahexaenoic acidQ is an essential fatty acid present in breast milk which is required for myelination of nervesQ.
Richest source of PUFA is safflower oilQ
Coconut oilQ is the poorest source of PUFA
75.12. Ans. (d) PGH2 (Ref: Robbins 9/e p84)
75.13. Ans. (d) Procalcitonin (Ref: Harrison 18th/3419)
Procalcitonin is an acute phase reactant which is now useful for being a marker of sepsis. It is in fact utilized for differen-
nflammation
tiating the bacterial and aseptic meningitis.

76. Ans. (d) Monocyte macrophages (Ref: Robbins 7th/82 83, 9/e p97)
Delayed type hypersensitivity (as seen in TB) results from accumulation of mononuclear cells around small veins and
venules, producing a perivascular cuffing. Monocytes transform into macrophages which undergo morphological changes
I to produce epithelioid cells.
77. Ans. (b) Microscopic polyangiitis (Ref: Robbins Illustrated 7th/540)
Microscopic polyangiitis is a small vessel vasculitis showing the presence of necrotizing inflammation of the affected
vessels without the presence of granuloma.
Systemic vasculitis causing granulomas Systemic vasculitis causing necrotizing inflammation
Giant cell arteritis Polyarteritis nodosa (PAN)
Takayasus disease Microscopic polyangiitis
Wegeners granulomatosis Wegeners granulomatosis
Churg-Strauss syndrome Churg-Strauss syndrome
78. Ans. (d) Mycoplasma (Ref: Robbins 8th/802 9/e p97)

Granulomatous inflammation is a distinctive pattern of chronic inflammatory reaction characterized by focal
accumulations of activated macrophages, which often develop an epithelial-like (epithelioid) appearance.
Tuberculosis is the prototype of the granulomatous diseases, but sarcoidosis, Crohns disease, cat-scratch disease,
lymphogranuloma inguinale, leprosy, brucellosis, syphilis, some mycotic infections, berylliosis, and reactions of
irritant lipids are also included.
In Robbins (8th ed, page 802), Yersinia has also been mentioned to be associated with granulomatous inflammation.
So, the answer of exclusion is Mycoplasma.
79. Ans. (c) Metastatic carcinoma of the lung (see below)
Friends, remember that fungal and mycobacterial granulomas are usually associated with central necrosis but all large
caseating granulomas come from small non-caseating granulomas. Granuloma can be seen in both Byssinosis and
Hodgkins lymphomas.
Granulomas are also seen in Hodgkins disease (Dorlands, 28/p 716)
So, metastatic carcinoma of lung is the answer of exclusion.
64
Inflammation
80. Ans. (c) Helper T-cell (Ref: Robbins 7th/83, Andersons pathology 10th/583 9/e p97-98)
Granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are trans-
formed into epitheliumlike cells surrounded by a collar of mononuclear WBC, principally lymphocytes and occasionally
plasma cells.
CD 4 Helper T-cells are involved in granuloma formation as it secretes IFN-, IL-2 and IL-12.
81. Ans. (b) Leprosy; (d) CMV; (e) Wegeners granulomatosis (Ref: Robbins 7th/83,8th/73, 9/e p98)
Caseous necrosis is characteristic of tubercular granuloma, rare in others type of granulomatous disease. TB granuloma is
a prototype of immune granuloma. These are caused by insoluble particles; typically microbes that are capable of inducing
a cell mediated immune response.
Granulomatous lesions may develop in liver in CMV infection.
82. Ans. (a) Phagocytosis (Ref: Robbins 7th/381, Harsh Mohan 6th/153, 9/e p97)
Epithelioid cells and giant cells are apposed to the surface and encompass the foreign body.
83. Ans. (d) Leprosy (Ref: Robbins 8th/73, 9/e p98)
Examples of Diseases with Granulomatous Inflammation
Disease Cause Tissue Reaction
Tuberculosis Mycobacterium Noncaseating tubercle (granuloma prototype): focus of epithelioid cells, rimmed by fibroblasts,
tuberculosis lymphocytes, histiocytes and Langhans giant cell.
Caseating tubercle: central amorphous granular debris, loss of all cellular detail; acid-fast bacilli
Leprosy Mycobacterium Acid-fast bacilli in macrophages; non-caseating granulomas
leprae
Syphilis Treponema Gumma: lesion enclosing wall of histiocytes; plasma cell infiltrate; central cells are necrotic
pallidum without loss of cellular outline
Cat-scratch Gram-negative Rounded or stellate granuloma containing central granular debris and recognizable neutrophils;
disease bacillus giant cells uncommon
84. Ans. (d) Pneumocystis carinii (Ref: Robbins 7th/216, 756, 9/e p98) I
nflammation
85. Ans. (a) Histoplasmosis (Ref: Robbins 8th/718; 7th/754-755, 739)
86. Ans. (b) Sarcoidosis (Ref: Robbins 8th/701, 7th/738, 9/e p98)
87. Ans. (d) P. carinii (Ref: Robbins 8th/246, 7th/82-83, 9/e p98)
88. Ans. (a) Epithelioid cell (Ref: Robbins 8th/73-74, 7th/82, 9/e p97-98)
89. Ans. (a) Histoplasmosis (Ref: Robbins 8th/717-718; 7th/676)
90. Ans. (b) T 1 (Ref: Robbins 8th/208, 9/e p210)
H
The history is highly suggestive of a sexually transmitted disease, syphilis that is characterized by the formation of
granuloma in the affected lesions. The formation of a granuloma is associated with activation of a TH1 cell which causes
release of cytokines like IFN- causing macrophage activation and IL-2 having an autocrine stimulatory effect.
91. Ans. (b) Cell-mediated immunity (Ref: Robbins 8th/73-4, 9/e p97-98)
The principle host defense in mycobacterial infections is cell-mediated immunity, which causes formation of granulomas.
In many infectious diseases characterized by granuloma formation, the organisms may persist intracellularly for years in
the granulomas to be a source of activation of the infection later.
While antibody-mediated phagocytosis and neutrophil ingestion of bacteria (options a and d) are a major source of host
defense against many bacteria but they are not active against Mycobacteria.
IgA-mediated hypersensitivity (option c) is not involved in the bodys defense against Mycobacteria.
92. Ans. (d) Monocytes (Ref: Robbins 7th/79-83, 381-386, 9/e p97)
Granulomatous inflammation is characterized by the presence of granulomas, which by definition are aggregates of
activated macrophages (epithelioid cells, not epithelial cells). These cells may be surrounded by mononuclear cells. The
source of macrophages (histiocytes) is monocytes from the peripheral blood.
9 2.1. Ans. (b) Monocyte macrophages (Ref: Robbins 9/e p97)
Monocytes and macrophages fuse together resulting in the formation of epithelioid cells giant cells.
Langhans giantQ cell is seen in tuberculosis. They have horse shoe shaped nucleus.
Reed Sternberg cells are seen in Hodgkins lymphomaQ.
Touton giant cells are seen xanthomaQ.
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9 2.2. Ans. (a) Toxoplaxmosis

This is a characteristic feature of toxoplasmosis.
Also know
Toxoplasmosis is transmitted by cat (definitive host). Man is the intermediate host .
Q Q
It is diagnosed by Sabin Feldman dye test . Q
ChorioretinitisQ is the commonest manifestation of this disease when transmitted congenitally. In the acquired
disease, there is usually absence of symptoms.
Drug of choice for toxoplasmosis is combination of pyrimethamine and sulfadiazineQ.
Drug of choice for toxoplasmosis in pregnancy is spiramycinQ.

92.3. Ans. (d) Amebiasis (Ref: Robbins 9/e p98)
93. Ans. (a) Developmental elasticity (Ref: Robbins 8th/82-5; Harrison 17th/426... Not in 9/ Edition of Robbins)
Stem cells show the property of developmental plasticity (Not developmental elasticity) which is also known as
transdifferentiation.
A change in stem cell differentiation from one cell type to another is called transdifferentiation, and the multiplicity of stem
th
cell differentiation options is known as developmental plasticity. Robbins 8 /85.
94. Ans. (a) Remnant skin appendages (Ref: Love & Bailey 23rd/189)
Skin consists of two layers. Epidermis which is the most superficial layer of the skin constantly replaced from the
basal layer and the dermis which is thicker than epidermis and contains adnexal structures. The importance of these
adnexal structures is that they contain epithelial cells can proliferate and can heal a partial thickness wound by
epithelialization.
95. Ans. (b) TB; (c) CLL; (d) Brucellosis (Ref: P.J. Mehta 14th 374)
Absolute lymphocytosis Relative lymphocytosis
1. Bacterial infections like tuberculosis, brucellosis, syphilis, pertussis, 1. All causes of neutropenia.
and toxoplasmosis. 2. Infective hepatitis
2. Viral infections like mumps, rubella, and infectious mononucleosis. 3. Convalescence from acute injection.
3. Leukemia (chronic lymphocytic). 4. Infant with infections, malnutrition and avitaminosis.
nflammation
4. Thyrotoxicosis
96. Ans. (c) Vitamin C (Ref: Robbins 7th/114, 9/e p106)

Healing is modified by a number of influences (including both systemic and local host factors) frequently impairing the
I quality and adequacy of both inflammation and repair.
Ascorbic acid deficiency causes reduced cross linking of tropocollagen to collagenQ
So, the patient has increased bleeding tendencies and poor wound healing.
97. Ans. (a) Associated with formation of multiple granulomas (Ref: Robbins 7th/62, 8th/56, 9/e p79, Harrison 18th/387)
It is a congenital and not acquired leucocyte function defect.
98. Ans. (b) Repairing by same type of tissue (Ref: Robbins 8th/92-94, 7th/88, 9/e p101)
99. Ans. (b) Myofibroblasts (Ref: Robbins 8th/104, 7th/113 , 9/e p105)
100. Ans. (c) Granulation tissue (Ref: Robbins 7th/107, 110, 112-113 , 9/e p103)
Tissue repair involves the formation of granulation tissue, which histologically is characterized by a combination of
proliferating fibroblasts and proliferating blood vessels. Proliferating cells are cells that are rapidly dividing and usually
have prominent nucleoli.
100.1. Ans. (c) Tenascin (Ref: Robbins 8/e p96)
Name of adhesion molecule Function
Osteonectin (SPARC) Tissue remodeling in response to injury ,
Angiogenesis inhibitor
Thrombospondins Inhibit angiogenesis
Osteopontin Regulates calcification
Mediator of leukocyte migration in inflammation,
Vascular remodeling
Fibrosis in various organs
Tenascin family Morphogenesis
Cell adhesion
66
Inflammation
SPARC is secreted protein acidic and rich in cysteine.

1 00.2. Ans. (c) Trans-differentiation (Ref: Robbins 8/e p85, 9/e p26-27)
Tissue stem cells which are thought to be lineage-committed multipotent cells, possess the capacity to differentiate into
cell types outside their lineage restrictions (called trans-differentiation). For example, hematopoietic stem cells may be con-
verted into neurons as well as germ cells.
1 00.3. Ans. (a) Misfolding of protein (Ref: Robbins 8/e p1308-9 , 9/e p1281)
Prions are abnormal forms of a cellular protein that cause transmissible neurodegenerative disorders. This group of disor-
ders includes:
Creutzfeldt-Jakob disease (CJD),
Q
Gerstmann-Strussler-Scheinker syndrome (GSS), Q
Fatal familial insomnia , and

Q
Kuru in humans;
Q
Scrapie in sheep and goats; mink-transmissible encephalopathy; chronic wasting disease of deer and elk; and bovine
spongiform encephalopathy Q
The prion protein (PrP) is both infectious and transmissible .

Q Q
These disorders are predominantly characterized by spongiform change caused by intracellular vacuoles in neu-
rons and glia.
In pathogenesis, the disease occurs when the PrP undergoes a conformational change from its normal -helix-
containing isoform (PrPc) to an abnormal -pleated sheet isoform, usually termed PrPsc (for scrapie). It is associated
with resistance to the digestive action of proteases.
1 00.4. Ans. (c) End of third week (Ref: Robbins 8/e p102-3, 9/e p106-108) Measurements in Wound Healing: Science and
Practice Springer 2012 pg 112-3
Measurements in Wound Healing maximum collagen production occurs at 20 days. The remodeling of the collagen
continues beyond this duration.
Also know for future NEET questions
TGF- is the most important fibrogenic agent I

nflammation
Wound strength is 10% after 1 weekQ; it increases rapidly during next 4 weeksQand becomes 70% at the end of 3rd
monthQ.
The tensile strength of the wound keeps on increasing as time progresses.
Collagen is the most abundant protein in the body
Type I collagen is the major component of extracellular matrix in skin.
Type III collagen which is also normally present in skin, becomes more prominent and important during the repair
process.
100.5. Ans. (c) Liver (Ref: Robbins 8/e p85-6, 9/e p28)
Name of the cell Location Function

Oval cells Q Canals of Herring of the liver Forming hepatocytes and biliary cells
Satellite cellsQ Basal lamina of myotubules Differentiate into myocytes after injury
Limbus cellsQ Canals of SchlemmQ Stem cells for the corneaQ
Ito cellsQ Subendothelial space of DisseQ Store vitamin AQ
Paneth cells Bottom of crypts Host defense against microorganisms
1 00.6. Ans. (b) Dilatation of capillaries.(Ref: Robbins 8/e p46, 102, 7/e p107, 9/e p106)
Direct quote.. the cutaneous wound healing is divided into the three phases: inflammation proliferation and maturation.
One of the earliest manifestations of inflammation is dilation of the capillaries.
100.7. Ans. (c) Oval cell.discussed in detail in a different question (Ref: Robbins 8/e p83, 7/e p91, 9/e p28)
1 00.8. Ans. (d) K (Ref: Robbins 9/e p442, 119)
All previous exam questions
Vitamin K is required for the activation of factors 2,7,9,10Q
The reason why vitamin K is required for these factors is the gamma carboxylation of glutamate . Q
Vitamin K is the other vitamin apart from vitamin D whose deficiency can cause osteoporosis . Q
Vitamin K deficiency can cause Hemorrhagic disease of newborn . Q
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Earliest indicator for vitamin K deficiency is increased PTQ value.

DietQ and intestinal bacteriaQ are the chief source of vitamin K in the human body.
LiverQ is the main organ for storage of vitamin KQ.

100.9. Ans. (b) Extensive cross linking of tropocollagen (Ref: Robbin 8/e p 105-6)
Fibrillar collagens (mostly type I collagen) form a major portion of the connective tissue in repair sites and are essential for
the development of strength in healing wounds.
Net collagen accumulation, however, depends not only on increased collagen synthesis but also on decreased degradation.
The recovery of tensile strength results from the excess of collagen synthesis over collagen degradation during the first 2
months of healing, and, at later times, from structural modifications of collagen fibers (cross-linking, increased fiber size) after
collagen synthesis ceases.
100.10. Ans. (b) Subset of stem cells normally circulate in peripheral blood (Ref: Robbin 9/e p 581)
Hematopoietic stem cells have two essential properties that are required for the maintenance of hematopoiesis: pluripotency
and the capacity for self-renewal. Pluripotency refers to the ability of a single HSC to generate all mature blood cells. When
an HSC divides, at least one daughter cell must self renew to avoid stem cell depletion. Self-renewing divisions occur
within a specialized marrow niche, in which stromal cells and secreted factors nurture and protect the HSCs. During stress,
HSCs are mobilized from the bone marrow and appear in the peripheral blood.
Remember HSC resemble blasts morphologically.

(Inflammation)
Celsus was the frost person to describe the four cardinal signs of inflammation: rubor (redness), tumor (swelling),
calor (heat), and dolor (pain). These signs are hallmarks of acute inflammation.
Rudolf Virchow added the fifth clinical sign loss of function (function laesa)
Elie Metchnikoff discovered the process of phagocytosis by observing the ingestion of rose thorns by amebocytes
of starfish larvae and of bacteria by mammalian leukocytes.
nflammation
Sir Thomas Lewis established the concept that chemical substances, such as histamine (produced locally in response to
injury), mediate the vascular changes of inflammation.
Increased vascular permeability is the hallmark feature of acute inflammation.
Endothelial cell contraction is the most common mechanism of increased vascular permeability.
I Selectins are responsible for rolling whereas integrins are required for adhesion.
Transmigration (also called diapedesis) requires PECAM molecule or CD31.
Chemotaxis: single direction targeted movement of WBCs like neutrophils caused by exogenous molecule (bacterial
products) or endogenous molecules (C5a, LTB4 or IL-8)
Opsonisation requires special chemicals called opsonins (complement proteins like C3b, lectins and antibodies)
Phagocytic receptors include mannose receptors, scavenger receptors and receptors for various opsonins.
Scavenger receptors were originally defined as molecules that bind and mediate endocytosis of oxidized or acetylated
low-density lipoprotein (LDL) particles that can no longer interact with the conventional LDL receptor.
The H2O2-MPO-halide system is the most efficient bactericidal system of neutrophils.
Nitroblue tetrazolium test is used for monitoring the functioning of phagocytes and is useful in patients suffering
from chronic granulomatous disease.
In the absence of effective TH17 responses, individuals are susceptible to fungal and bacterial infections, and the skin
abscesses that develop are cold abscesses, lacking the classic features of acute inflammation, such as warmth and
redness.
Arachidonic acid is derived from the conversion of essential fatty acid linoleic acid.
The prostaglandins are involved in the pathogenesis of pain and fever in inflammation. Also know that PGE2 is
hyperalgesic
Lipoxins are also generated from AA by the lipoxygenase pathway. They suppress inflammation by inhibiting the
recruitment of leukocytes. Formation of lipoxins requires two cell populations (leucocytes and platelets) for the tran-
scellular biosynthesis. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are
converted to lipoxins by platelets interacting with the leukocytes.
Stable tissues have a limited capacity to regenerate after injury the only exception being liver.
68
Inflammation
Neutrophil extracellular traps (NETs) are extracellular fibrillar networks which provide a high concentration of
antimicrobial substances at sites of infection. They are produced by neutrophils in response to chemicals mainly
interferons. NET formation is dependent on platelet activation and it is associated with the pathogenesis of
autoimmune conditions like SLE.
Eculizumab prevents the conversion of C5 to C5a. This inhibitor not only reduces the hemolysis and attendant
transfusion requirements in patients of paroxysmal nocturnal hemoglobinuria (PNH), but also lowers the risk of
thrombosis by up to 90%.

Neutrophil Extracellular Traps
Neutrophil extracellular traps (NETs) are extracellular fibrillar networks that provide a high concentration of
antimicrobial substances at sites of infection and prevent the spread of the microbes by trapping them in the fibrils.
They are produced by neutrophils in response to infectious pathogens (mainly bacteria and fungi) and inflamma-
tory mediators (e.g., chemokines, cytokines [mainly interferons], complement proteins, and ROS).
The extracellular traps consist of a viscous meshwork of nuclear chromatin that binds and concentrates granule
proteins such as antimicrobial peptides and enzymes.
In the process of NET formation, the nuclei of the neutrophils are lost, leading to death of the cells.
The formation of NETs is dependent on platelet activation.
The nuclear chromatin in the NETs, which includes histones and associated DNA, has been postulated to be a
source of nuclear antigens in systemic autoimmune diseases especially systemic lupus erythematosus (SLE).
Tertiary lymphoid organs Robbins 9th/96

The accumulated lymphocytes, antigen-presenting cells, and plasma cells cluster together to form lymphoid tissues
resembling lymph nodes. These are called tertiary lymphoid organs; this type of lymphoid organogenesis is often seen in
the synovium of patients with long-standing rheumatoid arthritis and in the thyroid in Hashimoto thyroiditis. I
nflammation
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CHAPTER
HEMODYNAMICS
3 Hemodynamics
In a normal blood vessel like capillary, there are two forces (Starling forces) acting on the Transudate is protein-poor and
cell-poor fluid.
fluid in the circulation. The hydrostatic pressure causes fluid movement from inside the
vessel to outside and the colloid osmotic pressure (mostly due to proteins) is responsible for
the reverse movement of fluid from outside the vessel to the inside. The capillary hydrostatic
and osmotic forces are normally balanced so that there is no net loss or gain of fluid across the Exudate is protein-rich and
capillary bed. However, increased hydrostatic pressure or diminished plasma osmotic pressure cell-rich fluid.
leads to a net accumulation of extravascular fluid (edema).
In edema, the excessive interstitial fluid can be either an exudate or a transudate.
A transudate is a fluid with low protein content (most of which is albumin) and a specific gravity of less
than 1.012. It is essentially an ultrafiltrate of blood plasma that results from osmotic or hydrostatic
imbalance across the vessel wall without an increase in vascular permeability.
An exudate is an inflammatory extravascular fluid that has a high protein concentration, cellular debris,
Concept
and a specific gravity above 1.020. It is formed mainly due to alteration in the normal permeability of
Breast lymphedema (inflamma-
small blood vessels in the area of injury.
tory carcinoma) is due to block-
Causes and conditions associated with edema age of subcutaneous lymphatics
by malignant cells.
Hydrostatic Plasma osmotic Lymphatic Sodium Inflammation

pressure pressure obstruction retention
(Lymphedema)
CHF
Liver cirrhosis After surgery Salt intake Acute and
Ascites (Cirrhosis)
Malnutrition or irratiation Renal chronic
Venous obstruction
Protein-losing Neoplasia perfusion inflamma-
due to thrombosis of gastroenteropathy Inflamma- RAAS tion
physical inactivity tory activity
Arteriolar dilation
When edema is influenced by gravity, it is called dependent edema and it is a

characteristic feature of congestive heart failure (particularly the right ventricle).
Edema due to a renal cause (as in Nephrotic syndrome) is more severe and affects all
parts of body equally. However, it is initially appreciated in tissue with loose tissue
matrix such as around eyes and is called periorbital edema.
Hyperemia Congestion
Passive process due to impaired venous outflow
Active process due to arteriolar dilation

Edema is absent Edema is present
Severe generalized edema is
called anasarca.

Red color of the tissues Blue red color of the tissue (due to deoxyhemoglobin)
Seen in Inflammation Seen in Right heart failure, portal venous obstruction
in cirrhosis.
In chronic passive congestion, there is chronic hypoxia and capillary rupture
leading to hemorrhage foci. Phagocytosis of red cells results in hemosiderin-laden
macrophages.
Pulmonary Congestion
In acute pulmonary congestion there is presence of engorged alveolar capillaries and focal intra- Heart failure cells are present
alveolar hemorrhage. in the lungs and not in the
heart. These are hemosiderin
In chronic pulmonary congestion there is presence of thickened and fibrotic septa and alveoli contain
laden macrophages.
hemosiderin laden macrophages (heart failure cells).
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Review of Pathology
Hepatic Congestion
Acute hepatic congestion manifest as central vein and sinusoidal distension with degeneration of
Fibrosis associated with Chronic central hepatocytes.
passive congestion of the liver
In chronic hepatic congestion, central region of lobule shows loss of cells and have red brown
(in heart failure) is called as
color which is accentuated against surrounding normal liver (called nutmeg liver). Initially there is
cardiac cirrhosis.
centrilobular necrosis and presence of hemosiderin laden macrophages. In long standing congestion
(as in heart failure), there is presence of hepatic fibrosis called cardiac cirrhosis.
HEMOSTASIS
It is defined as a sequence of events leading to cessation of bleeding by the formation of

a stable fibrin-platelet hemostatic plug. The process involves the vascular endothelium,
platelets and the coagulation system.

1. Vascular Endothelium
After an injury, there is transient vasoconstriction of the vessel due to endothelin. This is
followed by the activation of thrombogenic factors which include:

a. Alteration in the blood flow resulting in turbulence and stasis favoring the clot
formation.

b. There is release of tissue factor from the injured cells activating the factor VII
(extrinsic pathway) and exposure to subendothelial collagen causing activating
of factor XII (intrinsic pathway). The endothelial cells also release von Willebrand
factor (vWF) which binds to exposed collagen and facilitates platelet adhesion.

c. There is also release of inhibitors of plasminogen activator (PAIs) which inhibit
fibrinolysis. Reduction in the endothelial formation of antithrombotic factors
(like nitric oxide, prostacyclin and thrombomodulin) also occurs.

2. Platelets
Initially vWF binds with the collagen followed by the binding of the platelets with
Hemodynamics
vWF through the glycoprotein Ib factor. The platelets then undergo a shape change
and their degranulation occurs. The granules in the platelets can be

a. Alpha granules having P-selectin, fibrinogen, fibronectin, factors V and VIII,
platelet factor 4, platelet-derived growth factor, and transforming growth
factor-b.

b. Delta granules or delta bodies having ADP, ATP, ionized calcium, histamine,
serotonin, and epinephrine.
Concept The release of granule mediators result in release of calcium (required in the
coagulation cascade), ADP (potent mediator of platelet aggregation) and the
A defect in the glycoprotein Ib surface expression of phospholipid complexes, which provide the platform for the
factor results in defective platelet
coagulation cascade. The platelets also synthesize thromboxane A2 (TXA2) which
adhesion known as Bernard
Soulier syndrome whereas is a potent vasoconstrictor and is also responsible for platelet aggregation. The
deficiency of Gp IIb/IIIa lead to platelets bind to each other by binding to fibrinogen using Gp IIb-IIIa.
Glanzmann thrombasthenia, a
3. The Coagulation System
disorder having defective platelet
aggregation.
72
Hemodynamics
The clotting system can be activated by intrinsic or the extrinsic pathway. The
intrinsic pathway is activated by exposing factor XII to thrombogenic surfaces (like PT is prolonged by deficiency
glass and other negatively charged surfaces) whereas extrinsic pathway requires of VII, X, V, prothrombin (II)
exogenous trigger (provided originally by tissue extracts). The division is artifact and fibrinogen (I) and oral
because extrinsic pathway is physiologically relevant for after vascular damage anticoagulants like warfarin.
whereas intrinsic pathway is of relevance in vitro.
Prothrombin Time (PT)
It is used to monitor the functioning of the extrinsic and the common coagulation pathways.
Normal PT is 12-16 seconds. aPTT is prolonged by deficiency
Activated partial thromboplastin time (aPTT) of factors XII, XI, IX, III, X, V,

prothrombin and fibrinogen
It is used to monitor the functioning of the intrinsic and the common coagulation pathways.

and drugs like heparin.
Normal aPTT is 26-34 seconds.
A relatively rare cause of prolonged aPTT is presence of antibodies against coagulation plasma
proteins called inhibitors. It can be seen due to the following reasons:
Hemophilia A and B patients receiving clotting factors to control their bleeding episodes, Pregnancy,
Autoimmune diseases, Malignancies (lymphoma, prostate cancer) and Dermatologic conditions This
has been dealt extensively in chapter-8 of this book. Thrombin time is elevated in
afibrinogenemia, dysfibrinogen-
Thrombin time (TT) emia, heparin like inhibitors and

It is used for testing the conversion of fibrinogen into fibrin and depends on adequate fibrinogen DIC.
levels.
Bleeding time (BT)
It is the time taken for a standardized skin puncture to stop bleeding
It tests the ability of blood vessels to constrict and platelets to form a hemostatic plug.
BT is elevated in quantitative
Fibrin degradation products (FDPs)
(thrombocytopenia)and qualita-
They are used to assess the fibrinolytic activity and they are increased in disseminated tive (thrombasthenia) platelet
intravascular coagulation (DIC). defects.
Important anticoagulant substances are:
Hemodynamics

1. Antithrombin III It inhibits activity of thrombin and other factors like XIIa, XIa, Xa
and IXa. It is activated by binding to heparin- Like molecules.

2. Proteins C and S Vitamin K dependent proteins which inactivate Va and VIIIa.

3. Endothelial prostacyclin (PGI2) and nitric oxide (NO) are potent vasodilators and Thrombin is a procoagulant but
inhibitors of platelet aggregation. the thrombin-thrombomodulin

4. Tissue factor pathway inhibitor Derived from endothelium and inhibits tissue complex is an anticoagulant.
factor VIIa and Xa molecules.

5. Thrombomodulin is produced by all endothelial cells except those in the cerebral
microcirculationQ. It binds to thrombin and this complex activates protein C (in the
presence protein S), which finally inactivates factor V and VIII. This action result in
anticoagulant effect.
The binding of clotting factors II, VII, IX and X to calcium depends on the addition of g carboxyla-
tion of glutamic acidQ residues on these proteins using vitamin K as a cofactor. These clotting
proteins are prothrombotic. Proteins C and S are two other vitamin K-dependent proteins which
can inactivate factors Va and VIIIa. These are anticlotting factors.
THROMBOSIS
It is defined as the pathologic formation of intravascular fibrin-platelet thrombus.

Virchows triad is required for thrombus formation. Its components are:

1. Endothelial injury: It can be due to the factors like vasculitis, hypertension, turbulent
flow, bacterial endotoxins, homocystinuria, hypercholesterolemia, radiation etc. It
is particularly important for thrombus formation occurring in the heart or in the Virchows triad = Endothelial
arterial circulation. injury + Alterations in the
normal blood flow + Blood

2. Alterations in the normal blood flow: Both turbulence and stasis contribute to the hypercoagulability
development of thrombosis. Turbulence causes arterial whereas stasis causes venous
thrombosis. It can also be seen with hyperviscosity syndromes like polycythemia
and with deformed red cells as in sickle cell anemia.
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3. Blood hypercoagulability: It can be either primary or secondary hypercoagulable state.

Hypercoagulable states
Primary (Genetics) Secondary (Acquired)

Mutations in factor V (Most common) Prolonged bed rest or immobilization
Antithrombin III deficiency Homocysteinemia
Protein C or S deficiency Tissue damage (Surgery, fracture, burns)
Fibrinolysis defects Cancer
Homocysteinemia MI, Prosthetic cardiac valves
Allelic variations in prothrombin levels DIC (Disseminated intravascular coagulation)
Mutations in the methyl tetra hydro folate Heparin induced thrombocytopenia
(MTHF) gene Antiphospholipid antibody syndrome
Factor V mutation (also called Relationship between coagulation defect and site of thrombosis (updated from Harrison18th/462)
Leiden mutation) is the most
common inherited cause of Factor V mutation (also called Leiden mutation) is the most common inherited cause of
hypercoagulability hypercoagulability in which normal arginine is replaced by glutamine at position 506
making it resistant to degradation by protein C. This causes unchecked coagulation
and it manifest with recurrent deep venous thrombosis.
Antithrombin III, Protein C or Protein S deficiency are other genetic causes of
hypercoagulability manifesting typically as venous thrombosis and recurrent
thromboembolism in adolescence or early adult life.
All conditions mentioned above would have presence of venous thrombosis except
for the following:
Conditions with both arterial and venous thrombi
Hyperhomocystenemia is the HomocysteinuriaQ Essential thrombocythemiaQ
only mixed disorder (inherited Antiphospholipid antibodyQ CancerQ
Hemodynamics
as well as acquired) which can HyperhomocysteinemiaQ PNHQ

cause both venous and arterial Disseminated intravascular coagulationQ Polycythemia veraQ
thrombosis Heparin induced thrombocytopeniaQ DysfibrinogenemiaQ
Arterial and Venous Thrombi
An area of attachment to the underlying vessel or heart wall, frequently firmest at

the point of origin, is characteristic of all thromboses. Venous thrombi are called
as stasis thrombi because they are formed in the sluggish venous circulation.
These are also known as red thrombi as they contain more enmeshed red cells and
relatively few platelets. Arterial thrombus contains more platelets and relatively
less fibrin.
Feature Arterial thrombus Venous thrombus
Pathogenesis Endothelial injury or site of Stasis of blood
Lines of Zahn which are turbulence
produced by the alternating pale
Blood flow Associated with active blood flow Associated with sluggish blood
layers of platelets mixed with
flow
some fibrin and darker layers
containing more red cells. Sites Coronary, cerebral and femoral Superficial and deep leg veins,
arteries ovarian/periuterine veins
Propagation Grows in a retrograde manner from Grows in an antegrade manner
point of attachment from point of attachment
Arterial thrombi arising in heart Gross Lines of Zahn present Lines of Zahn absent
chambers or in the aortic lumen
Microscopic Pale platelet layer alternating with Red cells mixed with relatively less
usually adhere to the wall of the
dark red cell layer so also called as platelets, so also called as red
underlying structure and are
white thrombi thrombi
termed mural thrombi.
Occlusion Incomplete lumen occlusion Complete vessel occlusion
Complications Ischemia and infarction of organs Embolism, edema and ulceration
74
Hemodynamics
Postmortem clots are gelatinous with a dark red dependent portion where red cells have settled by
gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat. These are
usually not attached to the underlying wall whereas as discussed above, an area of attachment is
characteristic of all thrombosis. Thrombi may form on heart valves as seen in infective endocarditis;
nonbacterial thrombotic endocarditis and verrucous (Libman-Sacks) endocarditis.
EMBOLISM
An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried

downstream from its site of origin. It is most commonly composed of thromboembolism. The
emboli may also be composed of other types like atheroemboli, fat emboli (most commonly
with skeletal injuries), air emboli, amniotic fluid emboli and tumor emboli.
Pulmonary Emboli
Most of the pulmonary emboli arise in the deep leg veins above the level of the knee. Paradoxical
embolus is a rare embolus that can pass through an inter-atrial or inter-ventricular defect, thereby Most common site for venous
entering the systemic circulation. Most pulmonary emboli (60% to 80%) are clinically silent thrombosis is the deep leg
veins in below the knee.
because they are small. They rarely may cause pulmonary infarction (because lungs have dual
blood supply from pulmonary and bronchial vessels) manifesting clinically as breathlessness, pleuritic
pain, hemoptysis and pleural effusion. Sudden death may occur if >60% of the pulmonary circulation
is obstructed. Recurrent pulmonary emboli may also cause pulmonary hypertension which may lead
to cor pulmonale. Most of the pulmonary emboli
arise in the deep leg veins
Systemic Thromboembolism above (femoral veins) the level
Most of them arise in the heart and the major sites of arterial embolization are the lower extremities of the knee.
(75%), the brain (10%) and less commonly, the intestines, kidneys, spleen, and upper extremities.
Fat embolism
Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic symptoms
Hemodynamics
(irritability, restlessness and even coma), anemia, and thrombocytopenia (manifesting as diffuse
petechial rash). It is seen after fractures of long bones (which contain fatty marrow) or after soft-tissue
trauma. It is fatal only in 10% of cases. The pathogenesis involves both mechanical obstruction and
free fatty acids causing local toxic injury to endothelium. Fat embolism is seen after
fractures of long bones and is
Infarct fatal only in 10% of cases.
It is an area of necrosis caused by occlusion of either the arterial supply or the venous
drainage in a particular tissue. Nearly 99% of all infarcts result from thrombotic or embolic
events, and almost all result from arterial occlusion. Venous thrombosis usually causes
venous obstruction and congestion but can cause infarction (more in organs with a single
venous outflow like testis and ovary). The infarcts may be either red (hemorrhagic) or white
(anemic) and may be either septic or bland.
Feature Red infarcts White infarcts
Cause Arterial occlusion in loose tissues or Arterial occlusions in solid organs
Concept
organs having dual blood supply with end arterial circulation
Venous occlusion (in ovarian torsion) All infarcts tend to be wedge
shaped with the occluded ves-
Affected organs Lung and small intestine Solid organs (heart, spleen, kidney) sel at the apex and the periphery
Properties Ill define hemorrhagic margins which Well defined margins and of the organ forming the base.
change in color to brown progressively paler with time The infarct microscopically has
features of ischemic coagula-
Edema Usually present Usually absent tive necrosis.
Disseminated Intravascular Coagulation (DIC)/Consumption Coagulopathy
DIC is an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary

complication in a variety of diseases. It is characterized by activation of the coagulation
sequence that leads to the formation of microthrombi throughout the microcirculation of
the body. As a consequence of the thrombotic diathesis, there is consumption of platelets, fibrin, and
coagulation factors and, secondarily, activation of fibrinolytic mechanisms.
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Review of Pathology
Causes of DIC
Obstetrics Infections Neoplasm Massive Miscellaneous
complications tissue injury
- Abruptio - Gram negative - Ca pancreas
- Traumatic - Acute
placenta sepsis - Ca prostate
- Burns intravascular
- Retained dead - Meningococcemia - Ca lung
- Extensive hemolysis
fetus - Histoplasmosis - Ca stomach surgery - Snake bite
- Septic - Aspergillosis - Acute - Shock
abortion - Malaria promyelocytic - Heat stroke
- Amniotic fluid - Toxemia leukemia - Vasculitis
embolism - Aortic aneurysm
- Toxemia - Liver disease
Laboratory investigations in DIC reveal that

Platelet count is decreased

Prolonged PT/TT

Decreased fibrinogen

Elevated fibrin split products (D-dimers)
The management is to treat the underlying disorder.
SHOCK
It is defined as systemic hypoperfusion caused by reduction either in cardiac output or in the

effective circulating blood volume.
Causes of Shock
Cardiogenic shock: Presence of cardiac pump failure as seen with myocardial

Hemodynamics
infarction, cardiac arrhythmia, cardiac tamponade and pulmonary embolism.

Hypovolemic shock: Caused by reduction of blood volume due to hemorrhage, severe
burns and severe dehydration.
Neurogenic shock: Presence of generalized vasodilation due to anesthesia and CNS
injury.
Anaphylactic shock: Presence of generalized vasodilation due to type I hypersensitivity
reaction
Septic shock: It is due to release of endotoxins or bacterial cell wall lipopolysaccharides
(gram negative infections) resulting in production of cytokines like TNF-alpha, IL-
1and IL-6, vasodilation and hypotension, acute respiratory distress syndrome and
multiple organ dysfunction syndrome. Pathogenesis of septic shock is explained in
the flowchart below:
Concept
Most common cause of
septic shock is gram positive
bacteria now; so, the earlier
term of endotoxic shock is not
used now.
LPS: Lipopolysaccharide LBP: LPS Binding Protein TLR: Toll Like Receptor
76
Hemodynamics
S tages of Shock
Stage I: Stage of compensation in which perfusion to the vital organs is maintained
by mechanisms like increased sympathetic tone, catecholamine release and activation
of renin-angiotensin system.
Stage II: Stage of decompensation in which there is tissue hypoperfusion and other
features like development of metabolic acidosis, electrolyte disturbances and renal
insufficiency.
Stage III: Irreversible stage having irreversible tissue injury and multiple organ
failure which is not even corrected by the removal of the underlying cause or
correction of the hemodynamic disturbance.
Features of Shock
Brain Ischemic encephalopathy
Heart Coagulative necrosis or contraction band necrosis
Liver Fatty change with hemorrhagic central necrosis; shock liver
Kidneys Extensive tubular ischemic injury (Acute tubular necrosis) leading to oliguria and
electrolyte disturbances.
Adrenal Cortical cell lipid depletion.
GIT Hemorrhagic enteropathy.
Lungs are uncommonly affected but may show features of diffuse alveolar damage or shock lung.
F
Clinical eatures
In hypovolemic and cardiogenic shock, the patient presents with hypotension; a weak, rapid
pulse; tachypnea; and cool, clammy, cyanotic skin. In septic shock, however, the skin may
Hemodynamics
initially be warm and flushed because of peripheral vasodilation. Then, patients develop a
second phase dominated by renal insufficiency and marked by a progressive fall in urine
output as well as severe fluid and electrolyte imbalances.
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H emodynamics and hemostasis 8. All of the following are correct about Thromboxane A2
except: (AI 2001)
1. All are true about blood coagulation except? (AI 2011) (a) Low dose aspirin inhibits its synthesis
(a) Factor X is a part of both intrinsic and extrinsic (b) Causes vasoconstriction in blood vessels
pathway. (c) Causes bronchoconstriction
(b) Extrinsic pathway is activated by contact of plasma (d) Secreted by WBC
with negatively charged surfaces. 9. Coagulation defects associated with increased
(c) Calcium is very important for coagulation. coagulation are seen in: (PGI Dec 2006)
(d) Intrinsic pathway can be activated in vitro. (a) Increased Protein C
(b) Increased Protein S
2. Vitamin K is responsible for the carboxylation of which (c) Increased Anti-thrombin III
amino acid in the clotting factors? (AI 2011) (d) Protein C resistance
(a) Aspartate (e) Dysfibrinogenemia
(b) Glutamate 10. All of the following are anticoagulant substances
(c) Proline except (Karnataka 2006)
(d) Lysine (a) Antithrombin III
(b) Protein S
3. Edema in nephrotic syndrome occurs due to
(c) vWF
(a) Na+ and water restriction (AIIMS Nov. 2010)
(d) Nitric oxide
(b) Increased venous pressure
Hemodynamics
(c) Decreased serum albumin 11. Cause of edema is (UP 2002)

(d) Decreased fibrinogen (a) Decreased plasma protein concentration
(b) Increased lymph flow
4. Thrombomodulin thrombin complex prevents clotting (c) Increased ECF volume
because: (DPG 2011) (d) Increased plasma protein concentration
(a) Thrombomodulin inhibits prothrombin activator
(b) The complex activates antithrombin III
12. Endothelium derived relaxing factor (EDRF) is
associated with: (UP 2004)
(c) Thrombomodulin-thrombin complex activates heparin
(a) Ras (b) C-myc
(d) The complex removes thrombin and also activates
(c) Bcl (d) N NOS
protein C which inactivates the activated factors V
and VIII 13. Which is not involved in local hemostasis?
(a) Fibrinogen (RJ 2004)
5. Vitamin K associated clotting factors are: (b) Calcium
(a) IX, X (AI 2010) (c) Vitamin K
(b) I, V (d) Collagen
(c) VII, VIII
(d) I, VIII 14. Which is the following not synthesized in the liver?
(a) Factor II (Jharkhand 2005)
6. All endothelial cells produce thrombomodulin except (b) Factor VII
those found in: (AI 2005) (c) Factor IX
(a) Hepatic circulation (d) Factor VIII
(b) Cutaneous circulation 15. A 54 year old chronic alcoholic Adhiya Kumar is brought
(c) Cerebral microcirculation by his son as he has developed progressively increasing
(d) Renal circulation abdominal distension from past 3 months. The physician
7. Which of the following is a procoagulation protein? aspirates the abdominal fluid which is straw-colored
and clear and is found to have protein content (mainly
(a) Thrombomodulin (AI 2004)
albumin) of 2.3 g/dl. Which of the following is a major
(b) Protein C
contributor to the fluid accumulation in this patient?
(c) Protein S
(d) Thrombin

(a) Blockage of lymphatics

(b) Decreased oncotic pressure
78
Hemodynamics

(c) Decreased capillary permeability 19. Pale infarct is seen in all except: (AIIMS Nov. 2010)

(d) Inflammatory exudation (a) Lungs
(b) Spleen
Most Recent Questions (c) Kidney
(d) Heart
15.1. Tissue thromboplastin activates: 20. Congenital hypercoagulability states are all of the
(a) Factor VII
followings except
(b) Factor IV
(a) Protein C deficiency (AIIMS Nov. 2010)
(c) Factor VI
(b) Protein S deficiency
(d) Factor XII
(c) Anti-phospholipid antibody syndrome
1 5.2. Platelet adhesion to collagen is mediated by which of (d) MTHFR gene mutation
the following?
(a) Factor VIII
21. Fat embolism is commonly seen in: (DPG 2011)
(a) Head injuries (b) Long bone fractures
(b) Factor IX
(c) Drowning (d) Hanging
(c) Von willebrand factor
(d) Fibronectin 22. Virchows triad includes all except
(a) Injury to vein
1 5.3. Gandy gamma body is typically seen in chronic venous
(b) Venous thrombosis
congestion of which of the following?
(c) Venous stasis
(a) Lung
(d) Hypercoagulability of blood
(b) Kidney
(c) Spleen 23. Hypercoagulability due to defective factor V gene is
(d) Liver called: (AIIMS Nov 2003)
(a) Lisbon mutation
1 5.4. Extrinsic pathway of clotting factors is measured by?
(b) Leiden mutation
(a) Prothromin time
(c) Antiphospholipid syndrome
(b) Activated partial thromboplastin time (d) Inducible thrombocytopenia syndrome
(c) Bleeding time
(d) Clotting time 24. Arterial thrombosis is seen in (PGI June 2003)
Hemodynamics
(a) Homocysteinemia
(b) Anti-phospholipid syndrome
Thrombosis: embolism: Infarct
(c) Protein S deficiency
(d) Protein C deficiency
16. Histologic sections of lung tissue from 66-year-old woman, (e) Antithrombin III deficiency
Sheena with congestive heart failure and progressive
breathing problems reveal numerous hemosiderin-laden 25. Hemorrhagic infarction is seen in: (PGI Dec 2002)
cells within the alveoli. Which of the following is the cell (a) Venous thrombosis
(b) Thrombosis
of origin of these heart failure cells?
(c) Septicemia

(a) Endothelial cells
(d) Embolism

(b) Pneumocytes
(e) Central venous thrombosis

(c) Lymphocytes

(d) Macrophages 26. Hyperviscosity is seen in (PGI Dec 2003, 04)
(a) Cryoglobulinemia.
17. At autopsy, the spleen of a patient is noted to have a (b) Multiple myeloma.
thickened capsule and many small, scarred areas. (c) MGUS.
Microscopic examination of the scarred areas reveals (d) Lymphoma.
fibrosis with hemosiderin and calcium deposition. (e) Macroglobulinemia.
This type of spleen is usually seen in conjunction with
which of the following disorders? 27. Predisposing factor for venous thrombosis:

(a) Hepatic cirrhosis (a) AT III deficiency

(b) Hodgkins disease (b) Protein S deficiency
(c) Protein C deficiency

(c) Rheumatoid arthritis
(d) Dysfibrinogenemia

(d) Sickle cell anemia
18. Antiphospholipid syndrome is associated with all
28. Inherited coagulation disorders are:
(a) Protein C deficiency (PGI Dec 2005)
except: (AI 2012)
(b) Protein S deficiency
(a) Recurrent abortion (c) Leiden factor mutation
(b) Venous thrombosis (d) Lupus anticoagulant
(c) Pancytopenia (e) Anti-cardiolipin
(d) Antibody to lupus
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Review of Pathology
29. Which of the following statements about pulmonary preparation of a glycoprotein IIb/IIIa inhibitor. The
emboli is not correct? (Delhi PG 2009 RP) mechanism of action of this agent is the ability to
(a) 60-80% pulmonary emboli are clinically silent (a) Dilate coronary arteries.
(b) In more than 95% cases venous emboli originate (b) Inhibit platelet adhesion.
from deep leg veins (c) Inhibit platelet aggregation.
(c) Embolic obstruction of pulmonary vessels almost (d) Lyses thrombi
always cause pulmonary infarction
(d) Embolic obstruction of medium sized arteries may 37. A 62 year old man Ram Srinath is brought by his wife
result in pulmonary infarction Shanti Devi after sustaining a fall in the washroom
while taking bath. He has severe pain in his right leg.
30. Which one of the following inherited disorders Dr. Amit Shersia, the orthopedic surgeon diagnoses it
produces arterial thrombosis?
as fracture femur. He is discharged after administration
(a) Factor V Leiden mutation (Karnataka 2006)
of proper treatment. After about 12 days, Shanti
(b) Antithrombin deficiency
observes that her husband has developed a swollen
(c) Homocysteinemia
(d) Protein S deficiency right leg below the knee. Ram is unable to move his
limb properly and there is presence of tenderness too.
31. Heart failure cells are seen in (AP 2007) Which of the following is the most likely complication
(a) Chronic venous congestion of liver in him?
(b) Chronic venous congestion of lung (a) Hematoma of the right thigh
(c) Acute venous congestion of lung (b) Fat embolism
(d) Acute venous congestion of liver (c) Gangrene in the right foot
32. Necrosis with putrefaction is called as: (Bihar 2005) (d) Pulmonary thromboembolism
(a) Desiccation 38. A 27-year-old woman, Shama presents with a history
(b) Gangrene of losing pregnancies in the past 5 years. She also has
(c) Liquefaction a history of recurrent pains in her legs secondary to
(d) Coagulative necrosis recurrent thrombosis. Her symptoms are most likely
due to a deficiency of which one of the following
33. Lines of Zahn are found in: (Jharkhand 2006)
Hemodynamics
substances?
(a) Thrombus
(a) PA inhibitors (b) Protein C
(b) Infarct tissue
(c) Plasmin (d) Thrombin
(c) Postmortem clot
(d) All 39. A 20-year-old male, Akash fractured his right femur. He
was admitted to the hospital and over the next several
34. Chicken fat clot is: (Jharkhand 2006)
days developed progressive respiratory problems.
(a) Postmortem clot
Despite extensive medical intervention, he died 3 days
(b) Thrombus
later. At the time of autopsy oil red O-positive material
(c) Infarct
was seen in the small blood vessels of the lungs and
(d) All
brain. Which of the following was the most likely
35. The five stages of hemostasis are given below in random diagnosis?
order. Put them into their correct order. (a) Air emboli (b) Amniotic fluid emboli
(c) Fat emboli (d) Paradoxical emboli
(a) Clot dissolution
(b) Blood coagulation 40. A pregnant woman develops deep, boring pain of
(c) Vessel spasm her left thigh muscles associated with swelling and
(d) Clot retraction enhanced warmth of the same leg. The pain is worsened
(e) Formation of platelet plug by extending the foot. The superficial veins of the leg
are engorged. Her condition puts her at risk for which
(a) cabed
of the following?
(b) acbde
(a) Acute renal failure
(c) cebda
(b) Cerebral hemorrhage
(d) ecdba
(c) Hepatic infarction
36. A 64 year old man Ojas Alok Nath resides in a city. He is (d) Pulmonary embolus
a known case of hypertension and is a smoker too. One
Most Recent Questions
day, while watching tv, he developed severe pain in the
chest. He is rushed to the medical emergency of the city 40.1. White infarct is seen in:

hospital where this episode is diagnosed as unstable
(a) Lung (b) Intestine
angina. The emergency medical officer Dr. Smiley
Gupta immediately administers him an intravenous

(c) Heart (d) Ovary
80
Hemodynamics
40.2. Lines of Zahn occur in which of the following? 48. Which of the following is a feature of Disseminated
(a) Postmortem clot Intravascular Coagulation (DIC)?
(b) Infarct (a) Normal prothrombin time (Karnataka 2006)
(c) Embolus (b) Reduced plasma fibrinogen
(d) Coralline thrombus (c) Normal platelet count
(d) Normal clotting time
4 0.3. White infarcts are seen in the following except:
(a) Liver 49. A 29 year old woman Ruma is in labour but unfortunately
(b) Kidney during parturition, the placental membranes tear and
(c) Spleen amniotic fluid expressed into a lacerated cervical vein.
(d) Heart Which of the following is the woman most likely to
experience immediately following this event?
Shock, DIC and Miscellaneous
(a) Placental abruption

(b) Renal failure
41. All of the following are true about DIC except? (AI 2012)
(c) Respiratory distress
(a) Increased fibrinogen
(d) Splinter hemorrhages
(b) Increased activated partial thromboplastin time 50. Irshaan has been diagnosed with acute promyelocytic
(c) Decreased prothrombin time leukemia recently. He presents suddenly in the medical
(d) Increased fibrin degradation products emergency because of a dangerous complication of
42. The initiating mechanism in endotoxic shock is his malignancy called disseminated intravascular
(a) Peripheral vasodilatation (AIIMS Nov. 2010) coagulation ( dic ). In dic , micro emboli form leading
(b) Endothelial injury to obstruction of blood vessels and tissue hypoxia. The
(c) Increased vascular permeability common clinical signs observed in patient may be due
(d) Reduced cardiac output to which of the following?
43. The initiating mechanism in endotoxic shock is
(a) Immunologic failure
(a) Peripheral vasodilatation (AIIMS Nov. 2010)
(b) Renal failure
(b) Endothelial injury
(c) Right ventricular failure
(c) Increased vascular permeability
(d) Hepatic failure
Hemodynamics
(d) Cytokine release
51. A primiparous woman Ritu at term experiences
44. D-Dimer is the most sensitive diagnostic test for: placental abruption and is rushed to the operating
(a) Pulmonary embolism (DPG 2011) room for emergency Cesarean section. She develops
(b) Acute pulmonary oedema shortness of breath, cyanosis, and copious bleeding
(c) Cardiac tamponade from her surgical wounds. Levels of which of the
(d) Acute myocardial infarction following blood components is expected to rise in this
45. Shock lung is characterized by setting?
(a) Alveolar proteinosis (AIIMS May 2008; Nov 2007)
(a) Factor V
(b) Bronchiolitis obliterans
(b) Fibrin degradation products
(c) Diffuse pulmonary hemorrhage
(c) Fibrinogen
(d) Diffuse alveolar damage
(d) Plasminogen
46. The histological features of shock includes: 52. A 24-year-old pregnant Heena sustains a placental
(a) ATN abruption, and is admitted to the ICU where she begins
(b) Pulmonary congestion bleeding from multiple sites, including oral mucous
(c) Depletion of lipids in adrenal cortex membranes. Which of the following studies would be
(d) Hepatic necrosis most valuable in assessing this patients condition?
(e) Depletion of lymphocytes
(a) Partial thromboplastin time, kininogen, and factor
47. Conditions associated with incoagulable state are: VIII levels
(a) Abruption placentae (PGI Dec 2003, 2004)
(b) Platelet count, fibrinogen levels, and fibrin degradation
(b) Acute promyelocytic leukemia products
(c) Severe falciparum malaria
(c) Platelet count, thrombin time, and prekallikrein
(d) Snake envenomation levels
(e) Heparin overdose

(d) Prothrombin time and factor VIII levels
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E xplanations
1. Ans. (b) Extrinsic pathway is activated by contact of plasma with negatively charged surfaces (Ref: Robbins 8th/119, 9/e 118)
Contact of plasma with negative charged surface activates intrinsic and not extrinsic pathways.
2. Ans. (b) Glutamate (Ref: Robbins 8th/119, 9/e p119)
The binding of clotting factors II, VII, IX and X to calcium depends on the addition of carboxylation of glutamic acid
residues on these proteins. This step requires vitamin K as a cofactor.
Vitamin K dependent factors
Increasing clotting Inhibiting clotting
Clotting factors II, VII, IX and X Protein C and protein S
Proteins C and S are two other vitamin K-dependent proteins which can inactivate factors Va and VIIIa. These are
anticlotting factors.
3. Ans. (c) Decreased serum albumin (Ref: Robbins 8th/922, 9/e p115)
Na+ and water retention is now the more important cause of edema in nephrotic syndrome. For details see the Chapter on
Kidney.
Receptor Na+ and water retention is not to be confused with option (a) Na+ and water restriction.

4. Ans. (d) The complex removes thrombin and also activates protein C which inactivates the activated factors V and VIII
(Ref: Harrison 17th/364-5, Robbins 8th/116, 9/e p121)
5. Ans. (a) IX, X (Ref:Robbins 8th/118-119 9/e p119)
Hemodynamics
6. Ans. (c) Cerebral microcirculation (Ref: Ganong 21st/546, Robbins 7th/85, Robbins 8th/116, Harrison 17th/365, 9/e p121)
All endothelial cells except those in the cerebral microcirculation produce thrombomodulin, a thrombin protein, and express it on
their surface.

7. Ans. (d) Thrombin (Ref: Robbins 7th/127, Harrison 17th/364, 9/e p120-121)
Thrombin is clotting factor IIa which participates in coagulation cascade by converting factor I [soluble protein fi-
brinogen] to factor Ia [insoluble fibrin].
Protein C and protein S are vitamin K dependent anticlotting proteins (remember factor II, VII, IX and X are vitamin-
K dependent clotting factors). These act by inactivating factor Va and VIIIa.
Thrombomodulin-thrombin complex activates protein C and thus the complex acts as an anticoagulant.
8. Ans. (d) Secreted by WBC (Ref: Robbins 7th/68-70, 9/e p118)

Thromboxane A2 (TXA2) is synthesized and released from activated platelets (Not WBCs)
TXA is also a powerful vasoconstrictor and bronchoconstrictor.
2
Low does aspirin (50-325 mg) is used as antiplatelet drug because it inhibits COX irreversibly and decreases forma-
tion of TXA by platelets.
2
9. Ans. (d) Protein C resistance; (e) Dysfibrinogenemia (Ref: Harrison 16th/149l, 9/e p123)
10. Ans. (c) Von Willebrand factor (Ref: Robbins 7th/125-126/129-130, 9/e p121,118)
VWF (von Willebrand Factor) is produced by endothelial cells and it is required for platelet binding to collagen and other substances.
So, it is a procoagulant factor.
11. Ans. (a) Decreased plasma protein concentration (Ref: Robbins 8th/112; 7th/120-121, 9/e p114)
12. Ans. (d) nNOS (Ref: Robbins 8th/60, 7th/72-73, 9/e p80)
13. Ans. (c) Vitamin K (Ref: Robbins 8th/115-120, 7th/128, 9/e p118-119)
14. Ans. (d) Factor VIII (Ref: Robbins 8th/835; 7th/655, 9/e p47-118)
82
Hemodynamics
15. Ans. (b) Decreased oncotic pressure (Ref: Robbins 8th/112, 9/e p114)
The patient in the stem of the question is most likely having liver cirrhosis secondary to chronic alcoholism. An important
manifestation of this disease is reduced hepatic synthesis of albumin which is the most important contributor to plasma
oncotic pressure. Also, ascites is associated with increased sodium and water retention because of stimulation of the renin-
angiotensin aldosterone system (RAAS). A minor contribution is also because of hydrostatic forces (due to intra-hepatic
scarring and partial obstruction of the portal venous return) resulting in fluid transudation and increased secretion of
hepatic lymph.
1 5.1. Ans. (a) Factor VII (Ref: Robbins 8/e p119, 7/e p128, 9/e p118)
The extrinsic pathway is activated by tissue factor (thromboplastin) causing activation of factor VIIa. For details, refer to
text.
15.2 Ans. (c) Von willebrand factor (Ref: Robbin 8/e p116-8)
Direct lines.. Von Willebrand factor functions as an adhesion bridge between subendothelial collagen and the glycoprotein Ib (Gp Ib)
platelet receptor. Aggregation is accomplished by fibrinogen bridging GpIIb-IIIa receptors on different platelets.
15.3 Ans. (c) Spleen (Ref: Harsh Mohan 6th/52)
Gamna-Gandy bodies in chronic venous congestion (CVC) of the spleen is characterized by calcific deposits admixed with
haemosiderin on fibrous tissue.
15.4 Ans. (a) Prothromin time (Ref: Robbin 9/e p119)
Prothrombin time Extrinsic pathway Factor 5/7
Activated partial thromboplastin time Intrinsic pathway Factor 8
Bleeding time Platelet function and platelet count Platelet function and count
16. Ans. (d) Macrophages (Ref: Robbins 7th/79-82, 122, 562, 9/e p116)
Example of tissue macrophages are Kupffer cells (liver), alveolar macrophages (lung), osteoclasts (bone), Langerhans
cells (skin), microglial cells (central nervous system)
Hemodynamics
In the lung, alveolar macrophages can phagocytose the red blood cells that accumulate in alveoli in individuals with
congestive heart failure. These cells contain hemosiderin and are referred to as heart failure cells.
17. Ans. (a) Hepatic cirrhosis (Ref: Robbins 8th/634, 9/e p530)
The spleen shows the changes of chronic congestive splenomegaly, typically associated with hepatic cirrhosis. The de-
scribed small scars are called Gandy-Gamma nodules which are due to the result of organization of old hemorrhages.
Hodgkins disease (choice B) produces large splenic nodules in which Reed-Sternberg cells can be found surrounded by
mature lymphocytes, eosinophils, and neutrophils.
Rheumatoid arthritis (choice C) and many other chronic inflammatory disorders induce reactive hyperplasia of the spleen with
formation of many large germinal centers in the splenic follicles.
Sickle cell anemia (choice D) produces many small (often triangularly shaped) infarctions in the spleen.
18. Ans. (c) Pancytopenia (Ref: Harrison 17th/1795, Robbins 8th/123,215, 7th/133, 229, 9/e p124-125)
Antiphospholipid antibody syndrome is characterized by antibodies against plasma proteins in complex with phospholipid. In pri-
mary antiphospholipd antibody syndrome there is hypercoagulable state without evidence of autoimmune disorders. In associa-
tion with SLE or lupus, the name given is secondary antiphospholipd antibody syndrome. There is formation of antibody against
phospholipid beta 2-glycoprotein 1 complexQ. It also binds to cardiolipin antigen and lead to false positive test for syphilisQ.
It also interferes with in vitro clotting time and so, called as lupus anticoagulant. In vivo, these patients have hypercoagulable state
resulting in arterial and venous thrombosis resulting spontaneous recurrent miscarriage and focal or cerebral ischemia.
19. Ans. (a) Lungs (Ref: Robbins 8th/128, 9/e p129)

The Lungs have dual blood supply and so, they exhibit red infarct. The infarcts may be either red (hemorrhagic) or white
(anemic) and may be either septic or bland.
All infarcts tend to be wedge shaped with the occluded vessel at the apex and the periphery of the organ forming the base. The infarct
microscopically has features of ischemic coagulative necrosis.
20. Ans. (c) Anti-phospholipid antibody syndrome (Ref: Robbins 8th/123, 9/e p123)
Anti-phospholipid antibody syndrome is an acquired causes of hypercoagulability
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Hypercoagulable states
Primary (Genetics) Secondary (Acquired)

Mutations in factor V (Most common) Prolonged bed rest or immobilization
Antithrombin III deficiency Homocysteinemia
Protein C or S deficiency Tissue damage (Surgery, fracture, burns)
Fibrinolysis defects Cancer
Homocysteinemia MI, Prosthetic cardiac valves
Allelic variations in prothrombin levels DIC (Disseminated intravascular coagulation)
Mutations in the methyl tetra hydro folate Heparin induced thrombocytopenia
(MTHF) gene Antiphospholipid antibody syndrome
21. Ans. (b) Long bone fractures (Ref: Robbins 8th/126, 9/e p128)
22. Ans. (b) Venous thrombosis (Ref: Anderson 10th/387, Robbins 7th/130, 9/e p122)
The factors that predispose to venous thrombosis were initially described by Virchow in 1856 and are known as Virchows
triad. These include
Stasis Vascular damage Hypercoagulability
Q Q Q
23. Ans. (b) Leiden mutation (Ref: Robbins 7th/p131, Robbins 8th/122, 9/e p123)
Mutation in factor V gene is caused by the substitution of glutamine for the normal arginine residue at position 506.
It is known as Leiden mutation and it is the most common inherited cause of hypercoagulability.
Note: Lisbon mutation is associated with a mutation in thyroid peroxidase geneQ.

24. Ans. (a) Homocysteinemia; (b) Antiphospholipid syndrome (Ref: Harrison 18th/462, 9/e p123)
25. Ans. (a) Venous thrombosis; (b) Thrombosis; (d) Embolism (Ref: Andersons10th/2707)
Hemorrhagic infarction is seen in:
Hemodynamics
Hypercoagulable states (OCP use, pregnancy, polycythemia vera, malignancy etc.)

Embolism - Infarct is attributed to lysis of clot exposing infarct tissue and its permeable capillary bed to recirculating
blood.
Venous thrombosis.
26. Ans. (a) Cryoglobulinemia; (b). Multiple myeloma; (d) Lymphoma; (e) macroglobulinemia (Ref: Williams Hematology
6/1268)
Hyperviscosity is seen in
Multiple myeloma
Lymphoplasmacytic lymphoma (Waldenstroms macroglobulinemia)
Cryoglobulinemia
Myeloproliferative disorders
MGUS (Monoclonal Gammopathy of uncertain significance): Here, M Protein can be identified in the serum of 1% of
healthy individual >50 years of age and 3% in older than 70 yrs. It is the most common form of monoclonal gammopathy.
In MGUS less than 3g/dL of monoclonal protein is present in serum and there is no Bence Jones proteinuria.
Normal viscosity of blood is 1.8
27. Ans. All. (Ref: Harrison 16th- 686, Robbins 7th/132)
Dysfibrinogenemia produces hypercoagulable state and leads to thrombus formation in some patients. Other causes have
already been discussed.
28. Ans. (a) Protein C deficiency; (b) Protein S deficiency; (c) Leiden factor mutation (Ref: Harrison 16th/685; de Gruchys
5th/420, Robbins 9/e p123)
Congenital coagulation disorders
Hemophilia A and B Factor VII deficiency.
von Willebrands disease Factor X (Stuart) deficiency.
Fibrinogen absence or deficiency. Factor XII, XI deficiency.
Prothrombin absence or deficiency. Factor XIII deficiency.
Factor V deficiency. Fitzgerald factor (HMWK) deficiency.
84
Hemodynamics
29. Ans. (c) Embolic obstruction of pulmonary vessels almost always cause pulmonary infarction (Ref: Robbins 8th/126)
As discussed is text, most pulmonary emboli (60% to 80%) are clinically silent because they are small. With time, they
undergo organization and are incorporated into the vascular wall. Embolic obstruction of medium-sized arteries may
result in pulmonary hemorrhage but usually does not cause pulmonary infarction because of the dual blood flow into the
area from the bronchial circulation.
30. Ans. (c) Homocysteinemia (Ref: Robbins 7th/131, 8th/122, Harrison 18th/462, 9/e p123)
HyperhomocystenemiaQ is a mixed disorder (inherited as well as acquiredQ) which can cause both venous and arterial thrombosisQ.
31. Ans. (b) Chronic venous congestion of lung (Ref: Robbins 8th/535, 7th/122, 9/e p116)
32. Ans. (b) Gangrene (Ref: Robbins 8th/15; 7th/22, 9/e p43, 129)
33. Ans. (a) Thrombus (Ref: Robbins 8th/124; 7th/133, 9/e p125)
34. Ans. (a) Postmortem clot (Ref: Robbins 8th/124; 7th/133, 9/e p125)
35. Ans. (c) cebda (Ref: Robbins 8th/117-8, Harrison 18th/457-9, 9/e p116-119)
Hemostasis is divided into five stages:
Vessel spasm.
Formation of the platelet plug.
Blood coagulation or development of an insoluble fibrin clot.
Clot retraction.
Clot dissolution.
36. Ans. (c) Inhibit platelet aggregation (Ref: Robbins 8th/118, 9/e p117-118)
Glycoprotein IIb/IIIa inhibitors (tirofiban, eptifibatide and abciximab) prevent the action of the corresponding platelet
surface receptor glycoprotein complex, which is required for formation of fibrinogen bridges between adjacent platelets
(platelet aggregation).
37. Ans. (d) Pulmonary thromboembolism (Ref: Robbins 8th/126-127, 9/e p127)
The patient has prolonged immobilization of the limb resulting in venous stasis contributing to superficial and deep ve-
Hemodynamics
nous thrombosis. The most feared complication of the venous thrombi is their embolization to the lungs.
Gangrene may occur as a complication of arterial and not venous obstruction.
Hematomas usually appear immediately after a trauma and would have reduced in size after 12 days as has been
mentioned in the stem of the question.
Fat embolism occurs after fractures but symptoms appear 1-3 days after the trauma.
38. Ans. (b) Protein C (Ref: Robbins 7th/129-130, 9/e p124)
Differential diagnosis of recurrent spontaneous abortions in women includes deficiencies of protein C and protein S,
and the presence of the lupus anticoagulant, which is part of the anti-phospholipid syndrome.
39. Ans. (c) Fat emboli (Ref: Robbins 7th/135-137, 9/e p128)
An embolus is a detached intravascular mass that has been carried by the blood to a site other than where it was
formed. Most emboli originate from thrombi (thrombotic emboli), but they can also originate from material other
than thrombi (non- thrombotic emboli). Types of non-thrombotic emboli include fat emboli, air emboli, and amniotic
fluid emboli.
Fat emboli, which result from severe trauma and fractures of long bones, will stain positively with an oil red O stain
or Sudan black stain. They can be fatal as they can damage the endothelial cells and pneumocytes within the lungs.
40. Ans. (d) Pulmonary embolus (Ref: Robbins 8th/126, 9/e p127)
4 0.1. Ans. (c) Heart (Ref: Robbins 8/e p128, 9/e p129-130)
Feature Red infarcts White infarcts

Cause Arterial occlusion in loose tissues or organs Arterial occlusions in solid organs with end arterial
having dual blood supply circulation
Venous occlusion (in ovarian torsion)
Affected organs Lung and small intestine Solid organs (heart, spleen, kidney)
Properties III define hemorrhagic margins which change in Well defined margins and progressively paler with time
color to brown
Edema Usually present Usually absent
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4 0.2. Ans. (d) Coralline thrombus (Ref: Robbins 8/e p124, 9/e p125)
Thrombi often have grossly and microscopically apparent laminations called lines of Zahn; these represent pale platelet
and fibrin deposits alternating with darker red cellrich layers. Such laminations signify that a thrombus has formed in
flowing blood; their presence can therefore distinguish antemortem thrombosis from the bland non laminated clots occur-
ring in postmortem clots.
In veins thrombi form coral-like system with framework of platelets, fibrin and trapped white blood cells; this is a coralline
thrombus
40.3. Ans. (a) Liver..see explanation of earlier question. (Ref: Robbins 8/e p128, 7/e p138)
41. Ans. (c) Decreased prothrombin time (Ref: Robbins 8th/674, 9/e p134, 664-665)
Laboratory investigations in DIC the following:
Platelet count is decreased
Prolonged aPTT/PT/TT
Decreased fibrinogen
Elevated fibrin split products (D-dimers)
42. Ans. (b) Endothelial injury (Ref: Robbins 8th/page 130,131, 9/e p131-132)
The principle mechanisms for septic shock include:
Peripheral vasodilation and pooling of blood
Endothelial activation/injury
Leukocyte-induced damage
Disseminated intravascular coagulation
Activation of cytokine cascades
If the question talks about the initiating mechanism, it should be preferably answered as cytokin release. If this option is
not given then endothelial injury is the next best answer.
1. Thrombosis
2. Increase in vascular permeability
3. Vasodilation
The other three options are following this primary event of endothelial injury due to cytokine release.
Hemodynamics
43. Ans. (d) Release of cytokines (Ref: Robbins 8th/130,131, 9/e p132-133)
44. Ans. (a) Pulmonary Embolism (Ref: Robbins 8th/126, 9/e p127)
D-dimer is a fibrin degradation product, a small protein fragment present in the blood after a blood clot is degraded by fi-
brinolysis. It is so named because it contains two crosslinked D fragments of the fibrinogen protein. D-dimer concentration
may be determined by a blood test to help diagnose thrombosis. D-dimer testing is of clinical use when there is a suspicion
of deep venous thrombosis (DVT) or pulmonary embolism (PE). In patients suspected of disseminated intravascular co-
agulation (DIC), D-dimers may aid in the diagnosis.
45. Ans. (d) Diffuse alveolar damage (Ref: Harrison 17th/1680-1681; Robbins 7th/715, 9/e p134)
Shock lung is also known as acute respiratory distress syndrome, diffuse alveolar damage, acute alveolar injury and acute lung injury.
46. Ans. (a) ATN; (b) Pulmonary congestion; (c) Depletion of lipid in adrenal cortex and (d) Hepatic necrosis (Ref: Robbins
7th/141, 142, 9/e p134)
Shock is characterized by failure of multiple organ systems due to systemic hypoperfusion caused by reduction either in
cardiac output or in effective circulating blood volume.
Liver Fatty changes with hemorrhagic central necrosis.
Kidneys Extensive tubular ischemic injury (Acute tubular necrosis).
Lungs Pulmonary congestion with diffuse alveolar damage.
Adrenal Cortical cell lipid depletion.
Brain Ischemic encephalopathy.
Heart Coagulation necrosis or contraction band necrosis.
GIT Hemorrhagic enteropathy.
47. Ans. (a) Abruptio placentae; (b) Acute pro-myelocytic leukemia; (c) Severe falciparum malaria (d) Snake envenoma-
tion; (e) Heparin overdose. (Ref: Robbins 7th/657, KDT 5th/562, 9/e p664-665)
48. Ans. (b) Reduced plasma fibrinogen level (Ref: Robbins 7th/656-658, 9/e p664-665)
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Hemodynamics
49. Ans. (c) Respiratory distress (Ref: Robbins 8th/127)

Respiratory distress immediately follows amniotic fluid embolism as the emboli consisting of squamous cells, lanugo, and
mucus deposit in the pulmonary microcirculation, producing numerous tiny pulmonary infarcts. The dramatic respiratory
distress may also reflect the action of prostaglandins and other bioactive compounds present in high concentrations in the
amniotic fluid embolus.
Placental abruption (option a) is not a result of an amniotic fluid embolism.
Renal failure (option b) is most likely caused in peri-partum interval by eclampsia, hypovolemic shock, and ascending
infections. Amniotic fluid embolism may produce shock and renal failure as well.
Splinter hemorrhages (option d) are small hemorrhages seen on toes and fingers due to micro emboli arising in the
arterial circulation. Amniotic fluid emboli arise in the veins and deposit in the lungs.
50. Ans. (b) Renal failure (Ref: Robbins 8th/125, 673-4, 9/e p664-665)
In DIC, micro-emboli may obstruct blood vessels and cause tissue hypoxia and necrotic damage to organ structures, such
as the kidneys, heart, lungs, and brain. As a result, common clinical signs may be due to renal, circulatory, or respiratory
failure, acute bleeding ulcers or convulsions and coma. A form of hemolytic anemia may develop as red cells are damaged
as they pass through vessels partially blocked by thrombus.
51. Ans. (b) Fibrin degradation products (Ref: Robbins 8th/673-674 , 9/e p664-665)
DIC or consumptive coagulopathy represents pathological activation of the coagulation system by another underlying
disease, with consequent consumption and depletion of the cellular and humoral components of the coagulation cascade.
The fibrinolytic mechanisms are also activated, and an uncontrolled cycle of bleeding and clotting develops. As a
consequence, levels of all clotting proteins (options A and C) become depleted, platelet counts drop, and the fibrinolytic
proteins are depleted as well (option D).
Fibrin degradation products (option B), which are normally low in the serum, rise markedly in this disease.
52. Ans. (b) Platelet count, fibrinogen levels, and fibrin degradation products (Ref: Robbins 8th/673-674 , 9/e p664-665)
Disseminated intravascular coagulation (DIC) is characterized by consumption of both platelets and clotting factors.
Hemodynamics
The best tests to order are platelet count (which will be markedly decreased), serum fibrinogen level (which will be low), and fibrin
degradation products (which will be high).
Prothrombin time (PT) and Partial thromboplastin time (PTT) are relatively non-specific. Thrombin time (TT) is a more
specific measure of fibrinogen and would potentially be a useful test in this setting. However, specific measurement of
factor VIII, kininogen, or prekallikrein levels would not be rational in evaluating DIC.

(Hemodynamics)
Vitamin K dependent clotting factors are factors 2,7,9,10 as well as anti clotting factors like protein C and protein S.
Thrombin is a procoagulant but thrombin-thrombomodulin complex is an anticoagulant.
SLE is most commonly associated with secondary anti phospholipid antibody syndrome and formation of anti beta
2 glycoprotein antibody.
Leiden mutation is the most common inheritable cause of hypercoagulability.
White infarct occurs with arterial occlusions in solid organs with end-arterial circulation (e.g., heart, spleen, and
kidney).
Red infarcts occur in venous occlusions (e.g., testis), in loose tissues (e.g., lung), in organs with dual circulations (e.g.,
lung and small intestine).
Lines of Zahn are seen in antemortem clots.
Chicken fat appearance is seen in post mortem clots.

ADP is a component of dense body granules; thus, platelet activation and ADP release begets additional rounds of
platelet activation, a phenomenon referred to as recruitment.
Disseminated intravascular coagulation, hypotensive shock, and metabolic disturbances (including insulin resistance
and hyperglycemia) are referred to as the clinical triad of septic shock.
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CHAPTER 4
Genetics is the study of the genes. Genes are a part of chromosome and they code for a trait
Genetics
or character. The position of gene on a chromosome is called as a locus. Out of a total number The amount of the purine is
of 46 chromosome, 22 pairs of chromosomes are homologous and are called autosomes. The equal with the corresponding
23rd pair is alike only in the females (have 2 similar X chromosomes) whereas in a male there pyrimidine which is called
is one X chromosome and one Y chromosome. The X and Y are therefore referred to as sex Chargaffs rule.
chromosomes.
The genetic makeup of an individual is called genotype whereas the manifested physical feature is
called as phenotype.
The part of the DNA which is
The Gene are made up of nucleic acids like ribonucleic acid; RNA or deoxyribonucleic expressed is called exon and
acid; DNA. RNA is present only in the nucleus whereas DNA is present in both the nucleus the intervening region is called
intron.
and mitochondria of a cell. These nucleic acids are made up of nucleotides whose composition
includes nitrogenous base, a sugar (deoxyribose in DNA and ribose in RNA) and a phosphate
group. The nitrogenous base can be either a purine (adenine, guanine) or pyrimidine
(thymine, cytosine, uracil). The purines bind with the pyrimidines complementarily.
Alternate form of gene coding for different forms of a character is called allele. A normal gene has 2
alleles. When these code for same trait, it is known as homozygous state whereas if the alleles code
for different traits, it is called heterozygous state.
If an allele manifests itself in a heterozygous state, it is called as dominant. The alternate
allele which is unable to manifest itself in the heterozygous state is called as a recessive allele.
(So, A is Dominant and a is Recessive)
Mutation is a permanent
change in the DNA. The types
of the mutations are given
alongside.
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Blood group and histocompatibity

antigens (HLA)are examples of
co-dominant antigens.
SINGLE GENE DISORDERS WITH MENDELIAN/CLASSICAL INHERITANCE
a. Autosomal Dominant (AD) Inheritance Diseases

Mutated genes can express themselves in heterozygous state.

Usually cause defect in the synthesis of structural Q or non-enzyme proteins.
In AD inheritance, heterozgotes
with dominant mutant gene

These have variable onset (so, onset may be into adulthood).
express disease.

These are characterized by reduced penetranceQ (individuals inherit the gene
but can be phenotypically normal) and variable expressibility Q (the trait is seen
in the individuals carrying the mutant gene but is expressed differently among
individuals, e.g. patients of neurofibromatosis have variant from brownish skin
spots to multiple skin tumors in different patients).
Homozygous individual for the
dominant mutant gene usually
die prenatally.
Genetics
Examples of autosomal dominant disorders

(Mnemonic: Vo Familial Hypercholesterolemia Autosomal DOMINANT Hai)
Vo Von Willebrand DiseaseQ
Familial Familial Adenomatous PolyposisQ
Hypercholesterolemia Hypercholesterolemia (Familial)
Autosomal Adult polycystic kidneyQ
D Dystrophia myotonicaQ
O Osteogenesis imperfectaQ
M Marfan syndromeQ
I Intermittent porphyriaQ
N Neurofibromatosis-1Q
A AchondroplasiaQ
N Neurofibromatosis 2Q
T Tuberous sclerosisQ
Hai Huntingtons diseaseQ; Hereditary spherocytosisQ
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Genetics
There are the following types of autosomal dominant gene mutations:

Autosomal dominant disease mutations
Gain of Function Loss of Function
Dominant negative mutant
Protein product of the mutant allele has properties not Leads to the reduced production of a gene allele is associated with
normally associated with the natural/wild-type protein product or give rise to an inactive protein the more common loss
Less common More common of function mutation. Its
clinical examples includes
Affects normal proteins with toxic properties Affects regulatory proteins & subunits of Osteogenesis imperfecta, Ehler
multimeric proteins Danlos syndrome and Marfans
e.g. Huntingtons disease e.g. Osteogenesis imperfecta syndrome.
Concept
Dominant negative mutant allele is associated with the more common loss of function mutation.
This type of mutation leads to not only reduced production of a gene product but the inactive Concept
polypeptide interferes with the functioning of a normall allele in a heterozygote. This usually affects
structural proteins. At times, the inactive protein is a part of multiunit protein complex and it interferes In Huntingtons disease, the
with the normal functioning of other units of the same complex. protein formed huntingtin is
Example: Osteogenesis imperfecta different from normal protein
by the fact that it is toxic to the
The collagen molecule is made up of triple helical molecule made up of three collagen chains arranged neurons. So, gain of function
in a helical configuration. Each collagen chains in the helix must be normal for the normal assembly mutation increases the amount
and stability of the collagen molecule. If there is a single mutant collagen chain, normal collagen of the toxic protein and hence,
trimers cannot be formed, and hence there is a marked deficiency of collagen. neurological features in the
affected patients
SOME IMPORTANT AUTOSOMAL DOMINANT DISEASES
Marfan Syndrome
It is an autosomal dominant disease having mutation in the fibrillin geneQ on the chromosome
Genetics
15q21. Fibrillin behaves as a scaffolding protein for the alignment of elastic fibers. So, any
defect affects the following systems:
Skeletal Defects CVS changes Ocular changes

Features of Marfan Syndrome
Tall and thin builtQ Mitral valve prolapse causing Bilateral dislocation M - Mitral Valve Prolapse
Long and slender fingers and mitral regurgitaitonQ or subluxation of A - Aortic Aneurysm
hands (Archnodactyly)Q Medial degeneration causing the lens (know as R - Retinal Detachment
Hyperextensible joints dissecting aortic aneurysm and Ectopia lentisQ) F - Freely movable joints

(especially thumbQ) aortic regurgltationQ. (hyperextensible joints),
Inward depressed stemum Fibrillin protein defect.
(Pigeon breast deformityQ) A - Arachnodactyly
N - Nine feet height (very
Neurofibromatosis tall person)

Disease - Dislocation of lens
Neurofibromatosis (Ectopia lentis)
NF-1 (von Recklinghausen DiseaseQ) NF-2 (Bilateral Acoustic

NeurofibromatosisQ)
More common, seen in 90% patientsQ Less common, seen in 10%
Presence of neural tumors of neurofibromas in the body patients
which can be cutaneous, subcutaneous or plexiform Bilateral acoustic neuromasQ
6 or more pigmented skin lesions called cafe au lait spots Multiple meningiomaQ
Cause of death in Marfan
Pigmented iris hamartoma called Lisch NodulesQ. Cafe au lait spot are present but syndrome is Aortic dissection.
Associated skeletal muscle defects like scoliosis, bone Lisch nodules are absentQ. So, hypertension should be
cysts or tibial pseudoarthrosis treated at the earliest in these
Risk of development of meningioma, pheochromocytomas patients.
and Wilms tumorQ.
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Note:
NF1 gene is present on chromosome 17Q and its product called neurofibromin is a tumor
suppressor gene which normally causes decreased activity of p21 ras oncoprotein.
Juvenile myelomonocytic leu-

NF2 gene is present on chromosome 22Q and it normally produces merlin which is a protein
causing contact inhibition of proliferation of Schwann cells.
kemia is the commonest leuke-
mia seen in children suffering
So, any mutation in NF1 or NF2 causes increased chances of tumor formation.
from neurofibromatosis-1
Ehler Danlos Syndrome (EDS)
It is an inherited tissue disease due to defect in collagen structure or synthesis. The clinical
features include presence of hyperextensible skin (cigarette paper skin Q) which can be easily
injured as it is fragile. There is also presence of hyperextensible joints. There are different
variants of EDS having different modes of inheritance.
EDS type 3 (Hypermobility type) AD inheritance; presence of joint hypermobility; pain and
Mnemonics: Count the number dislocation
of letters in neurofibromatosis. It EDS type 4 (Vascular type) AD inheritance; defect in collagen type III; presence of thin
is 17, so, NF1 is due to mutation skin; easy bruising; arterial and uterine rupture, small joint
in gene on chromosome 17. NF2 hyperextensibility
gene can be remembered as two
letters (N and F) followed by 2 (of EDS type 6 (Kyphoscoliosis type) AR inheritance, mutation in the enzyme lysyl hydroxylase
NF2) i.e. chromosome 22. resulting in formation of unstable collagen; there is presence of
hypotonia, joint laxity, congenital scoliosis and ocular fragility.

b. Autosomal Recessive (AR) Inheritance Diseases

Mutant genes express themselves only in Homozygous state.Q

Usually cause defect in the synthesis of an enzyme protein.Q

These have an early uniform onsetQ (usually in childhood).

There is complete penetranceQ (persons having defective gene in homozygous
state will have disease as well).
Genetics
EDS type 3 is most common

Inborn errors of metabolismare usually inherited as autosomal recessive
type disorders.Q

If one parent is carrier and the other one is normal, autosomal recessive disorders
usually donot manifest but if an affected baby is born to such a couple, Uniparental
disomy (UPD) should be suspected. UPD occurs when a person receives two
EDS type 4 is most dangerous copies of a chromosome, or part of a chromosome, from one parent and no
type copies from the other parent.
Pedigree in Autosomal Recessive Disorders
Autosomal Recessive is the

most common Mendelian mode
of inheritance.
In AR inheritance, both parents

must have mutant gene.
92
Genetics
Examples of Autosomal Recessive Diseases

(Mnemonic: Fried Poori aur Garam CHAWAL MAST Hai) Uniparental disomy UPD should
Fried Friedrichs ataxiaQ be suspected in an individual
manifesting a recessive disorder,
Poori aur PhenylketonuriaQ where only one parent is a
Garam GalactosemiaQ carrier.
C Cystic fibrosisQ
H HemochromatosisQ
A a1 Antitrypsin deficiencyQ
W Wilsons diseaseQ
A AlkaptonuriaQ
L Lysosomal and glycogen storage diseasesQ
M Muscular atrophy (both spinal as well as neurogenic)
A Adrenal hyperplasiaQ (congenital)
S Sickle cell diseaseQ
T ThalassemiaQ
Hai HomocystinuriaQ
Some Important Autosomal Recessive Diseases

Most AR disorders involve enzyme
1. Phenylketonuria (PKU): It is caused by the deficiency of enzyme phenylanine deficiencies.
hydroxylase resulting in inability to convert phenylalanine to tyrosine and resultant
hyperphenylalaninemia. The clinical presentation is a child normal at birth but
developing profound mental retardation by 6 months of age. The absence of tyrosine
results in light-colored skin and hair. There is also presence of a mousy or musty
odor to the sweat and urine due to secondary accumulation of a metabolite called
Genetics
phenylacetate.
The management is done by the dietary restriction of phenylalanine.
2. Alkaptonuria (Ochronosis): It is caused by the deficiency of homogentistic acid oxidase
resulting in the accumulation of homogentistic acid. The latter has an affinity
for connective tissues (especially cartilage), resulting in a black discoloration
(ochronosis). The clinical features include the passage of normal coloured urine
(which turn black on exposure to air), black cartilage, discoloration of the nose and
ears and early onset of degenerative arthritis.
3. Glycogen Storage Diseases: These are a group of rare diseases that have in common
a deficiency in an enzyme necessary for the metabolism of glycogen, which results
in the accumulation of glycogen in the liver, heart, and skeletal muscle. Some salient
types include:
Type Name of disorder Enzyme deficiency
Type I Von Gierkes disease Glucose-6-phosphatase
Type II Pompes disease Acid maltase Tyrosine becomes an essential
Type III Coris disease Debranching enzyme amino acid in Phenylketonuria
Type IV Andersons disease Branching enzyme
Type V McArdles disease Muscle phosphorylase
Type VI Hers disease Hepatic phosphorylase
Type VII Taruis disease Phosphofructokinase 1(PFK-1)
4. Lysosomal Storage Diseases

Disease Enzyme Deficiency Accumulating Substance
Tay-Sachs disease Hexosaminidase A GM2 ganglioside Vitamin C/ascorbic acid provide
Niemann-Pick disease Sphingomyelinase Sphingomyelin partial relief in alkaptonuria
Gaucher disease Glucocerebrosidase Glucocerebroside

Fabry disease a-Galactosidase A Ceramide trihexoside
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Metachromatic leukodystrophy Aryl sulfatase A Sulfatide

Hurler syndrome a-1-Iduronidase Dermatan sulfate
Heparan sulfate
Hunter syndrome L-Iduronosulfate sulfatase Dermatan sulfate
Heparan sulfate
Vo Physics Chemistry Aur
Maths mein Hoshiyaar Tha is Mnemonic
for different types of glycogen
storage diseases in the exact [Tarun Has Nine Shirts; Most Are Saffron, Few Are Green]
order;
Disease Deficiency
For the enzymes see the
first letter and remember the
Tarun Tay Sachs Has Hexosaminidase
alphabets AB (Anderson with
Branching) and CD (Cori with
Nine Neimann Pick Shirts Sphingomyelinase
Debranching) Most Metachromatic leukodystrophy Are Saffron Aryl Sulfatase
Few Fabry Are Green Alpha Galactosidase
a.
Tay-Sachs Disease: It is caused by the deficiency of the enzyme hexosaminidase A
leading to accumulation of GM2 ganglioside in the lysosomes of the CNS and retina.
It is common in Ashkenazi Jews. Cherry red spot is seen in the retina whereas dilated
neurons with cytoplasmic vacuoles are seen in the CNS. The clinical presentation
includes normal child at birth with onset of symptoms by 6 months. It is associated
with progressive mental deterioration and motor incoordination and death by the
Tarun Has Nine Shirts; Most Are age of 2-3 years. Electron microscopy shows the presence of distended lysosomes
Saffron, Few Are Green with whorled membranes.

b. Niemann-Pick Disease: It is caused by the deficiency of the enzyme sphingomyelinase
leading to the accumulation of sphingomyelin within the lysosomes of the CNS
and reticuloendothelial system. It is also commoner in Ashkenazi Jews. There
is presence of a retinal cherry-red spot and CNS having distended neurons with a
foamy cytoplasmic vacuolization. The clinical presentation includes normal child at
Genetics
birth with onset of symptoms by 6 months. It is associated with progressive massive

splenomegaly, lymphadenopathy, mental deterioration and motor manifestations resulting
T Tay Sachs Disease in death by the age of 2 years.
A Autosomal recessive
c. Gaucher Disease: It is the most common lysosomal storage disorder caused by
Y Young Deaths (< 4 years) the deficiency of glucocerebrosidase leading to the accumulation of glucocerebroside
S Spot in the macula (Cherry predominantly in the lysosomes of the reticuloendothelial system. It is characterized
red spot)
A Ashkenazi Jews (more commonly by the presence of hepatosplenomegaly, hypersplenism leading to thrombocytopenia/
affected) pancytopenia, lymphadenopathy and bone marrow involvement leading to bone pain,
C Cytoplasmic vacuoles in deformities, and fractures. A subgroup of patients may also have CNS manifestations.
dilated neurons in CNS
H Hexosaminidase A deficiency

d. Mucopolysaccharidosis (MPS): These are a group of lysosomal storage disorders
characterized by deficiencies of the lysosomal enzymes required for the degradation
S Storage disease (Lysosomal)
of mucopolysaccharides (glycosaminoglycans). The clinical features of the patients
include mental retardation, cloudy cornea, hepatosplenomegaly, skeletal deformities and
coarse facial features, joint abnormalities and cardiac lesions.
(Mnemonic: Remember the hunter has an axe/X.)
Electron microscopy in Niemann-
Picks disease shows the pres- Most of the metabolic disorders have autosomal recessive inheritance except:
ence of distended lysosomes Her Hunter syndrome (X-linked recessive)
containing lamellated figures
Left Lesch Nyhan syndrome (X-linked recessive)
(zebra bodies). Eye Ocular albinism (X-linked recessive)
Has Hypercholesterolemia (familial) (Autosomal Dominant)
Five Fabrys disease (X-linked recessive)

Pimples Porphyria [Acute intermittent] (Autosomal Dominant)
Microscopically cells show the X-LINKED RECESSIVE DISORDER

presence of Gauchers cells
which are enlarged macrophages Males have an X and a Y chromosome. There is no corresponding locus for a mutant allele of
with a fibrillary (crumpled tissue- the X chromosome on the Y chromosome. The mutant recessive gene on the X chromosome
paper-like) cytoplasm. expresses itself in a male child because it is not suppressed by a normal allele whereas in the
94
Genetics
female, the presence of a normal allele on other X-chromosome prevents the expression of the
disease So, females only act as carriers.Q
All MPS are autosomal recessive
disorders except Hunter syndrome
which is an X-linked recessive
disorder.
Examples of X-linked recessive disorders

Less Lesch Nyhan syndromeQ
H Hemophilia A and BQ; Hunter syndromeQ
C Chronic granulomatous diseaseQ
G is G6PD deficiencyQ
Detected Duchhene muscular dystrophyQ, Diabetes insipidusQ In XR inheritance, asymptomatic
female carrier transmits mutant
Clinically in Color blindnessQ gene to 50% of sons.
A AgammaglobulinemiaQ (Brutons disease)
Fragile Fragile X syndromeQ, Fabry DiseaseQ
Genetics
Woman Wiskott Aldrich syndromeQ
X-LINKED DOMINANT DISORDERS
These are the conditions in which both heterozygous males and females are affected. All the
sons of the affected male are normal and all the daughters are affected. The affected female
transmits the disease to half of the sons and daughters.
Examples: Hypophosphatemic type of vitamin D resistant rickets; Incontinentia pigmenti,
Alport Syndrome and oro-facio-digital syndrome.
Examples of X-linked recessive

disorder can be remembered by
the following line
Less hCG is Detected Clinically
in A Fragile Woman
SINGLE GENE DISORDERS WITH NON-MENDELIAN INHERITANCE
Non-Mendelian Inheritance can be classified into the following categories:

Mitochondrial inheritance

Genomic Imprinting

Triple Repeat Mutations

Germline Mosaicism
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MITOCHONDRIAL INHERITANCE
Mutation in the mitochondrial DNA has the characteristic feature of maternal inheritanceQ
because the ovum contains the mitochondria with their abundant cytoplasm whereas sperms
contains minimal number of mitochondria. The fertilized oocyte degrades mtDNA carried
from the sperm in a complex process involving the ubiquitin proteasome system. So, while
mothers transmit their mtDNA to both their sons and daughters, only the daughters are able
to transmit the inherited mtDNA to future generations.
d denotes diseased whereas N denotes normal individuals.
All offspring of an affected female

will be having the disease and all
Genetics
daughters transmits the disease

further to their progeny.
Affected sons do not transmit

the disease to progeny
Salient features of these diseases

The organs most commonly affected in these diseases are the ones having large
number of mitochondria inside them. Such organs include CNS, skeletal muscle,
Mitochondrial inheritance is cardiac muscle, liver and kidneys.
governed by Population genetics
Tissues may have both normal/wild and mutant mitochondrial DNA.
principle and not by Mendelian
genetics.

Sons do not transmit the disease to progeny Q

Examples of mitochondrial inheritance are Lebers optic neuropathy, Leighs disease,
MELAS (mitochondrial encephalopathy, lactic acidosis and stroke like syndrome)
NARP syndrome (Neuropathy, ataxia, and retinitis pigmentosa.), Kearns-Sayre
syndrome, Chronic progressive external ophthalmoplegia and Pearson syndrome.
GENOMIC IMPRINTING
A person gets two alleles for a character; one from mother and second from father. Normally
these two alleles are similar. But, in some cases these alleles are differentially expressed. i.e.
either maternal gene become silent (only paternal gene express) or paternal gene become
silent (only maternal express). In such a condition, if the chromosome containing the gene
which is expressed undergoes deletion, there will be disease, whereas if homologous
undergoes deletion, nothing will happen.
Imprinting selectively inactivates either the maternal or paternal allele. Thus maternal imprinting refers
to transcriptional silencing of the maternal allele whereas paternal imprinting implies that the paternal
allele is inactivated.
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Genetics
Example of genomic imprinting disorder is microdeletion of chromosome 15q11-13. If

microdeletion occurs in maternal chromosome; Angelman syndrome results whereas
paternal chromosomal microdeletion may cause Prader-Willi syndrome. The presence of mixutre of more
than one type of an organellar
It is also seen in Beckwith Wiedmann syndrome and Albrights hereditary osteodystrophy. genome within a tissue is called
as heteroplasmy.
Genomic imprinting is defined

Molecular studies of cytogenetically normal patients with Prader Willi syndrome reveal that they
as differential expression of a
have two maternal copies of chromosome 15. gene based on chromosomal
Inheritance of both chromosomes of a pair from one parent is called uniparental disomy. So, inheritance from maternal or
Prader Willi Syndrome may be due to UPD of maternal chromosome 15. paternal origin
Similarly Angelman syndrome patients might have uniparental disomy of paternal chromosome
15.
TRIPLE REPEAT MUTATIONS

The mutation in this disease group is characterized by a long repeating sequence of three
Chromosome 15 has its own
nucleotides. It is characteristically different from other types of mutations because it is
MAP, so diseases associated
dynamic in nature. Dynamicity means that the degree of amplification of a sequence of three with this chromosome are Marfan
nucleotides increases during gametogenesis. syndrome, Angelman syndrome
Trinucleotide repeat disorders and Prader-Willi syndrome.
Expansions in non-coding regions Expansions in coding regions
Loss of function type mutation Gain of function type mutation
Genetics
Mutant proteins aggregate as intranuclear inclusions Mutant proteins interfere with other proteins
Examples: Examples: P for paternal and Prader Willi
Fragile X syndromeQ
Huntingtons diseaseQ whereas m for maternal and m is
Friedrichs ataxiaQ
Spinobulbar muscular atrophyQ (Kennedys present in Angelman
Myotonic dystrophyQ disease)

Spinocerebellar ataxia types 1, 2, 3, 6, 7Q
The trinucleotide repeat expansions in the non-coding regions involve different repeats as
Fragile X syndrome (CGGQ), Friedrichs ataxia (GAAQ) and Myotonic dystrophy (CTGQ).
Mom wears SARI it stands for

Seizures, Ataxia, Retardation and
Inappropriate laughter
Fragile X Syndrome
There is presence of triplet repeat mutations of CGG nucleotides. The mutation affects
the FMR-1 gene (Familial Mental Retardation 1 gene) present on the X chromosome. On
karyotyping, the chromosome appears as broken (so, called fragile site). It is the second most The trinucleotide repeat expan-
common cause of mental retardation (Down syndrome is the commonest cause). The clinical sions in the coding regions
features of patient include long face with a large mandible, large everted ears and large testicles have all the presence of CAG
repeat sequences.
(macro-orchidism).Q
In the normal people, the number of CGG repeats is from 10 to 55. There is amplification
of CGG repeat in carrier females to 55-200 CGG repeats which is called premutation. In diseased
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individuals, the CGG repeats range from 200-4000 repeats called full mutations. During the
process of oogenesis (Not spermatogenesis), amplification causes conversion of premutations
to full mutations. This is responsible for Shermans Paradox Q (the risk of mental retardation
is much higher in grandsons than the brothers of transmitting males as the grandsons acquire
a premutation from their grandfather which gets amplified to a mutation in their mother
ova).

Southern blot is useful for genetic counseling (it can differentiate between
premutation and mutation prenatally and postnatally).
Huntingtons Chorea
There is presence of CAG repeats associated with chromosome 4 that are responsible for
the production of an abnormal neurotoxic protein called HuntingtonQ. It is associated with
caudate nucleus atrophy. Clinical features include early onset of progressive dementia and
presence of choreiform movements (due to inhibition of GABAergic neurons).
In Anticipation, additional trinu-
cleotide repeats cause worsen- CONCEPT OF PLEIOTROPY
ing of clinical features with each
It describes the genetic effect of a single gene on multiple phenotypic traits. The underlying
successive generation.
mechanism is that the gene codes for a product that is used by various cells, or has a signaling function
on various targets. A classic example of pleiotropy is the human disease phenylketonuria.
Antagonistic pleiotropy refers to the expression of a gene resulting in multiple competing effects,
some beneficial but others detrimental to the organism. An example is the p53 gene, which suppresses
cancer, but also suppresses stem cells, which replenish worn-out tissue.
PCR is the method of choice for

GONADAL/GERMLINE MOSAICISM
diagnosis of fragile X syndrome Normally autosomal dominant disorders have affected parents but in some patients with
autosomal dominant disorders, the parents are not affected. In such patients, the disorder
Genetics
results from a new mutation in the egg or the sperm from which they were derived; as such,
their siblings are neither affected nor at increased risk of developing the disease.
However, in certain autosomal dominant disorders, exemplified by osteogenesis imperfectaQ and
tuberous sclerosisQ, phenotypically normal parents have more than one affected child. This may
appear to clearly violate the laws of Mendelian inheritance but is explained by gonadal mosaicism.
A Hunter puts an animal in a CAG
that has FOUR sides, four for Gonadal mosaicism results from a mutation that occurs postzygotically during early
association with chromosome 4. (embryonic) development. If the mutation affects only cells destined to form the gonads, the
gametes carry the mutation, but the somatic cells of the individual are completely normal.
Such an individual is said to exhibit germ line or gonadal mosaicism. A phenotypically
normal parent who has germ line mosaicism can transmit the disease-causing mutation to
the offspring through the mutant gamete. Since the progenitor cells of the gametes carry the
mutation, there is a definite possibility that more than one child of such a parent would be
affected. Gonadal mosaicism should not be confused with mosaicism (explained below).
MOSAICISM
Gonadal/Germline Mosaicism
is seen in osteogenesis imper-
fecta and tuberous sclerosis.
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Genetics
CHROMOSOMAL DISORDERS
A karyotype is a standard
Study of chromosomes is called karyotyping. It is done in cells like skin fibroblasts, peripheral
arrangement of a photographed
blood lymphocytes and amniotic cells. The normal number of chromosomes in a somatic cell or image stained chromosome
is diploid and is expressed as 46, XX or 46, XY. pairs in metaphase stage in

Mitosis is arrested in dividing cells in metaphase stage by use of colchicine. In this order of decreasing length.
stage, individual chromosomes take the form of two chromatids connected at the
centromere. The Short arm of chromosome is called p (petite) and long arm is
reffered to as q.
Banding technique and selected features
Q banding G banding R (Reverse) banding C banding
Dye used Quinacrine mustard Trypsin followed by Alkaline solution followed by Giemsa Chemical followed by
Giemsa Giemsa
Microscope used Fluorescence microscopy Light microscopy Light microscopy Light microscopy
Special features *Temporary *Permanent *Used for analyzing rearrangements *Used for studying
So, not usedQ for routine *MC techniqueQ for involving the terminal endsQ of chromosomal translocations
cytogenetic analysis routine cytogenetic chromosomes involving centromeric
analysis *Gives pattern opposite to G banding regionsQ
Appearance of
chromosomes
Note: Q, G and R banding produce bands along entire length of chromosomes whereas for specific chromosomal structures, other types of
Genetics
banding may be used. Some of these include T- banding (for Telomeres), C banding (for Constitutive heterochromatin) and NOR-banding
(for nucleolus-organizing regions).
Sometimes, fluorodeoxyuridine (FUdR)Q banding is also done. It is a direct inhibitor of thymidylate synthetase and it can induce folate-sensitive
fragile sites in chromosomes. Chromosomal fragile sites can induce mental retardation as is seen in fragile X syndromeQ.
TYPES OF CHROMOSOMES
Metacentric Centromere is in the center of the chromosome (the

chromosome has two equal arms).
Submetacentric Centromere is away from the center so that the arms are
unequal in size (one arm shorter than the other). X chromosome
is large submetacentricQ chromosome.
Centromere is almost at the tip (one end) of the chromosome
Acrocentric
(one arm is much longer than the other). Y chromosome is
small acrocentricQ chromosome
Telocentric Centromere is at the extreme end of the replicating chromosome
(chromosome has only one arm). Not seen in humansQ.
CYTOGENETIC ABNORMALITIES
Deletion
(Loss of genetic material)
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Balanced translocation
Robertsonian translocation Translocation between the 2 acrocenteric

chromosomes with breakpoint occurring close to the centromeres. So,
very large and very small chromosomes are obtained.
Inversion
Insertion, Deletion and Robert-

sonian translocation are asso- The gametes contain half the number of chromosomes (haploid) and are represented
ciated with change in genetic as (23, X) or (23, Y).
material An exact multiple of haploid chromosomes is called Euploidy (2n, 3n, 4n etc).
When exact multiple of haploid chromosomes is not present, it is called Aneuploidy.
Genome mutations involve loss or gain of whole chromosomes, giving rise to monosomy
or trisomy.
Unlike the above mentioned,

Genetics
inversion is NOT associated

with change in genetic materials
DOWN SYNDROME (TRISOMY 21)Q

It is the most common of the chromosomal disordersQ and a major cause of mental
retardation.Q
Note: Mitotic non-disjunction is responsible for development of mosaicism.
Genetics of Down syndrome.

Meiotic nondisjunction of chromosome 21 occuring in the ovum
Seen in 95% cases with trisomy 21. So, it is the commonest cause of Down syndrome
The extra chromosome is of maternal origin.
Both monosomy and trisomy Strong relation with maternal age
are types of genome mutations Robertsonian translocation
having aneuploidy.
Seen in about 4% of cases of Down syndrome.
The extra chromosomal material derives from the presence of a robertsonian translocation of the
long arm of chromosome 21 to another acrocentric chromosome (e.g., 22 or 14).
Most cases are frequently (but not always) familial.
No relation with maternal age
100
Genetics
Mosaicism
Seen in ~1% of Down syndrome patients
Most common cause of Down
syndrome is maternal meiotic
Results from mitotic nondisjunction of chromosome 21 during an early stage of
non-disjunction.
embryogenesis.
Patients have a mixture of cells with 46 and 47 chromosomes (mosaicism).
No relation with maternal age.

Important signs of the disease include:

Flat facial profile Advance maternal age has a
strong influence on the incidence

Mental retardation of trisomy 21 whereas it is not

Microgenia (abnormally small chin) related to advanced paternal

Oblique palpebral fissures with epicanthic skin folds (mongoloid slant) age.

Muscle hypotonia (poor muscle tone)

Flat nasal bridge

Single palmar fold (Simian crease)

Curvature of little finger towards other four fingers (Clinodactyly)

Protruding tongue or macroglossia Down syndrome associated with

White spots on the iris known as Brushfield spots Robertsonian translocation and

Excessive joint laxity including atlanto-axial instability
Mosaicism has no relation with
maternal age.

Excessive space between large toe and second toe (Sandle toe)

A single flexion furrow of the fifth finger

Higher number of ulnar loop dermatoglyphs
Complications of Down syndrome are:

Congenital cardiac defects (Most common is VSD)

Increased risk of leukemia particularly ALL (more commonly) and specifically the
megakaryoblastic form of AML (M7-AML)

Hypothyroidism
Genetics

Reduced fertility in females (Males are totally infertile)

Increased risk of respiratory tract infections
Screening for Down Syndrome

Many standard prenatal screens can discover Down syndrome. Amniocentesis and CVS are
considered invasive procedures, in that they involve inserting instruments into the uterus,
and therefore carry a small risk of causing fetal injury or miscarriage. The risks of miscarriage
for CVS and amniocentesis are often quoted as 1% and 0.5% respectively. There are several
common non-invasive screens that can indicate a fetus with Down syndrome. These are
normally performed in the late first trimester or early second trimester. Due to the nature
of screens, each has a significant chance of a false positive, suggesting a fetus with Down
syndrome when, in fact, the fetus does not have this genetic abnormality. Screen positives
must be verified before a Down syndrome diagnosis is made. Common screening procedures
Down syndrome patients are
for Down syndrome are given in the Table below.
having predisposition for
First and second trimester Down syndrome screens Hirschprungs disease, duo-
Screen When Detection False positive Description denal atresia, annular pan-
creas and Alzheimers disease
performed rate rate
(weeks
gestation)
Triple test 15-20 70% 5% Maternal serum -feto protein (Low) +
Estriol (Low) + hCG (High)
Triple test + inhibin-Alpha (High)
Quad screen 1520 81% 5%
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First Trimester 1013 85% 5% Ultrasound to measure:

Features of Down Syndrome Combined Test *Nuchal Translucency (Increased)

My Mental Retardation/ *Ductus venosus flow (reversed)
*Nasal bone (hypoplasia)
Micrognathia
+ hCG + Pregnancy associated
C Congenital heart disease/ plasma protein A; PAPPA (Low)
Cataracts
H Hypotonia/Hypothyroidism
Integrated Test 10-13 and 95% 5% Measurements from both the 1st
I Increased gap between 1st
1520 Trimester Combined test and the 2nd
and 2nd toe (Sandle toe) trimester Quad test to yield a more
L Leukemia risk/Lung problem accurate screening result.
(Increased risk of Respiratory
Tract Infections)
D Duodenal atresia
H Hirshsprungs disease/Hearing
loss
A Alzheimers disease/Atlanto-
axial instability
S Simian Crease
P Protruding tongue
R Round face/Rolling eye
(nystagmus)
O Occiput flat/Oblique palpabrel
fissure
B Brushfield spot/Brachycephaly Common features of both are mental retardation, rocker bottom feet and congenital heart
L Low nasal bridge/Language defects (VSD and PDA).
problem
E Epicanthic fold/Ear folded Note: Ectodermal scalp defects, cleft lip and cleft palate points towards diagnosis of trisomy 13 where-
M Mongolian slant/Myoclonus as elongated skull and simple arches on all digits suggest trisomy 18.
(Mnemonic: p for Patau and polydactyly as well as palate defects and e for Edward and extra occ-
ciput).
Genetics
TRISOMY 22
All three components of triple
test i.e. MSAFP, Estriol and hCG Cat Eye Syndrome is a rare condition caused by the partial trisomy of chromosome 22 (The
are low in Edward syndrome. short arm (p) and a small section of the long arm (q) of Chromosome 22 is present three
instead of the usual two times. The term Cat Eye syndrome was coined due to the particular
appearance of the vertical colobomas in the eyes of some patients.
Klinefelter Syndrome
MSAFP is increased in neural
tube defects whereas reduced It is the most common chromosomal disorder of males associated with hypogonadism and
in Down and Edward syndromes. infertility.
It is due to extra-X-chromosome. Classically, it is 47, XXY. Other variants can have 48
XXXY, rarely 49 XXXY or mosaics can be there with some cells containing normal 46,
XY and others 47, XXY.
Classically, it results from meiotic non- disjunction of sex chromosomes [40% during
spermatogenesis and 60% during oogenesis]. Mostly, non-disjunction occur during
Vertical colobomas are seen 1st meiotic division.
in the eyes of patient having cat
eye syndrome.
Extra X- chromosomes increase the female like features, i.e. feminization [as shown
by atrophic testes, lack of secondary sexual characteristics, gynecomastia]. Further,
Extra inactive X-chromosome appear as Barr body
Presence of single Y- chromosome is enough for male phenotype. Thus XY, XXY,
XXXY all are males.
Clinical Features of Klinefelter Syndrome

In Klinefelters syndrome, there
is testosterone and inhibin but Male sex
LH and FSH, respectively Hypogonadism
102
Genetics
Loss of secondary sexual characteristics

Subnormal IQ
Disproportionately long arms and legs
Gynecomastia
There is increased risk of breast carcinoma, germ cell tumors (like embryonal cell
carcinoma, teratoma and mediastinal germ cell tumors) and autoimmune diseases
like SLE.
Patients can develop cardiovascular problems. Most commonly associated is mitral
valve prolapse followed by varicose veins.
Due to less testosterone (hypogonadism), feedback inhibition is less and pituitary
produces more LH and FSH.
Turner Syndrome
Most common cause of sex chromosomal abnormality in the females.Q

Usually results from complete or partial monosomy of X chromosome and associated
with hypogonadism in phenotypic females.Q Patients have the (45X) karyotype or
may be mosaics.
Clinical features in infancy include edema of dorsum of hands and feet,Q neck webbing or Autoimmune thyroiditis is
edema of nape of neck (also produces cystic hygromaQ) and congenital cardiac defect not associated with Marfan
(particularly preductal coarctation of the aortaQ and bicuspid aortic valveQ). syndrome. It is seen with Down
Clinical features in adolescence and adulthood include short stature, low posterior hairline,
syndrome, Turner syndrome and
Congenital rubella syndrome
webbing of neck, cubitus valgus (increased carrying angle),Q streak ovariesQ (contributing
to infertility and amenorrhea), coarctation of the aorta, broad chest and widely spaced
nipples, short 4th metacarpal.
Noonan Syndrome
Genetics
It is a relatively common autosomal dominant congenital disorder considered to be a type of Turners syndrome is the most
dwarfism, that affects both males and females equally. It used to be referred to as the male important cause of primary
version of Turners syndrome; however, the genetic causes of Noonan syndrome and Turner amenorrhea.
syndrome are distinct. Genetics of Turner syndrome shows monosomy of X chromosome Pregnancy is overall the
commonest as well as the most
(XO) whereas in Noonan syndrome, mostly mutation in genes on chromosome 12 is noted.
important cause of secondary
The principal features include congenital heart defect, short stature, learning problems, amenorrhea
pectus excavatum, impaired blood clotting, and a characteristic configuration of facial
features which is quite similar to Turner syndrome.
Other Important Points

Autosomal monosomies (loss of one chromosome) are incompatible with fetal development and
are not found in live births. Only monosomy compatible with live birth is XO (Turner syndrome).
Most of the trisomies occur due to meiotic non- disjunction whereas Trisomy 7, mostly occur
due to mitotic non- disjunction.
Most of the meiotic non- disjunctions occur during 1st meiotic division. In Trisomy 18, it is
more commonly seen in 2nd meiotic division.
LYONS HYPOTHESIS
Only one of the X chromosome is genetically active.

Other X of the paternal or maternal origin undergoes pyknosis and is rendered
inactive.
Inactivation of either maternal or paternal X occurs at random among all the cells of
the blastocyst by about 16th day of embryonic life.Q
Inactivation of the same X chromosome persists in all the cells derived from each
precursor cell. Inactivation of X is because of a gene called Xist which is causing gene
silencing DNA methylation. So, all normal females are actually mosaics.
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Note: Number of drumsticks are equal to the number of Y-chromosomes. Thus, these are one in
a normal male (XY), zero in normal female (XX) and Turners syndrome (XO).
PEDIGREE ANALYSIS
The inactive X can be seen in
the interphase nucleus as a
small mass near the nuclear Symbols Used
membrane called as the Barr
Body or X chromatin. Male is represented as a square and female is represented as a circle. Affected individuals are
represented by filling the circle or square by shading.
Normal male Normal female Affected male Affected female
Number of Barr bodies = Number

of X chromosomes - 1.
So, they are absent in normal
males and Turner syndrome
whereas a normal female has 1
barr body
Two parents are joined by horizontal line and progeny is indicated by a vertical line.
Analysis
Step 1: First of all see whether there is mitochondrial inheritance or not. If female is transmitting
the disease to all offsprings (both males and females) and male is not transmitting the disease
to any child, it is mitochondrial inheritance.
Step 2: If mitochondrial inheritance is not present, now see whether the disease is inherited
Genetics
as dominant or recessive trait. In dominant inheritance, at least one member in all generations
will have disease whereas in recessive inheritance, there will be some generations without
disease also. Means, if offsprings of both unaffected parents carry the disease/character,
it is recessive whereas if both affected parents produce normal offspring, it is dominantly
inherited.
Step 3: Now see, whether it is sex-linked or autosomal by looking at the sex-predilection as

If male is transmitting the disease only to daughters (all daughters) and not to the
sons whereas female transmit the disease to half daughters and half of sons, it is
X-linked dominant.

If only males are affected in a pedigree, it is likely to be X-linked recessive disease
(females act as carriers; only transmit the disease and themselves remain unaffected).

If there is no sex-predilection and affected individuals transmit the disease to half of
the offsprings, it is autosomal dominant disorder.

If there is no sex-predilection and affected individuals transmit the disease to one
fourth of the offsprings, it is likely to be autosomal recessive disorder.
LOCATION OF IMPORTANT GENES ON CHROMOSOMES
Gene Chromosome Gene Chromosome

p73 1p RET 10
Folate transporter 21q WT-1 11p
Neuroblastoma 1p vWF 12
Rhodopsin 3 Retinoblastoma 13q
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Genetics
VHL 3p BRCA-1 17q

ADPKD-2 4q Fibrillin-1 15
ADC 5p Fibrillin-2 5
MHC 6p BRCA-2 13q
ARPKD 6 NF-1 17q
Cystic fibrosis 7q p53 17p
MET 7 NF-2 22q
Genetics
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MULTIPLE CHOICE QUESTIONS

SINGLE GENE DISORDERS WITH CLASSICAL INHERITANCE 7. Duchenne dystrophy is a: (Delhi PG-2006)
(a) Autosomal dominant disorder
1. Which of the following is an autosomal recessive (b) X-linked dominant disease
condition? (AI 2012) (c) Autosomal recessive disease
(a) Ataxia telangectasia (d) X-linked recessive disease
(b) Peutz Jeghers syndrome 8. Catastrophic variant of Ehler Danlos syndrome is
(c) Neurofibromatosis (a) I (b) II
(d) Tuberous sclerosis (c) III (d) IV
2. Which of the following is an autosomal dominant 9. Sickle cell disease is due to (UP 2005)
metabolic disorder? (AI 2004) (a) Point mutation
(a) Cystic fibrosis (b) Frame shift mutation
(b) Phenylketonuria (c) Nucleotide receptor blockage
(c) a-1 antitrypsin deficiency (d) Non sequence mutation
(d) Familial hypercholesterolemia
3. The approximate number of genes contained in the 10. All are autosomal dominant disorders except
(a) Albinism (UP 2007)
human genome is: (AIIMS Nov 2002) (b) Marfans syndrome
(a) 40,000 (c) Familial adenomatous polyposis
(b) 30,000 (d) Von-Hippel Lindau syndrome
(c) 80,000
(d) 1,00,000 11. In Marfans syndrome there is defect in protein
(a) Collagen (RJ 2000)
Genetics
4. True statements about -l anti-trypsin deficiency is (b) Elastin

(a) Autosomal dominant disease (PGI June 2003) (c) Fibrillin
(b) Emphysema (d) All
(c) Fibrosis of portal tract
(d) Diastase resistant positive hepatocytes 12. Neurofibromatosis is (RJ 2001)
(e) Orcein positive granules (a) Autosomal dominant
(b) AR
5a. Autosomal recessive diseases are (PGI June 2003) (c) X-linked recessive
(a) Hereditary spherocytosis (d) All
(b) Thalassemia
(c) Sickle cell anemia 13. Blue black pigmentation in alkaptonuria is due to
(d) Cystic fibrosis (a) Homogentisic acid (RJ 2002)
(e) Hemophilia A (b) Oxalic acid
(c) Glucouronic acid
5b. Autosomal dominant disorders are all except (d) All
(a) Hereditary spherocytosis (PGI Dec 2003)
(b) Thalassemia 14. A 26-year-old woman presents because of trouble
(c) Sickle cell anemia with her vision. Physical examination reveals a very
(d) Cystic fibrosis tall, thin woman with long, thin fingers. Examining
(e) Hemophilia her eyes reveals the lens of her left eye to be in the
anterior chamber. Her blood levels of methionine and
6. Which of the following disorders has been shown to be cystathionine are within normal levels. Which of the
genetically transmitted by single autosomal dominant following is the most likely cause of this patients signs
genes? (Delhi PG 2010) and symptoms?
(a) Catatonic schizophrenia
(a) Abnormal copper metabolism
(b) Phenylketonuria
(b) Decreased levels of vitamin D
(c) Creutzfeldt-Jakobs disease
(c) Decreased lysyl hydroxylation of collagen
(d) Huntingtons disease
(d) Defective synthesis of fibrillin

(e) Defective synthesis of type I collagen
106
Genetics
Most Recent Questions SINGLE GENE DISORDERS WITH NON CLASSICAL

INHERITANCE
14.1. Duchenne muscular dystrophy is inherited as:
(a) X linked 15. In Prader Willi syndrome, which of the following is
(b) Autosomal dominant increased? (AI 2012)
(c) Autosomal recessive (a) LH
(d) Codominant
(b) FSH
1 4.2. Inheritance of Gardner syndrome is: (c) TSH
(a) Autosomal recessive (d) Ghrelin
(b) Autosomal dominant
(c) X linkeddominant
16. NARP syndrome is seen in: (AI 2011)
(d) X linked recessive (a) Mitochondrial diseases
(b) Glycogen storage diseases
1 4.3. Which one of the following is an autosomal dominant
(c) Lysosomal storage diseases
disorder:
(a) Duchenns muscular dystrophy (d) Lipid storage diseases
(b) Fragile X syndrome 17. Maternal disomy of chromosome 15 is seen in:
(c) Fanconis anemia (a) Prader-Willi syndrome (AIIMS Nov 2010)
(d) Huntingtons chorea (b) Klinefelters syndrome
1 4.4. Adult polycystic kidney disease is inherited by: (c) Angelman syndrome
(a) Autosomal dominant (d) Turners syndrome
(b) Autosomal recessive
(c) X-linked
18. Two siblings with osteogenesis imperfecta have normal
(d) Mitochondrial parents. The mode of inheritance is explained by which
of the following?
1 4.5. Neurofibroma is having which of the following
(a) Anticipation (AIIMS May 2010)
inheritance?
(a) Autosomal dominant

(b) Genomic imprinting
(c) Germline mosaicism
(c) X-linked recessive
(d) New mutation
Genetics
(d) X-linked dominat 19. Mitochondrial DNA (mt-DNA) is known for all except:
1 4.6. Which of the following is the inheritance of (a) Maternal inheritance (DPG 2011)
Huntingtons chorea? (b) Heteroplasmy
(a) Autosomal dominant (c) Leber hereditary optic neuropathy is the prototype
(b) Autosomal recessive (d) Nemaline myopathy results due to mutations in mt-
(c) X-linked DNA
(d) Mitochondrial
1 4.7. Hemophilia is associated with:
20. Preferential expression of the gene depending upon the
parent of origin is called: (AI 2009)
(a) X chromosome (b) Y Chromosome
(a) Genomic imprinting
(c) Chromosome 3 (d) Chromosome 16
(b) Mosaicism
1 4.8. Which of the following is not X linked condition: (c) Alleles
(a) Duchenne muscular dystrophy
(d) Chimerism
(b) Emery-Dreifuss muscular dystrophy
(c) Facioscapulohumeral muscular dystrophy 21. Preferential expression of the gene depending upon the
(d) Becker muscular dystrophy parent of origin is called:
1 4.9. Which one is not a feature of cystic fibrosis? (a) Anticipation (AI 2008)
(a) Autososmal recessive disease (b) Germ line mosaicism
(b) Abonormal chloride transport (c) Genomic imprinting
(c) Affects intestine only (d) Aneuploidy
(d) Increased risk of pulmonary infections
22. Differential expression of same gene depending on
1 4.10.
Which of the following is an X-linked dominant parent of origin is referred to as: (AI 2005)
disorder? (a) Genomic imprinting
(a) Vitamin D resistant rickets
(b) Mosaicism
(b) Familial hypercholesterolemia
(c) Anticipation
(c) Red green color blindness
(d) Achondroplasia (d) Non-penetrance
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23. A couple has two children affected with tuberous 31. All of the following are characterized by trinucleotide
sclerosis. On detailed clinical and laboratory evaluation repeats affecting the non-coding regions except
(including molecular studies) both parents are normal. (a) Friedrichs ataxia
Which one of the following explains the two affected (b) Fragile X syndrome
children in this family? (c) Huntingtons disease

(a) Non penetrance (AIIMS May 2006) (d) Myotonic dystrophy

(b) Uniparental disomy 32. An 18 month old child Nonu is brought to a pediatrician.

(c) Genomic imprinting His mother noticed passage of altered color urine by him

(d) Germline mosaicism for past 2-3 days. Laboratory examination revealed it to
24. Genomic imprinting is associated with: be hematuria. Examination also reveals hypertension
(a) Silencing of paternal chromosome (PGI Dec 01) and an abdominal mass. A tumor is localized to the
(b) Silencing of maternal chromosome right kidney and biopsy reveals a stroma containing
(c) Angelman syndrome smooth and striated muscle, bone, cartilage, and fat,
(d) Prader Willi syndrome with areas of necrosis. The gene for this disorder has
(e) Gonadal mosaicism been localized to which of the following chromosomes?
25. Dominant negative inheritance is seen in:
(a) 5
(a) Ehler Danlos syndrome (PGI Dec 2002)

(b) 11
(b) Marfans syndrome

(c) 13
(c) Hunter syndrome

(d) 17
(d) Osteogenesis imperfecta 33. Majority of the human characteristics are determined
(e) Hereditary retinoblastoma by multiple pairs of genes, many with alternate codes,
accounting for some dissimilar forms that occur with
26. True statements regarding the mitochondrial genes certain genetic disorders. What type of inheritance
are: (PGI Dec 2002)
involves multiple genes at different loci, with each
(a) Paternal transmission
gene exerting a small additive effect in determining a
(b) Maternal transmission
trait?
(c) Mendelian inheritance
(d) Mitochondrial myopathy

(a) Polygenic inheritance

(b) Multifactorial inheritance
Genetics
(e) Horizontal inheritance

(c) Monofactorial inheritance
27. Mitochondrial DNA is (PGI June 2003)
(d) Collaborative inheritance
(a) Paternally inherited
(b) Maternally inherited
34. A 45-year-old male Arvind who was previously
diagnosed with depression is now experiencing
(c) Horizontal inheritance
(d) Vertical inheritance involuntary grimacing and strange movements of his
(e) Mendelian inheritance arms and legs. Neurological examination shows normal
strength and normal deep tendon reflexes. No sensory
28. Which of the following is/are an example/examples of deficits are noted. The patients grandfather died of a
non-Mendelian inheritance? neurological disease at 65 years old, and the patients
(a) Genomic imprinting (Delhi PG 2009) father died of a similar disease at 58. This patient has
(b) Uniparental disomy an earlier onset of disease than either his father or
(c) Mitochondrial inheritance grandfather is most likely explained by which of the
(d) All of the above following?
29. Increasing severity of mental retardation in male
(a) Increased penetrance
members over generations is a result of:
(b) Pleiotropy
(a) Mitochondrial DNA mutation
(c) Anticipation
(b) Frameshift mutation (Delhi PG 2009 RP)
(d) Mosaicism
(c) Y linked disorder 35. A young boy, Rinku is being evaluated for
(d) Trinucleotide repeat mutation developmental delay, mild autism, and mental
30. All of the following are chromosomal breakage retardation. Physical examination reveals the boy to
syndromes except (Karnataka 2004) have large, reverted ears and a long face with a large
(a) Fanconis anemia mandible. He is also found to have macroorchidism
(b) Ehler-Danlos syndrome (large testes), and extensive workup reveals multiple
(c) Blooms syndrome tandem repeats of the nucleotide sequence CGG in
(d) Ataxia telangiectasia his DNA Which of the following is the most likely
diagnosis?
108
Genetics
Fragile X syndrome
(a)
(b) Comparative genomic hybridization
Huntingtons chorea
(b)
(c) Western blotting
Myotonic dystrophy
(c)
(d) Karyotyping
(d) Spinal-bulbar muscular atrophy 40. Downs syndrome is associated with the clinical
Ataxia-telangiectasia
(e) manifestation of mental retardation. Which of the
36. A young man Ramkishore presents for an employment following is not associated with Downs syndrome?

(a) Trisomy 21 (AIIMS Nov 2011)
physical. He is very tall,has long fingers, and
hyperflexible joints. He states that he has always
(b) Mosaic 21
been called double jointed. Which of the following
(c) Translocation t (14,21), t (21,21)
disorders is associated with this syndrome?
(d) Deletion of 21

(a) Dissecting aortic aneurysm 41. The genetics involved in Down syndrome is:

(b) Hepatosplenomegaly (a) Maternal non-disjunction (AI 2010)

(c) Polycystic kidneys (b) Paternal non-disjunction

(d) Progressive neurologic dysfunction (c) Mosacism
(d) Monosomy
Most Recent Questions 42. Karyotyping is done for: (AI 2009)
(a) Chromosomal disorders
36.1. Genomic imprinting is seen in (b) Autosomal recessive disorders
(a) Klinefelters syndrome (c) Autosomal dominant disorders
(b) Downs syndrome (d) Linkage disorders
(c) Angelman syndrome
(d) Hydatidi form mole 43. Males who are sexually underdeveloped with
rudimentary testes and prostate glands, sparse pubic
3 6.2. Mitochondrial chromosomal abnormality leads to: and facial hair, long arms and legs and large hands and
(a) Lebers hereditary optic neuropathy feet are likely to have the chromosome complement of:
(b) Angelman syndrome (a) 45, XYY (AI 2004)
(c) Prader villi syndrome (b) 46, XY
(d) Myotonic dystrophy (c) 46, XXY
(d) 46, X
3 6.3. One of the following disorders is due to maternal
44. Which of the following procedures as routine technique
Genetics
disomy
(a) Prader Willi syndrome for karyotyping using light microscopy?
(b) Angelman syndrome (a) C-banding (AI 2003)
(c) Hydatidiform mole (b) G-banding
(d) Klinefelters syndrome (c) Q-banding
(d) Brd V-staining
3 6.4. In Huntington chorea the causative mutation in the
protein huntingtin is a 45. A married middle aged female gives history of repeated
(a) Point mutation abortions for the past 5 years. The prenatal karyogram
(b) Gene deletion of the conceptus is given below
(c) Frameshift mutation
(d) Trinucleotide repeat expansion
CHROMOSOMAL DISORDERS AND KARYOTYPING
37. No change of genetic material occurs in which of the

following cytogenetic abnormalities? (AIIMS Nov 2012)
(a) Deletion (b) Insertion
(c) Translocation (d) Inversion
38. Patient present with skin bullae on sun exposure. There
is a defect in which of the following?
(a) Thymidine dimers (AIIMS Nov 2012)
(b) Trinucleotide repeats
(c) Sugar changes This karyogram suggests the following: (AI 2003)
(d) DNA methylation (a) Klinefelters syndrome
(b) Turners syndrome
39. Which of the following tests is used to differentiate the (c) Downs syndrome
chromosome of normal and cancer cells?
(d) Pataus syndrome
(a) PCR (AIIMS Nov 2012)
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46. A nineteen year old female with short stature, wide 55. Barr body is not seen in: (Kolkata 2008)
spread nipples and primary amenorrhea most likely (a) Klinefelter syndrome
has a karyotype of: (AI 2003) (b) Turner syndrome
(a) 47, XX + 18 (c) Normal female
(b) 46, XXY (d) XXX syndrome
(c) 47, XXY
(d) 45 X
56. Karyotype is: (Jharkhand 2003)
(a) Size, shape and number of chromosome
47. Karyotyping most commonly done under light (b) Gene packing
microscopy: (AIIMS Nov 2009) (c) DNA assay
(a) G-banding (d) None
(b) Q banding
(c) C banding
57. A 36-year-old retarded man with a strong history of
mental retardation among male relatives undergoes
(d) R banding
genetic testing. His lymphocytes on metaphase arrest
48. Effective polymerase reaction was repeated for 3 show a breakpoint at q27.3 on the X chromosome. This
cycles on a DNA molecule. What will be the resulting man is at increased risk for which of the following
formation of the copies? (AIIMS Nov 2001) cardiovascular disorders?
(a) Double number of copies
(a) Aortic stenosis
(b) Three times the number of DNA molecule
(b) Atrial septal defect
(c) Four times the number of DNA molecule
(c) Mitral valve prolapse
(d) 8 times
(d) Tricuspid atresia
49. Y-chromosome is (AIIMS May 2007) 58. A 16-year-old female Bholi presents to Dr. Sindhu,
(a) Telocentric a gynecologist because she has never had menstrual
(b) Metacentric bleeding. She is 132 cm tall, weighs 44 kg, has swelling
(c) Submetacentric around the neck, increased carrying angle at the elbow
(d) Acrocentric and poorly developed secondary sexual characteristics.
50. Which of the following is true of Klinefelters On performing a pelvic ultrasound, the physician
syndrome: (PGI Dec 01) observes her ovaries are small and elongated. Which of
Genetics
(a) Chromosome pattern in 47 XXY the following is the most likely cause of this patients
(b) Mental retardation is present condition?
(c) Hypogonadism occurs
(a) Mitotic error in early development
(d) Increased FSH level
(b) Trinucleotide repeat expansion
(e) Eunuchoid proportions
(c) Uniparental disomy
51. The classic karyotype of Klinefelters syndrome is:
(d) Balanced reciprocal translocation
(a) 47 XXY (Karnataka 2009) 59. A 8-year-old boy Gullu with the Downs syndrome has
(b) 45 XO an intelligence quotient (IQ) in the mid-normal range.
(c) 48 XXXY Which of the following genetic mechanisms would
(d) 46 XY/47 XXY most likely account for the discrepancy between the
childs IQ and his appearance?
52. Chromosomal abnormality in Mongolism is
(a) Balanced translocation
(a) Trisomy 21 (Karnataka 2005)
(b) Trisomy 22

(b) Chiasma
(c) Trisomy 17

(c) Mosaicism
(d) Trisomy 5

(d) Spermiogenesis
53. Trisomy 13 is identified as (Karnataka 2005)

60. A tall man with gynecomastia and testicular atrophy
has a testicular biopsy that shows sparse, completely
(a) Edwards syndrome
hyalinized seminiferous tubules with a complete
(b) Pataus syndrome
absence of germ cells and only rare Sertoli cells. Leydig
(c) Downs syndrome
cells are present in large clumps between the hyalinized
(d) Klinefelters syndrome
tubules. Which of the following genetic disorders
54. In Down syndrome, there is non disjunction of should be suspected?
chromosome (RJ 2000,2002)
(a) Testicular feminization syndrome
(a) 13
(b) Trisomy 18
(b) 15
(c) Trisomy 21
(c) 18
(d) 47, XXY
(d) 21
110
Genetics
Most Recent Questions 63. In-situ DNA nick end labeling can quantitate:
(a) Fraction of cells in apoptotic pathways
60.1. Patau syndrome is due to which of the following? (b) Fraction of cells in S phase (AI 2005)
(a) Trisomy 21 (b) Trisomy 18 (c) p53 gene product
(c) Trisomy 21 (d) Trisomy 13 (d) bcr/abl gene
6 0.2. Osteogenesis imperfecta defect in: 64. The chances of having an unaffected baby, when both
(a) Collagen type I parents have achondroplasia, are: (AI 2005)
(b) Elastin (a) 0%
(c) Collagen type IV (b) 25%
(d) Fibrillin 2 (c) 50%
6 0.3. In marfan syndrome, the defect is in: (d) 100%
(a) Fibrillin I (b) Fibrillin II 65. Study the following carefully: (AI 2005)
(c) Collagen (d) Elastin
6 0.4. Karyotyping is done in which phase of cell cycle?
(a) Anaphase (b) Metaphase
(c) Telophase (d) S phase
6 0.5. The number of chromosomes in Turner syndrome is:
(a) 47 (b) 46
(c) 45 (a) 44
6 0.6. The number of chromosomes in Klinefelter syndrome
is:
(a) 47 (b) 46
(c) 45 (d) 44 Read the pedigree. Inheritance pattern of the disease in
the family is:
6 0.7. Chromosomes are visualized through light microscope (a) Autosomal recessive type
with resolution of: (b) Autosomal dominant type
(a) 5 Kb (b) 50 mb (c) X-linked dominant type
(c) 5 (d) 500 Kb
Genetics
(d) X-linked recessive type
6 0.8. Which of the following techniques can be used to detect 66. Kinky hair disease is a disorder where an affected child
exact localisation of a genetic locus? (AIIMS May, Nov 2013) has peculiar white stubby hair, does not grow, brain
(a) Chromosome painting degeneration is seen and dies by age of two years.
(b) FISH Mrs. A is hesitant about having children because her
(c) Comparative genomic hybridization two sisters had sons who had died from kinky hair
(d) Western blot disease. Her mothers brother also died of the same
condition. Which of the following is the possible mode
6 0.9. If a chromosome divides in an axis perpendicular to of inheritance in her family? (AI 2004)
usual axis of division it is going to form: (a) X-linked recessive
(a) Ring chromosome (b) X-linked dominant
(b) Isochromosome (c) Autosomal recessive
(c) Acrocentric chromosome (d) Autosomal dominant
(d) Subtelocentric chromosome
67. An albino girl gets married to a normal boy, what are
the chances of their having an affected child and what
PEDIGREE ANALYSIS, GENE LOCATION, LYON HYPOTHESIS are the chances of their children being carriers?

(a) None affected, all carriers (AI 2003)
61. BRCA 1 gene is located on? (AIIMS May 2011) (b) All normal
(a) Chromosome 13 (b) Chromosome 11 (c) 50% carriers
(c) Chromosome 17 (d) Chromosome 22 (d) 50% affected, 50% carriers
62. Males are more commonly affected than females in 68. The mother has sickle cell disease; Father is normal;
which of the following genetic disorders? Chances of children having sickle cell disease and
(a) Autosomal Recessive Disorder (AI 2010) sickle cell trait respectively are: (AI 2001)
(b) Autosomal Dominant Disorder (a) 0 and 100%
(c) X-linked Recessive Disorder (b) 25 and 25%
(d) X-linked Dominant Disorder (c) 50 and 50%
(d) 10 and 50%
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69. Father has a blood group B; Mother has AB; Children 77. A babys blood group was determined as O Rh negative.
are not likely to have the following blood group: Select the blood group the babys mother or father will
(a) O (AI 2001) not have (AIIMS Nov 2002)
(b) A (a) A, Rh positive
(c) B (b) B, Rh positive
(d) AB (c) AB, Rh negative
(d) O, Rh positive
70. Gene therapy is used for: (AIIMS May 2009)
78. Thalassemia occurs due to which mutation?
(a) Cystic fibrosis
(b) Sickle cell anemia (a) Missense (PGI Dec 2000)
(c) Thalassemia (b) Splicing
(d) All of the above (c) Transition
(d) Frame-shift
71. Gene for major histocompatibility complex is located (e) Truncation
on which chromosome? (AIIMS Nov 2008)
(a) Chromosome 10 79. Congenital syndrome associated with lympho-
(b) Chromosome 6 proliferative malignancy is: (PGI June 2005)
(a) Bloom syndrome.
(c) X chromosome
(b) Fanconis anemia
(d) Chromosome 13
(c) Turner syndrome.
72. Gene for folate carrier protein is located on (d) Chediak Higashi syndrome.
chromosome? (AIIMS Nov 2008, May 2008) (e) Ataxia telangiectasia
(a) Chromosome 10
(b) Chromosome 5
80. Loss of heterozygosity means: (PGI Dec 2005)
(a) Loss of single arm of chromosome.
(c) Chromosome 21 (b) Loss of mutant allele in mutant gene
(d) Chromosome 9 (c) Loss of normal allele in mutant gene
73. Ability of stem cells to cross barrier of differentiation to (d) Loss of normal allele in normal gene
transform into a cell of another lineage expressing the
molecular characteristics of different cell type with the
81. Long and short arm of chromosome are called
respectively (Delhi PG-2008)
ability to perform the function of the new cell type is
referred as: (AIIMS Nov 2007) (a) p and q
(b) q and p
Genetics

(a) De differentiation
(c) m and n

(b) Re differentiation
(d) r and s

(c) Trans-differentiation

(d) Sub differentiation 82. Cystic fibrosis transmembrane conductance regulator
74. If both husband and wife are suffering with gene is located on chromosome (UP 2005)
achondroplasia, what are their chances of having a (a) 5
normal child (AIIMS May 2004) (b) 6

(a) 0% (c) 7

(b) 25% (d) 8

(c) 50%
83. Which one of the following is not a germ cell tumor?

(d) 100%
(a) Dermoid (Nimhans 1991, AP 2000)

75. A one year old boy presented with hepatosplenomegaly
(b) Granulosa cell tumor
and delayed milestones. The liver biopsy and bone
marrow biopsy revealed presence of histiocytes (c) Choriocarcinoma
with PAS-positive Diastase-resistant material in the (d) Gynandroblastoma
cytoplasm. Electron-microscopic examination of these
histiocytes is most likely to reveal the presence of:
84. A relatively recent advancement is the use of a
technique called DNA fingerprinting. It is based in
(AIIMS Nov 2003) part on recombinant DNA technology and in part on

(a) Birbecks granules in the cytoplasm
those techniques originally used in medical genetics

(b) Myelin figures in the cytoplasm
to detect slight variations in the genomes of different

(c) Parallel rays of tubular structures in lysosomes
individuals. These techniques are used in forensic

(d) Electron dense deposit in the mitochondria
medicine to compare specimens from the suspect with

76. The gene that regulates normal morphogenesis during
those of the forensic specimen. What is being compared
development is: (AIIMS Nov 2002)
when DNA fingerprinting is used in forensics?

(a) FMR-1 gene

(a) The banding pattern

(b) Homeobox gene

(c) P-16 (b) The triplet code

(d) PTEN (c) The haplotypes

(d) The chromosomes
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Genetics
85. Individual II-2 in the associated pedigree was (a) Patient A

diagnosed with hemophilia A. Which one of the
following individuals would be most at risk for
(b) Patient B
developing also hemophilia A?
(c) Patient C
(d) Patient D
87.1. True statement about inheritance of an X linked

recessive trait is:
(a) 50% of boys of carrier mother are affected
(b) 50% of girls of diseased father are carrier
(c) Father transmits disease to the son
(d) Mother transmits the disease to the daughter
8 7.2. Gene for Wilms tumor is located on:
(a) Chromosome 1
(a) II-3 (b) Chromosome 10
(b) II-6 (c) Chromosome 11
(c) III-3 (d) Chromosome 12
(d) III-5 8 7.3. Male to male transmission is not seen in:
(e) III-8 (a) Autosomal dominant diseases
86. A 22-year-old woman, Sheena presents with (b) Autosomal recessive disease
progressive bilateral loss of central vision. You obtain (c) X-linked dominant disease
a detailed family history from this patient and produce (d) Genomic imprinting
the associated pedigree (dark circles or squares 8 7.4. Microarray is best characterised by:
indicate affected individuals). Which of the following (a) Study of multiple genes
transmission patterns is most consistent with this (b) Study of disease
patients family history? (c) Study of organisms
Genetics
(d) Study of blood group
8 7.5. The technique used for separation and detection of
RNA is which one of the following
(a) Northern blot
(b) Southern blot
(c) Eastern blot
(d) Western blot
8 7.6. Which of the following potentially represents the most
dangerous situation?
(a) Autosomal recessive (a) Rh+ve mother with 2nd Rh-ve child
(b) Autosomal dominant (b) Rh-ve mother with 2nd Rh+ve child
(c) X-linked recessive (c) Rh+ve mother with 1st Rh-ve child
(d) Rh-ve mother with 1st Rh+ve child
(d) X-linked dominant
(e) Mitochondrial 8 7.7. The CFTR gene associated what cystic fibrosis is located
on chromosome
87. A pathologist Dr. Gobind is examining four placentas (a) 5
from four different births. He notes the following (b) 12
characteristics in the four placentas: (c) 4
Patient A: fused dichorionic diamnionic (d) 7
Patient B: dichorionic diamnionic 8 7.8. In cystic fibrosis the most frequent pulmonary pathogen
Patient C: circumvallate placenta is
Patient D: monochorionic diamnionic. (a) Pseudomonas
Which of the patients unquestionably gave birth to (b) Enterococci
identical twins? (c) Staphylococci
(d) Klebsiella
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EXPLANATIONS
1. Ans. (a) Ataxia telangectasia (Ref: Robbins 8th/302-3, 1323-4, 9/e p242-243)
Ataxia telangiectasiais an autosomal recesive condition.
Patients have increased sensitivity to x-ray-induced chromosome abnormalities.
Characterized by an ataxic-dyskinetic syndrome beginning in early childhood, caused by neuronal degeneration
predominantly in the cerebellum, the subsequent development of telangiectasias in the conjunctiva and skin, and
immunodeficiency.
The nuclei of cells in many organs (e.g., Schwann cells in dorsal root ganglia and peripheral nerves, endothelial cells
as well as pituicytes) show a bizarre enlargement of the cell nucleus and are referred to as amphicytes.
The lymph nodes, thymus, and gonads are hypoplastic.
Clinical features include recurrent sinopulmonary infections and unsteadiness in walking.
Increased risk of development of lymphoid malignant disease (T-cell leukemia and lymphoma
All other options are autosomal dominant conditions.
2. Ans. (d) Familial hypercholesterolemia (Ref: Robbins 7th/152, 9/e p141)

Most of the metabolic disorders have autosomal recessive inheritance except:
Her Hers disease [Liver phosphorylase deficiency]
Left Lesch Nyhan syndrome
Eye Ocular albinism
Has Hunter syndrome and Hypercholesterolemia (familial)
Five Fabrys disease
Pimples Porphyria [Acute intermittent]
Note: All these exceptions have X linked recessive inheritance except acute intermittent porphyria and familial hypercholesterolemia
Genetics
which are autosomal dominant disorders.

3. Ans. (b) 30,000 genes (Ref: Robbinss 7th/1219, 8th/136)
Humans have a mere 30,000 genes rather than the 100,000 predicted only recently. Recent Robbins mentions the number
of genes to 20,000 to 25,000.
Genetics is the study of single or a few genes and their phenotypic effects.
Genomics is the study of all the genes in the genome and their interactions. DNA microarray analysis of tumors is
an excellent example of genomics in current clinical use.
Epigenetics is heritable changes in gene expression that are not caused by alteration in DNA sequences.
4. Ans. (b) Emphysema; (c) Fibrosis of portal tact; (d) Diastase resistance positive hepatocytes; (Ref: Robbins 7th - 911, 912 , 9/e p850-851)
This is an autosomal recessive disease characterized by deficiency of a - antitrypsin (important protease inhibitor).
There is portal tract fibrosis in neonatal hepatitis. About 10 - 20% of newborn with a antitrypsin deficiency develop
1
1
neonatal hepatitis and cholestasis.
Hepatocellular carcinoma develops in 2-3 % a - antitrypsin deficiency in adults.
The treatment and cure, for severe hepatic disease is orthotropic liver transplantation.
1
5a. Ans. (b) Thalassemia; (c) Sickle cell anemia; (d) Cystic fibrosis (Ref: Robbins 7th/151, 8th/141-2, 9/e p141)
Hereditary spherocytosis is an autosomal dominant disorder
Hemophilia is an X-linked recessive disease.
A broad generalization is that the physiologic metabolic enzyme deficiencies are all autosomal recessive whereas Structural defects
are autosomal dominant.
5b. Ans. (b) Thalassemia, (c) sickle cell disease, (d) cystic fibrosis, (e) hemophilia (Ref: Robbins 8th/652 , 9/e p141)
6. Ans. is d i.e. Huntingtons disease (Ref: Harrison 17th/401 Robbins 7th/1393, 8th/141,168 , 9/e p141)
7. Ans. (d) X-linked recessive disease (Ref: Robbins 7th/1336 , 9/e p142)
8. Ans. (d) IV (Ref: Robbins 8th/145-146, 7th/155-156 , 9/e p146)
9. Ans. (a) Point mutation (Ref: Robbins 8th/645; 7th/628 , 9/e p138)
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Genetics
10. Ans. (a) Albinism (Ref: Robbins 8th/141-142, 7th/151 , 9/e p141-142)
11. Ans. (c) Fibrillin (Ref: Robbins 8th/144, 7th/154 , 9/e p144)
12. Ans. (a) Autosomal dominant (Ref: Robbins 8th/140, 7th/151 , 9/e p140)
13. Ans. (a) Homogentisic acid (Ref: Robbins 8th/155-156, 7th/167-168 , 9/e p64)
14. Ans. (d) Defective synthesis of fibrillin (Ref: Robbins 7th/104, 154-155 , 9/e p144)
The stem describes a patient of Marfan syndrome which is an autosomal dominant disorder that results from defective
synthesis of fibrillin.
1 4.1. Ans. (a) X linked (Ref: Robbins 8/e p142 , 9/e p142)
X-linked recessive disorder can be remembered by the following line:
Less hCG is Detected Clinically in A Fragile Woman
Less Lesch Nyhan syndromeQ
H Hemophilia A and BQ; Hunter syndromeQ
C Chronic granulomatous diseaseQ
G is G6PD deficiencyQ
Detected Duchhene muscular dystrophyQ, Diabetes insipidusQ
Clinically in Color blindnessQ
A AgammaglobulinemiaQ (Brutons disease)
Fragile Fragile X syndromeQ, Fabry DiseaseQ
Woman Wiskott Aldrich syndromeQ
14.2. Ans. (b) Autosomal dominant (Ref: Robbins 8/e p816 , 9/e p806,809)
It is a subtype of familial adenomatous polyposis inherited as an autososmal dominant disorder.
Gardener syndrome Intestinal polyps + epidermal cysts + fibromatosis + osteomas (of the mandible, long bones
Q
Genetics
and skull).

1 4.3. Ans. (d) Huntingtons chorea (Ref: Robbins 8/e p141)
Autosomal dominant disorders
Vo Von Willebrand DiseaseQ

Familial Familial Adenomatous PolyposisQ
Hypercholesterolemia Hypercholesterolemia (Familial)
Autosomal Adult polycystic kidneyQ
D Dystrophia myotonicaQ
O Osteogenesis imperfectaQ
M Marfan syndromeQ
I Intermittent porphyriaQ
N Neurofibromatosis-1Q
A AchondroplasiaQ
N Neurofibromatosis2Q
T Tuberous sclerosisQ
Hai Huntingtons diseaseQ; Hereditary spherocytosisQ
14.4. Ans. (a)Autosomal dominantsee earlier explanation (Ref: Robbins 9/e p141)
1 4.7. Ans. (a) X chromosomeexplained earlier (Ref: Robbins 8/e p142, 9/e p142)
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14.8. Ans. (c)Facioscapulohumeral muscular dystrophy (Ref: Robbins 8/e p142, 1270)
Facioscapulohumeral muscular dystrophy is an autosomal dominant disorder characterised by facial weakness (dif-
ficulty with eye closure and impaired smile) and scapular winging.
Progressive Muscular Dystrophies
Type Inheritance Clinical Features
Duchennes XR Progressive weakness of girdle muscles
Unable to walk after age 12
Progressive kyphoscoliosis
Respiratory failure in 2d or 3d decade
Beckers XR Progressive weakness of girdle muscles
Able to walk after age 15
Respiratory failure may develop by 4th decade
Limb-girdle AD/AR Slow progressive weakness of shoulder and hip girdle muscles
Emery-Dreifuss XR/AD Elbow contractures, humeral and peroneal weakness
Congenital AR Hypotonia, contractures, delayed milestones
Progression to respiratory failure in some; static course in others
Myotonica (DM1, DM2) AD Slowly progressive weakness of face, shoulder girdle, and foot
dorsiflexion
Preferential proximal weakness in DM2
Facioscapulohumeral ADQ Slowly progressive weakness of face, shoulder girdle, and foot
dorsiflexion
Oculopharyngeal AD Slowly progressive weakness of extraocular, pharyngeal, and limb

muscles
14.9. Ans. (c) Affects intestine only (Ref: Robbins 9/e 466-471)
Cystic fibrosis is also known as salty baby syndrome or mucoviscidosis . It is an autosomal recessive genetic
Genetics
Q Q Q
disorder that affects most critically the lungs, and also the pancreas, liver, and intestine.
It is characterized by abnormal transport of chloride and sodium across epithelium, leading to thick, viscous secretions
Affected patients are prone to Pseudomonas infections for which a combination of 3 generation cepahalosporins
Q rd
and aminoglycoside is used.

Q
The most commonly used form of testing is the sweat test using the drug that stimulates sweating (pilocarpine
iontophoresis ).
Q
Patients require repeated use of antibiotics and lung transplantation (in later stages) to survive.
14.10. Ans. (d) Vitamin D resistant rickets (See Below)
Vitamin D resistant rickets X linked dominant due to PHEX gene
Familial hypercholesterolemia Autosomal recessive
Red green colour blindness X linked recessive
Achondroplasia Autosomal dominant
15. Ans. (d) Ghrelin (Ref: Robbins 8th/441-2, and 9/e 444, Pediatric endocrinology: mechanisms, manifestations, management
1st/26-8)
Ghrelin is a growth hormone secretagogue and the only gut hormone with orexigenic (means increasing food intake)
property.
It is primarily produced in the stomach. In children, its value is inversely related with body mass index and insulin
values. It is postulated to play an important role in hyperphagia.
Direct quote from Pediatric endocrinology fasting ghrelin levels were obtained in children with Prader Willi syndrome
and found to be elevated 3-4 times when compared to children who are obese.
Pancreatic polypeptide Y (PYY) is normally secreted from endocrine cells of the ileum and colon. It reduces energy intake
and its reduced levels in the patients of Prader Willi syndrome may contribute to hyperphagia and obesity.
16. Ans. (a) Mitochondrial Disorder (Ref: Harrison 17th/316-317, Robbins 8th/1328)
NARP syndrome (Neuropathy, ataxia, and retinitis pigmentosa), is a condition related to changes in mitochondrial DNA.
For details, see text.
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Genetics
17. Ans. (a) Prader-Willi syndrome (Ref: Robbins 8th/172)

Prader Willi syndrome could be present because of the following:
a. Deletion of paternal chromosome 15 or
b. Uniparental disomy of maternal chromosome 15.
For details, see text
18. Ans. (c) Germline mosaicism (Ref: Robbins 8th/173)
Gonadal mosaicism results from a mutation that occurs postzygotically during early (embryonic) development. If the
mutation affects only cells destined to form the gonads, the gametes carry the mutation, but the somatic cells of the
individual are completely normal. Such an individual is said to exhibit germ line or gonadal mosaicism. A phenotypically
normal parent who has germ line mosaicism can transmit the disease-causing mutation to the offspring through the
mutant gamete. Since the progenitor cells of the gametes carry the mutation, there is a definite possibility that more than
one child of such a parent would be affected. It is seen with tuberous sclerosis and osteogenests imperfecta.
19. Ans. (d) Nemaline myopathy results due to mutations in mt-DNA (Ref: Harrison 17th/2688, Robbins 8th/171)
Nemaline myopathy is not a mitochondrial disease
Nemaline Myopathy
Nemaline myopathy is a clinically heterogeneous condition and not a mitochondrial disease. Five genes have been associated with this
myopathy. All code for thin filamentassociated proteins, suggesting disturbed assembly or interplay of these structures as a pivotal
mechanism. Mutations of the nebulin (NEB) gene account for most cases, including both severe neonatal and early childhood forms,
inherited as autosomal recessive disorders.
20. Ans. (a) Genomic imprinting (Ref: Robbins 8th/171-173, 9/e 173)
21. Ans. (c) Genomic imprinting (Ref: Robbin 7th/186 , 9/e 173)
22. Ans. (a) Genomic imprinting (Ref: Harrisons 17th/413, 18th/518; Robbins 7th/186. 8th/171-2 , 9/e 173)
Genomic imprinting is the phenomenon that leads to preferential expression of an allele depending on its, parental origin.
It is also seen in (updated from HARRISON 18th):
Wiedmann syndrome (have two paternal but no maternal copies of chromosome 11).
Albrights hereditary osteodystrophy (short stature, brachydactyly and PTH resistance). There is mutation in the Gs a subunit;
Genetics
individuals express the disease only when the mutation is inherited from the mother).
23. Ans. (d) Germline mosaicism (Ref: Robbins 8th/173, 7th/187, Harrison 17th/1800, 9/e 174)
Germline mosaicism is seen with osteogenesis imperfecta and tuberous sclerosis. For details, see text.
24. Ans. (a) Silencing of paternal chromosome; (b) Silencing of maternal chromosome; (c) Angelman syndrome;
(d) Prader Willi syndrome: (Ref: Robbins 7th-1856, 8th/171-3 , 9/e 173)
25. Ans. (a) Ehler Danlos syndrome; (b) Marfans syndrome; (d) Osteogenesis imperfecta (Ref: Robbins 7th/151 , 9/e 144-146)
Dominant negative effects occurs when a mutant polypeptide not only loses its own function but also interferes with
the product of normal allele in a heterozygote, thus causing more severe effects than deletion or non-sense mutations in
the same gene. Structural proteins that contribute to multimeric structures are vulnerable to dominant negative effects, e.g.
collagen.
Seen in: Osteogenesis imperfecta, Ehler Danlos syndrome, Marfans syndrome.

26. Ans. (b) Maternal transmission; (d) Mitochondrial myopathy: (Ref: Harrison 18th/501, Robbins 8th/171)
Human mitochondrial DNA (mt DNA)
Examples include
Lebers Hereditary Optic Neuropathy,
Myoclonic Epilepsy with Ragged Red Fibers syndrome (MERRF),
Mitochondrial myopahty with Encephalopathy, Lactic Acidosis and Stroke (MELAS),
Autosomal dominant inherited mitochondrial myopathy with mitochondrial deletion (ADMIMY),
Kearns-Sayre syndrome,
Chronic progressive external ophthalmoplegia,
Pearson syndrome and
Neurogenic muscular weakness with ataxia and retinitis pigmentosa (NARP).
27. Ans. (b) Maternally transmitted. (Ref: Robbins 7th/185 , 9/e 171)
28. Ans. (d) All of the above (Ref: Robbins 8th/167 , 9/e 168)
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Non- Mendelian inheritance can be classified into following four categories:

Trinucleotide repeat mutation disorders Mitochondrial gene mutations Genomic imprinting Gonadal Mosaicism
Fragile- X syndrome Leber Hereditary Optic Neuropathy Prader-Willi Tuberous
Friedreichs Ataxia Kearns-Sayre syndrome syndrome sclerosis
Myotonic dystrophy Chronic progressive external (Paternal deletion) Osteogenesis
Huntington disease ophthalmoplegia Angelman imperfecta
Spinobulbar muscular atrophy Pearson syndrome syndrome
(Kennedy disease) Neurogenic muscular weakness with (maternal deletion)
Spinocerebellar ataxias ataxia and retinitis pigmentosa (NARP)
29. Ans. (d) Trinucleotide repeat mutation (Ref:Robbins 8th/169-171 , 9/e 169)
30. Ans. (b) Ehlers-Danlos syndrome (Ref: Robbins 7th/155-6, Table 5.5 174 , 9/e 145-146)
Chromosome breakage syndromes are associated with high level of chromosomal instability. Such conditions include.
Fanconi anemia, Bloom syndrome and Ataxia telangiectasia.
Ehlers-Danlos syndrome (EDS)
Genetic disorder resulting from defective synthesis of fibrillar collagen
Skin is extraordinary stretchable, extremely fragile and vulnerable to trauma, joints are hypermobile
Internal complications: rupture of colon, large arteries
31. Ans. (c) Huntingtons disease (Ref: Robbins 8th/168 , 9/e 168)
Huntingtons disease is characterized by trinucleotide repeats affecting the coding region. Rest all conditions mentioned
in the options affects the non-coding regions.
32. Ans. (b) 11 (Ref: Robbins 8th/480-1 , 9/e 479)

The diagnosis of this patient is Wilms tumor. It occurs in children and typically presents with an abdominal mass as well
as with hypertension, hematuria, nausea and intestinal obstruction. Since it is derived from mesonephric mesoderm, it can
include mesodermal derivatives such as bone, cartilage, and muscle. The Wilms tumor suppressor gene (WT-1) has been
localized to chromosome 11 (11p).
Other options

Genetics
Chromosome 5 (option a) is the site of the tumor suppressor gene APC, which is involved in the pathogenesis of colon cancer
and familial adenomatous polyposis.
Chromosome 13 (option c) is the site of the tumor suppressor gene for retinoblastoma and osteosarcoma (Rb) as well as the
BRCA-2 gene for breast cancer.
Chromosome 17 (option d) is the site of p53 (involved in most human cancers), NF-1 (neurofibromatosis type I), and BRCA-1
(breast and ovarian cancer).
33. Ans. (a) Polygenic inheritance (Ref: Robbins 8th/138 , 9/e 138)
Polygenic inheritance involves multiple genes at different loci, with each gene exerting a small additive effect in determin-
ing a trait. Multifactorial inheritance is similar to polygenic inheritance in that multiple alleles at different loci affect the
outcome; the difference is that multifactorial inheritance includes environmental effects on the genes.
34. Ans. (c) Anticipation (Ref: Robbins 8th/168-170 , 9/e 169; 1297)
Huntington disease manifests with the triad of movement disorder (chorea), behavioral abnormalities aggressiveness,
apathy or depression), and dementia. Huntington disease is transmitted as an autosomal dominant trait with 100%
penetrance, meaning that if a child inherits the abnormal gene, that child will inevitably develop Huntington disease. Most
patients develop symptoms in their 40s or 50s. An earlier age of onset is associated with a larger number of trinucleotide
repeats. During spermatogenesis, CAG repeats in the abnormal HD gene rapidly increase. Thus, patients who receive
an abnormal gene from their fathers tend to develop the disease earlier in life. (The number of trinucleotide repeats on
HD gene remains the same during maternal transmission.) The tendency for clinical symptoms to worsen and/or occur
earlier in subsequent generations is called anticipation.
Anticipation is common in disorders associated with trinucleotide repeats as in Fragile X syndrome, myotonic dystrophy and Frie-
dreich ataxia.
(Choice A) The transmission of an abnormal gene from a parent to a child does not always cause disease. The likelihood that the
properties of a gene will be expressed is called penetrance. Huntington disease is a disorder with 100% penetrance means all
individuals who have an abnormal HD gene will develop Huntington disease.
(Choice B) Sometimes, one gene mutation leads to multiple phenotypic abnormalities, a genetic phenomenon named pleiotropy.
In Huntington disease, pleiotropy is present because the mutation of one gene (HD) causes dysfunction of behavior, movement
and cognition.
(Choice D)The presence of two populations of cells with different genotypes in one patient is called mosaicism. Examples include
milder forms of Turner (genotype 46XX/45X0), Klinefelter (46XY/47XXY), and Down syndromes.
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Genetics
35. Ans. (a) Fragile X syndrome (Ref: Robbins 7th/149, 181-183 , 9/e 169-171)
The presentation in the stem of the question is characteristic of Fragile X syndrome.
36. Ans. is (a) i.e. Dissecting aortic aneurysm (Ref: Robbins 8th/145 , 9/e 145)
The patient has Marfan syndrome, an autosomal dominant disorder caused by a defect in the gene on chromosome 15 encoding fibrillin,
a 350 kD glycoprotein. Fibrillin is a major component of elastin associated microfibrils, which are common in large blood vessels and
the suspensory ligaments of the lens. Abnormal fibrillin predisposes for cystic medial necrosis of the aorta, which may be complicated
by aortic dissection. Other features of the syndrome are subluxated lens of the eye, mitral valve prolapse, and a shortened life span
(often due to aortic rupture).
36.1. Ans. (c) Angelman syndrome (Ref: Robbins 8/e p171-2 , 9/e 172)
Imprinting is a process associated with selective inactivation of either the maternal or paternal allele. Thus, maternal imprinting refers
to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated.
Imprinting occurs in the ovum or the sperm, before fertilization, and then is stably transmitted to all somatic cells through
mitosis. The genomic imprinting is best illustrated by the following disorders: Prader-Willi syndrome and Angelman
syndrome.
3 6.2. Ans. (a) Lebers hereditary optic neuropathy (Ref: Robbins 8/e p171 , 9/e 172)
Examples of mitochondrial inheritance are Lebers optic neuropathy, Leighs disease, MELAS (mitochondrial encephalopa-
thy, lactic acidosis and stroke like syndrome) NARP syndrome (Neuropathy, ataxia, and retinitis pigmentosa), Kearns-
Sayre syndrome, Chronic progressive external ophthalmoplegia and Pearson syndrome.
36.3. Ans. (d) Klinefelters syndrome (Ref: Robbins 8/e p165 , 9/e 173)
Maternal disomy is associated with disorders like Prader-Willi syndrome and Angelman syndrome. It is also seen in other
conditions like molar pregnancy and Beckwith-Wiedemann syndrome.
36.4. Ans. (d) Trinucleotide repeat expansion (Ref: Robbins 9/e p168)
Expansion of trinucleotide repeats is an important genetic cause of human disease, particularly neurodegenerative
disorders. There are three key mechanisms by which unstable repeats cause diseases:
Loss of function of the affected gene occurs in fragile X syndrome. In such cases the repeats are generally in non-
Genetics
coding part of the gene.
A toxic gain of function by alterations of protein structure as in Huntington disease and spinocerebellar ataxias. In
such cases the expansions occur in the coding regions of the genes.
A toxic gain of function mediated by mRNA as is seen in fragile X tremor-ataxia syndrome. In this condition, the
non coding parts of the gene are affected.
37. Ans. (d) Inversion (Ref: Robbins 8th/138, 160)

Inversion refers to a rearrangement that involves two breaks within a single chromosome with reincorporation of the
inverted, intervening segment. It can be of the following two types:
a. An inversion involving only one arm of the chromosome is known as paracentric.
b. If the breaks are on opposite sides of the centromere, it is known as pericentric.
Inversions are often fully compatible with normal development. It is not associated with change in genetic material.
Deletion refers to loss of a portion of a chromosome. Similarly, insertion would lead to increase (and not loss) in the
genetic material.
In a translocation, a segment of one chromosome is transferred to another. It can be of the following types:
In balanced reciprocal translocation, there are single breaks in each of two chromosomes, with exchange of material.
There is no loss of genetic material and so, the affected individual is likely to be phenotypically normal.
A balanced translocation carrier, however, is at increased risk for producing abnormal gametes.
In robertsonian translocation (or centric fusion), a translocation between two acrocentric chromosomes. Typi-
cally the breaks occur close to the centromeres of each chromosome. Transfer of the segments then leads to one
very large chromosome and one extremely small one. Usually the small product is lost. This loss is compatible
with a normal phenotype because it carries only highly redundant genes.
Therefore, deletion, insertion and Robertsonian translocation would lead to change in genetic material.
38. Ans. (a) Thymidine dimers (Ref: Robbins 8th/275, 302)

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Xeroderma pigmentosum
Autosomal recessiveQ inherited disorder of defective DNA repairQ.

Affected individuals are at increased risk for the development of skin cancers particularly following exposure to the UV light contained in
sun rays.
UV radiation causes cross-linking of pyrimidine residues, preventing normal DNA replication. Such DNA damage is repaired by the
nucleotide excision repair systemQ.
Deficiency of enzymes like UV specific endonuclease (commonest), DNA polymerase and DNA ligase is implicated
39. Ans. (b) Comparative genomic hybridization (Ref: Robbins 8th/179, Harrison 18th/512)
Comparative genomic hybridization (CGH) differentiates between cancer and normal cells.
Fluorescence in situ hybridization (FISH)
The majority of FISH applications involve hybridization of one or two probes of interest as an adjunctive procedure
to conventional chromosomal banding techniques. So, FISH can be utilized to identify specific chromosomes, charac-
terize de novo duplications or deletions, and clarify subtle chromosomal rearrangements. Its greatest utilization in
constitutional analysis is in the detection of microdeletionsQ.
In cancer cytogenetics, it is used extensively in the analysis of structural rearrangementsQ.
The usually performed FISH is metaphase FISH. However, interphase analysis can be used to make a rapid diagnosis
in instances when metaphase chromosome preparations are not yet available. Interphase analysis also increases the
number of cells available for examination, allows for investigation of nuclear organization, and provides results
when cells do not progress to metaphase.
The use of interphase FISH has increased recently, especially for analyses of amniocentesis samples and cancer cy-
togeneticsQ.
FISH comparative genomic hybridization (CGH) is a method that can be used only when DNA is available from a
specimen of interest. The entire DNA specimen from the sample of interest is labeled in one color (e.g., green),
and the normal control DNA specimen is indicated by another color (e.g., red). These are mixed in equal amounts
and hybridized to normal metaphase chromosomes. The red-to-green ratio is analyzed by a computer program that
determines where the DNA of interest may have gains or losses of material.
Genetics
40. Ans. (d) Deletion of 21 (Ref: Robbins 8th/161-162)

Down syndrome is characterized by trisomy 21 (NOT deletion of chromosome 21). For details see text.
41. Ans. (a) Maternal non-disjunction (Ref: Robbins 8th/161)
Genetics of Down syndrome
Meiotic nondisjunction of chromosome 21 occuring in the ovum is seen in 95% cases with trisomy 21 and is the so,
commonest cause of Down syndrome. The extra chromosome is of maternal origin.
There is a Strong relation with maternal age
It may also be seen with Robertsonian translocation and mosaicism.
42. Ans. (a) Chromosomal disorders (Ref: Robbins 8th/158)

Karyotyping is the study of chromosomes
Chromosomes are arrested in metaphase by Colchicine
These are then stained by many stains. Most commonly used stain is Giemsa stain, so called G-banding
The chromosomes are arranged in order of decreasing length
Any alteration in number or structure of chromosomes can be easily detected by karyotyping
43. Ans. (c) 46, XXY (Ref: Harrisons 17th/2340 2341, 411, Robbins 7th/179)
It is a typical case of Klinefelter syndrome. The features pointing towards this diagnosis are:
Male phenotype
Hypogonadism [rudimentary testes]
Decreased secondary sexual characteristics [sparse pubic and facial hairs]
Disproportionately long arms and legs.
Patients with Klinefelter syndrome have extra X chromosome, so they may be 47,XXY or 46XY/47 XXY mosaics.
None of the options appear correct as an extra X chromosome in the male should increase the total number of chromo-
somes to 47 and hence 47 XXY should be the most appropriate answer. However an extra X chromosome is the most
essential aspect and hence, within the available options, the best answer is 46 XXY.
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Genetics
44. Ans. (b) G-Banding (Ref: Harsh Mohan 6th/17, Robbins 8th/159, Cancer cytogenetics3rd/2010)
G banding is the most widely used technique for routine cytogenetic analysis. So, G banding is chosen as the answer of
choice. For details of different banding techniques, please see text.
45. Ans. (c) Downs syndrome (Ref: Robbins 7/175)
The given karyogram shows three chromosomes at 21 instead of a pair. It is called Trisomy 21.
Trisomy 21 is synonymous with Downs syndrome and is the most common of the chromosomal disorders. It is a
major cause of mental retardation.
Other trisomies are Edward syndrome (Trisomy 18) and Patau syndrome (Trisomy 13)
46. Ans. (d) 45X (Ref: Robbins 7/179-180)
Given features (Female, primary amenorrhea, short stature, widely spaced nipples) suggests the diagnosis of Turners syndrome.
Turners Syndrome
Turners syndrome is the most common sex chromosomal disorder in phenotypic females.
Turners syndrome results from complete or partial loss of one X chromosome (45, XO) and is characterized by hypogonadism in
phenotypic females
47. Ans. (a) G-banding (Ref: Harsh Mohan 6th/17, Robbins 8th/159, Cancer cytogenetics 2010/3rd edition)
Refer to the text for detail.
Q banding is easily ruled out because it does not require light microscopy. Cancer cytogenetics clearly mentions that sequence specific
techniques like T banding; C banding and NOR banding have been replaced by in situ hybridization techniques. G banding is the most
widely used technique for routine cytogenetic analysis. So, G banding is chosen as the answer of choice.
48. Ans. (d) Eight times (Ref: Harrison 17th/391)

Friends, the number of copies of the particle after n cycles of polymerase chain reaction is given by the formula 2 times n
the original copies. So, the number of copies after 3 cycles would be 2 = 8 times the original copies.
3
PCR is used to amplify DNA but RT PCR (reverse transcriptase PCR) can be used for studying mRNA.
49. Ans. (d) Acrocentric (Ref: Nelson 17th/382)
X chromosome is Submetacentric and Y chromosome is Telocentric.
50. Ans. (a) Chromosome pattern is 47 XXY; (b) Mental retardation is present; (c) Hypogonadism occurs; (d) Increased FSH
Genetics
level; (e) Eunuchoid proportions: (Ref: Harrison 16th-2215, 2216, Robbins 7th/179, 8th/165)
Klinefelters syndrome is defined as male hypogonadism that occurs when there are two or more X chromosomes or one
or more Y chromosomes. Characteristic changes are
Hypogonadism comprising small, firm testes
Hyalinized seminiferous tubules
Failure of development of secondary sexual characters
Chromosomal analysis reveals 47XXY chromosomal pattern (classic form) or 47XY/47XXY mosaicism.
Mental retardation is seen.
Plasma FSH, and LH level elevated.
Plasma testosterone level averages half normal, plasma estradiol level elevated.
Eunuchoid proportions is seen.
51. Ans. (a) 47XXY (Ref:Robbins 7th/179, 8th/161-2)
52. Ans. (a) Trisomy 21 (Ref: Robbins 7th/179, 8th/165)
53. Ans. (b) Patau syndrome (Ref: Robbins 7th/177)
54. Ans. (d) 21 (Ref: Robbins 8th/161, 7th/175-176)
55. Ans. (b) Turner syndrome (Ref: Robbins 8th/165-167, 7th/179)
56. Ans. (a) Size, shape and number of chromosome (Ref: Robbins 8th/158-159; 7 th/170)
57. Ans. (c). Mitral valve prolapse (Ref: Robbins 8th/169)
The patient in question is suffering from Fragile X Syndrome which is a familial form of mental retardation with features
like lax skin and joints, flat feet, large ears, long narrow face with prominent jaw and nasal bridge and macro-orchidism.
Mitral valve prolapse and aortic root dilatation are the serious complications of this disorder.
Aortic regurgitation related to aortic root dilatation and not stenosis (option a) is seen.
Common congenital cardiac malformations such as atrial septal defect (option b) or ventricular septal defect (option d) may be seen
with Downs syndrome and not Fragile X syndrome.
58. Ans. (a) Mitotic error in early development (Ref: Robbins 8th/165-6)
The patient described in the stem of the question appears to have Turner syndrome. The clinical manifestations of this
condition are as follows:
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Phenotypic features Urogenital anomalies Cardiac anomalies Lymphatic anomalies

*Short stature *Primary amenorrhea *Streak *Coarctation of the aorta *Cystic hygromas
*Webbed neck ovaries *Bicuspid aortic valve *Edema of extremities in
*High palate *Decreased estrogen and neonates
*Low posterior hair line gonadotropins
*Shield chest *Absent secondary sexual
*Widely spaced nipples
characteristics *Horseshoe kidney
*Short fourth metacarpal
Turner syndrome is genetically heterogeneous. The classic variant of complete monosomy (45, XO) occurs in a minority of
patients, with most having mosaicism. In the mosaic population, one genetic line contains cells with a normal number of
chromosomes (46, XX), while the other genetic line contains cells that are monosomic (45, XO). Both lines originate from
a single zygote. While trisomies and non-mosaic monosomies typically result from meiotic non-disjunction, mosaicism
arises secondary to mitotic errors after fertilization has taken place.
Sometimes, Turner syndrome individuals have normal karyotype (46 XX) with partial deletion of one or more arms of the
X chromosome. This defect is termed partial monosomy.
Other options
Trinucleotide repeat expansion is responsible for diseases like fragile X syndrome (CGG repeats), myotonic dystrophy (CTG
repeats), and Huntington disease (CAG repeats).
Uniparental disomy occurs in Prader-Willi syndrome (maternal uniparental disomy) and Angelman syndrome (paternal
uniparental disomy). Uniparental disomy is not associated with Turner syndrome.
In balanced form, a reciprocal (Robertsonian) translocation is clinically silent because there is no excess or shortage of genetic
material. An unbalanced trisomy 21 (in which one chromosome 14 contains the long arms of both chromosomes 14 and 21) is
responsible for Down syndrome.
59. Ans. is (c) i.e. Mosaicism (Ref: Robbins 8th/161)
Mosaicism is the term used when cells with more than one type of genetic constitution are present in the same organism.
The situation in the question uncommonly occurs when nondisjunction of chromosome 21 occurs during mitosis (rather
than meiosis) in one of the early cell divisions. The degree to which the individual expresses the characteristics of the
syndrome depends on the number of cells involved and their distribution.
Balanced translocation (choice A) does not produce features of any syndrome, because critical genetic material is not lost,
although progeny may be affected when the translocated chromosome is added to a complement of otherwise normal
Genetics
chromosomes.
Chiasma (choice B) refers to the X-shape of chromosomes undergoing exchange of genetic material in crossover.
Spermiogenesis (choice D) refers to the development of sperm precursors into mature sperm.
60. Ans. is (d) i.e. 47, XXY (Ref: Robbins 8th/165)
The testicular changes described are those observed in Klinefelters syndrome, most often due to 47, XXY genetics.
Testicular feminization syndrome (choice A) is due to a genetically determined unresponsiveness to testosterone that produces a
phenotypic female in an individual with 46, XY chromosomes.
Trisomy 18 (choice B) is Edwards syndrome, characterized by facial features that are small and delicate.
Trisomy 21 (choice C) is the most common trisomy, Down syndrome.
6 0.1. Ans. (d) Trisomy 13 (Ref: Robbins 8/e p162)

Trisomy 13 is known as Patau syndrome characterized by:
Mentalretardation, rocker bottom feet and congenital heart defects (VSD and PDA)
Cleft lip/palate
Polydactyly
Microcephaly
Eye defects (microphthalmia, iris coloboma, cataract, retinal dysplasia)
Capillary hemangiomata
Mnemonic: useful for AIIMS and NEET questions!
p for Patau and polydactyly as well as palate defects: Patau syndrome (trisomy 13)
Edward syndrome (trisomy 18): e for EdwardandExtra occiput (prominent occiput)
6 0.2. Ans. (a) Collagen type I (Ref: Robbins 8/e p1211-2)

Osteogenesis imperfecta (or brittle bone disease ) is a phenotypically diverse disorder caused by deficiencies in the
Q
synthesis of type 1 collagen .

Q
It is the most common inherited disorder of connective tissue.

It principally affects bone, but also impacts other tissues rich in type 1 collagen (joints, eyes, ears, skin, and teeth). It
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Genetics
is characterized by bone fragility, hearing loss, blue scleraQ and dentinogenesis imperfect.
Osteogenesis imperfecta usually results from autosomal dominant mutations in the genes that encode the1 and 2
chains of collagen.
60.3. Ans. (a) Fibrillin I (Ref: Robbins 8/e p144)
Fibrillin occurs in two homologous forms, fibrillin-1 and fibrillin-2, encoded by two separate genes, FBN1 and FBN2
mapped on chromosomes 15q21.1 and 5q23.31, respectively.
Mutations of FBN1 (affecting fibrillin-1 ) underlie Marfan syndrome
Q
Mutations of the related FBN2 gene (fibrillin-2 ) are less common, and are associated with congenital contractural
Q
arachnodactyly, an autosomal dominant disorder characterized by skeletal abnormalities.

60.4. Ans. (b)Metaphase (Ref: Robbins 8/e p158)
Revise NEET info!
Karyotyping is the study of chromosomes
Chromosomes are arrested in metaphase by Colchicine Q
These are then stained by many stains. Most commonly used stain is Giemsa stain , so called G-banding
Q Q
The chromosomes are arranged in order of decreasing length . Any alteration in number or structure of chromosomes can be easily
Q
detected by karyotyping
60.5. Ans. (c) 45 (Ref: Robbins 8/e p165)

Turner syndrome is the most common cause of sex chromosomal abnormality in the females. It usually results from com-
plete or partial monosomy of X chromosome and associated with hypogonadism in phenotypic females.Q Patients have the
(45X) karyotype or may be mosaics.
6 0.6. Ans. (a) 47 (Ref: Robbins 8/e p165)
Klinefelter syndrome is the most common chromosomal disorder of males associated with hypogonadism and infertility. It is due to
extra-X-chromosome. Classically, it is 47, XXY. Other variants can have 48 XXXY, rarely 49 XXXY or mosaics can be there
with some cells containing normal 46, XY and others 47, XXY.
60.7. Ans. (c) 5mb (Ref: Encyclopedia of Genetics 3/e p29)
Karyotype analysis detects both numerical and structural chromosomal aberrations (overall resolution is 5 Mega bases
Genetics
(Mb); breakpoint resolution is 5 to 15 Mb).
Table 1: Resolution provided by the various FISH techniques.
FISH technique Resolution
Metaphase spreads 2-3 Mb
Prometaphase spreads 1 Mb
Mechanically stretched chromosomes 200-3000 kb
Interphase nuclei 50-1000 kb
Fiber FISH 1-300 kb
Mb, megabase = 1000000 base pairs
60.8. Ans. (b) FISH (Ref: Robbin 8/e p 179)

FISH uses DNA probes that recognize sequences specific to particular chromosomal regions.. (Ref: Robbind 8/e p179
Bacterial artificial chromosomes that span the entire human genome were created. These DNA clones are labeled with
fluorescent dyes and applied to metaphase spreads or interphase nuclei. The probe hybridizes to its homologous genomic
sequence and thus labels a specific chromosomal region that can be visualized under a fluorescent microscope.
Uses and advantages of FISH
FISH can be performed on prenatal samples (e.g., cells obtained by amniocentesis, chorionic villus biopsy, or um-
bilical cord blood), peripheral blood lymphocytes, touch preparations from cancer biopsies, and even archival tissue
sections.
FISH has been used for detection of
Numeric abnormalities of chromosomes (aneuploidy);
For the demonstration of subtle microdeletions or complex translocations not detectable by routine karyotyping;
For analysis of gene amplification (e.g., HER2/NEU in breast cancer or N-MYC amplification in neuroblastomas);
For mapping newly isolated genes of interest to their chromosomal loci.
The ability of FISH to circumvent the need for dividing cells is invaluable when a rapid diagnosis is warranted
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Chromosome painting
It is an extension of FISH, whereby probes are prepared for entire chromosomes.
Limitation of this technique: the number of chromosomes that can be detected simultaneously by chromosome painting is
limited due to the availability of fluorescent dyes that emit different wavelengths of visible light.
This is overcome by the introduction of spectral karyotyping (also called multicolor FISH).
Comparative genomic hybridization
It is a method that can be used only when DNA is available from a specimen of interest. The entire DNA specimen from the
sample of interest is labeled in one color (e.g., green), and the normal control DNA specimen is indicated by another color
(e.g., red). These are mixed in equal amounts and hybridized to normal metaphase chromosomes.
The red-to-green ratio is analyzed by a computer program that determines where the DNA of interest may have gains or
losses of material.
Currently used for detection of cancer, mutations in mental retardation and the detection of microdeletions.
60.9. Ans. (b) Isochromosome (Ref: Robbin 8/e p160, The Principles of Clinical Cytogenetics 3/e p157-8)
Isochromosome formation results when one arm of a chromosome is lost and the remaining arm is duplicated, resulting in
a chromosome consisting of two short arms only or of two long arms.
An isochromosome has morphologically identical genetic information in both arms.
The most common isochromosome present in live births involves the long arm of the X.
The Xq isochromosome is associated with monosomy for genes on the short arm of X and with trisomy for genes on
the long arm of X.
The reason for the formation of an isochrome is the centromere misdivision. Instead of dividing longitudinally to
separate the two sister chromatids, the centromere undergoes a transverse split that separated the two arms from one
another... Principles of clinical cytogenetics
Genetics
Figure: Some of the mechanism proposed for isochromosome formation. *Because recombination occurs during normal meionic cell division
the arms of isochromromosome formed during meiosis would be identical only for markers close to the centromene
Previously asked questions on isochromosome
The most common isochromosome present in live births involves the long arm of the X is seen in patient s affected
with Turner syndrome.
Testicular germ cell carcinoma has the presence of gain of 12p throughisochromosome formationor amplification.
61. Ans. (c) Chromosome 17 (Ref: Robbins 8th/1078, Harrison 17th/563)

Features BRCA1 BRCA2
Chromosome 17q21 13q12.3
Function Tumor suppressor, Transcriptional regulation, Tumor suppressor, Transcriptional
Role in DNA repair regulation, Role in DNA repair
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Genetics
Features BRCA1 BRCA2

Age at onset Younger age (40s to 50s) 50 years
% Single gene hereditary disorders 52% 32%
Risk of other tumors (varies with Ovarian, Male breast cancer (lower than BRCA2), Ovarian, Male breast cancer Prostate,
specific mutation) Prostate, colon, pancreas pancreas, stomach, melanoma, colon
Pathology of breast cancers Greater incidence of medullary carcinomas , Similar to sporadic breast cancers
poorly differentiated carcinomas, ER-, PR-, and
Her2/neu-negative carcinomas, carcinomas with
p53 mutations
62. Ans. (c) X-linked Recessive Disorder (Ref: Robbins 8th/142)

Analysis of X linked recessive disorders
Males have an X and a Y chromosome. There is no corresponding locus for a mutant allele of the X chromosome on the Y
chromosome. The mutant recessive gene on the X chromosome expresses itself in a male child because it is not suppressed by
a normal allele whereas in the female, the presence of a normal allele on other X-chromosome prevents the expression of the
disease so, females only act as carriers.Q
63. Ans. (a) Fraction of cells in apoptotic pathways (Ref: The journal of Histochemistry & Cytochemistry:Volume 47 (5): 711-
717, 1996: Wikipedia)
In situ DNA nick end labeling is an in-situ method for detecting areas of DNA which are nicked during apoptosis.
Terminal deoxynucleotidyl transferase mediated dUTPbiotin nick end labeling (TUNEL) is a method for detecting apoptotic cells that
exhibit DNA fragmentation.
64. Ans. (b) 25% (Ref: Harrisons 17th/385)
Achondroplasia is an autosomal dominant condition.
Only one mutant allele is enough to cause disease. Thus, AA and Aa will be affected whereas aa will be unaffected. [A is
mutant allele whereas a is normal].
Genetics
As is clear from the diagram, 3 out of 4, i.e. 75% of children will be affected and 1 out of 4, i.e. 25% children will be unaf-
fected. However, please note that clinically the baby with AA genotype usually donot survive.
65. Ans. (d) X linked Recessive (Ref: Robbins 8th/142)
Presentation of disease only amongst males identifies the disorder as sex (X) linked. Because carrier mothers are not mani-
festing the disease, yet their sons do, the disorder can only be recessive. The disorder is thus X linked recessive.
66. Ans. (a) X linked Recessive (Ref: Robbins 7th/172, 8th/142)
The given disease is manifesting only in males, therefore it is sex-linked disease. Females are not affected, so they must be
carriers. This is a classical inheritance feature of X-linked recessive disorder.
Remember:
Male is having XY, i.e. only X-chromosome. So, even if one mutant allele is present on X-chromosome, it will manifest
(whether recessive or dominant).
Females are XX, so if one gene is mutated in X-chromosome, female will be phenotypically normal and genotypically carrier, if
inheritance is recessive but female will suffer from disease, if it is X-linked dominant.
There is no sex predilection in autosomal dominant or recessive disorders.
67. Ans. (a) None affected, all carriers (Ref: Harrison 17/2332)
Albinism is an autosomal recessive (AR) disorder
AR disorders express only in homozygous state, i.e. if both alleles are mutant
If A is normal allele and a is mutant, then the given cross in the question can be made as
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Thus genotypically all offsprings are carriers and Phenotypically, all of then will be normal.
68. Ans. (a) 0 and 100% (Ref: Harrison 17th/637)
Sickle cell anemia is an autosomal recessive disorder.
Sickle cell disease is the homozygous state of HbS (SS) where S stands for gene coding HbS.
Sickle cell trait is the heterozygous state of HbS (SA) where A stands for absent gene.
Normal individual has no gene for HbS (AA)
If the mother has sickle cell disease SS and father is normal AA all the offsprings will be SA. Thus % of sickle cell dis-
ease (SS) will be zero and that of sickle cell trait (SA) will be 100%.
69. Ans. (a) Blood group O (Ref: Harrison 17th/708)
Major blood group system is ABO system. These are based on the presence of antigen on surface of RBCs Four blood
groups according to this system are.
Blood Group Antigen Anti body (Isoagglutinins)
Genetics
A A Anti B
B B Anti A
AB A and B None
O None Anti A and Anti B
The genes that determine A and B phenotypes are found on chromosome 9p and are expressed in a Mendelian co-
dominant manner.
AB group is universal recipient (No antibody) and Blood group O is universal donor (No antigen)
Blood group according to alleles can be
A AA or Ai
B BB or Bi
AB AB
O ii
[i means allele containing gene for no antigen]
In the given question, father is blood group B [i.e. BB or Bi] and mother is AB. The cross can be
Thus, phenotypically blood group can be A (Ai), B (Bi, BB) or AB (AB). Thus, none of the children can have O blood
group.
70. Ans. (d) All of the above (Ref: Harrison 17th/420, 18th/547-551)
Gene transfer is a novel area of therapeutics in which the active agent is a nucleic acid sequence rather than a protein or
small molecule. Most gene transfers are carried out using a vector or gene delivery vehicle because delivery of naked DNA
126
Genetics
or RNA to a cell is an inefficient process. More clear-cut success has been achieved in a gene therapy trial for another form
of SCID, adenosine deaminase (ADA) deficiency. Other diseases likely to be amenable to transduction of hemaopietic stem
cells (HSCs) include
Wiskott-Aldrich syndrome
Sickle cell disease
Thalassemia.
Clinical trials using recombinant adeno-associated vectors are now ongoing for muscular dystrophies, alpha-1 antitrypsin
deficiency, lipoprotein lipase deficiency, hemophilia B, and a form of congenital blindness called Lebers congenital amau-
rosis.
71. Ans. (b) Chromosome 6 (Ref: Harrison 17th/2045)
The human major histocompatibility complex (MHC), commonly called the human leukocyte antigen (HLA) com-
plex, is a 4-megabase (Mb) region on chromosome 6 (6p21.3)Q that is densely packed with expressed genes.
72. Ans. (c) 21 (Ref: Harrison 17th/644)
Folate cofactors are one-carbon donors essential for the biosynthesis of purines and thymidylate. Mammalian cells are de-
void of folate biosynthesis and are therefore folate auxotrophs that take up folate vitamins primarily via the reduced folate
carrier (RFC). The gene for RFC is located on chromosome 21.
73. Ans. (c) Trans differentiation (Ref: Robbins 7th/92 & Harrison 17th/426)
Stem cell is defined as a cell with a unique capacity to produce unaltered daughter cells (self-renewal) and to generate spe-
cialized cell types (potency).
The prevailing paradigm in developmental biology is that once cells are differentiated, their phenotypes are stable. How-
ever, tissue stem cells, which are thought to be lineage-committed multipotent cells, possess the capacity to differentiate
into cell types outside their lineage restrictions (called trans-differentiation or stem cell plasticity). For example, hemat-
opoietic stem cells may be converted into neurons as well as germ cells.
74. Ans. (b) 25% (Ref: Robbins 8th/141, 7th/151)
Achondroplasia is an autosomal dominant disease.
Genetics
So, only 1 out of 4 children will be unaffected, i.e. 25% of children will be normal.
75. Ans. (c) Parallel rays of tubular structure in lysosomes (Ref: Robbin 8th/152-153)
PAS stain is a widely used stain which gives positive reaction with glycogen (primarily) and non glycogen sub-
stances like glycoprotein, glycolipids, proteoglycans and neutral mucins.
Whether the PAS positivity of a particular cell is due to presence of glycogen or due to latter can be differentiated with
diastase (glycogen digesting enzyme).
If the cell is PAS positive due to glycogen, the pretreatment with diastase will make it PAS negative. But if the cell
is PAS positive due to non glycogen substances, the cell will retain its PAS positivity even after pretreatment with
diastase. So, in the given question, the presence of PAS positive and diastase resistant material indicates presence of
non glycogen substances.
The clinical feature of delayed milestones and hepatosplenomegaly in 1 year old boy is suggestive of some lysosomal
storage disorder (like Niemann Picks disease).
This disease is characterized by the presence of large foam cells in bone marrow, liver and spleen. There is presence
of pleomorphic inclusion of lipids in lysosomes enclosed in concentric or parallel lamellae.
76. Ans. (b) Homeobox gene (Ref: Robbins 8th/452-3, 7th/305, 475)
Classes of genes known to be important in normal morphogenesis during development include
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Homeobox genes (HOX): The HOX genes have been implicated in the patterning of limbs, vertebrae, and craniofacial struc-
tures. HOX genes possess retinoic acid response elements (RAREs), and that the latter are required for mediating both
physiologic and pathologic effects of retinoids during development. Mutations of HOXD13 cause synpolydactyly
(extra digits) in heterozygous individuals and mutations of HOXA13 cause hand-foot-genital syndrome, character-
ized by distal limb and distal urinary tract malformations.
PAX genes: PAX genes are characterized by a 384 base pair sequence the paired box. They code for DNA-binding
proteins that are believed to function as transcription factors. In contrast to HOX genes, however, their expression
patterns suggest that they act singly, rather than in a temporal or spatial combination.
Mutation in PAX3 causes Waardenburg syndrome (congenital pigment abnormalities and deafness).
Mutation in PAX6 causes Aniridia (congenital absence of the iris)
PAX2 mutations cause the renal-coloboma syndrome (developmental defects of the kidneys, eyes, ears, and brain).
Translocations involving PAX3 and PAX7 are seen in alveolar rhabdomyosarcomas.
Translocations involving PAX5 are seen in subsets of lymphomas
Translocations involving PAX8 are seen in thyroid cancers.
Other options
FMR gene: It is involved in fragile X-syndrome.
PTEN gene: located on chromosome 10q is associated with endometrial cancers and glioblastoma.(phosphatase and tensin
homologue)
p16 blocks cell cycle and is a tumor suppressor gene.
77. Ans. (c) AB, Rh negative (Too obvious to explain friends)

78. Ans. (b) Splicing; (d) Frame-shift: (Ref: Harper 27th/415, Robbins 8th/648-9)
Important causes of thalassemia are:
b-thalassemia: A wide variety of mutations in b-globin gene may cause this including
Promoter region mutations
Chain terminator mutations include frameshift mutations.
Genetics
Splicing mutations
b0-thalassemia, associated with total absence of b-globin chains in the homozygous state. Its commonest cause is chain termination.
b+-thalassemia, characterized by reduced (but detectable) b-globin synthesis in the homozygous state. Its commonest cause is
splicing mutation.
a-thalassemia: Mutations in a-globin gene are mainly unequal crossing over and large deletions and less commonly nonsense and
Frame-shift mutations.
79. Ans. (a) Bloom syndrome; (b) Fanconis anemia; (d) Chediak Higashi syndrome; (e) Ataxia telangiectasia (Ref: Harrison
16th/643, 631, Robbins 7th/307)
Blooms syndrome, Fanconi anemia, Klinefelter syndrome, Ataxia telangiectasia and Kostman syndrome are associated
with myeloid leukemia.
80. Ans. (c) Loss of normal allele in mutant gene (Ref: Robbins 7th/299)
A child with inherited mutant RB allele in somatic cells is perfectly normal. Because such a child is a heterozygous at the Rb locus,
it implies that heterozygosity for the Rb gene does not affect cell behavior. Cancer develops when the cell becomes homozygous
for the mutant allele or in other words when the cell loses heterozygosity for the normal Rb gene (a condition known as LOH loss of
heterozygosity)
Thus, from these lines we interpret that loss of heterozygosity means loss of normal allele in mutant gene.
81. Ans. (b) q and p (Ref: Robbins 6th/166, 7th/171)
Short arm of a chromosome is designated p (for petit) and long arm is referred to as q
In a banded karyotype, each arm of the chromosome is divided into two or more regions by prominent bands.
The regions are numbered (e.g. 1, 2, 3) from centromere outwards.
Each region is further subdivided into bands and sub bands and these are ordered numerically as well.
Thus, the notation Xp 21.2 refers to a chromosomal segment located on the short arm of the x chromosome, in region 2,
band 1 and sub band 2.
82. Ans. (c) 7 (Ref: Robbins 8th/465; 7th/490)

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Genetics
83. Ans. (b) Granulosa cell tumor (Ref: Robbins 8th/1338; 7 th/1099)
84. Ans. (a) The banding pattern (Ref: Harrison 18th/521)
Banding patterns are analyzed in DNA fingerprinting to see if they match with the control specimen. Four bases i.e. gua-
nine, adenine, cytosine, and thymine (uracil is substituted for thymine in RNA) are responsible for making the genetic
code. A sequence of three of these bases forms the triplet code used in transmitting the genetic information needed for
protein synthesis. The small variation in gene sequence (called as a haplotype) is thought to account for the individual
differences in physical traits, behaviors, and disease susceptibility. Chromosomes contain all the genetic content of the
genome.
85. Ans. (e) III 8 (Ref: Robbins 7th/151- 152)
Hemophilia. A is X-linked recessive disorder. It will be manifested in female having both the mutant alleles (X h
Xh)
whereas X X will be carrier. On the other hand, in males, even one mutant gene will express, i.e. X Y will be affected
h h
male
In the given pedigree, I-1 and I-2, both are unaffected, therefore male should be normal (xy) and female should be
carrier (XhX)
Now, if we see the inheritance, it will be
Therefore, half of the daughters are carrier and half are normal whereas half of males are normal whereas other half
are affected.
In the given pedigree, II -5 (male) should be normal whereas II-2 (male) is affected. Females (II-3 and II-6) can be
Genetics
normal or carriers.
The affected male (XhY), transmits the mutant genes to females only and not to males. Therefore, in the given pedi-
gree, III-1, 2 will be normal. Females should be homozygous (XhXh) to manifest the disease, therefore III-3 and III-4
should be carriers.
As II-5 is a normal male, its progeny should be normal, if it is married to normal female (II-4). Thus, III-5, 6 and 7
should be normal
II-6 is a carrier female and therefore it will transmit the disease to sons. Thus, III-8 and III-9 have maximum risk of
being affected by Hemophilia A.
86. Ans. (e) Mitochondrial (Ref: Robbins 7th/33, 185, 1341-1342)
In mitochondrial inheritance, mothers transmit the entire mitochondrial DNA to both male and female offspring, but
only the daughters transmit it further. No transmission occurs through males.
87. Ans. is (d) i.e. Patient D Read explanation below
Patient D is the mother of identical (monozygotic) twins. The chorion forms before the amnion, so the possible combina-
tions are
Monoamnionic and monochorionic;
Diamnionic and monochorionic; and
Diamnionic and dichorionic (either fused or separated).
The first two of these possibilities are seen only in identical twins. However, the latter can be seen either in fraternal
or identical twins. Very early separation produces completely separate membranes with duplication of both chorion
and amnion; somewhat later separation produces one chorion and two amnions; and very late separation produces one
chorion and one amnion. A dichorionic, diamnionic placenta develops if splitting occurs early after fertilization, before
the chorion forms. This type of placenta may occur with either monozygotic or dizygotic twins. Thus, we are unable to
determine whether Patient A (choice A) or Patient B (choice B) had identical twins from the examination of the placentas.
Patient C (choice C) did not have a twin pregnancy.
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8 7.1. Ans. (a) 50% of boys of carrier mother are affected (Ref: Robbins 8/e p142)
Looking at the statements one by one:
Carrier mother contributes to the transfer of one of the two boys getting the affected chromosome. So, 50% of boys of
carrier mother are affected.
Option bAll girls having diseased father are affected as carriers because they get the affected X sperm from their
fathers. However, these girls are not going to manifest the disease.
Option cfathers cannot transmit the disease to their sons as they transmit just the Y chromosome to them
whereas the disease is X linked.
Option d mothers contribute to just one X chromosome and so, 50% of the daughters would become carriers
if t other was a carrier.
87.2 Ans. (c) Chromosome 11 (Ref: Robbins 8/e p479-80)
Easiest way to remember that info.. count the number of letters in Wilms tumour..yea it is exactly 11the location of
both genes associated with Wilms tumour
So, the two genes associated with Wilms tumour WT1 gene (located on chr 11p13)and WT2 gene (located on chr 11p15).
8 7.3. Ans. (c) X-linked dominant disease (Ref: Robbins 8/e p142)
Since a male transmits only the Y chromosome to his son, so obviously he cannot transmit any X linked disease.
8 7.4. Ans. (a) Study of multiple genes (Ref: Robbins 8/e p174)
Microarrays are gene chips used to sequence genes or portions of genes.In this technique, short sequences of DNA
(oligonucleotides) that are complementary to the wild-type sequence and to known mutations are tiled adjacent to each
other on the gene chip, and the DNA sample to be tested is hybridized to the array. Before hybridization the sample is
labeled with fluorescent dyes. The hybridization (and consequently, the fluorescent signal emitted) will be strongest at the
oligonucleotide that is complementary to wild-type sequence if no mutations are present, while the presence of a mutation
will cause hybridization to occur at the complementary mutant oligonucleotide.
87.5. Ans. (a) Northern blot
: RNA
Genetics
Northern Blot North : Roti

Southern Blot : DNA South : Dosa

Western Blot : Proteins West : Poha/Pizaa

87.6. Ans. (b) Rh-ve mother with 2nd Rh+ve child
Rh-ve mother with 2nd Rh+ve child can result in the development of hemolytic disease of newborn or erythroblastosis
fetalis. So, it is a dangerous condition.
This condition is a type II hypersensitivity reaction.

This is Not to be confused with Hemorrhagic disease of the newborn which is a coagulation disturbance in the newborns due

to vitamin K deficiency. As a consequence of vitamin K deficiency there is an impaired production of coagulation
factors II, VII, IX, X, C and S by the liver.
87.7. Ans. (d) 7 (Ref: Robbins 9/e p466)
87.8. Ans. (d) Pseudomonas (Ref: Robbins 9/e p469)
Pseudomonas aeruginosa species, in particular, colonize the lower respiratory tract, first intermittently and then chronically.
GOLDEN POINTS FOR QUICK REVISION / UPDATED INFORMATION FROM 9TH EDITION OF ROBBINS
(GENETICS)
Autosomal dominant disorders are characterized by expression in heterozygous state; they affect males and females
equally, and both sexes can transmit the disorder. It affects receptors and structural proteins.
Autosomal recessive diseases occur when both copies of a gene are mutated; enzyme proteins are frequently
involved. Males and females are affected equally.
X-linked disorders are transmitted by heterozygous females to their sons, who manifest the disease. Female carriers
usually are protected because of random inactivation of one X chromosome.
DiGeorge syndrome (thymic hypoplasia with diminished T-cell immunity and parathyroid hypoplasia with
hypocalcemia) and Velocardiofacial syndrome (congenital heart disease involving outflow tracts, facial dysmorphism,
and developmental delay)
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Genetics
Genomic Imprinting: Imprinting involves transcriptional silencing of the paternal or maternal copies of certain genes
during gametogenesis. For such genes, only one functional copy exists in the individual. Loss of the functional (not
imprinted) allele by deletion gives rise to diseases. These disorders are also called as the parent-of-origin effects on
gene function.
In Prader- Willi syndrome, deletion of band q12 on long arm of paternal chromosome 15 occurs. Genes in this
region of maternal chromosome 15 are imprinted so there is complete loss of their functions. Patients have mental
retardation, short stature, hypotonia, hyperphagia, small hands and feet, and hypogonadism.
In Angelman syndrome there is deletion of the same region from the maternal chromosome. Since genes on the cor-
responding region of paternal chromosome 15 are imprinted, these patients have mental retardation, ataxia, seizures,
and inappropriate laughter.
Inheritance of both chromosomes of a pair from one parent is called uniparental disomy. Angelman syndrome can
also result from uniparental disomy of paternal chromosome 15.
Genetics
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CHAPTER 5 Neoplasia
NEOPLASIA Concept
Neoplasia refers to the process of new growth. The important feature of the growth associated
Desmoplasia is a term used
with neoplasms is the fact that it is an uncoordinated growth of the tissue persisting even for stimulation of abundant
after the cessation of the stimulus which evoked the change. Oncology is the study of tumors collagenous stroma by the
or neoplasms. The tumors are usually composed of the: parenchymal cells.

1. Parenchyma Made up of proliferating neoplastic cells

2. Stroma Made up of connective tissue and blood vessels.
Benign Tumors
Adenoma Benign epithelial
These are usually denoted by adding a suffix - oma to the cell of origin, so, these may be tumor arising from glands or
arising from fibroblastic cells (fibroma); cartilage cells (chondroma) or osteoblasts (osteoma). forming a glandular pattern
Adenoma and Papilloma are examples of benign tumors. Papilloma Benign tumor with
fingerlike projections
Polyp Tumor producing
MALIGNANT TUMORS a visible projection above a
mucosal surface protruding in
Cancer is a generalized term used for all malignant tumors. These tumors can be of the the lumen.
following types:

1. Sarcoma - Arising from mesenchymal tissue.

2. Carcinoma Tumor of epithelial cell origin derived from any germ layer. If this
tumor is having a glandular pattern, it is called adenocarcinoma.
The divergent differentiation of parenchymal cells produces mixed tumors or pleomorphic tumors.
In teratoma, parenchymal cells are made up from more than one germ layer e.g. Dermoid cyst. Teratoma is derived from ecto-
derm, endoderm and mesoderm.
Choristoma - lesion with normal

differentiation but abnormal
site.
Characteristics of Neoplasia
I. Anaplasia: This is the hallmark of malignant transformation. The extent to which

neoplastic cells resemble normal cells both morphologically and functionally is Hamartoma - lesion with abnormal
called differentiation. An absence of differentiation is called anaplasia. differentiation but normal site.
The features of anaplasia are:

1. Pleomorphism It is the variation in the size and shape of the cells.

2. Hyperchromasia Increased nuclear material or DNA is responsible for dark
staining of the cells called hyperchromasia. In normal cells, the nuclear
cytoplasmic (or N: C) ratio is 1:4 whereas it becomes 1: 1 in anaplastic cells.

3. Increased mitosis gives rise to atypical bizarre mitotic figures. Anaplasia is the hallmark of

4. Loss of polarity due to disturbed orientation of anaplastic cells. malignant transformation.

5. Presence of tumor giant cells having big hyperchromatic nuclei.
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Concept of dysplasia
Dysplasia is characterized by the abnormal proliferation of the cells which also exhibit
pleomorphism. It is not cancer but can give rise to cancer as it is a preneoplastic lesion.
When dysplastic changes involve entire thickness of the epithelium but the lesion remains
confined to the normal tissue, it is called carcinoma in situ. When the cancer cells move beyond
the normal tissue, it is said to be invasive.
Dysplasia is a partially reversible Key differentiating features between Metaplasia, Dysplasia and Anaplasia
condition having intact base-
ment membrane. Feature Metaplasia Dysplasia Anaplasia
Definition Reversible change A change having loss An absence of
in which one in the uniformity of the differentiation (extent
differentiated cell individual cells and loss of to which neoplastic
type (epithelial or architectural orientation cells resemble
mesenchymal) is normal cells both
replaced by another morphologically and
Concept cell type functionally)
When dysplastic changes involve Pleomorphism Absent PresentQ in low grade PresentQ in high grade
entire thickness of the epithelium
(variation in the size
but the lesion remains confined
and shape of cells/
to the normal tissue, it is called
carcinoma in situ. nuclei)
Reversibility ReversibleQ Reversible in early stages IrreversibleQ
(irreversible if whole
epithelium is involved)
N:C ratio Normal (1:4) Increased () Increased ()
Hyperchromatism Absent Present (small degree) Present (high degree)
Mitotic figures Absent/minimal at Typical mitotic figuresQ Atypical mitotic
Neoplasia
normal places present at abnormal places figuresQ (multipolar

spindles) present at
abnormal places
Other features Absent Absent PresentQ
Malignant tumors have upregu- (Tumor giant cellsQ,
lation of telomerase activity. hemorrhage,
necrosis)
Example Barrets esophagus, Cervical dysplasia of Carcinoma of the
myositis ossificans squamous cells cervix, carcinoma
esophagus

II. Rate of growth: The growth of a tumor correlates with the level of differentiation.
Well-differentiated tumors have a slow proliferation rate. Recently, cancer stem cells
or tumor-initiating cells (T-ICs) have been identified in breast cancer, glioblastoma
multiforme (a brain tumor), and acute myeloid leukemia. These T-ICs are cells that
allow a human tumor to grow and maintain itself definitely when transplanted into
an immunodeficient mouse.
Usually, 109 cells produce a
clinically detectable tumor.

III. Local invasion: It is the second most reliable feature that differentiates malignant
from benign tumors. The benign tumors are slow growing, cohesive, expansile
masses that are usually capsulated. The malignant tumors show invasion, infiltration
and destruction of the surrounding tissue.

IV. Metastasis: It is the most reliable feature of a malignant tumor, characterized by
Almost all cancers can metasta- the spread of the tumor to other parts because of penetration into blood vessels,
size except glioma (malignancy lymphatics and the body cavities.
of central nervous system) and
the rodent ulcer (or basal cell
cancer of the skin).
134
Neoplasia
Pathways of spread
Direct seeding of body cavities Lymphatic spread Hematogenous sprad

and surfaces
Involvement of peritoneal Usual for carcinomas Usual for sarcomas
cavity (in ovarian cancer). Pattern of lymph node Thinner walls of veins Sentinel lymph node is useful
Surface of abdominal involvement follows causes preferential for breast cancer, malignant
viscera (mucus secreting natural route of lymphatic venous invasion in melanoma and vulval cancer.
appendicle cancer causing drainage. comparison to arterises.
pseudomyxoma peritonei). Sentinel lymph node is Liver and lungs are the
the first lymph node to most commonly affected
receive lymph flow from a organs.
primary tumor. Invasion of veins is
Seen in melanoma, breast particularly prominent
and colon cancer. is hepatocellular cancer
and renal cell cancer.
Precursor lesions are localized morphologic change that are associated with a high risk of
cancer. They can be of the following subtypes:
Precursor Lesions
Concept
Monoclonality of tumors is as-
sesed by ithe analysis of meth-
With inflammation Without inflammation Benign tumors with ylation patterns adjacent to the
malignant transformation highly polymorphic locus of the

Barret Esophagus due to
Endometrial hyperplasia
Colonic villous adenoma human androgen receptor gene
chronic reflux disease
Leukoplakia of the oral (HUMARA)and enzymes like

Squamous metaplasia of cavity/penis/vulva glucose-6-phosphate dehydro-
genase (G6PD), iduronate-2-sul-
bronchus due to smoking

Colonic metaplasia in fatase and phosphoglycerate
kinase.
Neoplasia
stomach due to pernicious
anemia
MONOCLONALITY OF TUMORS
Most of the cancers arise from single clone of the cells (monoclonal in nature) by genetic
transformation or mutation whereas non neoplastic proliferations are coming from multiple cells
(polyclonal in nature). Clonality of tumors can be assessed in women who are heterozygous for
polymorphic X-linked markers because random X inactivation results in all females being mosaics For Autosomal dominant cancer
with two cell populations. So, normally all females will be having both isoforms of the syndrome, just remember the
enzymes whereas malignant transformation results in a single marker being expressed. line:
For tumors with a specific translocation, such as in myeloid leukemias, the presence of the Very Rich, Cute and Nice Men
Hereditarily Like Familiar Females
translocation can be used to assess clonality. Immunoglobulin receptor and T-cell receptor
gene rearrangements serve as markers of clonality in B- and T-cell lymphomas, respectively.
GENETIC PREDISPOSITION TO CANCER/INHERITED CANCER SYNDROMES
I. Autosomal dominant cancer syndrome

Inheritance of a single mutant gene increases the risk of development of cancer.

Can be remembered as
Very
- Von Hippel Lindau (VHL) syndrome causing renal cell cancer Concept
Rich
- Retinoblastoma
Hereditary non polyposis
Cute and
- Cowden syndrome (PTEN gene) colon cancer (HNPCC) is an
Nice
- Neurofibromatosis 1, 2; Nevoid basal cell cancer syndrome autosomal dominant condition
Men
- Melanoma: MEN (Multiple Endocrine Neoplasia) 1 and 2 caused by defective DNA repair

Hereditarily - Hereditary nonpolyposis colon cancer genes. All others are conditions
associated with defective DNA
Like
- Li-Fraumeni syndrome, LKB1 gene in Peutz Jeghers syndrome repair genes are autosomal
Familiar - Familial adenomatous polyposis recessive.
Females - ovarian and breast tumor (will occur is females obviously)
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II. Familial cancers

These are cancers occurring at high frequency in families without a clear defined
pattern of transmission. These usually show early age of onset and are present
is 2 or more close relatives of the index case.

Include cancer of colon, ovary, breast, pancreas, etc.

III. Autosomal recessive cancer syndrome (all of these are caused due to Defective
DNA Repair)
Big - Bloom syndrome
F -
Fanconi anemia
A - Ataxia telangiectasia
PET scanning requires the
injection of 18 fluoro-deoxy-
X -
Xeroderma pigmentosum
glucose (18-FDG) (mnemonic: - Big FAX)

Precancerous conditions are non- neoplastic conditions associated with cancer include endometrial
hyperplasia, chronic gastritis, leukoplakia, ulcerative colitis and solar keratosis, etc.
The seven fundamental changes in cell physiology that together determine the malignant
phenotype are:

1. Self-sufficiency in growth signals: Due to oncogene activation
S phase is characterized by

2. Insensitivity to growth-inhibitory signals
doubling of the nuclear material.

3. Evasion of apoptosis: Presence of resistance to apoptosis
It is a point of no return in the

4. Limitless replicative potential: Presence of unrestricted proliferative capacity due to
cell cycle telomerase activity

5. Development of sustained angiogenesis

6. Ability to invade and metastasize

7. Genomic instability resulting from defects in DNA repair
The eighth hallmark effect is called Warburg effect or aerobic glycolysis. It is the
shifting of glucose metabolism by the cancer cells from the efficient mitochondria to glycolysis.
This increases the glucose requirement of the tumor cells and is used for PET scanning in which we
Neoplasia
inject 18F-fluorodeoxyglucose which is preferentially taken by actively dividing tumor cells and hence,
we make a diagnosis.
Cyclin D is the first cyclin to CELL CYCLE AND CONTROL MECHANISMS

increase in the cell cycle.
Cell cycle consists of five phases. These include:
Pre-synthetic phase

G1 :
S : Synthetic phase (DNA synthesis)
Post-synthetic pre-mitotic phase

G2 :
M : Mitotic phase: Cells divide and produce new cells, which either directly re-enter next
cycle or pass into nonproliferative G phase
G
0
0
: Quiescent state: Cells in this state remain quiescent for variable periods, but can be
The phosphorylation of RB is recruited in cell cycle if stimulated later.
a molecular ON-OFF switch for
the cell cycle.
Resting (non-dividing) cells are in the G0 stage of the cell cycle and must enter G1
stage for replication. The orderly progression of cells through the various phases of cell
cycle is controlled by cyclins and cyclin-dependent kinases (CDKs), and by their inhibitors.
CDKs are expressed constitutively during the cell cycle but in an inactive form
whereas cyclins are synthesized during specific phases of the cell cycle, and their
The initiation of DNA replica- function is to activate the CDKs.
tion involve the formation of an Cyclins D, E, A, and B appear sequentially during the cell cycle and bind to one or
active complex between cyclin more CDKs.
E and CDK2.
During the G1 phase of the cell cycle, cyclin D binds to and activates CDK4,
forming a cyclin D-CDK4 complex. This complex has a critical role in the cell cycle by
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phosphorylating the retinoblastoma susceptibility protein (RB). The phosphorylation

of RB is a molecular ON-OFF switch for the cell cycle. In its hypophosphorylated state,
RB prevents cells from replicating by forming a tight, inactive complex with the
transcription factor E2F. Phosphorylation of RB dissociates the complex and results
in activation of E2F. Thus, phosphorylation of RB eliminates the main barrier to cell-cycle
progression and promotes cell replication. Activated E2F results in transcription of target
genes essential for progression through the S phase. These include cyclin E, DNA
polymerases, thymidine kinase, dihydrofolate reductase, and several others.
Further progression through the S phase and the initiation of DNA replication involve the
formation of an active complex between cyclin E and CDK2. The next decision point in
the cell cycle is the G2/M transition. This transition is initiated by the E2F-mediated
transcription of cyclin A, which forms the cyclin A-CDK2 complex that regulates
events at the mitotic prophase. The main mediator that propels the cell beyond
prophase is the cyclin B-CDK1 complex, which is activated by a protein phosphatase
(Cdc 25). Cyclin B-CDK1 activation causes the breakdown of the nuclear envelope and The main mediator that propels
initiates mitosis. the cell beyond prophase is the
Complexes of CDKs with cyclins A and B regulate some critical events at the cyclin B-CDK1 complex.
G2/M transition, such as the decrease in microtubule stability, the separation
of centrosomes, and chromosome condensation. Exit from mitosis requires the
inactivation of cyclin B-CDK1.
Cell-Cycle Inhibitors
The activity of cyclin-CDK complexes is tightly regulated by inhibitors, called CDK inhibitors. There
are two main classes of CDK inhibitors: the Cip/Kip and the INK4/ARF families. G1/S check-point is controlled

The Cip/Kip family has three components, p21, p27, and p57, which bind to and by p53 whereas G2/M check-
inactivate the complexes formed between cyclins and CDKs. Transcriptional point has both p53 dependent as
activation of p21 is under the control of p53 well independent mechanisms.

The human INK4a/ARF locus (a notation for inhibitor of kinase 4/alternative reading
frame) encodes two proteins, p16INK4a and p14ARF, which block the cell cycle and
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act as tumor suppressors. p16INK4a competes with cyclin D for binding to CDK4
and inhibits the ability of the cyclin D-CDK4 complex to phosphorylate RB, thus
causing cell-cycle arrest at late G1 whereas p14ARF prevents p53 degradation.
Cell-Cycle Checkpoints
The cell cycle has its own internal controls, called checkpoints. There are two main checkpoints,
one at the G1/S transition and another at G2/M.
The S phase is the point of no return in the cell cycle, and before a cell makes the final
commitment to replicate, the G1/S checkpoint checks for DNA damage. If DNA
damage is present, the DNA repair machinery and mechanisms that arrest the cell
cycle are put in motion. The delay in cell-cycle progression provides the time needed
for DNA repair; if the damage is not repairable, apoptotic pathways are activated
to kill the cell. Thus, the G1/S checkpoint prevents the replication of cells that have
defects in DNA, which would be perpetuated as mutations or chromosomal breaks
in the progeny of the cell.
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DNA damaged after its replication can still be repaired as long as the chromatids have
Cells damaged by ionizing radi- not separated. The G2/M checkpoint monitors the completion of DNA replication
ation activate the G2/M check- and checks whether the cell can safely initiate mitosis and separate sister chromatids.
point and arrest in G2; defects in This checkpoint is particularly important in cells exposed to ionizing radiation.
this checkpoint give rise to chro- To function properly, cell-cycle checkpoints require sensors of DNA damage, signal
mosomal abnormalities. transducers, and effector molecules. The sensors and transducers of DNA damage
appear to be similar for the G1/S and G2/M checkpoints. The checkpoint effector
molecules differ, depending on the cell-cycle stage at which they act. In the G1/S
checkpoint, cell-cycle arrest is mostly mediated through p53, which induces the cell-
cycle inhibitor p21. Arrest of the cell cycle by the G2/M checkpoint involves both
p53-dependent (via cyclin A/cdK-2) and independent (via cdc 25) mechanisms.
Proteins of the RAD and ataxia
p53 links cell damage with DNA repair, cell-cycle arrest, and apoptosis. In response to DNA
damage, it is phosphorylated by genes that sense the damage and are involved in DNA repair.
telangiectasia mutated (ATM) p53 assists in DNA repair by causing G1 arrest and inducing DNA repair genes. A cell
families act as sensors.
with damaged DNA that cannot be repaired is directed by p53 to undergo apoptosis. With
Proteins of the CHK kinase
homozygous loss of p53, DNA damage goes unrepaired and mutations increase the chances
families act as transducers.
of malignant transformation.
Regulation of Cell Cycle
p53 is called as guardian of

the genome.
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Prophase: The chromatin is

condensing into chromosomes.
Metaphase: chromosomes align

at the metaphase plate.
Anaphase: The chromosomes

split and the kinetochore micro-
tubules shorten.
Telophase: the decondensing

chromosomes are surrounded
by nuclear membranes.
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CARCINOGENESIS
It is a multi-step process which requires accumulation of multiple genetic changes either

as germline or somatic mutations. The following four are the principal targets of genetic
damage:
I. Proto-Oncogenes
Proto-oncogenes (Normal genes required for cell proliferation and differentiation)
Oncogenes (Genes promoting autonomous cell growth in cancer cells)
Oncoproteins (Proteins lacking regulatory control and responsible for promoting Proto-oncogenes were discovered
cell growth) by Harold Varmus and Michael
Selected Oncogenes, their mode of activation and associated human tumors Bishop.
Category Proto- Mode of Associated human tumor

oncogenes activation
Growth factors
PDGF-b chain SIS Overexpression Astrocytoma
Osteosarcoma
Fibroblast growth HST-1 Overexpression Stomach cancer
factors INT-2 Amplification Bladder cancer
Neoplasia
Breast cancer
Melanoma
TGF-a TGFA Overexpression Astrocytomas
Hepatocellular carcinomas
HGF HGF Overexpression Thyroid cancer The non receptor excessive
tyrosine kinase activity associated
Growth factor: Receptors
with CML is countered by a
EGF-receptor family ERB-B1 Overexpression Squamous cell carcinomas of lung, gliomas specific tyosine kinase inhibitor
(EGFR) Amplification Breast and ovarian cancers drug called imatinib. This is
ERB-B2 an example of targeted drug
therapy
CSF-1 receptor FMS Point mutation Leukemia
Receptor for RET Point mutation Multiple endocrine neoplasia 2A and B,
neurotrophic factors familial medullary thyroid carcinomas
PDGF receptors PDGF-R Overexpression Gliomas
Receptor for stem KIT Point mutation Gastrointestinal stromal tumors and other
cell (steel factor) soft tissue tumors
Proteins involved in signal transduction
GTP-binding K-RAS Point mutation Colon, lung and pancreatic tumors
H-RAS Point mutation Bladder and kidney tumors
N-RAS Point mutation Melanomas, hematologic malignancies
Non-receptor ABL Translocation Chronic myeloid leukemia
tyrosine kinase Acute lymphoblastic leukemia
RAS signal BRAF Point mutation Melanomas
transduction
Contd...
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Contd...
WNT signal b-catenin Point mutation Hepatoblastomas, hepatocellular carcinoma
transduction Overexpression
Nuclear regulatory proteins
Transcriptional C-MYC Translocation Burkitt lymphoma
activators N-MYC Amplification Neuroblastoma, small cell carcinoma of lung
L-MYC Amplification Small cell carcinoma of lung
Cell-cycle regulators
Cyclins CYCLIN D Translocation Mantle cell lymphoma
Amplification Breast and esophageal cancers
CYCLIN E Overexpression Breast cancer
Cyclin dependent CDK4 Amplification or Glioblastoma, melanoma, sarcoma
kinase point mutation
The Important Oncogenes Include

The point mutation of the
RAS family gene is the single 1. RAS It is an example of signal transducing protein. Normally, inactive RAS binds to
most common abnormality of GDP and the presence of growth factor causes GDP to be exchanged by GTP causing
dominant oncogenes in human RAS activation. The activated RAS binds to its farnesyl transferase receptor causing
tumors.
increased activation of MAP kinase and promoting mitogenesis. The activated RAS
comes back to its normal inactive state due to the intrinsic GTPase activity which
gets augmented due to a group of proteins called GTPase Activating Proteins (or
GAP). Mutated RAS proteins bind to GAP without augmentation of GTPase activity
resulting is uncontrolled mitogenesis and tumor formation.
Neurofibromin (protein affected

Neoplasia
in neurofibromatosis 1) is an
example of GAP whose mutation
results in neurofibromatosis 1.
The different types of RAS affected in different tumors are:

K RAS Colon, lung and pancreatic tumors
N RAS Melanoma, blood tumors (AML)
H RAS Bladder and kidney tumors
2. ABL It possess non-receptor associated tyrosine kinase activity. C-ABL present on

chromosome 9 fuses with BCR gene on chromosome 22 and result in Philadelphia
chromosome (t 9;22). The fusion gene possesses uncontrolled tyrosine kinase activity
responsible for causing cancer development.
3. MYC Normally in the presence of growth factors, increased levels of MYC along
MYC is the most common with another protein, MAX form a heterodimer and cause activation of transcription.
nuclear transcription regulator Uncontrolled nuclear transcription gives rise to development of cancer. In the
affected in the human tumors. absence of growth factor, MYC can cause apoptosis. The types of MYC and the
tumors associated with their mutation include:

a. C MYC - Burkitts lymphoma

b. L- MYC - Small cell lung cancer [L- for lung]

c. N- MYC - Neuroblastoma [N for Neuroblastoma]
MYC gene is associated Loss of function mutations in RET oncogene result in intestinal aganglionosis and Hirschsprung
with Conflict model in disease
carcinogenesis Gain of function mutations in RET oncogene result in Multiple Endocrine Neoplasia (MEN 2A/2B)
syndromes.
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Neoplasia

II. Tumor Suppressor Genes
These genes normally regulate cell growth (they do not prevent tumor formation,
so the name is actually a misnomer). Any failure of growth regulation causes
development of cancer.
Selected Tumor Suppressor Genes involved in Human Neoplasms
Subcellular Gene Function Tumors associated Tumors associated
Location with Somatic with Inherited
Mutations Mutations
Cell surface TGF-b Growth inhibition Carcinoma of colon Unknown
receptor Cell adhesion Carcinoma of Familial gastric
E-cadherin stomach cancer
Inner aspect NF-1 Inhibition of RAS Neuroblastoma Neurofibromatosis
of plasma signal transduction type 1 and
membrane and of p21 cell-cycle sarcomas
inhibitor
Cytoskeleton NF-2 Cytoskeleton stability Schwannomas and Neurofibromatosis
meningiomas type 2, acoustic
schwannomas and
meningiomas
Cytosol APC/b- Inhibition of signal Carcinomas Familial
catenin transduction of stomach, adenomatous
colon, pancreas; polyposis coli/colon
melanoma cancer
PTEN PI-3 kinase signal Endometrial and Unknown
transduction prostate cancers
SMAD 2 and TGF-b signal Colon, pancreas Unknown
SMAD 4 transduction tumors Breast carcinoma is most
Neoplasia
Nucleus RB Regulation of cell cycle Retinoblastoma; Retinoblastomas, common malignancy in females
osteosarcoma, osteosarcoma in India.
carcinomas of It is associated with mutations in
breast, colon, lung BRCA1 and BRCA2 genes.
P53 Cell-cycle arrest and Most human Li-Fraumeni

apoptosis in response cancers syndrome; multiple
to DNA damage carcinomas and
sarcomas
WT-1 Nuclear transcription Wilms tumor Wilms tumor
P16 (INK4a) Regulation of cell cycle Pancreatic, breast Malignant
by inhibition of cyclin- and esophageal melanoma
dependent kinase cancers
BRCA-1 and DNA repair Unknown Carcinoma of
BRCA-2 female breast and
ovary; carcinomas
of male breast
KLF-6 Transcription factor Prostate Unknown
Some important tumor suppressor genes include:

1. RB gene RB gene was the first tumor

In the active or hypophosphorylated state, it is present in the non- multiplying suppressor
discovered.
gene to be
cells. The oncogenic viruses cause phosphorylation of RB resulting in its
inactivation. The RB inactivation results in cell multiplication by activation of
the transcription factor E2F (as discussed eariler under control mechanism of
cell cycle).
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The normal RB gene is present

on chromosome 13q14.
Concept of Loss of Heterozygosity (LOH)

Retinoblastoma is a prime example of a tumor which is associated with loss of
Retinoblastoma is associated heterozygosity. This term is mostly used in the context of oncogenesis.
with Concept of Loss of Retinoblastoma develops when both the normal alleles of the Rb gene are inactivated
Heterozygosity as well as or altered.
Knudsons Two Hit Hypothesis
In familial case of retinoblastoma, children are born with one normal and one defective
copy of the Rb gene.
Such a child is said to be heterozygous at the Rb locus (one allele of the gene is normal
while the other is a mutant). So, till the time there is heterozygosity for the Rb gene, the
cell behavior is not affected (no chances of cancer development).
When there is a mutation affecting the second allele, the chances of cancer increases.
It means that the cell loses heterozygosity for the normal Rb gene (called as loss
of heterozygosity).
Loss of heterozygosity is the basis of two hit hypothesis of cancers (Knudsons
hypothesis).
Knudsons Two Hit Hypothesis

According to this hypothesis, both the normal alleles should be inactivated for the
Neoplasia
development of retinoblastoma. Retinoblastoma can be of the following types:

a. Inherited/Familial Retinoblastoma (40%)
In hereditary cases of Retinoblastoma one genetic change (first hit) is inherited from the
affected parent therefore it is present in all the somatic cells of the body. But one genetic
change is not sufficient to produce cancer. The second mutation (second hit) is required
Familial Retinoblastoma is also to produce cancer. It occurs in the retinal cells (which are carrying the first mutation).
associated with increased risk of
osteosarcomas. b. Sporadic Retinoblastoma (60%)
In sporadic cases both mutations (hits) occur somatically within a single retinal cell
whose progeny then form the tumor.

2. p 53 gene
p53 is the most commonly
It is also known as molecular policeman and guardian of the genome. The gene is
present on chromosome 17p. The non-mutated p53 gene is also called as the wild
mutated gene in human cancers.
type of p53 gene and is associated with reduced risk of development of cancers.
Any inactivation of p53 prevents successful DNA repair in a cell leading to the
development of a tumor. The p53 gene codes for 53 KDa nuclear phophoprotein.

In most of the cases, the inactivating mutations in both the alleles of p53 are
acquired in somatic cells. However, sometimes individual may inherit one
mutant p53 allele and the second acquired hit may inactivate the normal p53
allele. This later condition is called Li-Fraumeni syndrome associated with
development of sarcoma, breast cancer, leukemia and brain tumors.

Human papilloma virus (HPV) causes inactivation of p53 through its E6 protein
and so, is responsible for development of cancer of anal and genital region.
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Neoplasia
The non-mutated p53 gene is

also called as the wild type of
p53 gene and is associated with
reduced risk of development of
cancers.
Cancers carrying p53 mutations

are relatively resistant to
chemotherapy and radiotherapy.
Concept
MicroRNAs (miRNAs) are small
RNA molecules which inhibit
gene expression. They DONOT
encode proteins. miRNAs get
incorporated into a multiprotein
complex called RISC (RNA-
induced silencing complex).
Then it can either cause target
Note: p73 (big brother of p53) and p63 are other members of the family of p53 gene. p63 is esential
mRNA cleavage or repress its
for the differentiation of stratified squamous epithelia. p73 has pro-apoptotic effects after DNA damage
translation.
Neoplasia
induced by the chemotherapeutic agents.
Mir34 family of miRNAs is
3. NF-1 and NF2 gene activated by p53 gene. The
NF- 1 gene gives rise to neurofibromin which is a GTPase activating protein (GAP). targets of mir34 include pro-
NF2 gives rise to neurofibromin 2 or merlin protein which inhibits the proliferation proliferative genes like cyclins
of Schwann cells. So, any mutation affecting any of these genes increases the chances and anti-apoptotic genes like
bcl2. This is an important
of development of cancer.
mechanism by which p53 gene

III. Genes Regulating Apoptosis is able to repress the function of
Apoptosis (or programmed cell death) is promoted by the genes bax, bad, bcl- Xs and other genes.
p53 whereas it is inhibited by bcl-2. Understandably, any increase in bcl-2 would
cause inhibition of apoptosis and development of cancer. Normally chromosome
14 has immunoglobulin heavy chain gene whereas chromosome 18 has bcl-2 gene.
In follicular lymphoma, there is presence of translocation t (14:18)Q which causes Small interfering RNAs
increased expression of bcl-2 thereby preventing apoptosis and inducing the (siRNAs) are similar to miRNA
development of cancer. except that siRNA precursors are

IV. Genes Inhibiting DNA Repair introduced by investigators into
the cell. So, they are now used
Defective DNA repair increases DNA instability increasing the chances of for studying gene function.
development of a cancer. This can be of the following three types:
Additional features of diseases

with defects in DNA repair by homo-
logous recombination include bone
marrow depression (Fanconis
anemia), developmental defects
(Bloom syndrome) and neural
symptoms (Ataxia telangiectasia).
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MULTI-STEP CARCINOGENESIS
The normal epithelium undergoes sequential mutations in different genes eventually leading
to development of carcinoma.
Multistep carcinogenesis is
best seen in cancers like colon
cancer
TUMOR GROWTH
SPREAD OF TUMORS
Detachment of tumor cells
Neoplasia
1.
Due to E-cadherin and ab-
normal catenin
Genes promoting metastasis
include ezrin (in rhabdomyosar-
2. Attachment to matrix compo-
nent fibronectin and laminin
coma and osteosarcoma)
due to integrins (on cancer
Genes inhibiting metastasis cells)
include NM23, KAI-1 (prostate
cancer) and Ki55 [malignant
3. Degradation of extracellular
matrix by serine, cysteine and
melanoma]
matrix metalloproteinases
4. Intravasation
5. Tumor cell embolus
6. Extravasation CD44 on T
cells used by tumor cells for
migration in lymphoid tissue
7. Metastatic deposit
Cancer causing agents
Sir Percival Pott demonstrated

the increased incidence of
scrotal skin cancer in chimney Chemical carcinogenesis Radiation exposure Microbial carcinogenesis
workers exposed to chemical
soot. I. Chemical Carcinogens
Chemical carcinogenesis has two steps called initiation and proliferation. Initiation
can be by two types of agents
144
Neoplasia

Direct acting agents These are mutagens causing cancer by direct damage or
a.
modification of DNA.
b.
Indirect acting agents (also called as procarcinogens) These require metabolic
conversion to form active carcinogens.
Concept
Initiators cause irreversible DNA damage. The proliferation of the tumor cells is done by Initiators cause irreversible
promoters (chemicals causing multiplication of already mutated cells). The promoters cause DNA damage. The proliferation
reversible DNA damage. The carcinogenic potential of a chemical is tested by Ames test of the tumor cells is done by
promoters (chemicals causing
Chemical Carcinogens multiplication of already mutated
cells). The promoters cause
Alkylating agents Acute myeloid leukemia, bladder cancer reversible DNA damage.
Androgens Prostate cancer
Aromatic amines (dyes) Bladder cancer
Arsenic Cancer of the lung, skin
Asbestos Cancer of the lung, pleura, peritoneum
Concept
Benzene Acute myelocytic leukemia
Chromium Lung cancer
In Ames test, a modified bacte-
Diethylstilbestrol (prenatal) Vaginal cancer (clear cell) rium Salmonella typhimurium
Epstein-Barr virus Burkitts lymphoma, nasal T cell lymphoma is used, which is unable to pro-
duce histidine due to absence
Estrogens Cancer of the endometrium, liver, breast
of histidine synthetase enzyme
Ethyl alcohol Cancer of the liver, esophagus, head and neck in it.
Immunosuppressive agents (azathioprine, Non-Hodgkins lymphoma The modified bacteria are first
cyclosporine, glucocorticoids) put on a histidine free medium
Nitrogen mustard gas Cancer of the lung, head and neck, nasal sinuses where it cannot grow.
Nickel dust Cancer of the lung, nasal sinuses Then it is put on the same me-
Neoplasia
dium but now having additionally
Oral contraceptives Bladder and cervical cancer the presence of the suspected
Phenacetin Cancer of the renal pelvis and bladder mutagen. In the second case,
the bacteria grow if the chemical
Polycyclic hydrocarbons Cancer of the lung, skin (especially squamous cell
has mutagenic potential.
carcinoma of scrotal skin)
The in vitro mutagenic potential
Schistosomiasis Bladder cancer (squamous cell)
correlates well with the carcino-
Sunlight (ultraviolet) Skin cancer (squamous cell and melanoma) genic potential in vivo.
Tobacco (including smokeless) Cancer of the upper aerodigestive tract, bladder
Vinyl chloride Liver cancer (angiosarcoma)
CLL is the only leukemia

NOT associated with ionizing
radiation exposure
Basal cell carcinoma is the

most common cancer due to
excessive UV light exposure.
Squamous cell carinoma may

develop in third degree burn
scars and orifices of chronically
draining sinuses (as in chronic
ostemyelitis)
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Infectious Organisms
BACTERIA (H. PYLORI)

H. pylori is the first bacterium classified as a carcinogen. H. pylori infection is implicated in the
HHV8 is associated with
Primary effusion lymphoma
genesis of both gastric adenocarcinomas and gastric lymphomas. The gastric lymphomas are
and Multicentric Castlemans of B-cell originQ and are called MALT lymphomas (marginal zone-associated lymphomas)
disease because the transformed B cells normally reside in the marginal zones of lymphoid follicles.
H. pylori infection results in the formation of H. pylori-reactive T cells, which cause polyclonal
B-cell proliferations. The MALT lymphoma is associated with t(11;18)Q translocation.
VIRUSES
HCV is associated with
Carcinogenic Viruses
Lymphoplasmacytic
lymphoma
RNA viruses DNA viruses

Human T cell leukemia virus-1 (HTLV-1) Hepatitis B virus (HBV)
Hepatitis C virus (HCV) Human herpes virus 8 (HHV8)
Human papilloma virus (HPV)
Epstein-Barr virus (EBV)
Pathogenesis
HTLV1 can cause T-cell leu- HTLV-1

kemia/lymphoma and demyeli- It is a RNA oncogenic virus which is transmitted by blood products, sexual intercourse or
nating disorder called Tropical breast feeding. It has attraction for CD4 T cells (similar to HIV). HTLV-1 has a gene TAX. The
spastic paraparesis.
TAX proteinQ causes
Neoplasia

1. Transcription of host genes involved in proliferation and differentiation of T-cells
(e-FOS, IL-2 genes)

2. Genomic instability by inhibiting DNA repair function and by inhibiting cell cycle
checkpoints activated by DNA damage
These contribute to increased chances of cancer by HTLV-1.
HCV
Hepatitis C virus (HCV) is also strongly associated with the development of hepatocellular
carcinoma. This is associated with its ability to cause chronic liver cell injury and inflammation
that is accompanied by liver regeneration. Mitotically active hepatocytes, surrounded by an
altered environment, are presumably prone to genetic instability and cancer development.
EBV
EBV is associated with mixed It is a DNA oncogenic virus. It causes infection of epithelial cells of oropharynx and B- cells
cellularity variant of Hodgkins because of the presence of CD21 moleculeQ on the surface of these cells. LMP-1 geneQ present
lymphoma in the EBV causes activation of NF- and JAK/STAT signaling pathways thereby promoting
B-cell survival and proliferation. (This increases the chances of B- cell lymphoma). Another
EBV-encoded gene, EBNA-2, transactivates several host genes like cyclin D and the src family
genes. The EBV genome also contains a viral cytokine, vIL-10 which prevents macrophages
and monocytes from activating T cells and is required for EBV-dependent transformation of
B cells. EBV acts a polyclonal B-cell mitogen followed by acquisition of t(8;14)Q translocation
Nasopharyngeal cancer is which ultimately results in development of Burkitts lymphoma.
the only T cell malignancy
amongst the cancers caused by *EBV belongs to the herpes family and can cause the following cancers:
EBV
African form of Burkitts lymphoma

B- cell lymphoma in immunosuppressed individuals

Hodgkins lymphoma

Nasopharyngeal cancer
146
Neoplasia
HBV
It encodes for HBx proteinQ which disrupts the normal growth control of infected liver
cells by activation of several growth promoting genes. HBx also causes inactivation of the tumor
suppressor gene p53. This results in HBV causing hepatocellular cancer.
HPV
It is responsible for development of squamous cell carcinoma of cervix and anogenital lesion
and in some cases, oral and laryngeal cancers. The virus gets integrated in the genome of host E6 gene product inhibits P53
cells which is essential for the malignant transformation of the affected cells HPV 16 (more suppressor gene
commonly) and HPV 18 (less commonly) are particularly important in carcinogenesis as they E7 gene product inhibits RB
suppressor gene
have viral genes E6 and E7 which causes Rb and p53 gene inactivation respectively. Since
both p53 and Rb are tumor suppressor genes, so, their inactivation increases the chances of
cancer development.
PARANEOPLASTIC SYNDROMES
Clinical syndromes Major forms of underlying Causal mechanism

cancer
Endocrinopathies
Cushing syndrome Small cell carcinoma of lung ACTH or ACTH-like
Pancreatic carcinoma substance
Neural tumors
Syndrome of inappropriate Small cell carcinoma of lung; Antidiuretic hormone or
antidiuretic hormone secretion Intracranial neoplasms atrial natriuretic hormones
Hypercalcemia Squamous cell carcinoma of lung Parathyroid hormone-
Breast carcinoma related protein (PTHRP),
Renal carcinoma TGF-a, TNF, IL-1
Neoplasia
Adult T-cell leukemia/lymphoma
Ovarian carcinoma Cushing syndrome is the most
common endocrinopathy.
Hypoglycemia Fibrosarcoma Insulin or insulin-like
Other mesenchymal sarcomas substance
Hepatocellular carcinoma
Carcinoid syndrome Bronchial adenoma (carcinoid) Serotonin, bradykinin
Pancreatic carcinoma
Gastric carcinoma
Polycythemia Renal carcinoma Erythropoietin Hypercalcemia is probably the
Cerebellar hemangioma most common paraneoplastic
syndrome.
Nerve and Muscle Syndromes
Myasthenia Bronchogenic carcinoma Immunologic
Disorders of the central and Breast carcinoma
peripheral nervous systems
Dermatologic Disorders
Trousseau phenomenon (Migra-
Acanthosis nigricans Gastric carcinoma Immunologic; secretion of
tory thrombophlebitis) is seen
Lung carcinoma epidermal growth factor
with pancreatic and broncho-
Uterine carcinoma
genic carcinoma
Dermatomyositis Bronchogenic, breast carcinoma Immunologic
Osseous, Articular, and Soft Tissue Changes
Hypertrophic osteoarthropathy Bronchogenic carcinoma Unknown
and clubbing of the fingers
contd...
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contd...
Vascular and Hematologic Changes
Venous thrombosis Pancreatic carcinoma Tumor products (mucins
(Trousseau phenomenon) Bronchogenic carcinoma that activate clotting)
Other cancers
Nonbacterial thrombotic Advanced cancers Hypercoagulability
endocarditis
Concept Anemia Thymic neoplasms Unknown
Grading of a cancer is based on Others
the degree of differentiation of
the tumor cells and the number Nephrotic syndrome Various cancers Tumor antigens, immune
of mitoses within the tumor as complexes
presumed correlates of the ACTH, adrenocorticotropic hormone; TGF, transforming growth factor; TNF, tumor necrosis factor; IL,
neoplasms aggressiveness. interleukin.
IMMUNOHISTOCHEMISTERY
Concept
The staging of cancers is based It is a method for diagnosis of cancer.
on the size of the primary
1. Categorization of undifferentiated malignant tumor: Sometimes, many tumors
lesion, its extent of spread to like anaplastic carcinoma, lymphoma, melanoma and sarcoma are difficult to
regional lymph nodes, and the distinguish with routine H and E staining because of poor differentiation. So,
presence or absence of distant immunohistochemical stains can help in diagnosis e.g.
metastases.

Presence of cytokeratin points to epithelial origin (carcinoma).

Presence of desmin is specific for muscle cell origin.

Presence of Leucocyte Common Antigen (LCA) points to lymphoma.

2. Determination of site of origin of metastatic tumor: There are markers that point to
the origin of tumor (primary) in a biopsy specimen of metastasis. Examples include
Neoplasia
PSA (for prostate cancer) and thyroglobulin (for thyroid cancer).

3. Prognostic or therapeutic significance: Estrogen/progesterone receptor detection
has therapeutic value in breast carcinomas. Receptor positive breast cancers are
susceptible to anti-estrogen therapy. Similarly, over-expression of erb-B2 protein
suggests a poor prognosis.
TUMOR MARKERS
Tumor markers are biochemical substances (include cell-surface antigens, cytoplasmic

proteins, enzymes, and hormones) which indicate the presence of a tumor.
Markers Associated Cancers
Hormones
Concept Human chorionic gonadotropin (hCG) Trophoblastic tumors, non-seminomatous testicular
hCG is a placental glycoprotein tumors
hormone composed by and Calcitonin Medullary carcinoma of thyroid
subunits. Alpha hCG is not
used as tumor marker because Catecholamine and metabolites Pheochromocytoma and related tumors
it is similar to the FSH, LH and Ectopic hormones See above
TSH. The beta subunit of hCG
is typically measured as a tumor Oncofetal Antigens
marker because it has unique a-Fetoprotein Liver cell cancer, non-seminomatous germ cell
sequence that are not shared tumors of testis
with other human glycoprotein
Carcinoembryonic antigen Carcinomas of the colon, pancreas, lung, stomach,
hormones. So, it is quite specific
and heart
and there is no cross reactivity
between beta subunits of these Isoenzymes
hormones.
Prostatic acid phosphatase Prostate cancer
Neuron-specific enolase Small cell cancer of lung, neuroblastoma
contd...
148
Neoplasia
contd...
Specific Proteins
Immunoglobulins Multiple myeloma and other gammopathies
Prostate-specific antigen and prostate- Prostate cancer
specific membrane antigen
Mucins and Other Glycoproteins
CA-125 Ovarian cancer
CA-19-9 Colon cancer, pancreatic cancer Valproate embyopathy is due
to mutation in HOX geneQ.
CA-15-3 Breast cancer
New Molecular Markers
p53, APC, RAS mutations in stool and serum Colon cancer
p53 and RAS mutations in stool and serum Pancreatic cancer
p53 and RAS mutations in sputum and serum Lung cancer
p53 mutations in urine Bladder cancer
Vitamin A induced embryopathy
The important antigens for the determination of specific tumor cell origin are:
is due to mutation in TGF-Q
Epithelial Tumors signaling pathway.

Breast: Alpha lactalbumin, GCDP-15, estrogen/progesterone

Thyroid: Thyroglobulin, calcitonin

Liver: AFP (a fetoprotein), HBsAg , keratin

Prostate: Prostatic acid phosphatase, prostate specific antigen

Mesothelioma: Keratin, Calretinin, mesothelin
Germ Cell Tumors

Human chorionic gonadotropin, AFP (a-fetoprotein)
t(12;15) (p13;q25) is associated
Mesenchymal Tumors with congenital infantile fibro-

Neoplasia
Endothelial tumors: Factor VIII, CD 34, sarcoma

Melanoma: HMB 45, S 100

Fibrohistiocytic tumors: Lysozyme, HAM 56

Myogenic tumors: Desmin, smooth muscle specific antigen, myoglobin
Neuroendocrine Tumors

Neuron specific enolase (NSE), chromogranin, synaptophysin

Malignant melanoma expresses HMB 45, S-100 and vimentin. HMB 45 is present
In malignant melanoma, HMB
in melanosomes and is more specific. S-100 is more sensitive but is non-specific 45 is more specific whereas
(also present in Langerhans cell histiocytosis, neural tumors, and sarcomas like S-100 is more sensitive.
liposarcoma and chondrosarcoma)

Neurofibroma (a neural tumor) shows the presence of S100 and GFAP (Glial
Fibrillary Acid Protein). Malignant tumors often lose expression of S-100
antigen.

Neuroblastoma expresses NSE, chromogranin and synaptophysin. NSE is more
specific whereas chromogranin and synaptophysin are more sensitive tumor
markers.

Angiosarcoma expresses factor VIII, vimentin and CD34 antigen
Type of tumors associated with intermediate filaments:

Intermediate Filament Normal Tissue Expression Tumor
Cytokeratin All epithelial cells Carcinoma
Vimentin Mesenchymal cells Sarcomas
Desmin Muscle cells Leiomyoma
Rhabdomyosarcoma In neuroblastoma, NSE is more
specific whereas chromogranin
Glial Fibrillary Acidic Protein (GFAP) Glial cells Astrocytoma and synaptophysin are more
Ependymoma sensitive tumor markers.
Neurofilament Neurons and Neural crest Pheochromocytoma
derivatives Neuroblastoma
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CONCEPT OF TUMOR LYSIS SYNDROME

Tumor lysis syndrome Tumor lysis syndrome is caused by destruction of large number of rapidly proliferating
is associated with Burkitt
neoplastic cells. It is characterized by
lymphoma, acute lymphoblastic
leukemia (ALL), chronic tumors
(CLL) and uncommonly solid Hyperuricemia (due to increased turnover of nucleic acids)
tumors. Hyperkalemia (due to release of the most abundant intracellular cation potassium)
It is associated with hypocalce- Hyperphosphatemia (due to release of intracellular phosphate)
mia and NOT hypercalcemia. Hypocalcemia (due to complexing of calcium with the elevated phosphate)
Lactic acidosis
Hyperuricemia can cause uric acid precipitation in the kidney causing acute renal failure.
Neoplasia
150
Neoplasia

NEOPLASIA: General Aspects
(c) Chronic ulcerative colitis

(d) Leiomyoma of the uterus
1. Which of the following helps in differentiation of 9. A strong propensity for vascular invasion is seen in:
follicular carcinoma from follicular adenoma of thyroid (a) Prostatic carcinoma (Karnataka 2008)
gland? (AI 2011, AIIMS May 2010) (b) Hepatocellular carcinoma
(a) Hurthle cell change (c) Bronchogenic carcinoma
(b) Lining of tall columnar and cuboidal cells (d) Gastric carcinoma
(c) Vascular invasion
(d) Increased mitoses 10. Earliest changes of neoplastic transformation as seen at
a microscopic level is called: (Karnataka 2004)
2. All are malignant tumors, except: (AI 2008) (a) Hyperplasia
(a) Chloroma (b) Metaplasia
(b) Fibromatosis (c) Dysplasia
(c) Askins tumor (d) Carcinoma in situ
(d) Liposarcoma
11. Squamous cell carcinoma spreads by: (RJ 2000)
3. The following is not a feature of malignant (a) Hematogenous route
transformation by cultured cells: (AI 2005) (b) Lymphatic route
(a) Increased cell density (c) Direct invasion
(b) Increased requirement for growth factors (d) All
(c) Alterations of cytoskeletal structures
(d) Loss of anchorage
12. Which one of the following tumors does not cause bony
metastasis? (AP 2000)
Neoplasia
4. Which of the following carcinoma most frequently (a) Renal cell carcinoma
metastasizes to brain? (AIIMS Nov 2005) (b) Gastric carcinoma
(a) Small cell carcinoma lung (c) Thyroid carcinoma
(b) Prostate cancer (d) Breast carcinoma
(c) Rectal carcinoma 13. Hamartoma is: (AP 2003)
(d) Endometrial cancer (a) Proliferation of cells in foreign site
5. Chemotherapeutic drugs can cause: (b) Proliferation of native cells in tissue
(a) Only necrosis (AIIMS May 2005) (c) Malignant condition
(b) Only apoptosis (d) Acquired condition
(c) Both necrosis and apoptosis 14. Sure sign of malignancy is: (AP 2005)
(d) Anoikis (a) Mitoses
6. Reversible loss of polarity with abnormality in size and (b) Polychromasia
shape of cells is known as: (AIIMS Nov 2001) (c) Nuclear pleomorphism
(a) Metaplasia (d) Metastasis
(b) Dysplasia 15. A lesion 3 cm away from gastroesophageal junction
(c) Hyperplasia contain columnar epithelium, such a type of lesion is:
(d) Anaplasia (a) Metaplasia (Bihar 2004)
7. Predisposing factors for skin cancer are: (b) Hyperplasia
(a) Smoking (PGI Dec 2000) (c) Dysplasia
(b) U-V-light (d) Anaplasia
(c) Chronic ulcer 16. Malignancy is typically associated with disordered
(d) Infrared light differentiation and maturation. Which of the following
8. Increased risk of cancer is seen in: mentioned options best describes anaplasia?

(a) Fibroadenoma of breast (Delhi PG 2009 RP) (a) Hepatic tumor cells synthesizing bile
(b) Bronchial asthma
(b) Skin tumor cells producing keratin pearls
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(c) Bronchial epithelial cells producing keratin pearls
(c) Selectins

(d) Muscle tumor cells forming giant cells
(d) Calmodulin
17. A 42 year-old woman Himanshi has an abnormal bloody 20.4. Which of the following is not a labile cell?
discharge from her left nipple. She underwent the (a) Bone marrow
investigations and was diagnosed with an early stage (b) Epidermal cells
breast cancer. Lumpectomy was performed and a slide (c) Small intestine mucosa
was sent to the laboratory. The pathologist comments (d) Hepatocytes
that there is significant desmoplasia in the surrounding
tissue. The term desmoplasia is best descriptive of
20.5. Which one is not the pre cancerous condition?
(a) Crohns disease
(b) Ulcerative colitis

(a) An irregular accumulation of blood vessels.
(c) Leukoplakia

(b) Metastatic involvement of surrounding tissue.
(d) Xeroderma pigmentosum

(c) Normal tissue misplaced within another organ.

(d) Proliferation of non- neoplastic fibrous connective 2 0.6. Which of the following features differentiates invasive
tissue. carcinoma from carcinoma in situ?
(a) Anaplasia
18. All of the following are true of familial cancers except (b) Number of mitosis
(a) Early age of onset
(c) Basement membrane invasion
(b) Arises in 2 or more relatives of index case
(d) Pleomorphism
(c) Sometimes multiple tumors are present
(d) Present with specific marker phenotype 2 0.7. Sure sign of malignancy is:
19. A 58 year old smoker Babu Bhai presents with long (a) Mitoses
standing epigastric pain, occasional vomiting and (b) Polychromasia
significant weight loss. He did not respond to antacid (c) Nuclear pleomorphism
and antibiotic therapy. A biopsy and other studies (d) Metastasis
confirmed that he has gastric cancer at a stage that is
associated with a very poor prognosis. Staging is based 20.8. Bimodality of incidence occurs in all, except
on which of the following? (a) Cancer penis in male
(b) Hodgkins diseases
Neoplasia
(a) Degree of anaplasia

(b) Degree of differentiation of tumor cells (c) Breast cancer in females

(c) Distribution and extent of disease (d) Leukemia

(d) Number of mitotic figures
20. Which of the following criteria can be used to determine CELLCYCLE AND ITS REGULATION
if a pheochromocytoma lesion is benign or malignant?
(a) Blood vessel invasion 21. Ionizing radiation affects which stage of cell cycle
(a) G2 S
(b) Cannot be determined by microscopic examination
(b) G1 G2
(c) Hemorrhage and necrosis
(c) G2 M
(d) Nuclear pleomorphism
(d) G0 G1
Most Recent Questions 22. The correct sequence of cell cycle is: (AI 2003)
(a) G0-G1-S-G2-M
2 0.1. Which of the following is most reliable feature of (b) G0-G1-G2-S-M
malignant transformation of pheochromocytoma? (c) G0-M-G2-S-G1
(a) Presence of mitotic figures (d) G0-G1-S-M-G2
(b) Presence of metastasis to other organs
(c) Vascular/ capsular invasion 23. During which phase of the cell cycle the cellular content
(d) All of the above of DNA is doubled: (AIIMS Nov 2005)
(a) Mitotic phase
20.2. Overgrowth of a skin structure at a localised region is: (b) G1 phase
(a) Hamartoma (c) G2 phase
(b) Malignant tumor (d) S phase
(c) Choristoma
(d) Polyp 24. The tumor suppressor gene p 53 induces cell cycle arrest
at: (AIIMS Nov 2005)
2 0.3. Cell-matrix adhesions are mediated by? (a) G2-M phase
(a) Cadherins (b) S-G2 phase
(b) Integrins (c) G1-S phase
(d) G0 phase
152
Neoplasia
25. Transition from G2 to M phase of the cell cycle is 31.2. Li Fraumeni syndrome is due to mutation of which
controlled by: (AIIMS Nov 2003) gene?
(a) Retinoblastoma gene product (a) p21
(b) p53 protein (b) p53
(c) Cyclin E (c) p41
(d) Cyclin B (d) p43
26. Fixed time is required for which steps of cell cycle: 3 1.3. Which of the following is not a cyclin dependent kinase
(a) S (PGI Dec 2000) (CDK) inhibitor?
(b) M (a) p21
(c) G1 (b) p27
(d) G2 (c) p53
(e) Go (d) p57
27. Regarding oncogenesis: (PGI June 2002) 3 1.4. Cells are most radiosensitive in:
(a) Topoisomerase II causes breaks in strands (a) S - phase
(b) p53 is the most common oncogene mutation causing (b) M -phase
malignancy in humans (c) Gl - phase
(c) At G2-M phase there is loss of inhibitors controlling (d) G0 - phase
cell-cycle
(d) Decrease in telomerase activity causes anti-tumor
effects GENETIC MECHANISMS OF CARCINOGENESIS: PROTO-
ONCOGENE, TUMOUR SUPPRESSOR GENE, DEFECTIVE
28. Regarding oncogenesis: (PGI Dec 2002) DNA REPAIR
(a) Proto-oncogenes are activated by chromosomal
translocation
(b) Malignant transformations involves accumulation of
32. All are true about Fanconi anemia, except: (Bihar 2006)
(a) Defect in DNA repair
mutations in proto-oncogenes and tumor suppressor (b) Bone marrow hyper function
genes (c) Congenital anomaly present

(c) Point mutation of somatic cells (d) Increased chances of cancer

Neoplasia
(d) Increase in telomerase activity causes anti-tumor
effects 33. HER2/neu receptor plays a role in (AIIMS Nov. 2010)

(e) At G2-M phase there is loss of inhibitors controlling (a) Predicting therapeutic response
cell cycle (b) Diagnosis of breast cancer
(c) Screening of breast cancer
29. The tumor suppressor gene P53 induces cell arrest at: (d) Recurrence of tumor
(a) G - M phase (AIIMS-Nov-05) (UP 2008)
2
(b) S- G phase 34. The most common secondary malignancy in a patient
2
(c) G - S phase having retinoblastoma is: (AI 2010)
1
(a) Osteosarcoma
(d) G - phase
0
(b) Renal cell carcinoma
30. Not a premalignant condition: (AP 2002) (c) Pineoblastoma
(a) Fragile X syndrome (d) Osteoblastoma
(b) Downs syndrome
(c) Blounts syndrome
35. Regarding Fanconi anemia, the wrong statement is:
(a) Autosomal dominant (AI 2010)
(d) Fanconis syndrome (b) Bone marrow show pancytopenia
31. Which is associated with G2M transition in cell cycle: (c) Usually aplastic anemia
(a) Cyclin A (Kolkata 2008) (d) It is due to defective DNA repair
(b) Cyclin B 36. True statements about p53 gene are all except: (AI 2008)
(c) Cyclin E (a) Arrests cell cycle at G1 phase
(d) Cyclin D (b) Product is 53 kD protein
(c) Located on chromosome 17
Most Recent Questions (d) Wild/non-mutated form is associated with increased
risk of childhood tumors
31.1. E cadherin gene deficiency is seen in:

(a) Gastric cancer 37. Growth factor oncogene is: (AI 2008)
(a) Myc

(b) Intestinal cancer
(b) Fos

(c) Thyroid cancer
(c) Sis

(d) Pancreatic cancer (d) Jun
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38. Rosettes are characteristically seen in: (AI 2008) 47. In the mitogen activated protein kinase pathway, the
(a) Retinoblastoma activation of RAS is counteracted by: (AIIMS May 2004)
(b) Melanoma (a) Protein kinase C
(c) Dysgerminoma (b) GTPase activating protein
(d) Lymphoma (c) Phosphatidyl inositol
(d) Inositol triphosphate
39. The normal cellular counterparts of oncogenes are
important for the following functions, except: (AI 2006) 48. Which of the following mutations in a tumor suppressor
(a) Promotion of cell cycle progression agent causes breast carcinoma? (AIIMS May 2002)
(b) Inhibition of apoptosis (a) p43 (b) p53
(c) Promotion of DNA repair (c) p73 (d) p83
(d) Promotion of nuclear transcription
49. True about proto-oncogenes is: (PGI June 06)
40. An example of a tumor suppressor gene is: (AI 2005) (a) Important for normal cell growth
(a) myc (b) May get converted into oncogenes
(b) fos (c) C-myc over-expression causes lymphoma
(c) ras (d) Their mutation causes retinoblastoma
(d) Rb (e) Deletion cause Sickle cell disease
41. Lynch syndrome is associated with cancers of the: 50. True about oncogene is: (PGI Dec 2002)
(a) Breast, colon, ovary (AIIMS Nov 2009) (a) Present in normal cell
(b) Breast, endometrium, ovary (b) They are of viral origin
(c) Breast, colon, endometrium (c) They are transduced from virus infected cells
(d) P53 is most common oncogene mutation causing
(d) Colon, endometrium, ovary
malignancy
42. Loss of heterozygosity associated with: (e) Viral oncogenes are identical with humans cellular
(a) Acute myeloid leukemia (AIIMS May 2008) oncogenes
(b) ALL 51. Cancer cell survival is enhanced by:
(c) Retinoblastoma (a) Suppression of p53 protein (PGI June 2003)
(d) Promyelocytic leukemia (b) Over expression of p53 gene
Neoplasia
43. Which is not a tumor suppressor gene? (c) bcl-2

(a) WT-1 (AIIMS May 2008) (d) bax
(b) Rb (e) bad
(c) p53 52. Following are required for normal growth:
(d) ras (a) Proto-oncogenes (PGI Dec 2003)
44. The inheritance pattern of familial Retinoblastoma is: (b) Tumor suppressor genes
(a) Autosomal recessive (AIIMS Nov 2005) (c) Oncogenes
(b) Autosomal dominant (d) DNA repair genes
(c) X-linked dominant 53. Xeroderma pigmentosum is caused due to a group of
(d) X-linked recessive closely related abnormalities in:
(a) Mismatch repair (Delhi PG 2010)
45. Which of the following is known as the guardian of (b) Base excision repair
the genome? (AIIMS May 2005)
(c) Nucleotide excision repair
(a) p53
(d) SOS repair
(b) Mdm2
(c) p14 54. Increased expression of which of the following causes
(d) ATM oncogenesis (Delhi PG-2004)
(a) IGF receptor
46. The following statements are true about Tumor (b) EGF receptor
Suppressor Gene p53, except: (AIIMS Nov 2004)
(c) GH receptor
(a) It regulates certain genes involved in cell cycle regu-
(d) Aldosterone receptor
lation
(b) Its increased levels can induce apoptosis 55. Tumor suppressor genes are all, except (Delhi PG-2004)
(c) Its activity in the cells decreases following UV irra- (a) APC
diation and stimulates cell cycle (b) p53
(d) Mutations of the p53 gene are most common genetic (c) Rb
alteration seen in human cancer (d) C-myc
154
Neoplasia
56. Angiogenesis is: (UP 2007)

(d) Chromosome 11
(a) Formation of the new blood vessels
(b) Repair by connective tissues
59. Proto-oncogene erb-B is not related to: (Kolkata 2003)
(a) Breast carcinoma
(c) Formation of the blood clot
(b) Small cell lung carcinoma
(d) All of the above
(c) Non-small cell lung carcinoma
57. Medullary carcinoma of thyroid is associated with (d) Ovarian carcinoma
mutation in: (AP 2003)
(a) RET
60. Most common genetic mutation in carcinogenesis
involves: (Kolkata 2008)
(b) RAS
(a) p53 (b) Rb
(c) NF
(c) HPC (d) PTEN
(d) Rb
6 1 to 63. Read the following paragraph and answer questions
58. APC gene is located on which chromosome: 61-63.
(a) Chromosome 5 (AP 2008)
(b) Chromosome 6
It is now evident that most cases of sporadic colon cancer
develop through the stepwise accumulation of various
(c) Chromosome 9
mutations. This transformation process is given in the
diagram on next page.
61. Which of the following genes is most likely marked in (c) Receptor tyrosine kinase
the flowchart depiction as X? (d) Retinoic acid receptor protein
Neoplasia
(a) N-myc
(b) K-ras
65. A patient Madhu undergoes total thyroidectomy for
a mass lesion of the thyroid. During the surgery it is
(c) Cyclin D
(d) p53 found that the parathyroid glands appeared enlarged.
The thyroid lesion shows neuroendocrine-type cells
62. Which of the following is a true statement regarding the and amyloid deposition. This patients thyroid and
above gene? parathyroid lesions may be related to which of the
(a) It is associated with the conflict model of oncogenes following oncogenes?
(b) It is called as guardian of the genome
(a) bcl-2 (b) C-myc
(c) It is active in hypopohosphorylated form
(c) Ret (d) L-myc
(d) It is active in hyperphosphorylated form
63. Which of the following genes is most likely marked in 66. ophthalmoscopic
Dr. Marwah, a pediatrician, performing an
examination on a four-year-old boy,
the flowchart as Y?
(a) Cyclin D notices several small pigmented nodules in his irises.
(b) K-ras He also notices six light brown macules on the trunk
(c) Wt-1 gene of the child of variable sizes. This boy may have a
(d) p53 propensity to develop tumors in which of the following
structures?
64. Aisha, a 51 year old woman discovers a lump in her left (a) Bladder (b) Colon
breast on a weekly self-examination. Mammography is
performed which confirms the presence of a suspicious (c) Peripheral nerve (d) Skin
mass, and needle core biopsy is performed to
determine whether the mass is malignant. Dr. Devesh, Most Recent Questions
the pathologist confirmed the mass to be malignant and
said that the tissue demonstrates amplification of her-2/

66.1. RET gene mutation is associated with which malignancy?
neu oncogene. What kind of protein is the gene product

(a) Pheochromocytoma
of Her-2/neu?
(b) Medullary carcinoma thyroid

(a) GTPase
(c) Lymphoma

(b) GTPase-activating protein
(d) Renal cell carcinoma
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66.2. Endometrial carcinoma is associated with which of the (a) Medulloblastoma

following tumor suppression gene mutation? (b) Pinealoblastoma
(a) P53 (b) Rb (c) Neuroblastoma
(c) PTEN (d) APC (d) Hemangioblastoma
6 6.3. The tumor suppressor gene p 53 induces cell cycle arrest
at: ETIOLOGICAL AGENTS FOR CANCER: CHEMICAL,
(a) G2 M phase (b) S G2 phase RADIATION, MICROBES, MULTISTEP CARCINOGENESIS
(c) G1 S phase (d) G0 phase
6 6.4. MYC gene is:
67. Post transplant lymphoma is caused by which of the
following? (AIIMS May 2012)
(a) Protein kinase inhibitor (a) CMV (b) EBV
(b) Growth factor inhibitor (c) Herpes simplex (d) HHV-6
(c) GTPase
(d) Transcription activator
68. H. pylori infection is associated with development of
which malignancy: (DPG 2011)
6 6.5. Retinoblastoma is associated with which of the (a) MALTomas
following tumours? (b) Atherosclerosis
(a) Osteoclastoma (c) Sarcoma
(b) Hepatocellular cancer (d) Gastrointestinal stromal tumor (GIST)
(c) Squamous cell cancer 69. Helicobacter pylori infection is associated with all of
(d) Osteosarcoma the following conditions, except: (DPG 2011)
6 6.6. An example of a tumour suppressor gene is: (a) Peptic ulcer disease
(a) Myc (b) Fos (b) Gastric adenocarcinoma
(c) Ras (d) RB (c) B cell lymphoma
(d) Burkitts lymphoma
6 6.7. Which of the following is DNA repair defect?
(a) Retinoblastoma
70. Tumors associated with organisms are all except:
(b) Neurofibromatosis (a) Hepatocellular cancer (AIIMS Nov 2009)
(b) Non-small Cell Carcinoma of Lung
(c) Xeroderma pigmentosum
Neoplasia
(c) Gastric cancer

(d) MEN-I
(d) Nasopharyngeal cancer
6 6.8. Which of the following gene defect is associated with
development of medullary carcinoma of thyroid:
71. Which of the following is essential for tumor metastasis?
(a) Angiogenesis (AIIMS Nov 2008, DNB 2009)
(a) RET Proto Oncogene
(b) Fap gene (b) Tumorogenesis
(c) Rb gene (c) Apoptosis
(d) BRCA 1 gene (d) Inhibition of tyrosine kinase activity
6 6.9. All of the following are tumor markers, except: 72. Which of the following statements about carcinogenesis
(a) Beta-2 macroglobulin is false? (AIIMS May 2006)
(b) HCG (a) Asbestos exposure increases the incidence of lung
(c) Alpha-fetoprotein cancer
(d) CEA (b) Papilloma viruses produce tumors in animals but
not in humans
6 6.10. An example of a tumor suppressor gene is:
(c) Exposure to aniline dyes predisposes to cancer of the
(a) Myc
(b) Fos urinary bladder
(c) Ras (d) Hepatitis B virus has been implicated in hepatocel-
(d) Rb lular carcinoma
6 6.11. Knudson two hit hypothesis is seen with 73. Which of the following is an oncogenic RNA virus?
(a) Melanoma (a) Hepatitis B virus (Delhi PG 2009 RP)
(b) Retinoblastoma (b) Human papilloma virus
(c) Ulcerative colitis (c) Epstein Barr virus
(d) Crohn disease (d) Hepatitis C virus
66.12. Retinoblastomas arising in the context of germ-line 74. LMP-1 gene plays a role in oncogenesis induced by:
mutations not only may be bilateral, but also may (Karnataka 2008)
be associated with _______ (so called trilateral (a) Human T cell leukemia virus type I
retinoblastoma) (b) Hepatitis B virus
156
Neoplasia

(c) Epstein-Barr virus hepatosplenomegaly, a skin rash, hypercalcemia, and

(d) Human papilloma virus an elevated white blood count. This man has most
likely developed which of the following?
75. Skin cancers develop due to sunlight exposure induced
(a) AIDS
by: (Karnataka 2006)
(a) UVA rays (b) UVB rays

(b) Autoimmunity
(c) UVC rays (d) UVD rays

(c) Delayed hypersensitivity reaction

(d) Leukemia
76. Most radiosensitive tumor is: (RJ 2003)
(e) Recurrent infection
(a) Renal cell carcinoma
(b) Carcinoma colon Most Recent Questions
(c) Hepatocellular carcinoma
(d) Testicular seminoma 82.1. Thorium induced tumor is which of the following?
77. Smoking is a risk factor for all carcinomas, except: (b) Lymphoma
(a) Oral (RJ 2006)
(c) Angiosarcoma of liver
(b) Bronchial
(d) Astrocytoma
(c) Bladder
(d) Thyroid 8 2.2. Radiation exposure during infancy has been linked to
which one of the following carcinoma?
78. Workers exposed to polyvinyl chloride may develop (a) Breast (b) Melanoma
following liver malignancy: (AP 2002)
(c) Thyroid (d) Lung
(a) Cholangiocarcinoma
(b) Fibrolamellar carcinoma 8 2.3. The following parasitic infections predispose to
(c) Angiosarcoma malignancies?
(d) All of the above (a) Paragonimus westermani
79. Which among the following is not a neoplastic virus: (b) Guinea worm infection
(a) Cytomegalovirus (Bihar 2006) (c) Clonorchiasis
(b) Hepatitis B virus (d) Schistosomiasis
(c) Human papilloma virus 8 2.4. Kaposis sarcoma is seen with:
(d) All of these (a) HCV (b) HPV
Neoplasia
80. A 37-year-old man, Gagan presents with increasing (c) HSV (d) HHV
abdominal pain and jaundice. He gives a history of 8 2.5. UV radiation has which of the following effects on the
intake of groundnuts which did not taste appropriate. cells?
Physical examination reveals a large mass involving (a) Prevents formation of pyrimidine dimers
the right side of his liver, and a biopsy specimen (b) Stimulates formation of pyrimidine dimers
from this mass confirms the diagnosis of liver cancer (c) Prevents formation of purine dimers
(hepatocellular carcinoma). Which of the following (d) All of the above
substances is most closely associated with the
pathogenesis of this tumor? 8 2.6. The most radiosensitive cells are:

(a) Aflaxotin B1 (a) Neutrophils (b) Lymphocytes

(b) Direct-acting alkylating agents (c) Erythrocytes (d) Megakaryocytes

(c) Vinyl chloride 82.7 The SI unit of radiation absorbed dose is

(d) Azo dyes (a) Rad (b) Becquerel

(e) eta-Naphthylamine (c) Gray (d) Sievert
81. Biopsy of an ulcerated gastric lesion of a 26-year-old 8 2.8. One of the following leukemia almost never develops
smoker Akki demonstrates glands containing cells with after radiation?
enlarged, hyperchromatic nuclei below the muscularis (a) Acute myeloblastic leukemia
mucosa. Two tripolar mitotic figures are noted. With (b) Chronic myeloid leukemia
which of the following infectious agents has this type (c) Acute lumphoblastic leukemia
of lesion been most strongly associated? (d) Chronic lymphocytic leukemia

(a) Epstein-Barr virus

(b) Helicobacter pylori
PARANEOPLASTIC SYNDROMES, TUMOUR MARKERS,

(c) Human papilloma virus

(d) Molluscum contagiosum virus TUMOUR LYSIS SYNDROME
82. A man Alok Nath contracts HTLV-1 infection 83. A 20 year old female was diagnosed with granulose cell
through sexual contact. Twenty-one years later
tumor of the ovary. Which of the following bio markers
he develops generalized lymphadenopathy with
would be most useful for follow-up of patient?
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(a) CA 19-9 (AIIMS Nov 2011) 92. For which one of the following tumors Gastrin is a
(b) CA50 biochemical marker? (AIIMS May 2005)
(c) Inhibin (a) Medullary carcinoma of thyroid
(d) Neuron specific enolase (b) Pancreatic neuroendocrine tumor
(c) Pheochromocytoma
84. Alpha fetoprotein is a marker of: (AI 2010)
(d) Gastrointestinal stromal tumor
(a) Hepatoblastoma
(b) Seminoma 93. All of the following are examples of tumor markers,
(c) Renal cell carcinoma except:
(d) Choriocarcinoma (a) Alpha-HCG (a-HCG) (AIIMS Nov 2004)
(b) Alpha-Feto protein
85. Hyperglycemia associated with: (AI 2010) (c) Thyroglobulin
(a) Multiple myeloma (d) Beta 2-microglobulin
(b) Ewing sarcoma
(c) Osteosarcoma 94. Which of the following tumors have an increased
(d) Chondroblastoma elevation of placental alkaline phosphatase in the serum
as well as a positive immunohistochemical staining for
86. Which of the following is Not associated with placental alkaline phosphatase?
thymoma? (AI 2010)
(a) Seminoma (AIIMS May 2004)
(a) SIADH
(b) Hepatoblastoma
(b) Myasthenia gravis
(c) Polymyositis
(d) Peripheral neuroectodermal tumor
(d) Hypogammaglobinemia
95. In tumor lysis syndrome, all of the following are seen,
87. Which of the following is not true about except: (AIIMS May 2002)
Neuroblastoma? (AI 2009) (a) Hypernatremia (b) Hypercalcemia
(a) Most common extracranial solid tumor in childhood (c) Hyperkalemia (d) Hyperphosphatemia
(b) >50% patients present with metastasis at time of di-
agnosis
96. Uses of tumor marker are: (PGI Dec 2000)
(a) Screening of a cancer
(c) Lung metastases are common
Neoplasia
(b) Follow up of a cancer patient, esp. for knowing about

(d) Involve aorta and its branches early
recurrence
88. Migratory thrombophlebitis is associated with all of (c) Confirmation of a diagnosed cancer
the following malignancies, except: (AI 2008) (d) For monitoring the treatment of a cancer
(a) Prostate
(b) Lung
97. True about Carcinoembryonic antigen (CEA):
(a) Useful for screening of carcinoma colon
(c) GIT
(b) Gives confirmative evidence of Ca. colon
(d) Pancreas
(c) Helpful for follow-up after resection (PGI June 01)
89. HMB 45 is a tumor marker for: (AI 2008, DNB 2008) (d) Levels decrease immediately after resection of tumor
(a) Neuroblastoma (e) Tumor size correlates with CEA level
(b) Neurofibroma 98. CA125 is associated with: (PGI June 2002)
(c) Malignant melanoma (a) Colon ca (b) Breast ca
(d) Angiosarcoma (c) Ovarian ca (d) Bronchogenic ca
90. AFP is a marker of: (AIIMS Nov 2009) (e) Pancreatic ca
(a) Hepatoblastoma 99. Secondaries are common in all, except:
(b) Seminoma (a) Skull (PGI June 01)
(c) Sertoli-Leydig cell tumor (b) Hand and feet bones
(d) Choriocarcinoma (c) Proximal limb bones
91. An undifferentiated malignant tumor on (d) Pelvic
immunohistochemical stain shows cytoplasmic (e) Vertebrae
positivity of most of the tumor cells for cytokeratin. The 100. Hybridoma refers to (Delhi PG 2009 RP)
most probable diagnosis of the tumor is: (a) Collision tumor

(a) Sarcoma (AIIMS May 2006) (b) A tumor of brown fat

(b) Lymphoma (c) A hamartoma

(c) Carcinoma (d) A technique for raising monoclonal antibodies

(d) Malignant melanoma
158
Neoplasia
101. BCL2 is a marker for: (Delhi PG-2007) 111.

a-fetoprotein is seen in all except: (AP 2002)
(a) Follicular lymphoma
(a) Hepatocellular carcinoma (AI 1997)
(b) Mycosis fungoides
(b) Carcinoma colon (UP 1996)
(c) B-cell lymphoma
(c) Pancreatic carcinoma
(d) Mantle cell lymphoma
(d) Germ cells of testes
102. Alpha-fetoproteins are a marker of: 112. The diagnostic tumor marker of liver carcinoma is:
(a) Secondaries in liver (Karnataka 2005) (a) CEA (AP 2007)
(b) Cholangiocarcinoma (b) AFP
(c) Hepatoma (c) CA - 125
(d) None of the above (d) All of the above
103. Increased level of alpha fetoprotein is found in 113. Spontaneous regression of tumor is seen in:
(a) Yolk sac tumor (UP 2001) (a) Wilms tumor (Kolkata 2002)
(b) Seminoma (b) Neuroblastoma
(c) Teratoma (c) Acute monocytic leukemia
(d) Choriocarcinoma (d) Hepatoblastoma
104. Migratory thrombophlebitis is seen in: (UP 2007) 114. All of the following about tumor markers are properly
(a) Disseminated cancer matched, except: (Kolkata 2003)
(b) Rheumatic heart disease (a) Prostate cancer - PSA
(c) Libman-Sachs endocarditis (b) Colon cancer - CEA
(d) All of the above (c) Ovarian cancer CA 125
(d) Cholangiocarcinoma - AFP
105. A 65 years old male diagnosed by biopsy a case of
lung carcinoma, with paraneoplastic syndrome and 115. Popcorn calcification is seen in: (Kolkata 2005)
increased calcium. Probable cause is (UP 2008) (a) Chondrosarcoma (b) Fibrous dysplasia
(a) Parathyroid hormone (c) Osteoblastoma (d) Wilms tumor
(b) Parathyroid hormone related peptide
(c) Calcitonin 116. Which one of the following is a frequent cause of serum
(d) Calcitonin related peptide alpha- fetoprotein level greater than 10 times the normal
upper limit?
Neoplasia
(Bihar 2004)
106. Which is associated with polycythemia: (RJ 2001) (a) Seminoma
(a) Gastric carcinoma (b) Hepatocellular carcinoma of liver
(b) Fibrosarcoma (c) Cirrhosis of liver
(c) Cerebellar hemangioblastoma (d) Oat cell tumor of lung
(d) All
117. Rise of AFP is noted in all except: (Jharkhand 2004)
107. Serum AFP is increased in all, except: (RJ 2003) (a) Hepatocellular carcinoma
(a) Acute hepatitis (b) Cirrhosis
(b) Hepatocellular carcinoma (c) Germ cell tumor
(c) Hepatoma (d) Kidney tumor
(d) Bladder carcinoma
118. Catecholamines are increased in: (Jharkhand 2004)
108. Carcinoembryonic antigen is elevated in all, except: (a) Neuroblastoma
(a) Alcoholic cirrhosis (RJ 2004) (b) Retinoblastoma
(b) Ca colon (c) Medulloblastoma
(c) Ulcerative colitis (d) Nephroblastoma
(d) Emphysema
119. A 60-year-old man, Shibu is found to have a 3.5-cm
109. Desmoid tumor arises from: mass in the right upper lobe of his lung. A biopsy of
(a) Wall of the intestine (TN 1991)(AP 2000) this mass is diagnosed as a moderately differentiated
(b) Anterior abdominal wall squamous cell carcinoma. Workup reveals that no bone
(c) Submucosa metastases are present, but laboratory examination
(d) Appendix reveals that the mans serum calcium levels are 11.5
mg/dL. This patients paraneoplastic syndrome is most
110. Alpha-fetoprotein is a tumor marker of: likely the result of the ectopic production of which of
(a) Carcinoma ovary (AP 2001)
the following substances?
(b) Liver malignancies
(c) Endodermal sinus tumor of testis

(a) Parathyroid hormone
(d) Both (b) and (c)

(b) Parathyroid hormone-related peptide

(c) Calcitonin

(d) Calcitonin-related peptide
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120.
During a routine physical examination, a 45-year-old 123.3. Marker for ovarian carcinoma in serum is:
woman Nusheen is noted to have a ruddy complexion. (a) CA-125
Her hematocrit is 52%. Her lungs are clear and she does
(b) Fibronectin
not smoke. Serum erythropoietin levels are elevated.
(c) Acid Phosphatase
Cancer of which of the following organs is the most
likely cause of her increased hematocrit?
(d) PSA

(a) Breast
(b) Colon
123.4. Which of the following is a marker for carcinoma of
lung and breast?

(c) Kidney
(d) Stomach
(a) CEA (b) AEP

121. A 62 year-old woman Omvati with advanced, metastatic (c) HCG (d) CA-15-3
lung cancer develops profound fatigue and weakness

and alternating diarrhea and constipation. Physical 123.5. Secondaries of all the following cause osteolytic lesions
examination demonstrates hyperpigmentation of except:
skin, even in areas protected from the sun. Tumor
(a) Prostate
(b) Kidney
involvement of which endocrine organ is most strongly
(c) Bronchus
(d) Thyroid
suggested by this patients presentation?

123.6. Sacrococcygeal teratoma, marker is:
(a) Adrenal gland (b) Endocrine pancreas (a) CEA (b) - HCG

(c) Ovaries
(d) Pituitary gland (c) S100 (d) CA-125
122. An old man Velu presents with complaints of 123.7. Which of the following mutation is seen in malignant
abdominal and back pain, malaise, nausea, 8 kg weight melanoma?
loss and weakness, which have been present for 3 or
(a) N-myc (b) CDKN2A
4 months. His history also reveals several episodes of
unilateral leg swelling, which have involved both legs
(c) RET (d) Rb

at different times. These findings are most consistent 123.8. Marker of small cell cancer of lung is:
with which of the following diagnoses?
(a) Chromogranin (b) Cytokeratin

(a) Pancreatic cancer
(c) Desmin
(d) Vimentin

(b) Primary sclerosing cholangitis
123.9. Which of the following is tumor marker of seminoma?

(c) Splenic infarction (a) AFP (b) LDH
Neoplasia

(d) Reflux esophagitis
(c) PLAP (d) HCG
123. A
65-year-old woman Ramkali presents to the 123.10. Which of the following is a special stain for
emergency room with a pathologic fracture of the shaft rhabdomyosarcoma?
of her humerus. X-ray studies demonstrate multiple
(a) Cytokeratin
(b) Synaptophysin
lytic and blastic bone lesions. Biopsy of one of these
lesions shows adenocarcinoma. Which of the following
(c) Desmin
(d) Myeloperoxidase
is the most likely source of the primary tumor?
123.11. The most common cause of malignant adrenal mass is

(a) Breast
(b) Colon
(a) Adrenocortical carcinoma

(c) Kidney
(d) Lung
(b) Malignant Phaeochromocytoma

(c) Lymphoma
(d) Metastasis from another solid tissue tumor
123.12. Commonest cancer in which metastasis is seen in
123.1. Tumor that follows rule of 10 is: brain in
(b) Oncocytoma

(a) Breast (b) Lung
(c) Lymphoma

(c) Kidney (d) Intestines
(d) Renal cell carcinoma 123.13. Which of the following is incorrect about neuro-
123.2. Which of the followingis a squamous cell carcinoma blastoma ?
marker?
(a) Most common abdominal tumor in infants
(a) Vimentin (b) Desmin
(b) X-ray abdomen shows calcification
(c) Cytokeratin (d) Glial fibrillary acid protein
(c) Can show spontaneous regression

(d) Urine contains 5H.I.A.A
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Neoplasia
EXPLANATIONS
1. Ans. (c) Vascular invasion (Ref: Robbins 8th/1123, 9/e p1094)
Robbins clearly write. Microscopically, most follicular carcinomas are composed of fairly uniform cells forming small follicles.
Follicular carcinomas may be grossly infiltrative or minimally invasive. The latter are sharply demarcated lesions that may be
impossible to distinguish from follicular adenomas on gross examination. This distinction requires extensive histologic sampling
of the tumor-capsule-thyroid interface, to exclude capsular and/or vascular invasion. Extensive invasion of adjacent thyroid
parenchyma makes the diagnosis of carcinoma obvious in some cases.
Ideal answer for a question for diagnosis of follicular cancer is capsular invasionQ (better than even vascular invasion) but in the
given options, vascular invasion is the answer of choice.
Follicular Carcinoma: brushing up key points

It is the 2nd most common form of thyroid cancer
Seen in women of older age (40-50 yrs.)
Vascular invasion is common (less lymphatic spread) to bone, lung, liver etc.
Microscopically, there is presence of cells forming small follicles having colloid with NO Psammoma bodies. Uncommonly, cells
have abundant, eosinophilic cytoplasm called as Hurthle cells Q
Differentiation from follicular adenoma is based on the presence of capsular invasion preferably and not on vascular invasion . Q
2. Ans. (b) Fibromatosis: (Ref: Robbins 7th/770, 783-4, Harrison 16th/633, 9/e p1221-1222)
Fibromatosis are a group of fibroblastic proliferations. Though they are locally aggressive, they do not metastasize.
Fibromatosis
Superficial Fibromatosis Deep Fibromatosis
Neoplasia
*Palmar fibromatosis (Dupuytren contracture) *Also called desmoids tumors
*Plantar fibromatosis *Greater tendency to recur
*Penile fibromatosis (Peyronies disease) *Grow in a locally aggressive manner
*Arise isolated or as component of Gardner syndrome
3. Ans. (b) Increased requirement of growth factors (Ref: Biology of the cell (2003) 357-364)
Both normal cells and cancer cells can be cultured in-vitro. However, they behave quite differently
Normal cell Cancer cell
Show replicative senescence i.e. cells pass through limited They are immortal i.e. proliferate indefinitely in culture.
number of cell divisions before they decline in vigor and die. It Cancer cells in culture produce telomerase
may caused by inability to synthesize telomerase
Normal cells show the phenomenon of contact inhibition i.e. Show no contact inhibition. Even after the surface of dish is covered,
they proliferate until the surface of culture dish is covered by the cells continue to divide
single layer of cells just touching each other
Nutrients and growth factors must be supplied to them in their Do not require growth factors
tissue culture medium
Normal karyotype is present Mostly show abnormal karyotype
4. Ans. (a) Small cell carcinoma of lung (Ref: Harrison 17th/2458; Robbins 8th/1339, 7th/1410 , 9/e p1315)
Small cell carcinoma of lung most commonly metastasize to the brain. It accounts for about 40% of brain metastases.
Other Tumors Metastasizing to Brain are carcinomas of Breast, Melanoma, Kidney, GIT
5. Ans. (c) Both necrosis and apoptosis (Ref: Harrison 17th/519 , 9/e p303, 315)
Chemotherapeutic drugs can cause both necrosis and apoptosis, but it is apoptosis which is the basis of action of
chemotherapeutic drugs.
Anoikis refers to death of epithelial cells after removal from the normal milieu of substrate, particularly from cell to cell contact.
6. Ans. (b) Dysplasia discussed in details in text. (Ref: Robbins 7th/273-274 , 9/e p271)
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7. Ans. (a) Smoking; (b) U-V-light; (c) Chronic ulcer: (Ref: Harrison 16th/497, Robbins 9/e p1155)
Risk factors
Melanoma Basal cell and squamous cell carcinoma
Family history of Exposure to UV light principally UV-B
melanoma Male sex and Older age
Persistently changing Exposure to sun, arsenic, smoking, cyclic aromatic hydrocarbons in tar, soot or shale
mole HIV, HPV infection, immunosuppression.
Presence of clinically Ionizing radiations, thermal burns
atypical mole Certain scars and chronic ulcerations
Immunosuppression Heritable conditions like albinism, Xeroderma pigmentosum, genetic mutations (PATCHED gene)
Sun exposure Premalignant conditions like Actinic keratosis, Bowens disease, Erythroplasia of Queyrat.
8. Ans. (c) Chronic ulcerative colitis (Ref: Robbins 8th/276 , 9/e p279)
Certain non-neoplastic disordersthe chronic atrophic gastritis of pernicious anemia, solar keratosis of the skin, chronic ulcerative
colitis, and leukoplakia of the oral cavity, vulva, and penishave such a well-defined association with cancer that they have
been termed precancerous conditions.
9. Ans. (b) Hepatocellular carcinoma (Ref: Robbins 7th/925 , 9/e p274)
Renal cell cancer and hepatocellular cancer have high tendency invasion of vascular channels.
10. Ans. (c) Dysplasia (Ref: Robbins 7th/275, 276, 5 , 9/e p271-272)
Dysplasia is the loss of uniformity of individual cells as well as their architectural orientation.
Carcinoma in situ (dysplastic changes are marked but lesion remains confined to normal tissue: pre-invasive neoplasm).
Basement membrane is intact.
Anaplasia is Complete lack of differentiation of cells both morphologically and functionally (Invasive Ca)
11. Ans. (b) Lymphatic route (Ref: Robbins 8th/269, 7th/279-280 , 9/e p273)
12. Ans. (b) Gastric carcinoma (Ref: Robbins 8th/986; 7th/824 , 9/e p1207)
13. Ans. (b) Proliferation of native cells in tissue (Ref: Robbins 8th/262; 7th/272 , 9/e p267)
14. Ans. (d) Metastasis (Ref: Robbins 8th/269; 7th/268,279, 9/e p272)
Neoplasia
15. Ans. (a) Metaplasia (Ref: Robbins 8th/10,265; 7th/10 , 9/e p271)
16. Ans (d) Muscle tumor cells forming giant cells (Ref: Robbins 8th/262-5, 9/e p270)
Neoplastic cells may be similar to normal cells found in the tissue of origin, which defines the malignancy as well
differentiated or low grade. Alternatively, the neoplastic cells may lack most of the characteristic features of normal
cells found in the tissue of origin, which defines the malignancy as poorly differentiated or high grade. Tumors that
contain neoplastic cells in the midst of this spectrum are termed moderately differentiated or medium grade. If the
neoplastic cells are described as anaplastic, they demonstrate a complete lack of differentiation.
Features of Anaplastic tumors
Loss of cell polarity and normal tissue architectureQ
Significant variation in shape and size of cells (cellular pleomorphism) Q
Deep staining of nuclei (hyperchromatismQ) and nuclear pleomorphism
Larger nuclei than those found in normal cells of the same tissue (high nucleus-to-cytoplasm ratioQ)
Numerous often abnormal mitosesQ
Giant multinucleated tumor cellsQ
The appearance of giant multinucleated cells in a muscle tumor would therefore suggest anaplasia.
(Choice A) Cells in hepatic tissue would be expected to synthesize bile. Therefore a hepatic tumor that synthesizes bile is
described as being well-differentiated not anaplastic.
(Choice B and C) Cells in the epithelium would be expected to produce keratin pearls. Therefore an epithelial tumor that
produces keratin pearls would be described as well-differentiated not anaplastic.
17. Ans. (d) Proliferation of non- neoplastic fibrous connective tissue (Ref: Robbins 8th/260, 9/e p266)
Desmoplasia refers to proliferation of non-neoplasitc fibrous connective tissue within a tumor and is common in breast
cancer. An irregular accumulation of blood vessels is known as a hemangioma. An area of tissue misplaced within another
organ is known as a choristoma.
18. Ans. (d) Present with specific marker phenotypes. (Ref: Robbins 8th/275)
The familial cancers are associated with the cancer occurring at a higher frequency in certain families without a clearly
defined pattern of transmissionQ. Features that characterize familial cancers include
162
Neoplasia
Early age at onsetQ

Tumors arising in two or more close relatives of the index caseQ
Sometimes multiple or bilateral tumorsQ
Familial cancers are not associated with specific marker phenotypes . Q
19. Ans. (c) Distribution and extent of disease (Ref: Robbins 8th/323 , 9/e p332)
Staging is based on clinical evaluation of the distribution and extent of the disease process and is contrasted with grading
(based on histopathologic evaluation of a malignant neoplasm).
Mnemonic: Staging includes Size (extent of disease) and Spread (distribution) of the tumor.
20. Ans. (b) Cannot be determined by microscopic examination (Ref: Robbins 8th/1159-1161, 9/e p1135)
Pheochromocytomas, and their related counterparts in extra-adrenal sites called paragangliomas, are notorious because
the only reliable indicator of metastatic potential is the presence of distant metastases. Very malignant-appearing tumors
may not metastasize and benign-appearing tumors may produce metastases. These tumors should all be considered
potentially malignant.
2 0.1. Ans. (b) Presence of metastasis to other organs (Ref: Robbins 8/e p1159-1161, 9/e p1135)
Friends read these lines form Robbins to get a concept.. There is no histologic feature that reliably predicts clinical
behavior. Several histologic features, such as numbers of mitoses, confluent tumor necrosis, and spindle cell morphology, have
been associated with an aggressive behavior and increased risk of metastasis, but these are not entirely reliable. Tumors
with benign histologic features may metastasize, while bizarrely pleomorphic tumors may remain confined to the adrenal
gland. In fact, cellular and nuclear pleomorphism, including the presence of giant cells, and mitotic figures are often seen
in benign pheochromocytomas, while cellular monotony is paradoxically associated with an aggressive behavior. Even
capsular and vascular invasion may be encountered in benign lesions. Therefore, the definitive diagnosis of malignancy
in pheochromocytomas is based exclusively on the presence of metastases.
2 0.2. Ans (a) Hamartoma (Ref: Robbins 8/e p262, 9/e p13)
An overgrowth of a skin structure at a localized region is likely to be indigenous as well as benign; this is more likely to be
a hamartoma.
When a neoplasm, benign or malignant, produces a macroscopically visible projection above a mucosal surface and
Neoplasia
projects, for example, into the gastric or colonic lumen, it is termed a polyp
Hamartomas present as disorganized but benign-appearing masses composed of cells indigenous to the particular site.
Choristoma is a congenital anomaly which is described as a heterotopic rest of cells.
2 0.3. Ans (b) Integrins (Ref: Robbins 8/e p49, 9/e p24)
The cell adhesion molecules (CAMs) are classified into four main families:
Immunoglobulin family CAMs
Cadherins
Integrins: bind to extracellular matrix (ECM) proteins such as fibronectin, laminin, and osteopontin providing a con-
nection between cells and extracellular matrix (ECM)
Selectins
2 0.4. Ans. (d) Hepatocytes (Ref: Robbins 8/e p81-4, 7/e p90-91, 9/e p101)
Permanent cells Quiescent cells Labile cells
Cannot divide in postnatal life Low level of replication which increases only on stimulation Rapid rate of replication
Neurons, skeletal muscles Liver cells, kidney cells Skin, GIT, oral cavity
20.5. Ans. (a) Crohn disease (Ref: Robbins 9/e p279)

Ideal answer to this question is none but in the given situation, the answer of choice is Crohn disease because in
the comparison of the two types of inflammatory bowel disease, Crohn disease is less likely to be associated with
progression to cancer of the bowel.
20.6. Ans. (c) Basement membrane invasion (Ref: Robbins 9/e p271)
Basement membrane invasion is the most important differentiating feature between invasive carcinoma from
Q
carcinoma in situ.
20.7. Ans. (d) Metastasis (Ref: Robbins 9/e p272)

Metastasis is the most reliable feature of a malignant tumor, characterized by the spread of the tumor to other parts
because of penetration into blood vessels, lymphatics and the body cavities.
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20.8 Ans. (a) Cancer penis in male (Ref: Various books, internet)
Diseases showing bimodality of age presentation (Mnemonic: ABCDEGH)
1. Aortic stenosis/acute leukemia A.L.L > A.M.L
2. Breast cancer (Before advent of mammography
3. Crohns disease
4. Dermatomyositis
5. Enthesioneurobalstoma
6. Thyroglossal cyst
7. Hodgkins lymphoma
8. Vulvar carcinoma but NOT penile cancer
21. Ans. (c) G2M (Ref: Robbins 8th/286; Harrison 17th/516, 9/e p289)
Direct quote from Robbins. The G2/M checkpoint monitors the completion of the DNA replication and checks whether
the cell can safely initiate the mitosis and separate sister chromatids. This checkpoint is particularly important in cells
exposed to ionizing radiation. Cells damaged by ionizing radiation activate G2/M checkpoint and arrest in G2.
22. Ans. (a) G0-G1-S-G2-M (Ref: Robbins 7th/90, 9/e p25)
G1/S check-point is controlled by p53 whereas G2/M check-point has both p53 dependent as well independent
mechanisms.
23. Ans. (d) S phase (Ref: Robbins 8th/86, 7th/90, 9/e p25)
24. Ans. (c) G1-S Phase (Ref: Robbins 7th/292, 9/e p295)
G1/S check-point is controlled by p53 whereas G2/M check-point has both p53 dependent as well as independent
mechanisms.
p53 induces the synthesis of p21 which inhibits cyclin D/Cdk4. This results in stoppage of activation of Rb and cell
cycle is arrested in G1/S phase.
25. Ans. (d) Cyclin B (Ref: Robbins 7th/290-291, Robbins 8th/285-286 , 9/e p25-26)
Examples of cyclin/CDK complexes controlling the cell cycle.
Cyclin B/CDK1 Regulates the transition from G2 to M phase
Neoplasia
Cyclin D/CDK4 Regulates the transition from G1-S

Cyclin D/CDK6
Cyclin E/CDK2
Cyclin A/CDK2 and cyclin B/CDK1 Active in S phase
26. Ans. (a) S; (b) M; (d) G : (Ref: Grays anatomy 38th/55)

2
The time taken for S, G and M phases are similar for most cell types, occupying about 6, 4 and 2 hours respectively.
2
The duration of G shows considerable variation. It can be as short as 2 hours in rapidly dividing cells like embryonic
1
tissues or as long as 12 hours in some adult tissues.
G phase is most variable because, in this phase cells are not committed to DNA replication. They can either enter
1
resting state or progress to next cell division.
27. Ans. (a) Topoisomerase II causes break in strands; (c) At G2 M phase there is loss of inhibitors controlling cell cycle
and (d) Decrease in telomerase activity causes anti-tumor effects. (Ref: Harrison 16th/453, 454, Robbins 7th/43, 292)
Topoisomerase I nicks DNA, relieving torsional tension of the replicating helix.
Topoisomerase II introduces the double strand break to avoid DNA tangle.
p53 it is a tumor supresser gene.
With each cell division, there is some shortening of specialized structures called telomeres (present at ends of chromosomes). In
germ cells, telomere shortening is prevented by the enzyme telomerase. This enzyme is absent from most somatic cells, and hence
they suffer progressive loss of telomeres. Introduction of telomerase into normal human cells causes considerable extension of their
life span, thus supporting that telomerase loss is causally associated with loss of replication activity. So, decrease telomerase
activity causes anti tumor effect.
Loss of inhibitors controlling cell cycle occurs at G1-S phase/G2-M phase.
28. Ans. (a) Proto-oncogenes are activated by chromosomal translocation; (b) Malignant transformation involves accumulation
of mutations in the proto-oncogenes and tumor suppressor gene in stepwise fashion; (c) point mutations of somatic cells; (e)
At G2 M phase there is loss of inhibitors controlling cell cycle (Ref: Robbins 7th/290, 314, 315, 9/e p284-286)
Activation of proto-oncogene results in cancer causing oncogenes by following mechanisms:
164
Neoplasia
1. Single point mutation e.g. ras oncogene.

2. Gene amplification e.g. n-myc amplification in neuroblastoma.
3. Chromosomal translocation e.g. t (8:14) in Burkitt lymphoma results in c-myc over-expression and hence the tumor.
4. Promoter insertion.
5. Enhancer insertion.
The cell cycle has its own internal controls called checkpoints. There are two main checkpoints:
1. G -S transition- The S-phase is the point of no return in cell cycle. G -S checkpoint checks for DNA damage and
1 1
prevents replication of defective cells.
2. At G M transition- The G M checkpoint monitors the completion of DNA replication and checks whether the cell
2 2
can safely initiate cell division. Loss of inhibitors at this stage can lead to division of faulty cells and can lead to
carcinogenesis.
Defect in cell-cycle checkpoint components is a major cause of genetic instability in cancer cells.
29. Ans. (c) G - S phase (Ref: Robbins 8th/290-292, 7th/302-303 , 9/e p294-295)
1
30. Ans. (a) Fragile X syndrome (Ref: Robbins 8th/169-170; 7th/181-183, 9/e p169)
31. Ans. (b) Cyclin B (Ref: Robbins 8th/286, 7th/290, 9/e p26)
3 1.1. Ans. (a) Gastric cancer (Ref: Robbins 8/e p96, 785, 9/e p291)
Cadherin is derived from the calcium-dependent adherence protein. It participates in interactions between cells of the
same type. The linkage of cadherins with the cytoskeleton occurs through the catenins. The cell -to-cell interactions mediated
by cadherin and catenins play a major role in regulating cell motility, proliferation, and differentiation and account for the
inhibition of cell proliferation that occurs when cultured normal cells contact each other (contact inhibition).
Reduced function of E-cadherin is associated with certain types of breast and gastric cancer.
Mutation and altered expression of the Wnt/-catenin pathway is implicated in in gastrointestinal and liver cancer
development.
31.2. Ans. (b) p53 (Ref: Robbins 8/e p274, 290, 9/e p293-294)
The p53 gene is located on chromosome 17p13.1 , and it is the most common target for genetic alteration in human
Q Q
tumors.
A little over 50% of human tumors contain mutations in this gene.
Neoplasia
In most cases, the inactivating mutations affect both p53 alleles and are acquired in somatic cells (not inherited in the
germ line).
Less commonly, some individuals inherit one mutant p53 allele. The inheritance of one mutant allele predisposes
individuals to develop malignant tumors because only one additional hit is needed to inactivate the second,
normal allele. Such individuals, said to have the Li-Fraumeni syndromeand have a greater chance of developing a
malignant tumor at a younger age. These people tend to develop multiple primary tumors.
Themost common types of tumors are sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal
cortex.
3 1.3. Ans. (c) p53 (Ref: (Ref: Robbins Illustrated 7/e p p 292, (Ref: Robbins 8/e p286, 9/e p25-26)
Cyclins form complex with cyclin dependent kinases and regulate the transition of cell cycle from one stage to the other.
These CDK complexes in turn are regulated by CDK inhibitor. The inhibitors control the cell cycle by balancing the activity
of CDKs. The signals from these inhibitors determine whether a cell progresses through the cell cycle.
Changes in the level of these inhibitors may occur in some tumors, or possibly in aging cells.

The cyclin dependent kinase inhibitors are
- p21 - p27 - p57 - p15 - p16 - p18 - p19
31.4. Ans. (b) M phase
Cells are most radiosensitive in G M interphase
2
Cells are least radiosensitive in S phase
32. Ans. (b) Bone marrow hyper function (Ref: Robbins 8th/663; 7th/647, 9/e p630)
33. Ans. (a) Predicting therapeutic response (Ref: Ackerman s surgical pathology 9th/1818, Robbins 8th/1090, 9/e p1062)
Friends, direct quote from Robbins.HER2/neu overexpression is associated with poorer survival but its main importance
is as a predictor of response to agents that target this transmembrane protein (examples trastuzumab or lapatinib).
The overexpression is due to amplification of the gene HER2/neu located on 17q21.
Ackerman writes. HER2/new encodes a transmembrane glycoprotein with tyrosine kinase activity and its overexpression
is a good predictor of response to herceptin (trastuzumab) but not a good predictor of response to chemotherapy or overall
survival.
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34. Ans. (a) Osteosarcoma (Ref: Robbins 8th/287,1338, 1365, 9/e p293)
Retinoblastoma is the most common primary intraocular malignancy of children. Involvement of both eyes with
pineal gland is called as trilateral retinoblastoma.
The pinealoblastoma in association with retinoblastoma is a primary tumor.
In approximately 40% of cases, retinoblastoma occurs in individuals who inherit a germ-line mutation of one RB allele.
This variant of retinoblastoma (familial retinoblastoma) is inherited as an autosomal dominant trait and is associated
with osteosarcoma. Osteosarcoma is therefore the commonest secondary maligancy associated with retinoblastoma.
35. Ans. (a) Austosomal dominant (Ref: Robbins 8th/302, Harrison 665, 9/e p314-315)
Fanconis anemia is an autosomal recessive disease characterized by progressive pancytopenia , increased risk of
Q Q
malignancy (solid tumors and AML ) and congenital developmental anomalies like short stature, caf au lait spots,
Q
abnormalities affecting thumb, radius and genitourinary tract.

Fanconis anemia is associated with BRCA gene. The Fanconi anemia proteins and BRCA proteins form a DNA-dam-
age repair proteins to correct intrastrand and interstrand DNA cross links induced by chemical cross-linking agents.
36. Ans. (d) Wild/non-mutated form is associated with increased risk of childhood tumors (Ref: Robbin 7th/302-303,
Harrison 17th/499-500, 8th/290-2, 9/e p294)
p53 gene is a tumor suppressor gene also known as guardian of the genome located on short arm of chromosome
Q
17 (17p). Its wild/non mutated form is associated with reduced risk of tumors.
Q
37. Ans. (c) sis (Ref: Robbins 7th/182)

A number of nuclear transcription factors are the products of oncogenes like myc, fos, jun, myb and rel. Out of these
myc is most commonly involved in tumors . Q
SIS oncogene is the only example of a growth factor oncogene in the given options. Its over expression is seen in
cancers like astrocytoma and osteosarcoma. The other growth factor are described is text.
38. Ans. (a) Retinoblastoma (Ref: Robbins 7th/1442; Neuropathology for the Neuroradiologist: Rosettes and Pseudorosettes
by F.J. Wippold and A. Perry)
Rosettes consist of a halo or spoke-wheel arrangement of cells surrounding a central core or hub.
Neoplasia
Rosettes may be considered primary or secondary manifestations of tumor architecture. Primary rosettes form as a char-
acteristic growth pattern of a given tumor type, whereas secondary rosettes result from the influence of external factors on
tumor growth.
Types of Flexner-Wintersteiner Homer-Wright True Ependymal Perivascular Neurocytic rosette
rosette rosettes rosettes Rosette Pseudorosette
Diagram
Feature *A halo of cells *A halo of cells *The halo-like cluster *A halo of cells *Rosette is similar
surrounds a largely surrounds a central of cells in each rosette surrounds a blood to the Homer Wright
empty central hub. hub that contains a surrounds an empty vessel rosette,but the
Small cytoplasmic meshwork of fibers central lumen *Called pseudo central fiber-rich
extensions from the because the central neuropil island is
cells project into the structure is not actually larger and more
lumen formed by the tumor irregular
itself, but instead
represents a native,
non-neoplastic element
Contd...
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Neoplasia
Contd...
Types of Flexner-Wintersteiner Homer-Wright True Ependymal Perivascular Neurocytic rosette
rosette rosettes rosettes Rosette Pseudorosette
Related RetinoblastomaQ, Supratentorial Ependymoblastoma Medulloblastomas, Central neurocytoma
tumors Pineoblastomas, PNETs, (rare form of PNET) PNETs,
Medulloepitheliomas RetinoblastomaQ, Central neurocytomas,
Pineoblastomas Glioblastomas,
Pilomyxoid
astrocytomas
*Neuropil-rich rosettes are referred to as pineocytomatous rosettes in pineocytomas and neurocytic rosettes in central neurocytoma.
These are similar to the Homer Wright rosette, but they are generally larger and more irregular in contour.
39. Ans. (c) Promotion of DNA repair (Ref: Robbins 7th/293, 295), http://www.nature.com/scitable/topicpage/proto-onco-
genes-to-oncogenes-to-cancer-883 by Heidi Chial, 9/e p284)
The normal cellular counterpart of oncogene is known as proto-oncogene. Proto-oncogenes are important for cellular
function related to growth and proliferation. Proteins encoded by these genes may function as growth factor ligands and
receptors, signal transducers, transcription factors and cell cycle components.

Chial writes that proto-oncogenes encode proteins that function to stimulate cell division, inhibit cell differentiation,

and halt cell death. All of these processes are important for normal human development and for the maintenance of
tissues and organs. Oncogenes, however, typically exhibit increased production of these proteins, thus leading to

increased cell division, decreased cell differentiation, and inhibition of cell death. So, we can say that These genes may
also inhibit apoptosis.
Promotion of DNA repair is the function of tumor suppressor genes. Promotion of DNA repair is protective from
oncogenesis and is not the function of proto-oncogenes.
40. Ans. (d) Rb (Ref: Robbins 7th/300, Harrison 17th/499, 496, 9/e p290)
Tumor suppressor genes are the genes whose products down regulate the cell cycle, and thus apply brakes to cel-
lular proliferation.
Rb gene is a tumor suppressor gene whereas Myc, fos and ras are all examples of proto-oncogenes.
Neoplasia
41. Ans. (d) Colon, endometrium, ovary (Ref: Harrison 17/page 575, Robbins 8th/821-822, 9/e p810)
Lynch syndrome is an autosomal dominant disorder
Q
It is also called as Hereditary Non-polyposis Colon Cancer (HNPCC) syndrome Q
It is caused because of defective DNA repair genes leading to microsatellite instability.

Q
There is increased chance of multiple cancers (colorectal area, endometrium, ovary, stomach, ureter, brain, small intestine,
hepatobiliary tract and skin)
42. Ans. (c) Retinoblastoma (Ref: Robbins 7th/299, 9/e p292-293)

Retinoblastoma is a prime example of a tumor which is associated with loss of heterozygosity.
Rb gene is a tumor suppressor gene located on chromosome 13 q14 . Q
Retinoblastoma develops when both the normal alleles of the Rb gene are inactivated or altered
43. Ans. (d) ras (Ref: Robbins 7th/295, 9/e p286)

44. Ans. (b) Autosomal dominant (Ref: Robbins 7th/1442, 299-300, 9/e p292-293)
Retinoblastoma is a prime example of a tumor which is associated with loss of heterozygosity.
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Retinoblastoma develops when both the normal alleles of the Rb gene are inactivated or altered.
Familial retinoblastoma is associated with autosomal dominant inheritanceQ whereas the Rb gene is having
autosomal recessive inheritance.
Hereditary/Familial retinoblastoma Non-Hereditary/Sporadic retinoblastoma
Seen in 40% cases Seen in 60% cases
Usually bilateral and multifocal Usually unilateral and unifocal
Can also develop extraocular tumors
(osteosarcoma and pinealoblastoma)
45. Ans. (a) p53 (Ref: Robbins 7th/302, 303, 304, 9/e p293)
46. Ans. (c) Its activity in the cells decreases following UV irradiation and stimulates cell cycle (Ref: Robbins 7th/302, 303,
8th/290-291, 9/e p293-294)
p53 is a tumor suppressor gene, located on chromosome 17. It is also called as Guardian of the genome.
At the time of DNA injury following irradiation, its level increases and it acts to cause cell cycle arrest (G1/S)
The cell cycle arrest is to allow time for DNA repair. If repair is unsuccessful, p53 causes apoptosis of the cell by
activating bax (apoptosis inducing gene). So, any exposure to UV irradiation would cause increased activity of p53
gene resulting in apoptosis and cell death.
47. Ans. (b) GTPase activating protein (Ref: Robbins 8th/282, 7th/296-297, 9/e 286)
Activated ras is present in association with GTP. Enzyme GTPase will degrade GTP to GDP and result in inactivation of
ras. Thus, GTPase activating protein will counteract the activation of ras.
48. Ans. (b) p 53 (Ref: Robbins Illustrated, 7th/1134, 9/e 294)
Mutation in p53 tumor suppressor gene is strongly associated with breast cancer, as well as many other sarcomas and
carcinomas. This condition is called as Li-Fraumeni syndrome.
49. Ans. (a) Important for normal cell growth; (b) Oncogenesis; (c) C-myc over-expression causes lymphoma (Ref: Robbins
7th/292, 293, 295, 9/e 284)
Genes that promote autonomous cell growth in cancer cells are called oncogenes and their normal cellular counter-
parts are called proto-oncogenes.
Neoplasia
Proto-oncogenes are important for cellular function related to growth and proliferation.
Proto-oncogenes may be converted into cellular oncogenes that are involved in oncogenesis.
c-myc proto-oncogenes is expressed in virtually all eukaryotic cells and its persistent expression or over-expression
is commonly found in tumors. Dysregulation of c-myc expression resulting from translocation of gene occurs in
Burkitts lymphoma.
50. Ans. (c) They are transduced from virus infected cells (Ref: Ananthnarayan 7/580-1, Robbins 7th/293, 302)
Viral oncogenes (V-onc) commonly known as cancer genes which encode proteins triggering transformation of
normal cells into cancer cells.
Proto-oncogenes are the normal cellular genes that promote normal growth and differentiation.
Oncogenes isolated from cancer cells are called cellular oncogenes (C-onc).
Proto-oncogenes are converted to oncogenes and cause cancer by:
Transduction into retrovirus (V-oncs) or
Changes in situ that affect their expression and function thereby converting them into cellular oncogene (C-
oncs).
The transduction of oncogenes by the virus (e.g. retrovirus) is through recombination with DNA of a (normal) host
cell that had been infected by the virus. Thus, they are of host cell origin. The virus act as transducing agent, carrying
oncogenes from one cell to another.
Viral oncogenes do not contain introns and thats how they are different from human oncogenes.
51. Ans. (a) Suppression of P 53; (c) bc1-2 (Ref: Robins 7th/306, 274, 9/e 302)
Cell survival would be seen when they are prevented from apoptosis. Genes that favor cell survival and protect from
apoptosis are: - bcl-2 , bcl-xL
Genes that favor programmed cell death are: bax, bad, bcl-xL and p53.
52. Ans. (a) Proto-oncogenes; (b) Tumor suppressor genes; (d) DNA repair genes (Ref: Robbins 7th/290, 298, 9/e 280)
53. Ans. is (c) i.e. Nucleotide excision repair (Ref: Harrison 17th/d/387 Robbins 7th/d 287, 9/e 314)
168
Neoplasia
54. Ans. (b) EGF Receptor (Ref: Robbins 7th/295, 9/e 285)
55. Ans. (d) C-Myc (Ref: Robbins 7th/295, 300, 9/e 288)
C-myc is a proto-oncogene of transcriptional activator category and is associated with Burkitts lymphoma.
Important points about p53
Located on chromosome 17 (17p 13.1).
Single most common target for genetic alteration in human tumors.
Also known as Guardian of the Genome or molecular policeman.
p53 is not a cyclin-dependent inhibitor, rather it elicits p21 which in turn is a CDK inhibitor and mediates
G1/S arrest. So, it also called Guardian of G1 checkpoint. It induces DNA repair of genes (via GADD45). In case repair fails it
induces apoptosis via BAX (the pro-apoptotic gene).
Inheritance of mutated p53 gene increases the chances of multiple malignancies and is called Li-Fraumeni syndrome.
Mutation in p53 gene causes the resistance in tumors to radiation and chemotherapy.
56. Ans. (a) Formation of the new blood vessels (Ref: Robbins 8th/297; 7th/71-72, 9/e 305)
57. Ans. (a) RET (Ref: Robbins 8th/1124-1126, 7th/295, 9/e 284)
58. Ans. (a) Chromosome 5 (Ref: Robbins 8th/823, 7th/862, 9/e 296)
59. Ans. (b) Small cell lung cancer (Ref: Robbins 8th/722-723, 9/e 285)
60. Ans. (a) p53 (Ref: Robbins 8th/290-292, 7th/302-303, 9/e 294)
61. Ans. (b) K-RAS (Ref: Robbins 8th/308, 9/e 811)
Read explanation below
Mostly colon adenocarcinoma develops from pre-existing adenomatous polyps (adenomas). Colon adenomas usually
occur in patients in 50-60 years old and are considered premalignant. Early detection and excision of adenomatous polyps
is therefore, an effective prophylaxis for colon adenocarcinoma.
The malignant potential of adenomatous polyps is determined by the following:
Size of the polyp:

< 1cm - Unlikely to undergo malignant transformation

Neoplasia
> 4cm- 40% risk of malignancy
Microscopic/Histologic appearance: Villous adenomas are more prone to be malignant than tubular adenomas.
Degree of dysplasia.
The transformation of normal mucosal cells into malignant ones is caused by a series of gene mutations called the adeno-
ma-to-carcinoma sequence. This sequence includes the following steps:
Progression from normal mucosa to a small adenomatous polyp: Due to mutation of APC tumor suppressor gene.
Increase in the size of the polyps: It is due to mutation of K-ras proto-oncogene.
Malignant transformation of adenoma into carcinoma requires mutation of two genes: p53 and DCC.
Increase in the size of adenomatous polyps (and, therefore, increase in their malignant potential) is attributed to K-ras
protooncogene mutation which results in unregulated cell proliferation.
62. Ans. (d) It is active in hyperphosphorylated form (Ref: Robbins 8th/282-3, 9/e 286)
K-Ras is the proto-oncogene which is active in its phosphorylated form.
Rb gene is active in its hypophosphorylated form.
P53 gene is called as guardian of the genome.
Myc gene promotes the cell growth in the presence of growth factors but it causes apoptosis in the absence of growth factors. So,
it is said to be in a state of conflict because its activity is dependent on the absence or presence of growth factors.
63. Ans. (d) p53 (Ref: Robbins 8th/308, 9/e 294)

Read explanation of the above question and then read the text below
1. Colon cancer is one of the common malignancy whose incidence increases with age, and it affects males and females equally. The
risk factors are discussed in detail in the chapter on GIT.
2. P53 gene also called as the molecular policeman triggers apoptosis of cells with damaged DNA. Mutation of p53 allows cells with
genomic errors to enter the cell cycle. This mutation is considered the last hit in the adenoma-to-carcinoma sequence. Malignant
transformation of adenoma into carcinoma requires mutation of two genes: p53 and DCC.
Evaluating the other options,
(Choice A): Cyclin D is a protein that regulates cell cycle. Its overexpression is seen in breast, lung, and esophageal
cancers, and certain types of lymphomas.
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(Choice B): K-ras protooncogene mutation is responsible for increase in the size of adenomatous polyps. Its mutation
leads to uncontrolled cell proliferation.
(Choice C) The mutation of WT-1, an anti-oncogene, leads to the development of Wilms tumor.
64. Ans. (c) Receptor tyrosine kinase (Ref: Robbins 8th/281, 9/e 1062)
Her-2/neu (also known as c-erb B2) is a receptor tyrosine kinase related to epidermal growth factor receptor. It is amplified
at the DNA level and over-expressed at the protein level in some breast cancers. Trastuzumab is a monoclonal antibody
targeted against her-2/neu.
Ras is a proto-oncogene mutated in a number of cancers. NF-1 is a GTPase-activating protein (GAP) aberrantly expressed in
neurofibromatosis. A mutated variant of a retinoic acid receptor is expressed in M3 AML (acute promyelocytic leukemia).
65. Ans. (c) Ret (Ref: Robbins 8th/1123-1124, 9/e 284)
The thyroid lesion is medullary carcinoma of the thyroid. The coexistence of parathyroid hyperplasia suggests Sipples
syndrome (MEN II). These patients also tend to develop pheochromocytoma. Both MEN II and MEN III are associated
with the ret oncogene. Please revise:
Associate bcl-2 (option A) with follicular and undifferentiated lymphomas.
Associate C-myc (option B) with Burkitts lymphoma.
Associate L-myc (option D) with small cell carcinoma of the lung.
66. Ans. (c) Peripheral nerve (Ref: Robbins 8th/1341, 9/e 298)
The disease is neurofibromatosis (von Recklinghausens disease), which is characterized by caf-au-lait spots (the light
brown macules), Lisch nodules (pigmented iris hamartomas), and multiple peripheral nerve tumors (neurofibromas). The
neurofibromas are initially benign, but may undergo malignant transformation. Caf-au-lait spots are not considered to be
premalignant lesions of skin (option D).
66.1. Ans. (b) Medullary carcinoma thyroid (Ref: Robbins 8/e p280, 9/e 284)
The RET protein is a receptor for the glial cell linederived neurotrophic factor and structurally related proteins that pro-
mote cell survival during neural development. RET is normally expressed in neuroendocrine cells, such as parafollicular
C cells of the thyroid, adrenal medulla, and parathyroid cell precursors. Point mutations in the RET proto-oncogene are
associated with dominantly inherited MEN types 2AQ and 2BQ and familial medullary thyroid carcinomaQ.
RET gene mutation is more commonly associated with medullary thyroid cancer than pheochromocytoma.
Neoplasia
Clinical significance of RET(Ref: Robbins 8/e p

All individuals carrying germline RET mutations are advised to undergo prophylactic thyroidectomy to prevent the inevitable
development of medullary carcinomas.
6 6.2. Ans. (c) PTEN (Ref: Robbins 8/e p294, 9/e 298)
Direct quote from Robbins PTEN (Phosphatase and tensin homologue) is a membrane-associated phosphatase en-
coded by a gene on chromosome 10q23 that is mutated in Cowden syndrome, an autosomal dominant disorder marked
by frequent benign growths, such as tumors of the skin appendages, and an increased incidence of epithelial cancers,
particularly of the breast, endometrium, and thyroid.
66.3. Ans. (c) G S phase (Ref: Robbins 8/e p290-1, 9/e 294)
1
The cell cycle has its own internal controls, called checkpoints. There are two main checkpoints, one at the G1/S tran-
sition and another at G2/M.
In the G1/S checkpoint, cell-cycle arrest is mostly mediated through p53, which induces the cell-cycle inhibitor p21.
Arrest of the cell cycle by the G2/M checkpoint involves both p53-dependent (via cyclin A/cdK-2) and independent
(via cdc 25) mechanisms.
As can be deduced from above mentioned information that the p53 is associated with both the types of checkpoints.
However, G2/M checkpointcan take place even without p53. Hence, option c is the preferred answer.
66.4. Ans. (d) Transcription activator (Ref: Robbins 8/e p288)
A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, are transcription factors
that regulate the expression of growth-promoting genes, such as cyclins.
Out of all these,MYC is most commonly involved in human tumors Q
MYC gene is associated with Conflict model in carcinogenesis

Tumors associated with different subtypes of MYC
C-MYC Translocation Burkitt lymphoma
N-MYC Amplification Neuroblastoma, small-cell carcinoma of lung
L-MYC Amplification Small-cell carcinoma of Lung
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Neoplasia
66.5. Ans. (d) Osteosarcoma (Ref: Robbins 8/e p293)

Retinoblastoma develops when both the normal alleles of the Rb gene are inactivated or altered.
Familial retinoblastoma is associated with autosomal dominant inheritanceQ whereas the Rb gene is having auto-
somal recessive inheritance.
Hereditary/Familial retinoblastoma Non-Hereditary/Sporadic retinoblastoma

Seen in 40% cases Seen in 60% cases(more common )
Usually bilateral and multifocal Usually unilateral and unifocal
Can also develop extraocular tumors
(osteosarcoma and pinealoblastoma)
66.6. Ans. (d) RBexplained earlier (Ref: Robbins 9/e p291)

66.7. Ans. (c) Xeroderma pigmentosum (Ref: Robbins 8/e p275, 9/e 314)
6 6.8. Ans. (a) RET Proto Oncogene (Ref: Robbins 8/e p280, 9/e 284)
66.9. Ans. (a) Beta-2 macroglobulin (Ref: Robbins 8/e p327)
Beta-2 microglobulin and not beta macroglobulin may be used as a tumor marker (as in multiple myeloma).
Neoplasia
66.10. Ans. (d) Rb (Ref: Robbins 8/e p286, 7/e p299-300, 9/e 291)
66.11. Ans. (b) Retinoblastoma (Ref: Robbins 9/e p 290)
66.12. Ans. (b) Pinealoblastoma (Ref: Robbins 9/e p 1339)

Retinoblastoma is the most common primary intraocular malignancy of children. In the sporadic cases, both RB alleles
are lost by somatic mutations. Retinoblastomas arising in the context of germline mutations are often bilateral. In addition,
they may be associated with pinealoblastoma (trilateral retinoblastoma).
67. Ans. (b) EBV (Ref: Robbins 8th/230, Harrison 18th/921, 1124, 9/e 327)
Infectious Agent Lymphoid Malignancy
Epstein-Barr virus Burkitts lymphoma
Postorgan transplant lymphoma
Primary CNS diffuse large B cell lymphoma
Hodgkins disease
Extranodal NK/T cell lymphoma, nasal type
HIV Diffuse large B cell lymphoma
Burkitts lymphoma
Hepatitis C virus Lymphoplasmacytic lymphoma
Helicobacter pylori Gastric MALT lymphoma
Human herpesvirus 8 Primary effusion lymphoma
Multicentric Castlemans disease
HTLV-I Adult T cell leukemia/lymphoma
68. Ans. (a) MALToma (Ref: Harrison 17th/1858, Robbins 8th/316, 9/e 329)
69. Ans. (d) Burkitts lymphoma (Ref: Robbins 7th/814, Robbins 8th/315-6, 9/e 329)
70. Ans. (b) Non-small Cell Carcinoma of Lung (Ref: Robbins 8th/277, 878, 9/e 325-329)
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CANCERS ASSOCIATED WITH INFECTIOUS AGENTS

Opisthorchis, Cholangiosarcoma, colon carcinoma Liver flukes (Opisthorchis viverrini)
cholangitis
Bile acids
Chronic cholecystitis Gallbladder cancer Bacteria, gallbladder stones
Gastritis/ulcers Gastric adenocarcinoma, MALT Helicobacter pylori
Hepatitis Hepatocellular carcinoma Hepatitis B and/or C virus
Mononucleosis B-cell non-Hodgkin lymphoma and Hodgkin Epstein-Barr virus
lymphoma, nasopharyngeal cancer
AIDS Non-Hodgkin lymphoma, squamous cell Human immunodeficiency virus, human herpesvirus
carcinoma, Kaposis sarcoma type 8
Osteomyelitis Carcinoma in draining sinuses Bacterial infection
Pelvic inflammatory Ovarian carcinoma, cervical/anal carcinoma Gonorrhea, chlamydia, human papillomavirus
disease, chronic cervicitis
Chronic cystitis Bladder, liver, rectal carcinoma Schistosomiasis
Non small cell lung cancer is not reported to be associated with any infectious organism.
71. Ans. (a) Angiogenesis (Ref: Harrison 17th/. 509, Robbins 9/e 305-306)
Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to other parts of the
body via the bloodstream or the lymphatic system. To do so, malignant cells break away from the primary tumor and
degrade proteins of the extracellular matrix (ECM). One of the critical events required for metastasis is the growth of a
new network of blood vessels, called tumor angiogenesis.
Without vascularization or angiogenesis, the tumor can grow only 1-2 mmQ. Vessels are also required for nutrition.
Vascularisation promoted by VEGF and bFGF and inhibited by Angiostatin, Endostatin and TumstatinQ.
It has been found that angiogenesis inhibitors would therefore prevent the growth of metastases.
Neoplasia
72. Ans. (b) Papilloma viruses produce tumors in animals but not in humans (Ref: Harrison 17th/487)
All the options mention about the carcinogens. Human papilloma virus is the most common etiological factor for cervical
cancer
73. Ans. (d) Hepatitis C virus (Ref: Robbins 8th/315, 9/e 328)
Hepatitis C virus (HCV) is only oncogenis RNA virus in the options. Others mentioned are oncogenic DNA viruses.
74. Ans. (c) Epstein-Barr Virus (Ref: Robbins 7th/325-327, 9/e 328)
LMP-1 gene plays a role in oncogenesis induced by EBV. For details, see text.
75. Ans. (b) UV-B rays (Ref: Robbins 7th/323 , 9/e 324)
Ultraviolet radiation is of 3 types; UV-A, UV-B and UV-C.
UVA causes melanin oxidation with transient immediate darkening. Repeated exposure to UV radiation cause degen-
erative changes in elastin and collagen leading to wrinkling increased laxity and a leathery appearance. It is however
used therapeutically in PUVA therapy for the management of vitiligo, psoriasis and cutaneous T cell lymphomaQ.
UVB can cause skin damage by formation of reactive oxygen species and formation of pyrimidine dimmers between
adjacent pyrimidines on the same DNA strand. The latter can cause double base substitutions in the p53 resulting in
the development of skin cancers. So, it is the most dangerous for humans. Exposure to UV rays also induces DNA
repair, apoptosis or cell cycle arrest. The absence of this protective mechanism is seen in patients of Xeroderma pig-
mentosum causing high incidence of skin cancers.
UVC is not reaching earth because it gets filtered by the protective ozone layer.
76. Ans. (d) Testicular seminoma (Ref: Robbins 8th/989, 7th/1041)
77. Ans. (d) Thyroid (Ref: Robbins 8th/273-274, 7th/419 , 9/e 415)
78. Ans. (c) Angiosarcoma (Ref: Robbins 8th/274; 7th/550, 923 , 9/e 519)
79. Ans. (a) Cytomegalovirus (Ref: Robbins 8th/317-318; 7th/325 , 9/e 325-326)
80. Ans. (a) Aflatoxin B1 (Ref: Robbins 7th/319-323, 924 , 9/e 323)
Vinyl chloride is associated with angiosarcoma of the liver, not hepatocellular carcinoma.
Azo dyes, such as butter yellow and scarlet red, have induced hepatocellular cancer in rats, but no human cases have
172
Neoplasia
been reported.
There has been an increase in bladder cancer in workers in the aniline dye and rubber industries
Aflatoxin B1, a natural product of the fungus Aspergillus flavus, is associated with the high incidence of hepatocel-
lular carcinoma
Hepatitis B virus is also highly associated with liver cancer.
81. Ans. (b) Helicobacter pylori (Ref: Robbins 8th/785, 9/e 329)
The patient has gastric carcinoma, which has been linked to prior gastric infection with Helicobacter pylori.
Epstein-Barr virus (option A) has been linked to African Burkitts lymphoma and nasopharyngeal carcinoma.
Human papilloma virus (option C) has been linked to a variety of warts, condyloma, and genital cancers.
Molluscum contagiosum virus (option D) is a poxvirus that causes small tumor-like papules of the skin.
82. Ans. (d) Leukemia (Ref: Robbins 8th/312, 9/e 325)
HTLV-1, or human T-cell lymphotrophic virus 1, is an enveloped, single-stranded, RNA retrovirus whose infection can
lead to T-cell leukemia 20-30 years after the infection. The HTLV-associated T-cell leukemia generally presents as described
in the stem of the question and is very aggressive, progressing to death in less than 1 year.
82.1. Ans. (c) Angiosarcoma of liver (Ref: Robbins 8/e p877 , 9/e 519)
Angiosarcoma of the liver is a highly aggressive tumor which is associated with exposure to:
Vinyl chlorideQ
,
Arsenic , or
Q
Thorotrast .
Q
Thorotrast is a suspension containing particles of the radioactive compound thorium dioxide. It emits alpha particles due
to which it has been found to be extremely carcinogenic.
82.2. Ans. (c) Thyroid (Ref: Robbins 8/e p312, 425 and internet, 9/e p 325)
The most radiosensitive organ sites in children in order of sensitivity are the thyroid gland, breasts, bone marrow
(leukemia), brain and skin.
82.3. Ans. (c) Clonorchiasis (Ref: Robbins 8/e p880, 9/e p 874)
The following two parasites have definitive etiological association with malignancies:
Clonorchis sinensis: cholangiocarcinoma
Q
Neoplasia
Opisthorchis viverrini: cholangiocarcinoma Q
Schistosoma haematobium : squamous cell cancer of urinary bladderQ
Schistosoma japonicum: colorectal cancer Q
8 2.4. Ans. (d) HHV (Ref: Robbins 8/e p313, 9/e p 254)
Kaposi sarcoma is caused by HHV-8 (Human Herpes Virus-8)or KS-associated herpesvirus (KSHV)
Q
It is a vascular tumor
Most primary KSHV infections are asymptomatic.
It can be treated by administration of interferon-, adjunct chemotherapy or radiation therapy
Classic KS is largely restricted to the surface of the body, and surgical resection is usually adequate for an excellent
prognosis.
82.5. Ans. (b) Stimulates formation of pyrimidine dimers (Ref: Robbins 8/e p312, 9/e p314)
Direct quote from Robbins.. The carcinogenicity of UV-B light is attributed to its formation of pyrimidine dimers in
DNA. This type of DNA damage is repaired by the nucleotide excision repair pathway. The importance of the nucleotide
excision repair pathway of DNA repair is illustrated by the high frequency of cancers in individuals with the hereditary
disorder xeroderma pigmentosum..
82.6. Ans. (b) Lymphocytes (Ref: Robbins, 9/e p430)
The most radiosensitive cell in the blood is the lymphocytes . Q
The least radiosensitive cell in the blood is the platelets .

Q
DNA is the most sensitive intracellular organelle to radiation.

Q
82.7. Ans. (c) Gray (Ref: Robbins 9/e p428)

Gray (Gy) is a unit that expresses the energy absorbed by the target tissue per unit mass.
82.8. Ans. (d) Chronic lymphocytic leukemia (Ref: Robbins 9/e p 431)
The main sources of ionizing radiation are x-rays and gamma rays (electromagnetic waves of very high frequencies), high-
energy neutrons, alpha particles (composed of two protons and two neutrons), and beta particles, which are essentially
electrons.
Diagnostics is the most common source of radiation exposure in human beings.
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Cancers associated with radiation Cancers not associated with radiation

ALL, AML and CML CLL
Cancer of thyroid, breast and lung. Hodgkins lymphoma
Cancer of CNS, bladder, ovary Cancer prostate/testis/cervix
83. Ans. (c) Inhibin (Ref: Robbins 8th/1050, 9/e p1032)
Granulosa cell tumor
The most common type of ovarian tumor that is composed of cells that stain positively with inhibin .Q
Histologically, the cells may form Call-Exner bodies Q
The tumor cells may secrete estrogens and cause precocious sexual development in girls or increase the risk for endometrial
hyperplasia and carcinoma in women.
Less commonly granulosa cell tumors can secrete androgens and produce masculinization.

Concept: for future exam
Tumor cells in Sertoli-Leydig tumors (Androblastomas) may stain positively with inhibin, but Call-Exner bodies are not
present. Sertoli-Leydig tumors also may secrete androgens and produce virilization in women.
The granulosa cell tumors vary in their clinical behavior, but they are considered to be potentially malignant.

84. Ans. (a) Hepatoblastoma (Ref: Robbins 8th/327, 7th/339, 9/e p869-870, Harsh Mohan 6th/637)
AFP is glycoprotein synthesized in fetal life by yolk sac, fetal liver and fetal gastrointestinal tract. It is a marker of
hepatocellular cancer and non-seminomatous germ cell tumors of testes. Elevated plasma AFP is also found less
regularly in carcinomas of the colon, lung, and pancreas.
Important points about hepatoblastoma
Arising from hepatic parenchymal cells
The most common tumor of young childhood

Neoplasia
More commonly seen in boys

The concentration of AFP is very high
A characteristic feature of hepatoblastomas is the frequent activation of the Wnt/-catenin signaling pathway by stabilizing
mutations of -catenin, contributing to the process of carcinogenesis.

85. Ans. (c) Osteosarcoma > (a) Multiple myeloma (Ref: Journal.Cancer 42:603-610, 1978)
The journal writes that.. The clinical manifestations, resulting from the production of metabolically active
substances by neoplastic tissue, have been labeled paraneoplastic syndromes. Adolescent patients with primary
osteosarcoma demonstrate abnormal glucose, insulin and growth hormone responses to oral glucose loading in 78%
of the study population. No statistical association exists between any two of the three factors and, therefore, no primary
abnormality can be identified. High somatomedin levels were noted in 72% of the group studied accompanied by
simultaneous elevations of growth hormones. Studies of adrenal, gonadal and gonadotropic hormones were essentially
normal, thereby ruling these out as associated endocrine abnormalities.
Hyperglycemia is also associated with chondrosarcoma and fibrosarcoma.
Some reports associate hyperglycemia with multiple myeloma too but we would prefer osteosarcoma as the answer
here because the chances of hyperglycemia is more with osteosarcoma than multiple myeloma.
86. Ans. (a) SIADH (Ref: Robbins 8th/636-637, 9/e p626-627)
Thymoma is the commenest anterior mediastinal tumor which causes symptoms due to compression on the mediastinal
structures. It is associated with the following paraneoplastic syndromes:
Myasthenia gravis (most common) Q
Acquired hypogammaglobulinemia Q
Pure red cell aplasia Q
Graves disease
Pernicious anemia
Dermatomyositis-polymyositis
Cushing syndrome.
Epstein-Barr virus may be associated with thymomas.
Thymoma is the commonest anterior mediastinal tumor.

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Neoplasia
87. Ans. (d) Involves aorta and its branches early (Ref: Robbins 8th/475-479, 9/e p476-479)
See text in chapter-18
88. Ans. (a) Prostate (Ref: Robbin 7th/354, 9/e p332)
Migratory thrombophlebitis (Trousseau sign ) is particularly associated with adenocarcinomas of the pancreas,
Q
colon and lung because of associated paraneoplastic syndrome resulting in hypercoagulability.

Q
89. Ans. (c) Malignant melanoma: (Ref Anderson pathology 144-152, 9/e p1149)
Malignant melanoma expresses HMB 45, S-100 and vimentin.
HMB 45 is present in melanosomes and is more specific . Q
S-100 is more sensitive but is non-specific (also present in Langerhans cell histiocytosis, neural tumors, and sarcomas
Q
like liposarcoma and chondrosarcoma)

90. Ans. (a) Hepatoblastoma (Ref: Robbins 8th/327, 7th/339, , 9/e p869-870, Harsh Mohan 6th/637)
91. Ans. (c) Carcinoma (Ref: Robbins 8th/324, 7th/336-337, 9/e p334)
Immunohistochemistry is used for making categorization of undifferentiated tumors. The important examples include:
Cytokeratin (carcinoma), Desmin (Leiomyoma and Rhabdomyosarcoma) and vimentin (Sarcomas).
92. Ans. (b) Pancreatic neuroendocrine tumor (Ref: Harrison 17th/2354, Robbins 9/e 1121)
G astrin is secreted by Gastrinomas, which are neuroendocrine tumors most commonly found in duodenum.
M arker of medullary carcinoma of thyroid is calcitonin and GIST is CD117 (c-kit).
93. Ans. (a) Alpha-hCG (a-hCG) (Ref: Robbins 7th/1045, 1046, 9/e 337-338, C.S.D.T. 11th/1071)
Human chorionic gonadotropin (hCG)
The beta subunit of hCG is typically measured as a tumor marker because it has unique sequence that are not shared with
other human glycoprotein hormones. So, it is quite specific.
Alpha hCG is not used as tumor marker because it is similar to the FSH, LH and TSH. So there can be cross reactivity
between beta subunits of these hormones.
94. Ans. (a) Seminoma (Ref: Harrison 17th/1925 & Robbins 8th//988-989)
The normal serum alkaline phosphate consists of 4 isoenzymes secreted from the following sites:
a. Liver, b. Bone, c. Intestine,
Neoplasia
d. Placenta
They are best differentiated by electrophoresis. Another approach is based on the differentiation between the different
isoenzymes on the basis of heat susceptibility.
Alkaline phosphatase from individual tissues differ in susceptibility to inactivation by heat. The finding of an elevated serum alkaline
phosphatase level in a patient with a heat-stable fraction strongly suggests that the placenta or a tumor is the source of the
elevated enzyme in serum. Susceptibility to inactivation by heat increases, respectively, for the intestinal, liver, and bone alkaline
phosphatase, bone being by far the most sensitive and the liver being most resistant.
Mnemonic: bone burns but liver lasts
The conditions having elevated placental alkaline phosphatase include:
Seminoma
Choriocarcinoma
Third trimester of pregnancy
95. Ans. (b) Hypercalcemia (Ref: Harrison, 17th/1736)
Tumor lysis syndrome is associated with hyperphosphatemia due to release of intracellular phosphate by the destroyed
cancer cells. This is followed by a decrease in serum calcium levels.
96. Ans. (a) Screening of a cancer; (b) Follow up of a cancer patient, esp. for knowing about recurrence; (d) For
monitoring the treatment of a cancer (Ref: Robbins 7th/338, 9/e p338)
Uses of Tumor Markers
Screening of Cancer e.g. in prostate carcinoma (PSA), ovarian carcinoma (CA-125).
Follow-up a cancer patient especially for knowing recurrence e.g. AFP in hepatocellular carcinoma, CEA in
colon carcinoma.
For monitoring of a cancer e.g. AFP + HCG in testicular malignancy, AFP in hepatocellular carcinoma.
Prognosis of a cancer e.g. HCG; AFP in testicular malignancy, CEA in colon Ca.
Tumor markers are not specific, so, cannot be used for confirmation of diagnosis. Confirmation is done by biopsy
97. Ans. (a) Useful for screening of Ca. colon; (c) Helpful for follow up after resection; (d) Levels decrease immediately
after resection of tumor (Ref: Harrison l6th/530, 531, Robbin 9/e p338)
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Carcino embryonic antigen is used in Colon carcinoma as follows;

For screening of carcinoma colon
For follow-up after resection
Early knowledge about tumor recurrence and metastasis
Levels of CEA are elevated in 70% of patients but are poorly correlated with cancer stage.
After complete surgical resection, CEA level should be normalized, persistent levels imply a poor prognosis.
Diagnosis of colon carcinoma is confirmed by colonoscopy and biopsy as some benign and other malignant conditions
also show high values of CEA:
Pancreatic, breast and stomach carcinoma
Alcoholic cirrhosis
Hepatitis
IBD
98. Ans. (c) Ovarian carcinoma (Ref: Harrison 16th/439, Robbins 9/e p337)
99. Ans. (b) Hand and feet bones: (Ref: Robbins 7th/1303, 9/e 1207)
Metastasis may occur any bone but most commonly involve axial skeleton (e.g. vertebra, pelvis, ribs. skull. sternum)
> Proximal femur > humerus.
Metastasis in small bone of hand and feet are uncommon and usually originates in cancer of lung, kidney and colon
Skeletal metastasis are typically multifocal, however carcinoma of kidney and thyroid produce solitary lesions.
100. Ans. (d) A technique for raising monoclonal antibodies (Ref: Harsh Mohan 6th/15)
101. Ans. (a) Follicular lymphoma (Ref: Robbin 7th/675, 9/e 594-595)
The hallmark of follicular lymphoma is a (14; 18) translocation, which leads to the juxtaposition of the IgH locus on
chromosome 14 and BCL 2 locus on chromosome 18.
This translocation is seen in most but not all follicular lymphomas and leads to over-expression of BCL2 protein.
B-cell lymphoma is associated with breakpoint involving the BCL 6 locus on chromosome 3.
Mantle cell lymphoma is associated with a locus on chromosome 11 variously known as BCL1 or PRAD1.
Neoplasia
102. Ans. (c) Hepatoma (Ref: Robbins 7th/338, 9/e p337)

AFP is glycoprotein synthesized in fetal life by yolk sac, fetal liver and fetal GIT. It is a marker of HCC, hepatoma and
non-seminomatous germ cell tumors of testes.
103. Ans. (a) Yolk sac tumor (Ref: Robbins 8th/990, 1049; 7th/1041, 1043, 9/e p977)
104. Ans. (a) Disseminated cancer; (this is known as Trosseau sign ) (Ref: Robbins 8th/322, 7th/335, 9/e p332)
Q
105. Ans. (b) Parathyroid hormone related peptide (Ref: Robbins 8th/728, 7th/333, 9/e p330)
106. Ans. (c) Cerebellar hemangioblastoma (Ref: Robbins 8th/665, 7th/334, 9/e p331)
107. Ans. (d) Bladder carcinoma (Ref: Robbins 8th/327, 7th/338, 9/e p338)
108. Ans. (c) Ulcerative colitis (Ref: Robbins 8th/327, 7th/1339, 9/e p338)
109. Ans. (b) Anterior abdominal wall (Ref: Robbins 8th/1251-1252; 7th/1319, 9/e p1222)
110. Ans. (d) Both b and c (Ref: Robbins 8th/326-327; 7th/338-339, 825-826, 9/e p337)
111. Ans. (b) Carcinoma colon (Ref: Robbins 8th/327; 7th/339, 9/e p337)
112. Ans. (b) AFP (Ref: Robbins 8th/327, 7th/338, 9/e p873)
113. Ans. (b) Neuroblastoma (Ref: Robbins 8th/475, 7th/502, 9/e p476)
114. Ans. (d) Cholangiocarcinoma - AFP (Ref: Robbins 8th/880-881, 7th/926-927, 9/e p337)
115. Ans. (a) Chondrosarcoma (Ref: Robbins 8th/1230, 7th/1299)
116. Ans. (b) Hepatocellular carcinoma of liver (Ref: Robbins 8th/876, 7th/338, 9/e p873)
117. Ans. (d) Kidney tumor (Ref: Robbins 8th/326-327; 7th/338, 9/e p337)
118. Ans. (a) Neuroblastoma (Ref: Robbins 8th/478; 7th/504, 9/e p476)
119. Ans. (b) Parathyroid hormone related peptide (Ref: Robbins 7th/333-335, 9/e p330)
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Neoplasia
Bronchogenic carcinomas are associated with the development of many different types of paraneoplastic syndrome.
Ectopic secretion of ACTH may produce Cushings syndrome
Ectopic secretion of anti-diuretic hormone may produce hyponatremia
Hypocalcemia may result from the production of parathyroid hormone- related peptide, patients with this type of
paraneoplastic syndrome have increased calcium levels and decreased PTH levels.
Other tumors associated with the production of PTHrP include clear cell carcinomas of the kidney, endometrial
adenocarcinomas, and transitional carcinomas of the urinary bladder.
120. Ans. (c) Kidney (Ref: Robbins 8th/665, 9/e p331)
Renal cell carcinoma can lead to overproduction of erythropoietin and thereby cause secondary polycythemia. Other causes
of secondary polycythemia are diseases that impair oxygenation, including pulmonary diseases (including smoking) and
congestive heart failure.
Colon cancer (option B) and stomach cancer (option D) can present with anemia secondary to blood loss.
121. Ans. (a) Adrenal gland (Ref: Robbins 8th/1156-1157, 9/e p1130)
This is Addison disease, in which severe adrenal disease produces adrenocortical insufficiency. Causes include autoim-
mune destruction, congenital adrenal hyperplasia, hemorrhagic necrosis, and replacement of the glands by either tumor
(usually metastatic) or granulomatous disease (usually tuberculosis being the commonest cause in India). The symptoms
can be subtle and nonspecific (such as those illustrated), so a high clinical index of suspicion is warranted. Skin hyper-
pigmentation is a specific clue that may be present on physical examination, suggesting excess pituitary ACTH secretion.
(The ACTH precursor has an amino acid sequence similar to MSH, melanocyte stimulating hormone.) Most patients
have symptoms (fatigue, gastrointestinal distress) related principally to glucocorticoid deficiency. In some cases, however,
mineralocorticoid replacement may also be needed for symptoms of salt wasting with lower circulating volume.
Except in the case of primary pancreatic cancer, complete tumor replacement of the endocrine pancreas (option B) would
be uncommon. In any event, pancreatic involvement would be associated with diabetes mellitus.
Involvement of the ovaries (option C) by metastatic tumor (classically gastric adenocarcinoma) would produce failure of
menstruation.
Involvement of the pituitary gland (option D) could produce Addisonian symptoms, but the pigmented skin suggests a
primary adrenal problem rather than pituitary involvement.
Neoplasia
122. Ans. (a) Pancreatic cancer (Ref: Robbins 8th/321, 903, 9/e p332)
Pancreatic carcinoma often presents with vague abdominal, back, and gastrointestinal complaints; and physical examina-
tion is generally normal. The significant weight loss and the migrating thrombophlebitis (Trousseaus sign) is pointing
towards the diagnosis, which should be confirmed with ultrasonography or CT. Migratory thrombophlebitis is mostly
associated with tumors of the pancreas, lung, and colon.
123. Ans. (a) Breast (Ref: Robbins 8th/1235, 9/e p1207)
Breast cancer is unusual in that it produces both lytic and blastic metastases to bone. Breast and prostate cancers are the
most common sources of bone metastases, but prostate metastases are usually blastic.
Colon cancer (choice B) does not usually metastasize to bone.
Kidney cancer (choice C), lung cancer (choice D), GIT and malignant melanoma produce lytic lesions when they
metastasize to bone.
123.1. Ans. (a) Pheochromocytoma (Ref: Robbins 8/e p1159, 9/e p1134)
Pheochromocytomas have been associated with arule of 10s.
10% of pheochromocytomas are extra-adrenal , occurring in sites such as the organs of Zuckerkandl and the carotid
Q
body.
10% of sporadic adrenal pheochromocytomas are bilateral .
Q
10% of adrenal pheochromocytomas are biologically malignant , defined by the presence of metastatic disease.
Q
10% of adrenal pheochromocytomas are not associated with hypertension .

Q
One traditional 10% rule that has now been modified pertains to familial cases. Now almost25% of individuals with
pheochromocytomas and paragangliomas harbor a germline mutation in the succinate dehydrogenase genes.
Also note that
Notably, malignancy is more common (20% to 40%) in extra-adrenal paragangliomas, and in tumors arising in
the setting of certain germline mutations.
Patients with germline mutations are typically younger at presentation than those with sporadic tumors and more
often harbor bilateral disease. Pheochromocytoma is associated with germline mutation.
1 23.2. Ans. (c) Cytokeratin (Ref: Robbins 8/e p324, 9/e p334)
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Tumors and associated filaments

Intermediate Filament Normal Tissue Expression Tumor
Cytokeration All epithelial cells Carcinoma
Vimentin Mesenchymal cells Sarcomas
Desmin Muscle cells Leiomyoma Rhabdomyosarcoma
Glial fibrillary acidic protein (GFAP) Glial cells Astrocytoma ependymoma
Neurofilamnet Neurons and neural crest derivatives Pheochromocytoma neuroblastoma
123.3. Ans. (a) CA-125 (Ref: Robbins 8/e p327, 9/e p337)
HORMONES
Human chorionic gonadotropin Trophoblastic tumors, nonseminomatous testicular tumors
Calcitonin Medullary carcinoma of thyroid
Catecholamine and metabolites Pheochromocytoma and related tumors
ONCOFETAL ANTIGENS
-Fetoprotein Liver cell cancer, non-seminomatous germ cell tumors of testis
Carcinoembryonic antigen (CEA) Carcinomas of the colon, pancreas, lung, stomach, and heart
ISOENZYMES
Prostatic acid phosphatase Prostate cancer
Neuron-specific enolase Small-cell cancer of lung, neuroblastoma
SPECIFIC PROTEINS
Immunoglobulins Multiple myeloma and other gammopathies
Prostate-specific antigen and prostate-specific membrane Prostate cancer
Neoplasia
antigen
MUCINS AND OTHER GLYCOPROTEINS
CA-125 Ovarian cancer
CA-19-9 Colon cancer, pancreatic cancer
CA-15-3 Breast cancer
NEW MOLECULAR MARKERS
p53, APC, RAS mutants in stool and serum Colon cancer
p53 and RAS mutants in stool and serum Pancreatic cancer
p53 and RAS mutants in sputum and serum Lung cancer
p53 mutants in urine Bladder cancer
1 23.4. Ans. (a) CEA.See table above (Ref: Robbins 9/e p337)
1 23.5. Ans. (a) Prostate (Ref: Robbins 8/e p1235, 9/e p1207)
Carcinomas of the kidney, lung, and gastrointestinal tract and malignant melanoma produce lytic bone destruction.
Other metastases elicit a sclerotic response, particularly prostate adenocarcinoma, which may do so by secreting
WNT proteins that stimulate osteoblastic bone formation.
Most metastases induce a mixed lytic and blastic reaction
123.6. Ans. (b) - HCG (Ref: Robbins 8/e p474, 9/e p474-475 The Essentials of Clinical Oncology p490)
Sacrococcygeal teratomas are the most common teratomas of childhood, accounting for 40% or more of cases). They
occur with a frequency of 1 in 20,000 to 40,000 live births, and are four times more common in girls than boys
Serum alpha fetoprotein is a useful marker for sacrococcygeal teratoma. Some books mention that even beta HCG is
elevated in some patients.
1 23.7. Ans. (b) CDKN2A (Ref: Robbins 8/e p1174, 9/e p1147)
Please do not get confused with the first option friends. Melanomas are associated with N-Ras and not N-myc.
Coming to the other options,
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Neoplasia
Direct quote from Robbins. The CDKN2A gene (is mutated in approximately 40% of pedigrees with autosomal
dominant familial melanoma.
1 23.8. Ans. (a) Chromogranin (Ref: Robbins 8/e p726-727, 9/e p717)
Direct quote from Robbins.. The occurrence of neurosecretory granules, the ability of some of these tumors to secrete
polypeptide hormones, and the presence of neuroendocrine markers such as chromogranin, synaptophysin and CD57
(in 75% of cases) and parathormone-like and other hormonally active products suggest derivation of this tumor from
neuroendocrine progenitor cells of the lining bronchial epithelium.
1 23.9. Ans. (c) PLAP (Ref: Robbin 8/e p988-9)
Robbins Seminoma cells are diffusely positive for c-KIT, OCT4 and placental alkaline phosphatase (PLAP), with
sometimes scattered keratin-positive cells
123.10. Ans. (c) Desmin (Ref: Robbin 8/e p1253)
Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood and adolescence. It usually appears before
age 20
Ultrastructurally, rhabdomyoblasts contain sarcomeres, and immunohistochemically they stain with antibodies to
the myogenic markers desmin, MYOD1 and myogenin.

Other questions from same topic: for AIIMS/NEET
Most common location is the head and neck or genitourinary tract, where there is little if any skeletal muscle as a normal
constituent.
Rhabdomyoblasts are also known as tadpole or strap cells
Rhabdomyosarcoma is histologically subclassified into embryonal, alveolar, and pleomorphic variants. The
embryonal variant is the commonest.
123.11. Ans. (c) Metastasis from another solid tissue tumor (Ref: Robbin 9/e p 1133)
Metastases to the adrenal cortex are significantly more common than primary adrenocortical carcinomas.
Even Harrison says The most common cause of adrenal tumors is metastasis from another solid tumor like breast
cancer and lung cancer.
Neoplasia
Malignant Prevalence
Adrenocortical carcinoma 2-5
Malignant pheochromocytoma <1
Adrenal neuroblastoma <0.1
Lymphoma (incl primary adrenal lymphoma) <1
Metastases (most frequent: breast, lung) 15
123.12. Ans. (b) Lung (Ref: Robbin 9/e p 1315)

123.13. Ans. (d) Urine contains 5H.I.A.A (Ref: Robbin 9/e p 478)
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy.
About 90% of neuroblastomas, regardless of location, produce catecholamines, which are an important diagnostic feature
(i.e., elevated blood levels of catecholamines and elevated urine levels of the metabolites vanillylmandelic acid and
homovanillic acid.
Increased urinary 5HIAA is a feature of carcinoid tumour and not neuroblastoma.
(NEOPLASIA)
Chromosomal translocation is the commonest cause of activation of proto-oncogenes.
Blood cancers (the leukemias and lymphomas, sometimes called liquid tumors) are derived from blood-forming cells
that normally have the capacity to enter the bloodstream and travel to distant sites. So, they are always considered
as malignant.pg 272-3
Carcinogenesis..pg 281
Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time:
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a. Mutations that contribute to the development of the malignant phenotype are referred to as driver mutations.
The first driver mutation that starts a cell on the path to malignancy is the initiating mutation, which is typically
maintained in all of the cells of the subsequent cancer.
b. Loss-of-function mutations in genes that maintain genomic integrity is a common early step in carcinogenesis,
particularly in solid tumors. There is also increased frequency of the mutations that have no phenotypic consequence,
so-called passenger mutations. The latter are more common than driver mutations.
c. During oncogenesis, there is competition among tumor cells for access to nutrients and microenvironmental niches.
This leads to formation of subclones with the capacity to overgrow their predecessors. Thus, the tumors tend to
become more aggressive over a period of time and are referred to as tumor progression.
d. By the time the tumours are clinically evident, their constituent cells are often extremely heterogeneous genetically.
Clinical importance
This also leads to an important clinical consequence: cancer cells after a cycle of effective chemotherapy or radiotherapy becomes resistant
Neoplasia
because of the survival advantage of those cells which were intrinsically resistant to the drugs/radiotherapy.
Warburg effect..pg 283
It is the phenomenon in which rapidly growing cells (both benign and malignant) upregulate glucose and glutamine uptake and decreases
their production of ATP per glucose molecule. This is responsible for providing metabolic intermediates which are useful for cellular growth
and maintenance.
This is due to the fact that rapidly growing cells have the M2 isoform of pyruvate kinase.
Oncogene addiction
Oncogene addiction is a phenomenon in which tumor cells are highly dependent on the activity of one or more oncogenes. This is exempli-
fied by the BCR-ABL tyrosine kinase activity required for most CML tumor cells to proliferate and survive. Hence, inhibition of this activity is
a highly effective therapy.
Lewis Thomas and Macfarlane Burnet coined the term immune surveillance, which implies that a normal function of the immune system
is to constantly scan the body for emerging malignant cells and destroy them.
Robbins 9th/ 315
After encountering antigen mature B cells express a specialized enzyme called antigen-induced cytosine deaminase (AID), which
catalyzes both immunoglobulin gene class switch recombination and somatic hypermutation. Errors during antigen receptor gene assembly
and diversification are responsible for many of the mutations that cause lymphoid neoplasms.
Cancer-Enabling Inflammation..315-6
Inflammatory cells increase the risk of cancers by different mechanisms like:

i. Release of factors that promote proliferation

ii. Removal of growth suppressors,
180
Neoplasia
i ii. Enhanced resistance to cell death,

iv. Inducing angiogenesis,
v. Activating invasion and metastasis
vi. Evading immune destruction
Previous AIIMS Question!
The detachment of epithelial cells from basement membranes and from cell-cell interactions can lead to a particular
form of cell death called anoikis.
COX2 inhibitors decrease the incidence of colonic adenomas and are now approved for treatment of patients with
familial adenomatous polyposis
Potential Future Exam Questions from New Data!
All trans retinoic acid is a highly effective therapy is the first example of differentiation therapy, in which immortal
tumor cells are induced to differentiate into their mature progeny, which have limited life spans. It is used for
treating patients with acute promyelocytic leukemia. .Robbins 9th/ 317
Chromothrypsis is a process in which a chromosome is shattered and then re-assembled in a haphazard way.
It is seen in is found in up to 25% of osteosarcomas and at a relatively high frequency in gliomas as well.
Robbins/9th 318
Epigenetics in cancer
Epigenetics refers to factors other than the sequence of DNA that regulate gene expression (and, thereby, cellular phenotype).
These factors include histones modifications catalyzed by
enzymes associated with chromatin regulatory complexes; DNA methylation, and other less well characterized proteins that
regulate the higher order organization of DNA (e.g., looping of enhancer elements onto gene promoters).
Epigenetic changes have important roles in many aspects of the malignant phenotype, including the expression of cancer genes,
Neoplasia
the control of differentiation and self renewal, and even drug sensitivity and drug resistance.
Cancers Showing Epigenetic Changes

Gene(s) Function Tumor (Approximate Frequency of Mutation)
DNMT3A DNA methylation Acute myeloid leukemia (20%)
MLL1 Histone methylation Acute leukemia in infants (90%)
MLL2 Histone methylation Follicular lymphoma (90%)
CREBBP/EP 300 Histone acetylation Diffuse large B cell lymphoma (40%)
ARD1A Nucleosome Positioning/chromatin remodeling Ovarian deer cell carcinoma (60%) endometrial carcinoma (30%-40%)
SNF5 Nucleosome Positioning/chromatin remodeling Malignant rhaboid tumor (100%)
PERM1 Nucleosome Positioning/chromatin remodeling Renal carcinoma (30%)
At a glance: Mechanism of Action of Major Tumor Suppressor Genes
APC
It encodes a factor that negatively regulates the WNT pathway in colonic epithelium by promoting the formation of a complex
that degrades -catenin.
It gets mutated in familial adenomatous polyposis, autosomal dominant disorder associated with development of
thousands of colonic polyps and early onset colon carcinoma; tumor development associated with loss of the single
normal APC allele. It is also mutated in about 70% of sporadic colon carcinomas; tumor development associated with
acquired biallelic defects in APC
E-cadherin:
It is a cell adhesion molecule that plays an important role in contact-mediated growth inhibition of epithelial cells.
It also binds and sequesters -catenin which is a signaling protein that functions in the WNT pathway.
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Germline loss-of-function mutations in the E-cadherin gene (CDH1) associated with autosomal dominant familial
gastric carcinoma.
CDKN2A:
It encodes two tumor suppressive proteins, p16/INK4a, a cyclin-dependent kinase inhibitor that augments RB function, and
ARF, which stabilizes p53

Germline loss-of-function mutations are associated with autosomal dominant familial melanoma

Biallelic loss-of-function seen in leukemias, melanomas, and carcinomas
TGF- pathway
It is an inhibitor of cellular proliferation in normal tissues
Frequent loss-of-function mutations involving TGF- receptors (colon, stomach, endometrium) or downstream signal
transducers (SMADs, pancreas) in diverse carcinomas
PTEN
It encodes a lipid phosphatase that is an important negative regulator of PI3K/AKT signaling
Germline loss-of-function mutations associated with Cowden syndrome, autosomal dominant disorder associated
with a high risk of breast and endometrial carcinoma
NF1
It encodes neurofibromin 1 which is a GTPase that acts as a negative regulator of RAS
Germline loss-of-function mutations cause neurofibromatosis type 1 (autosomal dominant disorder associated with
neurofibromas and malignant peripheral nerve sheath tumors)
NF2
It encodes neurofibromin 2 (also called merlin), a cytoskeletal protein involved in contact inhibition
Germline loss-of-function mutations cause neurofibromatosis type 2, autosomal dominant disorder associated with
a high risk of bilateral schwannomas
Neoplasia
WT1: encodes a transcription factor that is required for normal development of genitourinary tissues
Germline loss-of-function mutations associated with Wilms tumor, a pediatric kidney cancer; similar WT1 mutations
also found in sporadic Wilms tumor
PTCH1: encodes membrane receptor that is a negative regulator of the Hedgehog signaling pathway
Germline loss-of-function mutations cause Gorlin syndrome (AD disease with a high risk of basal cell carcinoma and
medulloblastoma)
VHL
It is responsible for degradation of hypoxia-induced factors (HIFs), transcription factors that alter gene expression in response
to hypoxia
Germline mutation is associated with von Hippel-Lindau syndrome, autosomal dominant disorder associated with a
high risk of renal cell carcinoma and pheochromocytoma
Acquired biallelic loss-of mutations are common in sporadic renal cell carcinoma
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CHAPTER 6
Immunity is the defensive power of the body (protecting the body from various infections). It
Immunity
can be of two types: innate immunity and adaptive immunity. Innate immunity (also known Innate immunity
as natural or native immunity) refers to defense mechanisms that are present since birth * Present from birth
and have evolved to recognize microbes. It is the first line of defense. It is non-specific and * First line of defense
has no memory. Adaptive immunity (also called acquired or specific immunity) consists of * No prior exposure to antigen
mechanisms that are stimulated by microbes and are capable of recognizing non-microbial * Non-specific
substances also. Adaptive immunity develops later (after exposure to antigens). It is more * No memoryQ is seen
specific as well as powerful as well as has memory.
The major components of innate immunity are

1. Epithelial barriers like intact skin that blocks entry of environmental microbes

2. Cells like phagocytic cells (mainly neutrophils and macrophages), Natural killer
(NK) cells, Dendritic cells

3. Plasma proteins (proteins of the complement system, mannose binding lectin and Adaptive/Acquired immunity
* Acquired in nature
C-reactive protein)
* Second line of defense
The innate immunity is due to presence of pattern recognition receptors (PRR). These
* Prior exposure to antigen is
are peptide molecules on the leukocytes which recognize particular structural pattern on a presentQ
micro-organism called pathogen associated molecular patterns (PAMPs). A similar group of * Specific
molecules released by injured cells is called danger associated molecular patterns (DAMP, * MemoryQ is seen
uric acid is an example). The PRR can be of two types:
Soluble pattern recognition receptors Surface pattern recognition receptors
Mannose receptors (for mannose binding lectin) Scavenger receptors (on macrophages)
C-reactive protein Toll like receptors
NOD-like receptors
RIG-like receptors
Toll-like receptors causes the
Some important Toll like receptors (TLR) and the molecules they recognize are: k
activation of NF- b (master

TLR-2: peptidoglycan of gram + bacteria; lipopolysaccharide of leptospiraQ switch to the nuclear factor) and

TLR-3: dsRNA viruses AP-1.

TLR-4Q: Chlamydia and lipopolysaccharide of Gram () bacteriaQ except leptospira
Signaling by Toll-like receptors causes the activation of nuclear transcription factors
(NF-b and AP-1). This result in recruitment of inflammatory cytokines, endothelial adhesion
molecules (E-selectin) and proteins involved in microbial killing mechanisms (inducible
nitric oxide synthase). All Gram () bacteria recognize
The adaptive immune system consists of lymphocytes and their products like antibodies. TLR-4 except leptospira which
It has two components: cellular (or cell mediated) and humoral immunity. The former is protective recognises TLR-2
against intracellular microbes whereas the latter is effective against extracellular microbes.
IMMUNE CELLS
Apart from the leucocytes, our focus here would be to discuss the other important immune
cells (lymphocytes and antigen presenting cells) in detail.
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1. T-lymphocytes (Thymus Derived)

CD-3 is known as pan T-cell
marker. It is also involved in They constitute 60-70% of peripheral blood lymphocytes and are located in the paracortical
T-cell activation. areas of lymph node and the periarteriolar sheaths of spleen. These cells have an antigen specific
T cell receptor (TCR) [composed of a and b polypeptide chains in 95% cases] to bind with
the antigen. The ab T cells are present in blood and tissues. The other 5% cells have TCR
composed of g/d chains and are present mostly at the epithelial/mucosal surface. A large
number of TCRs can be generated because of rearrangement of genes coding for and
polypeptide chains. When an antigenic peptide comes in contact with TCR, it activates a
The ratio of CD4 and CD8 T-cell particular T cell only and not all the cells. This is called as clonal selection.
is normally 2:1 Demonstration of TCR gene rearrangement by southern blot is a molecular marker of T cell lineage.
The cells have on their surface cluster differentiating (CD) molecules by which they can
be readily identified. The CD molecules present on T cells are CD1, CD2, CD3, CD4, CD5,
CD7, CD8 and CD28. The T cell having CD4 molecule is called CD4+ T cell or the Helper T
cell and that having CD8 molecule is called as CD8+ T cell or Cytotoxic/Killer T cell. CD4+
T cells secrete cytokines and help macrophages and B cells to fight infections whereas CD8+
T cells destroy host cells having microbes like viruses and tumor cells.
Helper T cell (or CD4+ T cell) is
known as the master regulator CD3 is involved in signal transduction and is also called as a Pan T cell marker. The T
of the immune system. cells also have presence of CD40 ligand on their surface which is required for B cell activation
and induction of immunoglobulin isotype switching. (Described later).
The activation of T cells requires two signals
Signal 1: Comes from binding of the TCR to MHC bound antigen. The CD4 or CD8 act as co-
receptors and enhance this signal.
Immunity
Signal 2: Comes from the interaction of CD28 with co-stimulatory molecules B7-1 and B7-2
present on the antigen presenting cells.
CD 45 is called as Leukocyte
common antigen (LCA) The activated T cells gives rise to two groups of cells: effector T cells which manage
the antigen at that time only and some differentiate into long lived memory cells (for future
exposure to the same antigen).
Location of cell Molecular marker

All leucocytes CD45 and CD45RB
Medullary thymocytes (Naive T- cells) CD45 RA and CD45RC
Short Story: T-cell activation is Cortical thymocytes (Memory T-cells) CD45RO
like starting a vehicle. We put in
a key and turn on the ignition of
the car engine (Signal 1). But the
car would move only when we
put the gear (signal 2). If we dont
put the car in gear, the engine
will make the car lose its fuel and
the car will stop without moving
(anergy).
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Immunity
Interaction between APC and T cell

Importance of signal 2 in immunity
Signal 2 ensures that the activation of the T cells is not taking place by chance. It is due to a
particular antigen only. So, it acts like a safety signal.
Secondly, if by any mistake, the APC present a self antigen (normal body tissue), signal 2 is not
generated. In the absence of signal 2, T cell undergoes anergy. This is an important mechanism
of peripheral immunological tolerance.
Concept of Superantigen
Antigen which does notQ require antigenic processing and not specific for a T cell receptor (TCR)
Attaches itself outsideQ the antigen binding cleft
Attaches to a chain of MHC II with b chain of T cell receptorQ (TCR)
Causes T cell activation and massive release of cytokines like TNF-a and IL-1 Concept
Examples include staphylococcal toxic shock syndrome toxin 1Q (TSST-1), Streptococcal
Cytotoxic T cell (or CD8+ T
erythrogenic exotoxinQ
Immunity
cell) binds only to antigens
presented with Class I MHC
molecules. So, they are called
Types of CD4+ Helper Cells as MHC-I restricted. These
recognize endogenous peptides.
Concept
Helper T cell binds only to
antigens presented with Class
II MHC molecules. So, they are
called as MHC-II restricted.
These recognize exogenous
peptides.

Recently a new group of T cells have been discovered called as NK-T cells. These
T cells express markers normally present on Natural Killer cells and recognize
glycolipid antigens displayed by MHC-like molecule CD1. These are important
defense mechanisms against microorganisms like Listeria monocytogenes and M
tuberculosis.
Naive T cell (TH0) can get differentiated into either TH1cell or TH2 cell. The differentiation
towards TH1 cell is driven by strong innate response and intracellular organisms (TB,
Listeria). TH1 cells release IL-2 and IFN-g which causes cytotoxic T cell activation and
granuloma formation. Constitutively which means most of the times physiologically, TH0
cell differentiates into TH2 cell. TH2 cells release IL-4 and IL-5 which cause B cell activation
and multiplication leading to antibody formation.
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Diagram of different T helper cells
2. Antigen Presenting Cells
Antigene presenting cells When an antigen enters inside the body, it is phagocytosed by the neutrophils following
include B cell, macrophages and which the antigenic peptides are released in the circulation. However, if antigen presenting
dendritic cells. cells phagocytose the antigen, they process it inside themselves and present on their surface
in association with MHC molecule. This processed antigen is now presented to the T cells.
Immunity
The part of the antigen associated

with MHC molecule on the APC
is called as aggretope.
The antigenic part in contact with

TCR is called epitope.
The part of the antigen associated with MHC molecule on the APC is called as aggretope
whereas the antigenic part in contact with TCR is called epitope. MHC molecules can be of
two types: MHC I and MHC II (described later).
Details about APCs
Macrophage associated markers MACROPHAGES

include CD13, CD14, CD15 and CD33. These cells have a role in induction (in cellular immunity) and the effector (in humoral
CD133 induces formation of immunity) phase of immune response. They process and present antigen to T cells for
glioma
induction of cell mediated immunity (CMI). They get activated by the presence of IFN- and
are the effector cells in humoral immunity as they phagocytose opsonised microbes.
DENDRITIC CELLS
These are important antigen presenting cells in the body and can be of the following types:
Langerhans cells are Immature
dendritic cells within the epidermis.

a. Interdigitating dendritic cells (dendritic cellsQ) are the most important antigen-
presenting cells for initiating primary immune responses against protein antigens.
Why is the dendritic cell most important antigen presenting cell?
1. These cells are located under epithelia (a common site of entry of microbes and
foreign antigens) and in the interstitia of all tissues (site of antigen production).
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Immunity
2. Dendritic cells express many receptors (like TLRs and mannose receptors)
for capturing and responding to antigens. These cells also express the same
chemokine receptor as do naive T cells. They are recruited to the T-cell zones
of lymphoid organs because of specialised post capillary venules called high
endothelial venules (HEV), where they are ideally located to present antigens Concept
to recirculating T cells.
HEV are lined by simple cuboidal
3. Dendritic cells express high levels of MHC class II molecules as well as the co- cells as opposed to regular
stimulatory molecules B7-1 (CD80) and B7-2(CD86). Thus, they have all the venules lined by endothelial
necessary molecules required for presenting antigens to and activating CD4+ cells.
T cells.

b. Follicular dendritic cells are present in the germinal centers of lymphoid follicles in
the spleen and lymph nodes.

These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen
bound to antibodies or complement proteins. Such cells are required for the
Follicular dendritic cells act as
process of Affinity Maturation (production of antibodies having high affinity reservoir for HIV in acquired
for antigens). immunodeficiency syndrome (AIDS).
3. B-lymphocytes (Bone Marrow Derived)
They constitute 10-20% of peripheral blood lymphocytes and are located in the cortical areas
of lymph node, white pulp of spleen and mucosa associated lymphoid tissue of pharyngeal tonsils and
Peyers patches of GIT.
These cells have a B cell receptor (BCR) composed of IgM and IgD on their surface to bind
with the antigen. BCR has unique antigen specificity. The rearrangement of immunoglobulin
gene can give rise to different types of BCRs. The antigen however binds to the complementary
BCR only (clonal selection).
Immunity
The presence of rearranged immunoglobulin genes in a lymphoid cell is used as a molecular marker
of B-lineage cells.
B cell associated markers are CD10 (CALLA), CD19, CD20, CD21 (EBV receptor),
CD22, CD23.
B cells have Iga and Igb on their cell membrane which are required for signal transduction
(similar to CD3 of the T cells). They also have CD 40 molecule on its surface.
CD19 is involved in signal
Detail of antigenic interaction with B cells and T cells
transduction and is called as a
The activation of T cells requires two signals Pan B cell marker.

Signal 1: Comes from binding of the TCR to MHC bound antigen.

Signal 2: Comes from the interaction of CD28 with co-stimulatory molecules B7-1 and
B7-2 present on the antigen presenting cells.
Competence signal (CD40-

CD40L interaction) is required
for the following functions:

1. B cell mitogen

2. Required for isotype switching.

3. Affinity maturation
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In addition to these two, there is a Competence signal is due to interaction between

CD40 molecules on B cells with CD 40 ligand on T helper cells. It results in the release of
cytokines like IL-4 and IL-5. These cytokines cause B cell proliferation resulting in formation
of plasma cells and memory cells.
The change in the class of the

antibody being produced by the
plasma cell is called as Isotype
Switching
The plasma cells secrete immunoglobulins. These can of different classes or isotypes
like IgG, IgM, IgD, IgA and IgE. Initially, the first antibody produced by the plasma cell is
Concept IgM and later, other antibodies like IgG, IgA etc. are produced due to change in the nature of
heavy chains. Isotype Switching is due to IFN- and IL-4. Polysaccharide and lipid antigens
Hyper- IgM immunodeficiency
produce mainly IgM whereas protein antigens induce production of different isotypes of
is a paradoxical T-cell disorder
in which a defect in CD40 ligand antibodies (IgG, IgA, IgE etc.).
(normally present on Tcells) Isotype/Class Switching
prevents isotype switching IgM IgA, IgE, IgG
in B lymphocytes. So, these (Due to change in heavy chain)
patients have reduced levels of
IgG, IgE and IgA but increased
IMPORTANT POINTS ABOUT ANTIBODIES
levels of IgM. It is an X linked
disorder. Patients have recurrent
infections with P. jiroveci
Ig G Present in maximum concentration the human body
Q
Immunity
affecting respiratory tract.

Important for secondary immune response Q
Can cross the placenta Q
Ig A Resent in physiological secretions of the body

Q
Present in monomer form in serum and as dimer form in glandular secretions

Q
Responsible for activation alternate pathway Q
Ig M Important for primary immune response Q
Having maximum molecular weight Q
One antibody has two heavy

Having maximum size Q
chains and two light chains.
Within light and heavy chains, Present as a pentamer Q
three hypervariable regions Also known as Millionaires antibody Q
exist HV 1, 2 and 3 Functions as B cell receptor Q
IgM and IgG (IgM > IgG) are responsible for activation of classical pathway
Q Q Q
Ig D Functions as B cell receptor Q
Ig E Increased in allergic conditions Q
Also known as homocytotropic antibody Q
Also called reaginic antibody Q
The efficiency of immuno-

globulin transfer across placenta: The antibodies produced remove the antigen by different mechanisms like complement
Ig G1> Ig G3> Ig G4> Ig G2 activation (by membrane attack complex formation), opsonisation (for preferential killing)
and antibody dependent cytotoxicity.
Cell Mediated Immunity
It is for more important for intracellular pathogens, virus infected/malignant cells and
endogenous antigens. It is mediated by CD8 T cells, macrophages and natural killer cells.
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Immunity
Endogenous antigen is expressed with MHC I molecule by the nucleated cells. These cells are
also destroyed in the process, so, the preferred name for them is Target cells and not APCs.
Antigen activated CD8T cells undergo proliferation. They release perforin-granzyme

molecules and express Fas Ligand both of which initiate apoptosis of Target cells.
NATURAL KILLER CELLS (NK CELLS) OR NULL CELLS OR NON-T, NON-B LYMPHOCYTES
NK cells are also called Large granular lymphocytes as they are morphologically larger than
both T and B lymphocytes and contain azurophillic granules (which are absent in both T and
B lymphocytes). They constitute 5-10% of peripheral blood lymphocytes. They arise in both
bone marrow and thymic microenvironments. NK cells are activated in presence of IL-2 to
Lymphocyte activated killer (LAK) cells. These cells express the following molecules:
NK cells are unique as they are
CD16Q: Surface receptors for Fc portion of IgG capable of direct cell lysis which
is:
CD56Q: Surface receptors for NCAM 1 Not mediated by an immune
response
Immunity
CD8 and CD2: Some T-cell lineage markers (less common)
MHC unrestricted
They are first line defense against cancer and virus infected cells. So, functionally NK cells Does not involve an antigen
antibody interaction
share features of both monocyte- macrophages and neutrophils. The hyporesponsiveness of
NK cells is seen in patients of Chediak-Higashi syndrome.
The NK cells express activating and inhibitory receptors. The functional activity of
the NK cells is regulated by a balance between signals from these receptors. Normal cells
are not killed because inhibitory signals from normal MHC class I molecules override
activating signals. The ability of NK cells to kill target cells is inversely related to target
cell expression of MHC class I molecules. If virus infection or neoplastic transformation
disturbs or reduces the expression of class I MHC molecules, inhibitory signals delivered to
NK cells are interrupted and lysis occurs. IL 2 and IL 15 stimulate proliferation of NK cells
whereas IL 12 stimulates NK cells to secrete IFN-g.
Major Histocompatibility Complex (MHC) or Human Leucocyte Antigen (HLA) Complex
MHC is a cluster of genes located on short arm of chromosome 6 (6pQ) whose main physiologic
function is to bind peptide fragments of foreign proteins for presentation to antigen-specific
T cells.
It is classified into three classes namely class I, II and III genes. The class I genes MHC is a cluster of genes located
on short arm of chromosome 6
includes HLA-A, -B, -C, - E, -F and -G. HLA-A,-B and -C gene codes for MHC I molecule (6p).
and the HLA-E molecule is the major self-recognition target for the natural killer (NK) cell
inhibitory receptors. HLA-G is expressed selectively in extravillous trophoblasts, the fetal
cell population directly in contact with maternal tissues. It provides inhibitory signals to
both NK cells and T cells and maintains maternofetal tolerance and the function of HLA-F
remains largely unknown. The class II genes include HLA-D and code for MHC II molecule
whereas the class III gene codes for the complement and other proteins.
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Class III genes code for:

Complement components C2
and C4 of classical pathway
(Not C3)
Properdin factor B of alternate
pathway
Tumor necrosis factor: Alpha
and Beta
Heat shock protein 70
Enzyme tyrosine hydroxylase
MHC I molecule is present on all

the nucleated cells and platelets
It is not present on mature MHC-I MOLECULE
RBCs.
It consists of a chain (heavy chain) linked to b2 microglobulin (light chain; not encoded within MHC)
and binds to peptides that are derived from proteins synthesized within the cell like the viral
antigens. The antigen binding cleft is formed by a1and a2 chain of the MHC molecule (distal
a domains of MHCQ). The antigens binding with MHC I molecule are presented to CD8+ T
cells. As discussed earlier, cytotoxic T cells/CD8+ T cells are MHC-I restricted.
Structure of antigen binding cleft of MHC molecule on the surface of APC
Immunity
MHC-II molecule
MHC II molecule is present on
macrophages, dendritic cells, It consists of a chain linked to b-chain. The antigen binding cleft is formed by a1 and b1 chain
B cells and their expression can of the MHC molecule (distal a and b domains of MHCQ). The antigens binding with MHC
be induced on endothelial cells II molecule are presented to CD4+ T cells. As discussed earlier, helper T cells/CD4+ T cells
and fibroblasts by IFN- are MHC-II restricted.
Mnemonic
Normal CD4: CD8T cell ratio is 2:1. So, MHC 2 with CD4 and MHC 1 with CD8.
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Immunity
Concept
As described earlier, MHCII molecule is required for the development of graft versus host disease.
In a condition associated with a congenital deficiency of MHC II molecule as Bare Lymphocyte
Syndrome, the affected individuals would never develop Graft versus host disease even on being
given mismatched bone marrow transplantation. They also have absence or deficiency of CD4T cells
and so, also have hypogammaglobulinemia. These individuals have normal number of CD8T cells.
HLA and Disease Association
HLA- class I
B-27 Spondyloarthropathies
Ankylosing spondylitis
Reiters syndrome
Acute anterior uveitis
Reactive arthritis
Psoriatic arthritis
B-8 Hyperthyroidism [Graves disease]
Myasthenia gravis
B-51 Behcets disease
B-47 Congenital adrenal hyperplasia
CW6 Psoriasis vulgaris
HLA- class II
DR-2 - Japanese SLE
- Multiple sclerosis DR-2 has negative association
- Narcolepsy with type 1 DM i.e. genetic
- Goodpastures syndrome association with protection from
DM
DR-3 - Myasthenia gravis
- Graves disease
Immunity
- Type I DM
- Dermatitis herpetiformis
- Chronic active hepatitis
- Caucasian SLE
- Sjogrens syndrome
DR-4 Type 1 DM
Pemphigus vulgaris
Rheumatoid arthritis
DR-5 Juvenile (pauciarticular) arthritis
DR-8 Type I DM
DQ-1 Pemphigus vulgaris
DQ - Gluten sensitive enteropathy [celiac sprue]
DQ-7 Bullous pemphigoid
DQ-8 Type 1 DM
DISORDERS OF THE IMMUNE SYSTEM
Hypersensitivity Reactions
These are caused by the activity of the immune system detrimental to the host in response to
exposure of the antigens.
TYPE I HYPERSENSITIVITY REACTION/ANAPHYLACTIC TYPE/IMMEDIATE TYPE OF

HYPERSENSITIVITY REACTION
It is defined as a rapidly developing immunologic reaction occurring within minutes after
the combination of an antigen with antibody bound to mast cells in individuals previously
sensitized to the antigen. It is commonly referred to as allergy.
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PATHOGENESIS
The clinical features are usually The first step is the stage of sensitization or priming in which there is entry of the antigen
seen during the second time inside the body for the first time where it is captured by the antigen presenting cells and
antigen exposure subsequent to presented to the T cell which then differentiates into TH2 cell. The TH2 cell releases mediators
sensitization or priming
like IL-3, IL-4 and IL-5. IL-4 causes activation of B cell leading to the release of IgE from them
whereas IL-5 is responsible for activating the eosinophils. The secreted IgE then binds to mast
cells in the circulation because of presence of Fc receptors on the mast cells. So, in the initial
exposure or sensitization, there is presence of mast cells in the circulation having the presence
of IgE on their surface.
The cell critical in the
The subsequent exposure to the same antigen causes the features in two phases. In the
pathogenesis is the mast
cell whereas TH2 also plays initial phase (within minutes of antigen exposure), there is release of preformed mediators of the
an important role in the mast cell due to their degranulation causing the release of histamine, proteases and chemotactic
pathogenesis. factors. Histamine causes vasodilation, bronchoconstriction and increased permeability. Late
phase (2-24 hours after antigen exposure) is marked by the release of secondary mediators
from the mast cells that include prostaglandins, leukotrienes, cytokines and platelet activating
factor (PAF). PGD2 is abundant in lung mast cells and causes bronchoconstriction as well
as increased mucus production. The secondary mediators are responsible for the effects like
Histamine is responsible for the bronchospasm, increased mucus production and recruitment of the inflammatory cells at
early clinical features because it
is preformed mediator.
the site of inflammation. PAF causes bronchospasm, increased permeability and release of
PAF is the major mediator of the histamine and is considered to be important in the initiation of the late-phase response. The release
late phase reaction of various mediators is responsible for the clinical features seen in type I hypersensitivity
reaction.
CONCEPT
Anaphylactic hypersensitivity reaction should not be confused with anaphylactoid reaction. The
IgE is the most important anti-
important differences are:
body to cause type I hyper-
*Anaphylactoid reaction occurs on first antigenic exposure
sensitivity reactions.
Immunity
*It is also short lived because its pathogenesis involves only degranulation of the mast cells and not
cytokine synthesis.
Examples of type I hypersensitivity includes:

Localized hypersensitivity Systemic hypersensitivity
IL-4 is responsible for the - Bronchial asthma Anaphylaxis due to:
secretion of IgE from the B - Hay fever/allergic rhinitis - Antibiotics: Most commonly penicillin (therefore, a test
cells. - Food allergies dose should always be given before administration of
- Atopic dermatitis penicillin to any patient)
IL-5 is the most potent eosinophil- - Urticaria - Bee stings
activating cytokine known. - Angioedema - Insect bites
TYPE II HYPERSENSITIVITY REACTION/ANTIBODY MEDIATED/CYTOLYTIC

HYPERSENSITIVITY REACTION
Type II hypersensitivity is mediated by antibodies directed toward endogenous or exogenous
specific antigens present on cell surfaces or extracellular matrix. The effector mechanisms for
this reaction include:
Concept
I. Opsonisation and Complement- and Fc Receptor-Mediated Phagocytosis
If there is presence of low
concentration of antibodies on
The antibodies are formed against the antigens and these are responsible for
complement system activation resulting in the formation of membrane attack
the cells then they are killed by
complex (MAC) leading to destruction of the antigen. The antibodies may also cause
phagocyte and complement
independent process known opsonisation (through C3b and C4b) and Fc receptor mediated phagocytosis.
as antibody dependent
II. Complement and Fc Receptor-Mediated Inflammation
cellular cytotoxicity (ADCC). When antibodies deposit in extracellular tissues, the injury is because of inflammation
It is mediated by neutrophils, and not phagocytosis or lysis of cells. The deposited antibodies activate complement
macrophages and NK cells. system leading to recruitment of neutrophils and monocytes. These cells also bind
to the deposited antibodies via their Fc receptors. The activated leukocytes release
enzymes resulting in tissue damage.
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Immunity

III. Antibody mediated cellular dysfunction
In this mechanism, the antibodies directed against cell-surface receptors impair or
dysregulate function without causing cell injury or inflammation.
Examples of type II hypersensitivity reaction
Opsonization and Complement- and Fc Transfusion reactions My- Myasthenia gravis
Receptor-Mediated Phagocytosis Erythroblastosis fetalis Blood- Blood transfusion re-
Autoimmune hemolytic anemia actions
Autoimmune thrombocytopenic purpura Group- Goodpasture syndrome
Complement and Fc Receptor-Mediated Goodpasture syndrome and Graves disease
Inflammation Vasculitis due to ANCA Is- Insulin resistant diabe-
Acute rheumatic fever tes, ITP
Vascular rejection in organ grafts R - Rheumatic fever
h- Hyperacute graft rejec-
Antibody mediated cellular dysfunction Myasthenia gravis (against acetylcholine receptor)
tion

Graves disease (against TSH receptor)
Pemphigus vulgaris (against epidermal cadherin)

Positive- Pernicious anemia and
Pemphigus vulgaris
Pernicious anemia (against intrinsic factor)
Insulin resistant diabetes (against insulin receptor)
TYPE III HYPERSENSITIVITY REACTION OR IMMUNE COMPLEX DISEASE

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at
the sites of deposition. The antigen can be either endogenous or exogenous. The immune
complexes once formed may be present in the circulation (circulating immune complexes) or
may get deposited inside the vessels or extravascular sites (in situ immune complex). They may
either be generalized or localized. Systemic or generalized immune complex disease has the
following phases:
Phase I or Immune Complex Formation
It is characterized by the formation of the antibody about 5 days after introduction of the
Immunity
antigen. The small or intermediate immune complexes are most pathogenic. The large
complexes are rapidly removed by the macrophages.
Phase II or Immune Complex Deposition
In this phase, the immune complexes get deposited in the glomeruli, joints, skin, heart,
serosal surfaces and the blood vessels.

S :Serum sickness, Schick test
and SLE
Phase III

H :Hypersensitivity pneumonitis
and Henoch Schonlein Pur-
Immune complex mediated inflammation is seen 10 days after antigen administration and
pura
results in the development of vasculitis, glomerulonephritis and arthritis. The immune
A :Arthus reaction
complexes cause inflammation by activation of the complement system resulting in the
R :Reactive arthritis and
neutrophilic infiltration, vasodilation and edema. They also cause activation of the intrinsic Rheumatoid arthritis, Raji
pathway of coagulation system and microthrombi formation contributing to tissue ischemia assay
and necrosis.
P :Polyarteritis nodosa (PAN)
and Post Streptococcal glo-
The blood vessels show intense neutrophilic infiltration and necrotizing vasculitis
merulonephritis (PSGN)
having the presence of fibrinoid necrosis.
Examples of type III hypersensitivity include:
Localized hypersensitivity Systemic hypersensitivity
*Arthus reaction *SLE
*Farmers lung *Reactive arthritis
*Hypersensitivity pneumonitis *Henoch Schonlein purpura
*Polyarteritis nodosa *Post streptococcal glomerulonephritis
*Serum sickness
*Type II lepra reaction
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CONCEPT
The difference between type II and type III hypersensitivity reactions is that in the former, the antigen is
tissue specific whereas in type III it is non-specific. In type II reaction, the tissue injury is direct (because
antigen is intrinsic component of target cell) whereas in type III, it is mediated by the deposition of
antigen antibody complexes in different tissues.
TYPE IV OR CELL MEDIATED HYPERSENSITIVITY REACTION

The cell-mediated type of hypersensitivity is initiated by antigen-activated (sensitized) T
lymphocytes. It includes the delayed type hypersensitivity reactions mediated by CD4+ T cells,
and direct cell cytotoxicity mediated by CD8+ T cells.

1. Pathogenesis of delayed type hypersensitivity reactions (mediated by CD4+ T
cells)
The first step is the entry of the antigen inside the body where it is captured by the
APCs and presented to the T cell which then differentiates into TH1 cell (remember
that in type I hypersensitivity, the nave T-cells differentiate into TH2 cells). The sensitized
TH1 cells enter the circulation and remain in the memory pool of the body. When
there is re-exposure of the same individual to the antigen for the subsequent time,
Antibody-mediated hyper- there is release of cytokines like TNF-a, lymphotoxin, IFN-, IL-2 and IL-12.
sensitvity reactions types I, II
and III. TNF-a and lymphotoxins have effects on endothelial cells leading to extravasation of
Type IV hypersensitivity: cellular lymphocytes and monocytes.
immunity IL-2 causes proliferation of antigen specific T-cells.
The collective release of these mediators recruits a lot of inflammatory cells at the
site of inflammation. The activated macrophages give rise to epithelioid cells and
these cells surrounded by a collar of lymphocytes all around lead to formation
of a granuloma. This granuloma formation is seen with tuberculin test, and other
intracellular pathogens like mycobacterium, fungi and some parasites. Delayed type
hypersensitivity reaction is also important in transplant rejection.
Immunity
2. Pathogenesis of T cell mediated cytotoxicity (mediated by CD8+ T cells)

IFN-g causes activation of Cytotoxic T lymphocytes (CTL) cause destruction of antigen bearing target cells
macrophages. particularly the tumor cells, the virus infected cells and allogeneic tissue during graft
rejection. There are two mechanisms involved in this:

Perforin granzyme dependent killing: The mediators present in the lysosomal
granules of the CTLs like perforin cause pore formation and the granzyme
activates apoptosis on entering the cells via these pores.

Fas-Fas ligand dependent killing: Activated CTL express Fas ligand which can
IL-12 is produced by bind to Fas expressed on the target cells leading to apoptosis.
macrophages and dendritic cells
and is critical in the pathogenesis Examples of Type IV Hypersensitivity Include:
of delayed hypersensitivity
because it induces the TH1 *Tuberculin reaction *Lepromin test *Multiple sclerosis
response. *Chronic graft rejection *Contact dermatitis *Sarcoidosis
*Temporal arteritis
*Primary biliary cirrhosis *Type I lepra reaction
*Tumor immunity *Resistance to viral infections *Crohns disease
TRANSPLANT REJECTION
It is a complex process in which both cellular and humoral immunity plays a role.
T cell Mediated Rejection
The T cell mediated rejection is also called as cellular rejection and it has two pathways:

Direct pathway in which the interstitial dendritic cells of the donor present the antigen
to the CD4 and CD8 T cells of the host. The host CD4 Tcells differentiate into TH1 cells
and similar to delayed hypersensitivity cause graft injury. CD8 T cells differentiate
into cytotoxic T lymphocytes and cause graft tissue damage by perforin-granzyme
and FasFas ligand pathways.
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Immunity
Indirect pathway in which the dendritic cells of the recipient present the antigen to
CD4 Tcells. There is no involvement of the CD8 T cells.
Antibody Mediated Rejection or Humoral Rejection
It is also known as rejection vasculitis and takes place by two mechanisms:

Hyperacute rejection takes place when there is preformed anti-donor antibodies
present in the circulation of the recipient. It takes place within minutes to hours and
The direct pathway is important
is associated with previous blood transfusions, multiparous lady or already rejected for acute graft rejection
transplant. It is an example of type II hypersensitivity reaction.

Acute rejection is seen within days to months after transplantation. The mechanisms
involved include inflammation, complement dependent cytotoxicity and ADCC.
The indirect pathway is important
MORPHOLOGY OF TRANSPLANT REJECTION for chronic graft rejection.
Hyperacute rejection
It takes place in individuals with preformed antibodies usually within minutes to hours of
transplantation. The preformed antibodies result in immune complex disease with the presence of
neutrophils within arterioles, glomeruli and peritubular capillaries and fibrin-platelet thrombi in vessel
wall. There is presence of necrosis of the renal cortex. The initial target of the anti-
bodies is the graft vasculature.
Acute rejection
It is seen days to months after transplantation. It can be acute humoral rejection or acute cellular
rejection.
The acute cellular rejection is seen within few months after transplantation. There is presence of
endothelitis with the presence of CD4 and CD8 T cells in the interstitium along with the mononuclear
cells in the glomerular and peritubular capillaries.
Hyperacute rejection is type II
The acute humoral rejection or rejection vasculitis is mediated primarily by anti-donor antibodies and
hypersensitivity reaction.
it manifests mainly as damage to the blood vessels in the form of necrotizing vasculitis with endothelial
Immunity
cell necrosis, neutrophilic infiltration, deposition of immunoglobulins, complement, and fibrin, and
thrombosis. There is associated necrosis of the renal parenchyma.
Chronic rejection
Acute rejection is type II + type
It occurs months to years after transplantation. In this, the vascular changes consist of dense, IV reactions hypersensitivity
obliterative intimal fibrosis in the cortical arteries resulting in glomerular loss, interstitial fibrosis and reaction.
tubular atrophy, duplication of basement membranes of the glomeruli (also called as chronic transplant
glomerulopathy). The renal interstitium also has mononuclear cell infiltrates containing large numbers
of plasma cells and eosinophils.
Concept
GRAFT VERSUS HOST DISEASE (GVHD)/RUNT DISEASE (in animals)
Acute rejection can be reversed
Graft versus host disease occurs in any situation in which immunologically competent with immunosuppressive drugs
like cyclosporine, muromonab
cells or their precursors are transplanted into immunologically crippled patients and the
and steroids.
transferred cells recognize alloantigens in the host. It occurs most commonly in the setting
of allogenic bone marrow transplantation. The recipients of bone marrow transplants are
immunodeficient because of either their primary disease or prior treatment of the disease
with drugs or irradiation. When such recipients receive normal bone marrow cells from
allogenic donors, the immunocompetent T cells present in the donor marrow recognize the Both acute as well as chronic
rejection are usually irreversible
recipients HLA antigen as foreign antigen and reacts against them. Both CD4+ and CD8+T
cells recognize and attack host tissues.
ACUTE GVHD
It is characterized by an erythematous maculopapular rash; persistent anorexia
or diarrhea, or both; and by liver disease with increased serum levels of bilirubin,
alanine and aspartate aminotransferase, and alkaline phosphatase.
Diagnosis usually requires skin, liver, or endoscopic intestinal biopsy for confirmation. In all GVH reaction: skin rash/dermatitis,
these organs, endothelial damage and lymphocytic infiltrates are seen. jaundice and diarrhea.
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*Skin: Epidermis and hair follicles are damaged.

*Liver: Small bile ducts show segmental disruption.
*Intestines: Destruction of the crypts and mucosal ulceration may be noted.
GVHD developing within the Clinical Staging and Grading of Acute Graft-versus-Host Disease
first 3 months post transplant is
termed acute GVHD. Clinical Stage Skin LiverBilirubin (mg/dL) Gut
1 Rash <25% body surface 23 Diarrhea 5001000 mL/d
2 Rash 2550% body 36 Diarrhea 10001500
surface mL/d
3 Generalized 615 Diarrhea >1500 mL/d
erythroderma
4 Desquamation and bullae > 15 Ileus
The risk of graft versus host can Overall Clinical Skin Stage Liver Stage Gut Stage
be decreased by Depletion of T Grade
cells from graft I 12 0 0
II 13 1 1
III 13 23 23
IV 24 24 24
*Grade I acute GVHD is of little clinical significance, does not affect the likelihood of
survival, and does not require treatment. In contrast, grades II to IV GVHD are associated
with significant symptoms and a poorer probability of survival, and they require aggressive
therapy.
CHRONIC GVHD
GVHD developing or persisting
beyond 3 months post- Chronic GVHD resembles an autoimmune disorder with malar rash, sicca syndrome,
Immunity
transplant is termed chronic arthritis, obliterative bronchiolitis, and bile duct degeneration and cholestasis.
GVHD.
Because patients with chronic GVHD are susceptible to significant infections, they
should receive prophylactic trimethoprim-sulfamethoxazole.

Infection with cytomegalovirus is particularly important.
Autoimmune Disorders
Tolerance (unresponsiveness) to self-antigens is an important fundamental property of the

immune system. The breakdown of tolerance is the basis of autoimmune diseases. Tolerance
can be of the following subtypes:
1. Central tolerance: immature lymphocytes that recognize self-antigens in the central

(generative) lymphoid organs are killed by apoptosis; in the B-cell lineage, some of the self-
reactive lymphocytes switch to new antigen receptors that are not self-reactive.
PTPN-22 is the most frequently 2. Peripheral tolerance: mature lymphocytes that recognize self-antigens in peripheral tissues
implicated gene in autoimmunity. become functionally inactive (anergic), or are suppressed by regulatory T lymphocytes, or
die by apoptosis.
The causes of a failure of self-tolerance and the development of autoimmunity include:

In rheumatic heart disease,

1. Inheritance of susceptibility genes that may disrupt different tolerance pathways,
streptococcal proteins cross

2. Infections and tissue alterations that may expose self-antigens and activate APCs and
react with myocardial proteins lymphocytes in the tissues due to molecular mimicry between microbial antigens
causing myocarditis. and self molecules.
Detailed Role of infections in autoimmunity.
EBV and HIV can cause

1. Antigenic cross reactivity: this is due to similarity is the microbial antigenic structure
and the self antigens. This is also known as molecular mimicry.
autoimmune diseases
polyclonal B cell activation
by

2. Upregulation of co-stimulatory molecules by infectious organisms.

3. Polyclonal B cell activation: caused by EBVQ and HIVQ resulting in production of
autoantibodies.
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Immunity
4. Alteration of tissue antigens: infections may alter tissue self antigens so that they
activate T cells and loose the property of self tolerance. Anti-double stranded DNA
antibody and the antibody
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) against Smith (Sm) antigen
Highly specific for SLE.
SLE is an autoimmune multi-system disorder of unknown etiology characterised by loss of
self tolerance and production of auto-antibodies. It is more commonly seen in the females Antinuclear antibody (ANA)
affecting them around the age of 20-30s. The deficiency of early complement proteins (C1, C2 Highly sensitive for SLE
and C4) has been postulated to be associated with increased incidence of SLE. The auto-antibodies
in this condition are formed against DNA, histones, non histone proteins bound to RNA and
nucleolar antigens. These are collectively called as antinuclear antibodies (ANA). Anti Ro Antibody Neonatal
lupus
Clinical significance of anti nuclear antibodies Anti-P antibody Associated
Antiphospholipid antibody syndrome is characterized by antibodies against plasma proteins with lupus psychosis
in complex with phospholipid. In primary antiphospholipd antibody syndrome there is Anti-SS-A and Anti-SS-B anti-
hypercoagulable state without evidence of autoimmune disorders. In association with SLE or lupus, body- Associated with congenital
the name given is secondary antiphospholipd antibody syndrome. There is formation of antibody heart block and cutaneous lupus
against phospholipid beta 2-glycoprotein 1 complexQ. It also binds to cardiolipin antigen and lead
to false positive test for syphilisQ. It also interferes with in vitro clotting time and so, called as lupus
anticoagulant. In vivo, these patients have hypercoagulable state resulting in arterial and venous
thrombosis resulting spontaneous recurrent miscarriage and focal or cerebral ischemia.
Anticardiolipin antibodies may
The clinical criteria for the diagnosis of SLE include any 4 of the following mentioned produce a false positive VDRL
11 criteria: test for syphilis.
Malar rash Serositis- Pleuritis or pericarditis

Discoid rash Renal disorder
Photosensitivity Hematological disorder Diffuse proliferative or type IV
Oral ulcer Immunological disorder glomerulonephritis is the most
Arthritis Antinuclear antibody common and most serious
renal lesion
Neurological disorder- Seizure or psychosis in the absence of known drug/metabolic abnormality.
Immunity
ORGAN INVOLVEMENT
The presence of subendothelial
Kidney: WHO classification of renal involvement or lupus nephritis is as follows: deposits gives rise to wire loop

Class I - Minimal or no change lesions on light microscopy in

Class II - Mesangial lupus glomerulonephritis SLE.

Class III - Focal proliferative glomerulonephritis

Class IV - Diffuse proliferative glomerulonephritis.

Class V - Membranous glomerulonephritis
The LE cell is any phagocytic
Heart There is development of Libman-Sacks endocarditisQ having vegetations on both the leukocyte (neutrophil or macro-
sides of the valvular surface. There is also presence of pericarditis. phage) that has engulfed the
denatured nucleus of an injured
Mouth Oral ulcers are usually painless
cell.
Joints Non-erosive arthritis involving 2 or more peripheral joints with tenderness and effusion.
Tart Cell is usually a monocyte
Skin Erythematous rash present over malar region is also called butterfly rash. Exposure to which has ingested another cell
sunlight accentuates the erythema. or nucleus of another cell.
Blood Presence of autoimmune cytopenia (anemia, neutropenia or thrombocytopenia). The
presence of LE cell or hematoxylin body is also seen.
If ANAs can bind to exposed cell nuclei, the nuclei may lose their chromatin pattern, and ecome SLE is an example of both
type II (hematological features)
homogeneous to produce lupus erythematosus (LE) bodies.
Almost all the patients having SLE have hematological manifestations clinically. and type III (visceral lesions)
SLE NephropathyQ has the findings called as full house phenomenon hypersensitivity reactions.
SJOGREN SYNDROME
It is an autoimmune disorder characterised by the destruction of lacrimal and salivary glands Sjogren syndrome: dry eyes; dry
mouth.
resulting in the inability to produce tears and saliva. It is more commonly seen in females. Diagnosis is confirmed with lip
It can be primary when it is called sicca syndrome and it may also be secondary to other biospy
autoimmune disorders; rheumatoid arthritis being most commonly associated disorder.
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There is presence of anti-ribonucleoprotein antibodies like SS-A (Ro) and SS-B (La). The
Sjogren syndrome: presence of presence of former is associated with early disease onset, longer disease duration, and
anti-ribonucleoprotein antibodies extraglandular manifestations, such as cutaneous vasculitis and nephritis.
like SS-A (Ro) and SS-B (La). Clinical features include dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca),
the latter due to lymphocytic infiltration and destruction of the lacrimal gland. Mickulicz
syndrome include lacrimal and salivary gland enlargement of whatever cause. Patients with
Sjogren syndrome have an increased risk of developing lymphoid malignancies.
Sjogren syndrome: presence of
anti-ribonucleoprotein antibodies MIXED CONNECTIVE TISSUE DISEASE (MCTD)
like SS-A (Ro) and SS-B (La). It is a disease seen in a group of patients who are identified clinically by the coexistence
of features suggestive of SLE, polymyositis, rheumatoid arthritis, and systemic sclerosis.
These patients have high titers of antibodies to RNP particle-containing U1 RNP. The factors
lending distinctiveness to mixed connective tissue disease include the reduced incidence of
renal involvement and a good response to corticosteroids.
SCLERODERMA
It is an autoimmune disorder characterised by fibroblast stimulation and collagen deposition in
Diffuse Scleroderma: anti-DNA the skin and internal rgans. The skin is most commonly affected, but the gastrointestinal tract,
topoisomeraseQ antibodies kidneys, heart, muscles, and lungs also are frequently involved.
Limited scleroderma: anti-
It is more commonly seen in the females and is due to release of growth factors acting on the
fibroblasts like fibroblast growth factor (FGF), platelet derived growth factor (PDGF) and cytokines
centromereQ antibodies
like IL-1.
The disease has two categories:

Diffuse Scleroderma is characterized by presence of anti-DNA topoisomeraseQ
antibodies (Scl-70). There is widespread skin involvement at onset, with rapid
CREST Syndrome= Calcinosis,
progression and early visceral involvement. The symptoms include dysphagia,
Raynaud phenomenon, Esophageal malabsorption, arrhythmia (due to cardiac fibrosis), exertional dyspnea and renal
dysmotility, Sclerodactyly and insufficiency.

Limited scleroderma is characterized by the presence of anti-centromereQ antibodies.
Immunity
Telangiectasia.
The skin involvement is often confined to fingers, forearms, and face. Since the
visceral involvement occurs late; so, the clinical course is relatively benign. Some
patients develop CREST syndromeQ whose features include Calcinosis, Raynaud
phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia.
ANA: the sensitivity of antinuclear antibodies determination is higher than 95% for systemic lupus
erythematosus although specificity is fairly low. The different patterns which are seen are:

Homogeneous: systemic lupus erythematosus.
Peripheral:
connective tissue diseases.
Speckled: systemic lupus erythematosus, mixed connective tissue disease, Sjgrens syndrome,
polymyositis or scleroderma.
Nucleolar: approximately 50-70% of the patients with overlapping scleroderma and polymyositis/
dermatomyositis syndromes and in 1/3rd patients with systemic scleroderma,
especially those with renal complications.
X-LINKED AGAMMAGLOBULINEMIA OF BRUTON

It is an X-linked immunodeficiency disorder characterized by the failure of B-cell precursors (pro-B
Concept cells and pre-B cells) to mature into B cells due to mutation of B-cell tyrosine kinase (Btk). Btk is
Brutons disease usually does required for the maturation of pre-B cell to mature B cell. The disease is seen almost entirely
not become apparent until in males. In most cases, recurrent bacterial infections of the respiratory tract, such as acute
about 6 months, when maternal
immunoglobulins are depleted.
and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, are present. The
causative organisms are Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus
aureus in most of the patients.
The classic form of this disease has the following characteristics:
Germinal centers of lymph nodes,

B cells are absent or markedly decreased in the circulation and the serum levels of all classes of
immunoglobulins are reduced.
Peyer patches, the appendix, Absence of plasma cells.
and tonsils are under developed T cell mediated reactions are normal.
or rudimentary
It is associated with an increased risk of other autoimmune disorders.
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Immunity
WISKOTT - ALDRICH SYNDROME

Triad of WAS=
Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive diseaseQ. thrombocytopenia+eczema+
It is caused by mutations in the WASP gene located on short arm of chromosome X. The WASP recurrent infections
protein is expressed in cells of all hematopoietic lineages. It is required for cytoskeletal integrity
and signal transduction that are particularly important in platelets and T cells.
The disorder is seen in male patientsQ and becomes symptomatic in children. It is characterized
by bruising caused by thrombocytopeniaQ, eczemaQ (itchy rash), recurrent infectionsQ, bloody In WAS, IgM, IgA and IgE,
diarrhea (due to thrombocytopenia)and a propensity for autoimmune disorders and malignanciesQ normal IgG levels may be
(mainly lymphoma and leukemia). elevated.
In Wiskott-Aldrich syndrome, the platelets are smallQ, have a shortened half life and do not function
properly. They are removed by the spleen, which leads to low platelet counts. Splenomegaly may
be seen.
Diagnosis
The diagnosis is made on the basis of clinical parameters, the blood film and low Decreased levels of Wiskott-
Aldrich syndrome protein (WASP)
immunoglobulin levels.
and/or confirmation of a
Treatment causative mutation provide the
most definitive diagnosis.
It is done with bone marrow transplantation. The alternatives include intravenous
immunoglobulin infusions or splenectomy.
COMMON VARIABLE IMMUNODEFICIENCY

Most patients with common variable immunodeficiency have normal or near-normal Common variable immuno-
numbers of B cells in the blood and lymphoid tissues which are not able to differentiate deficiency: characterized by
hypogammaglobulinemia
into plasma cells. Patients have intrinsic B-cell defects (defective cytokine receptor called
affecting all the antibody classes
BAFF which normally promotes B cell differentiation and survival) as well as abnormalities (but sometimes only IgG) even
of T cell-mediated regulation of B cells. The clinical manifestations include recurrent with near-normal numbers of
sinopulmonary pyogenic infections, recurrent herpesvirus infections and persistent diarrhea B Cells.
Immunity
caused by G. lamblia. It affects both sexes equally, and the onset of symptoms is relatively
late (in childhood or adolescence). These patients have a high frequency of autoimmune
diseases like rheumatoid arthritis and increased risk of lymphoid malignancy (particularly
in women).
DIGEORGE SYNDROME OR VELOCARDIOFACIAL SYNDROME

It is a T-cell deficiency due to deletion of chromosome 22q11.2. The patients have a loss of
T cell-mediated immunity (owing to hypoplasia or lack of the thymus), tetany (owing to
lack of the parathyroids), and congenital defects of the heart and great vessels. They may
also have abnormal facies with defects in the mouth and ears. The absence of cell-mediated
immunity results in the development of recurrent fungal and viral infections.
DiGeorge syndrome: failure of
Mnemonic: (CATCH 22) development of the third and
C Cardiac abnormalities (especially tetralogy of Fallot) fourth pharyngeal pouches
A Abnormal facies
T Thymic aplasia Absence of the parathyroid
C Cleft palate glands and the thymus.
H Hypocalcemia (due to hypoplasia or lack of parathyroids)
22 22q11 deletion
ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

This retroviral disease is caused by the human immunodeficiency virus (HIV). It is
characterized by the triad of immunosuppression associated with opportunistic infections,
secondary neoplasms, and neurologic manifestations. The major routes of HIV infection are:

1. Sexual contact
It is the most common mode of spread of the infection throughout the world.
It is usually through heterosexual contact. The virus is present in semen, both
extracellularly in the seminal fluid (called as free form of the virus) and within
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the lymphocytes. It enters the recipients body through abrasions in mucosa. The
transmission of the virus can occur by either direct entry of virus into the blood vessels
AIDS is the commonest
secondary immunodeficiency or into the mucosal dendritic cells. The presence of any other concomitant sexually
disorder transmitted disease causing genital ulcerations increases the risk of transmission of
HIV also. Gonorrhea and Chlamydia also act as cofactors for HIV transmission primarily by
increasing the seminal fluid content of inflammatory cells carrying HIV.
2. Parenteral inoculation
Parenteral transmission of HIV is a broad term which includes transmission through:
Sexual contact: Least
a. Intravenous drug abusers (the largest group): transmission occurs through
efficacious yet most common shared needles, syringes etc.
mode of spread of HIV infection.
b. Patients receiving blood or blood components (like hemophiliacs receiving
The male to female transmission
factor VIII or IX concentrates)
is more common as compared
c. Infected patient to the physician through needle stick injury:
to transmission from females to The transmission through the parenteral route can be prevented with the
males screening of the blood and taking precautions like the universal precautions
like not recapping the needle after taking blood sample of a patient and use of
disinfectants like hypochlorite for blood spillages.
3. Passage of the virus from infected mother to newborn (mother to child transmission
or vertical transmission)
The risk of transmission of HIV
The transmission from an infected to the child can take place through:
is 0.3% with needle stick injury

a. Transplacental spread
whereas the risk of hepatitis B is
b. Infected birth canal during normal vaginal deliveryQ: it is the MC route for
30%. vertical transmission.

c. Ingestion of breast milk
The transmission through the vertical route can be reduced by the use of elective
caesarean section and the use of antiviral drugs like nevirapine and zidovudine.
(For details, refer to Review of Pharmacology by the same authors.)
Immunity
Vertical transmission is the

Note: HIV infection cannot be transmitted by casual personal contact in the home, workplace, or
commonest cause for AIDS in
school, and insect bites. HIV is most efficaciously transmitted by contaminated blood transfusion
the pediatric population.
and least efficaciously by sexual contact.
ETIOLOGY AND PATHOGENESIS

HIV is a retrovirus belonging to the lentivirus family and is of two types HIV-1 and HIV-2.
There are two strains of HIV which are:
The commonest cause of AIDS
in India is HIV-1 group M
a. Macrophage-tropic (R5 virus) strain: it infects both monocytes/macrophages and T
subtype C cells

b. T-cell tropic (X4 virus) strain: it infects only activated T cell lines.
The HIV-1 virion is spherical and contains an electron-dense, cone-shaped core containing
the major capsid protein p24, nucleocapsid protein p7/p9, the viral RNA, and viral enzymes
(protease, reverse transcriptase, and integrase) surrounded by a lipid envelope derived from
Concept the host cell membrane. p24 is the most readily detected viral antigen and is the target for
R5 strains use CCR5 as their the antibodies used to diagnose HIV infection in blood screening. The viral envelope has
coreceptor which is expressed two glycoproteins (gp120 and gp41) required for HIV infection of cells. The HIV-1 proviral
on both monocytes and T cells, genome contains the genes gag, pol and env which encode for large proteins which must be
X4 strains bind to CXCR4 broken down to form small mature proteins.
expressed on T cells and not on The other genes which regulate the replication of HIV include:
monocytes/macrophages.
tat (transactivator) gene is critical for virus replication
Almost 90% of HIV infections
are initially transmitted by R5
vpr protein facilitates HIV infection of macrophages. Although most retroviruses require cell
division for their replication, still HIV-1 can multiply in differentiated nondividing macrophages
strains. However, during the because of vpr gene.
course of infection, X4 viruses
replace R5 strains due to
nef protein affects T-cell activation, viral replication, and viral infectivity and reduces surface
expression of CD4 and MHC molecules on infected cells.
mutations in genes that encode vpu promotes CD4 degradation and affects virion release.
gp120.
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Immunity
The two major targets of HIV infection are the immune system and the CNS. The
profound immunodeficiency is the hallmark of AIDS. The viral envelope gp120 interacts Acute Stage : Macrophage affected
with CD 4 molecule. The commonly affected CD 4 cells in the human body include helper T Chronic Stage : TH1 cells affected
cellsQ (worst affected), monocyte-macropahges and dendritic cells. This binding leads to a
conformational change causing exposure of a new recognition site gp 41 for the co-receptors.
The virus then fuses with the host cell membrane.
Defective CCR5 receptors lead to protective effect of providing resistance to the development of AIDS.
Once inside the cell, the reverse transcriptase of the HIV forms a single stranded DNA
HIV: cytotoxic to CD4 T Cells
which is used for the formation of double stranded DNA (dsDNA) by DNA polymerase leading to loss of cell-meditated
enzyme. The dsDNA then integrates into host cell by the enzymatic action of integrase. The immunity.
viral particle is now called as HIV provirus. The provirus may remain non transcribed for
sometime (latent infection) or the proviral DNA may be transcribed to form complete viral
particles budding from the cell membrane. This is responsible for causing damage to host
cell membrane followed by their apoptosis. The released viral particles spread through
circulation and usually enter lymphoid organs which act as reservoir sites. Macrophages
are also infected by the virus early; they are not lysed by HIV and they transport the virus to
tissues specially the brain.
The viremia is controlled by the host immune response and the patient then enters a
phase of clinical latency. During this phase, viral replication in both T cells and macrophages
continues unchecked. There continues a gradual erosion of CD4+ cells by the cytopathic
effects of the virus, apoptosis of the infected cells and killing of virus infected cells by virus
specific cytotoxic T lymphocytes. This is leading to decline in CD4+ cell count and the patient
developing clinical symptoms.
Major Abnormalities of Immune Function in AIDS Follicular dendritic cell in
germinal center of lymph node
Lymphopenia Decreased Altered T-Cell Polyclonal B-Cell Altered Monocyte is a potential reservor of HIV
T-Cell Function Function In Vitro Activation Functions
In Vivo
Immunity
Predominantly Preferential Decreased Hypergamma- Decreased
due to selective loss of memory proliferative response globulinemia and chemotaxis and
loss of the CD4+ T cells and to mitogens, circulating immune phagocytosis
helper-inducer Decreased alloantigens, and complexes
T-cell subset; delayed-type soluble antigens
inversion of hypersensitivity
CD4:CD8 ratioQ
Susceptibility to Decreased helper Inability to mount Decreased HLA
neoplasms and function for de novo antibody class II antigen
opportunistic pokeweed mitogen- response to a new expression and
infections induced B-cell antigen or vaccine reduced antigen
immunoglobulin presentation to T
production cells
Natural History of HIV
The acute retroviral syndrome

It is seen for 3-12 weeks and is characterized by high levels of plasma viremia, and widespread
seeding of the lymphoid tissues. The initial infection is controlled by the development of an antiviral
immune response. Clinically, this stage is associated with a self-limited acute illness with nonspecific
symptoms, including sore throat, myalgias, fever, rash, weight loss, and fatigue, and clinical features,
such as rash, cervical adenopathy, diarrhea, and vomiting.
The middle chronic phase
This is characterized by a period of clinical latency. It is usually lasting for an average duration of 10
years. In this phase, there is a continuous battle between the virus and the host immune cells. The
immune system is intact, but there is continuous HIV replication, predominantly in the lymphoid tissues,
which may last for several years. Patients are either asymptomatic or develop persistent generalized
lymphadenopathy. The patients may have minor opportunistic infections as thrush and herpes zoster.
Persistent lymphadenopathy with significant constitutional symptoms (fever, rash, fatigue) reflects the
onset of the crisis phase.
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The final phase or the stage of crisis

The weight loss is so severe that
It is associated with the loss of host immune cells in the battle and the progression to AIDS. It is
AIDS is also known as Slims
disease characterized by the patient presenting with a long-lasting fever (>1 month), fatigue, weight loss, and
diarrhea.
CLINICAL FEATURES
The typical adult patient with AIDS presents with fever, weight loss, diarrhea, generalized
*M. tuberculosis is the most lymphadenopathy, multiple opportunistic infections, neurologic disease and secondary
common infection with HIV in neoplasms.
India The opportunistic infections seen are:
Bacterial infections Viral infections Fungal infections Protozoal infections
M. tuberculosis Cytomegalovirus Candidiasis Cryptosporidium
Candidiasis is the most Salmonella Herpes simplex virus Pneumocystis Isosporidium
common fungal infection in AIDS Nocardiosis Varicella zoster virus jiroveci Toxoplasmosis
in India Atypical myco- JC virus causing Pro- Cryptococcosis
Pneumocystis jiroveci is the bacterial infec- gressive multifocal Histoplasmosis
most common fungal infection in tions leukoencephalopahty Coccidiomycosis
AIDS in World
Neoplasms in AIDS
Kaposis sarcoma is the most

1. Kaposis sarcomaQ: It is caused due to infection with Kaposi sarcoma herpesvirus
(KSHV) or human herpes virus -8 (HHV8). It is characterized by the proliferation of
common cancer seen in patients
having AIDS
spindle-shaped cells that express markers of both endothelial (vascular or lymphatic)
and smooth muscle cellsQ. KSHV infection is related to rare B cell lymphomas in
AIDS patients known as body cavity based primary effusion lymphoma and to a
multicentric B-cell lymphoproliferative disorder called as Castleman disease.
Stomach is the most common 2. Lymphomas: AIDS related lymphomas include
extranodal site for development
i. Systemic lymphomas having the CNS as the most common extranodal site for
Immunity
of lymphoma in non HIV development of lymphomaQ,

patients.

ii. Primary CNS lymphoma found more commonly in AIDS than in general
population

iii. Body cavity lymphomas present as pleural, peritoneal or pericardial effusions.
CNS is the most common

These tumors are more frequently seen in patients with CD4+ T cell count <50 per
microlitre.
extranodal site for development
of lymphoma in AIDS 3. Genital cancers including cancer of the cervix and the anal cancers due to infection
with human papilloma virus (HPV).
Neurological Manifestations in AIDS
The neurological manifestations are due to the involvement of the microgliaQ. These include
Toxoplasma gondii is responsible 1. Opportunistic infections
for 50% of all mass lesions in the
CNS
2. Neoplasms
3. Aseptic meningitis
4. Peripheral neuropathies
5. AIDS-dementia complex Q
6. Vacuolar myelopathy: It is a disorder of the spinal cord found in 20% to 30% of patients with AIDS.
AIDS-dementia complex is the The findings resemble those of subacute combined degeneration, though serum levels of vitamin
most common neurological B12 are normal.
manifestation of HIV infection 7. Meningoencephalitis: HIV encephalitis is characterized microscopically as a chronic inflammatory
reaction with widely distributed infiltrates of microglial nodules around the small blood vessels
Inflammatory myopathy is the
commonest skeletal muscle showing abnormally prominent endothelial cells and perivascular foamy or pigment-laden
disorder in HIV. macrophages. These nodules also contain the macrophage-derived multinucleated giant cell.
8. Inflammatory myopathyQ: The histological findings include muscle fiber necrosis and phagocytosis,
interstitial infiltration with HIV-positive macrophages. Characteristically vasculitis is absentQ.
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Immunity
Diagnosis of HIV infection or AIDS
The diagnosis of HIV is established with the following tests:

Concept
ELISAQ is used for the detection of antibodies against viral proteins. This is the most sensitive
Window period is the term
and the best screening test for the diagnosis of AIDS.
Western blotQ is the most specific or the confirmatory test for HIV. used for initial 2-4 weeks when
Direct detection of the viral infection is with p24 antigen capture assay, reverse transcriptase the patient is infectious and the
polymerase chain reaction (RT-PCR), DNA-PCR and culture of the virus from the monocytes and screening test is negative during
which the investigation of HIV is
CD4+ T cells.
made using polymerase chain
The management of the disease is done by the Highly active antiretroviral therapy reaction for detection of viral
(HAART) details of which can be referred from Review of Pharmacology by the same nucleic acids.
authors.
Some patients with advanced disease in HIV paradoxically deteriorate on initiating the antiviral therapy.
This ironical disorder whose basis in not understood is called Immune reconstitution inflammatory
syndrome.
Amyloidosis (Beta-Fibrillosis)
It is a group of diseases having in common the deposition of amyloid (a pathologic

proteinaceous substance, deposited between cells in various tissues and organs of the body).
Amyloid appears as an amorphous, eosinophilic, hyaline, extracellular substance with the
light microscope. Its progressive accumulation can cause pressure atrophy of adjacent cells.
Nature of Amyloid
Amyloid is seen to be made up of nonbranching fibrils of indefinite length and a diameter of

approximately 7.5 to 10 nm by the electron microscope. X-ray crystallography and infrared Amyloid
EM: nonbranching fibrils of
spectroscopy demonstrate a characteristic cross--pleated sheet conformation responsible for
indefinite length
the birefringence. Chemically, 95% of the amyloid is made up of fibril proteins.
Immunity
X-ray crystallography and
CLASSIFICATION OF AMYLOIDOSIS infrared spectroscopy: character-
istic cross--pleated sheet
Primary Amyloidosis conformation
It is associated with immunocyte dyscrasias like multiple myeloma or any other B cell neoplasm.
The tumor cells in multiple myeloma secrete light chains of the immunoglobulins of either
lamda or kappa type which get deposited in the tissues as amyloid. The chemical nature of
the amyloid is ALQ (A for amyloid and L for light chain).
Secondary Amyloidosis (also called as Reactive Systemic Amyloidosis)

It is usually seen secondary to chronic inflammatory conditions like rheumatoid arthritisQ
(most commonly), tuberculosis, bronchiectasis, chronic osteomyelitis, inflammatory bowel
disease, ankylosing spondylitis and two cancers namely renal cell cancer and Hodgkins
disease. There is release of IL-1 and IL-6 which act on the liver cells leading to the secretion of
SAA protein which gives rise to AA protein being deposited in this condition. The chemical
nature of amyloid is AAQ.
Hemodialysis associated Amyloidosis

It is caused by the deposition of the b2 microglobulin which is a component of MHC class I
molecule and can not be filtered through the cuprophane dialysis membrane. It gets deposited
in the synovium, joints and the tendon sheaths. The chemical nature of the amyloid is Ab2Q.
Heredofamilial Amyloidosis
i. Familial Mediterranean fever is an autosomal recessive condition characterized by
development of attacks of fever associated with inflammation of serosal surfaces
(pleura, peritoneum and synovial membrane). The amyloid protein deposited is AA
protein and the protein associated with this condition is called pyrinQ.
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ii. Familial amyloidotic neuropathies (several types):
Primary Amyloidosis: B cell This is a group of autosomal dominant conditions in which both peripheral and
neoplasm; AL autonomic nerves are involved. There is deposition of ATTR (A for amyloid and
TTR is for transthyretin, a protein which transports thyroxine and retinol). The
Secondary Amyloidosis: Chronic
transthyretin deposited in this condition is a mutant form of the normal proteinQ.
inflammation: AA

iii. Systemic senile Amyloidosis
Chronic renal failure: Ab2 This is a condition characterized by the deposition of structurally normal
Alzheimer disease: Ab
transthyretinQ, the chemical nature of amyloid is ATTR and it is usually deposited
in the heart of aged individuals leading sometimes to the development of restrictive
Familial Mediterranean fever: AA; cardiomyopathy.
involvement of pyrin.
LOCALIZED AMYLOIDOSIS
There is presence of nodular deposits most often in lung, larynx, skin, urinary bladder,
tongue and around the eyes.

i. Senile cerebral amyloidosis
It is seen in Alzheimers disease in which there is deposition of b-amyloid protein.
So, chemical nature of amyloid is AbQ.

ii. Endocrine
It is associated with:
Medullary thyroid cancer: calci-

Medullary carcinoma of thyroid having the deposition of ACalQ derived from
calcitonin
tonin is the tumor marker and
also forms amyloid; ACal

Islet of Langerhans in Type II DM having deposits of AIAPPQ derived from Islet
Amyloid Peptide

iii. Isolated Atrial Amyloidosis
In this condition, there is deposition of AANF derived from Atrial natriuretic factor.

iv. Prion disease
In this condition, there is deposition of misfolded prion proteins PrPsc derived from
Immunity
normal prion protein PrP.
Summary of clinical conditions and the chemical nature of amyloid

S.No. Amyloid protein Precursor Disease
1. AL Ig light chain Multiple myeloma (primary amyloidosis)
2. AA SAA Secondary or reactive amyloidosis
3. Ab2m b2 microglobulin Hemodialysis
Associated amyloidosis
4. Ab Ab precursor protein Senile cerebral Alzheimers
5. ATTR Mutant Transthyretin Familial amyloidotic neuropathy
Normal Transthyretin Systemic senile amyloidosis
6. ACal Calcitonin Medullary carcinoma of thyroid
7. AIAPP Islet amyloid polypeptide Type II diabetes
8. AANF ANP Isolated atrial amyloidosis
Misfolded prion protein (PrPsc) disease
Spleen involvement in amyloi-
dosis 9. Aa Fibrinogen Familial renal amyloidosis
Red pulp: Lardaceous spleen
White pulp: Sago spleen Morphology in Amyloidosis
Kidney
It is the most common and most serious form of organ involvement and is usully involved in secondary
Remember, red is called Lal
amyloidosis. There is deposition primarily in the glomerular basement membrane, mesangium and
in hindi; so, when red pulp
the interstitial peritubular tissue. Arteries and arterioles are also affected.
is involved, remember it is
lardaceous spleen Spleen
There is splenomegaly. If there is involvement of splenic follicles, it is called as Sago spleen and if
there is involvement of splenic sinuses and red pulp it is called as Lardaceous spleen.
204
Immunity
Liver
It is first deposited in the space of Disse and later result in hepatomegaly. The liver function tests
are usually normal.
Heart
It is more commonly associated with primary amyloidosis. It is the most important organ involved in
senile systemic amyloidosis. Clinically, there may be development of arrhythmia and it is also the most
important cause of restrictive cardiomyopathy. There is deposition in the focal subendocardial region.
Adrenals Macroglossia is the most
The intercellular deposits begin initially in zona glomerulosa. specific feature of AL type
of amyloidosis. (Ref Wintrobe
GIT 12th/2442)
The GI tract may be involved through the gingiva to the anus. The deposition of the amyloid in the
tongue results in the nodular enlargement of tongue called macroglossia or the tumor forming amyloid
of the tongue.
Clinical features are non-specific and the symptoms are seen depending on the organ
predominantly affected in the disease. Deposition of the amyloid in long term hemodialysis
takes place in joints and in the carpal ligament of the wrist, the latter leading to development
of carpal tunnel syndrome.
Diagnosis
The diagnosis is made by the microscopic examination of the biopsy from renal tissue, rectum,
abdominal fat aspiration and gingiva. The rectum is the best site for taking the biopsyQ. The
staining of abdominal fat aspirateQ is quite specific but has low sensitivity. Grossly, the
organs are enlarged and firm with a waxy appearance. The cut surface on painting with
iodine imparts a yellow color which on application of sulfuric acid (H2SO4) gives a blue violet
color.
Immunity
STAINING FOR AMYLOID Congo red
Congo red: It is the most widely used specific stain for amyloid. Pink red color under normal light
Iodine staining: It is used for unfixed specimen or histological section. Amyloid microscopy
stains mahogany brown and if sulfuric acid is added, it turns violet. Apple green birefringence in
Thioflavin T and S give secondary immunofluorescence with ultraviolet light. the polarized light.
Thioflavin T is more useful for demonstrating juxtaglomerular apparatus of the
kidney.

Metachromatic stains like crystal violet and methyl violet give rose pink appearance.

Amyloid is PAS positive.
The condition has usually poor prognosis.
Appearance of Amyloid
On light microscopy and standard tissue stains Amorphous eosinophilic extracellular substance
(H and E)
Congo red stain on ordinary light Pink or red color to tissue deposits
Congo red stain on polarizing microscopy Apple green birefringenceQ
Fluorescent stains (thioflavin T and S) Yellow color under UV light
Electron microscopy Nonbranching fibrilsQ of indefinite length and a
diameter of approximately 7.5 to 10 nm.
X-ray crystallography and infrared spectroscopy Characteristic cross b pleatedQ sheet conformation
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IMMUNE CELL: GENERAL ASPECTS 8. The following feature is common to both cytotoxic
T-cells and NK cells: (AI 2002)
1. Which of the following features is not shared between (a) Synthesize antibody
T cells and B cells? (AIIMS Nov 2012) (b) Require antibodies to be present for action
(a) Antigen Specific Receptors (c) Effective against virus infected cells
(d) Recognize antigen in association with HLA class II
(b) Class I MHC Expression
markers
(c) Positive selection during development
(d) All of the above 9. MHC restriction to antigen presentation is not done
for: (AIIMS May 2009)
2. CD4 is not important for which of the following? (a) Killing of viruses by cytotoxic cells
(a) Antibody production (AIIMS May 2011) (b) Killing of bacteria by helper cells
(b) Cytotoxicity of T cells (c) T cell activation in autoimmunity
(c) Memory B cells (d) Graft rejection
(d) Opsonisation
10. Most potent stimulator of naive T cell is?
3. Type 1 MHC presents peptide antigen to T cell , so that (a) Mature dendritic cell (AI 2011, AIIMS Nov 08)
peptide binding site is formed by: (AI 2010) (b) Follicular dendritic cell
(a) Alfa and Beta chain (c) Macrophages
(b) Distal domain alfa 1 and 2 (d) B cell
(c) Alfa and beta microglobulin 11. Natural killer cells attacks which of the following
(d) Proximal domain alfa 1 and 2 cells: (AIIMS Nov 2006)
(a) Cells which express MHC1
Immunity
4. Function of CD4 is all except: (AI 2009)

(b) Cells which are not able to express MHC1
(a) Memory (c) MHC cells which express MHC2
(b) Immunoglobin production (d) Cells which are not able to express MHC
(c) Activation of macrophages
(d) Cytotoxicity 12. Toll like receptors, recognize bacterial products and
stimulates immune response by: (AIIMS Nov 2006)
5. A super-antigen is a bacterial product that (AI 2008) (a) Perforin and granzyme mediated apoptosis
(a) Binds to B7 and CD28 co-stimulatory molecules (b) FADD ligand apoptosis
(b) Binds to the beta chain of TCR and MHC class II (c) Transcription of nuclear factor mediated by NFB
molecules of APC stimulating T cell activation which recruits cytokines
(c) Binds to the CD4 + molecule causing T cell activation (d) Cyclin
(d) Is presented by macrophages to a larger-than-nor- 13. The following interleukin is characteristically produced
mal number of T helper CD4 + lymphocytes in a TH response:
1
(AIIMS Nov 2004)
(a) IL-2 (b) IL-4
6. Memory T cells can be identified by using the following (c) IL-5 (d) IL-10
marker: (AI 2003)
(a) CD45RA 14. CD-95 has a major role in: (AIIMS Nov 2003)
(b) CD45RB (a) Apoptosis
(c) CD45RC (b) Cell necrosis
(d) CD45RO (c) Interferon activation
(d) Proteolysis
7. All of the following statements about NK cells are true 15. Which of the following chemical mediators of
except: (AI 2003)
inflammation is an example of a C-X-C or alpha
(a) They are derived from large granular cells
Chemokine? (AIIMS Nov 2003)
(b) They comprise about 5% of human peripheral lym- (a) Lipoxin LXA4
phoid cells (b) Interleukin IL-8
(c) They are MHC restricted cytotoxic cells (c) Interleukin IL-6
(d) They express IgG Fc receptors (d) Monocyte Chemo-attractant Protein MCP-1
206
Immunity
16. The complement is fixed best by which of the following 25. The normal ratio of CD4 to CD8 is (UP 2005)
immunoglobulins: (AIIMS May 2002) (a) 1: 1
(a) IgG (b) 2: 1
(b) IgM (c) 8: 1
(c) IgA (d) 10: 1
(d) IgD 26. CD4 cells is used to identify which of the following
17. Antigen presenting cells are which of the following: (a) MHC I (AP 2007)
(a) Astrocytes (AIIMS May 2002) (b) MHC II
(b) Endothelial cells (c) T cells
(c) Epithelial cells (d) B cells
(d) Langerhans cells 27. CD3 is marker for: (Jharkhand 2006)
(a) Monocyte (b) T cell
18. Antigen presenting cells are: (PGI June 2006)
(c) B cell (d) None
(a) Langerhans cell
(b) Macrophage 28. Which of the following is not true about innate
(c) Cytotoxic T cells immunity?
(d) Helper T cells (a) It is present prior to antigenic exposure
(e) B lymphocyte (b) It is relatively non-specific
(c) Memory is seen
19. Perforins are produced by: (PGI Dec 2001) (d) It is the first line of defense
(a) Cytotoxic T cells
(b) Suppressor T cells 29. Which one of the listed receptors is the type of receptor
(c) Memory helper T cells on leukocytes that binds to pathogen-associated
(d) Plasma cells molecular patterns (PAMPs) and mediates immune
(e) NK cells response to bacterial lipopolysaccharide?

(a) Cytokine receptor
20. Cell surface molecules involved in peripheral tolerance
(b) G-protein-coupled receptor
induction are: (PGI Dec 2003)
(c) Mannose receptor
Immunity
(a) B and CD
7 28
(d) Toll-like receptor
(b) CD and CD
40 40L
(c) CD and CD
34 51
(d) B and CD
7 3
29.1. NK cell CD marker is:
21. Marker for B-Lymphocyte: (PGI Dec 2004) (a) 16 (b) 60
(a) CD34 (c) 32 (d) 25
(b) CD33
2 9.2. Immunity against cancer cells:
(c) CD19
(a) Basophills (b) Eosinophils
(d) CD20
(c) NK cells (d) Neutrophils
(e) CD22
2 9.3. NK cells express:
22. IL-1 causes (Delhi PG-2008) (a) CD 15, CD 55 (b) CD 16, CD 56
(a) Increased leukocyte adherence (c) CD 16, CD 57 (d) CD 21, CD 66
(b) Fibroblast proliferation
(c) Increased collagen synthesis 2 9.4. Which of the following immune cells have the
expression of CD8 on their surface?
(a) T-cells (b) B-cells
23. Antigen presenting cells present in skin are called (c) Null cells (d) Macrophages
(a) Langerhans cells (Delhi PG-2004)
2 9.5. The following interleukin is characteristically produced
(b) Kupffers cells in a TH1 response?
(c) Microglia (a) IL-2 (b) IL-4
(d) Melanocytes (c) IL-5 (d) IL-10
24. Plasma cells (UP 2004) 2 9.6. Most potent stimulator of Nave T-cells:
(a) Contain nucleus (a) Mature dentritic cells
(b) Helps in the formation of antibody (b) Follicular dendritic cells
(c) Are deficient in cytoplasm (c) Macrophages
(d) Are derived from T-cells (d) B-cell
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29.7. Macroglobulin is derived from: 37. MHC-II positive cells are all except: (PGI Dec 2000)
(a) B cells (b) T cells (a) B cells (b) T cells
(c) Both (d) Natural killer cells (c) Macrophages (d) Platelets
2 9.8. Kupffer cells are found in: (e) RBCs
(a) Heart (b) Lungs
(c) Liver (d) Spleen
38. True about MHC: (PGI June 2003)
(a) Transplantation reaction
2 9.9. Birbeck granules are present in (b) Autoimmune disease
(a) Merkel cell (b) Langerhans cell (c) Immunosuppression
(c) Langhans cell (d) Melanocyte (d) Involved in T-cell function
(e) Situated at long arm of chromosome 6
2 9.10. Which of the following immunoglobulin does not fix
complement? 39. Epitope binding floor of the MHC molecule conists of
(a) IgA (b) IgG (a) Alpha helices (Karnataka 2007)
(c) IgM (d) IgE (b) Beta pleated structure
(c) Alpha and beta-1 chain
(d) Beta-2 microglobin
MHC
30. MHC class III genes encode: (AI 2003)
(a) Complement component C3 39.1. MHC class I are present on all except
(b) Tumor necrosis factor (a) Platelets (b) All nucleated cells
(c) Interleukin 2 (c) RBCs (d) WBCs
(d) Beta 2 microglobulin
3 9.2. HLA B27 is not seen in which of the following?
31. The HLA class III region genes are important elements (a) Ankylosing spondylitis
in: (AI 2003) (b) Reiters syndrome
(a) Transplant rejection phenomenon (c) Rheumatoid arthritis
(b) Governing susceptibility to autoimmune diseases (d) Psoriatic arthritis
(c) Immune surveillance
3 9.3. The role played by Major Histocompatibility Complex
(d) Antigen presentation and elimination
Immunity
1 and 2: (AIIMS May 2013)

32. HLA is located on: (AIIMS Nov 2009) (a) Transduce the signal to T cells following antigen
(a) Long arm of chromosome 6 (DNB 05,09) recognition
(b) Long arm of chromosome 3 (b) Mediate immunogenic class switching
(c) Short arm of chromosome 6 (c) Present antigens for recognition by T cell antigen
(d) Short arm of chromosome 3 receptors
(d) Enhance the secretion of cytokines
33. HLA B27 is positive in: (AIIMS Nov 2009)
(a) Ankylosing spondylitis 3 9.4. Antigen presented along with HLA class II stimulate
(b) Rheumatoid arthritis (a) CD8 cell
(c) SLE (b) CD4 cell
(d) Behet syndrome (c) CD2 cell
(d) CD19 cell
34. Mixed lymphocyte culture is used to identify:
(a) MHC class I antigen (AIIMS Nov 2002) 3 9.5. Major histocompatibility complex class I is seen on
(b) MHC class II antigen which of the following cell?
(c) B lymphocytes (a) Macrophages only
(d) T helper cells (b) All body cells
(c) B cell only
35. HLA typing is useful in: (PGI June 2006) (d) All blood cells except erythrocytes
(a) Disputed paternity
(b) Thanatology
(c) Organ transplant HYPERSENSITIVITY REACTIONS
(d) Dactylography
36. True about MHC-class II: 40. What type of hypersensitivity reaction is seen in
(PGI June 2006) myasthenia gravis? (AI 2012)
(a) Not involved in innate immunity (a) Type 1hypersensitivity reaction
(b) Cytotoxic T-cell involved (b) Type 2hypersensitivity reaction
(c) Present in nucleated cells (c) Type 3hypersensitivity reaction
(d) Present in B-cells (d) Type 4hypersensitivity reaction
208
Immunity
41. Hemolytic disease of newborn is an example of: 50. Which of the following diseases is/are mediated
(a) Type 3 hypersensitivity reaction (DPG 2011) through complement activation: (PGI Dec 03)
(b) Type 2 hypersensitivity reaction (a) Atopic dermatitis
(c) Arthus reaction (b) Graft versus Host disease
(d) Type 4 hypersensitivity reaction (c) Photoallergy
(d) Necrotizing vasculitis
42. Raji cell assays are used to quantitate: (DPG 2011) (e) Urticaria
(a) Complement levels
(b) Immune complexes
51. Which of following statements is not true about
Mycobacterium tuberculosis infection?
(c) T cells
(d) Interferon levels
(Delhi PG 2009 RP)
(a) M. tuberculosis leads to development of delayed
43. Hypersensitivity pneumonitis is classically a/an: hypersensitivity
(a) Allergic reaction (AI 2009) (b) Lymphocytes are the primary cells infected by M.
(b) Type II hypersensitivity tuberculosis
(c) Immune complex mediated hypersensitivity (c) Positive tuberculin test signifies cell mediated hyper-
(d) Cell mediated hypersensitivity sensitivity
44. The immunoglobulin involved in type I hypersensitivity (d) Tuberculin test does not differentiate between
reaction is: (AI 2007) infection and disease.
(a) IgE (b) IgM 52. A man after consuming sea food develops rashes. It is
(c) IgA (d) IgG due to: (Delhi PG-2008)
(a) IgE mediated response
45. Arthus reaction is what type of hypersensitivity (b) Complement activation
reaction: (AI 2007), (UP03) (c) Cell mediated response
(a) Localized immune complex (d) None of the above
(b) Ag-Ab reaction
(c) Complement mediated 53. Granuloma in Sarcoidosis is called (Delhi PG-2004)
(d) Ab mediated (a) Hard sore (b) Soft sore
(c) Hard tubercle (d) Caseating granuloma
46. A 40 year old man has chronic cough with fever 54. Myasthenia gravis may be associated with
for several months. The chest radiograph reveals
Immunity
(a) Thymoma (Karnataka 2004)
a diffuse reticulondular pattern. Microscopically
(b) Systemic lupus erythematosus
on transbronchial biopsy there are focal areas of
(c) Hyperthyroidism
inflammation containing epitheloid cell granuloma,
Langhans giant cells, and lymphocytes. These
findings are typical for which of the following type of 55. Which of the following type of hypersensitivity reaction
hypersensitivity immunologic responses: is found in blood transfusion reaction?

(a) Type I (AIIMS May 2003) (a) Anaphylactic type (UP 2001)

(b) Type II (b) Cytotoxic type

(c) Type III (c) Type III hypersensitivity

(d) Type IV (d) Cell mediated hypersensitivity
47. Ram Devi presented with generalized edema sweating 56. Which of the following type of hypersensitivity
and flushing tachycardia and fever after bee sting. This reactions occurs in Farmers lung (UP 2008)
is: (AIIMS Nov 2001) (a) Type I (b) Type II
(a) T cell mediated cytotoxicity (c) Type III (d) Type IV
(b) IgE mediated reaction 57. Tuberculin test positivity indicates (AP 2005)
(c) IgG mediated reaction (a) Good humoral immunity
(d) IgA mediated hypersensitivity reaction (b) Infection with mycobacterium
(c) Good cell mediated immunity
48. Example of Type IV Hypersensitivity is/are: (d) None
(a) Farmers lung (PGI June 2006)
(b) Contact hypersensitivity
(c) Immediate hypersensitivity
(d) Myasthenia gravis 5 7.1. Myasthenia gravis is most commonly associated with
49. Example of Type II Hypersensitivity is/are: which of the following?
(a) Blood transfusion reaction (PGI June 2006) (a) Thymoma
(b) Arthus reaction (b) Thymic carcinoma
(c) Hay Fever (c) Thymic hyperplasia
(d) Post-streptococcal glomerulonephritis (d) Lymphoma
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57.2. Cell mediated immunity is: (c) Chronic rejection

(a) Type I (b) Type II (d) Acute humoral rejection
(c) Type III (d) Type IV
64.2. Principal cause of death in renal transplant patient is
57.3. Antibody found in patients with myasthenia gravis is (a) Uraemia
directed against (b) Malignancy
(a) Acetylcholine (c) Rejection
(b) Acetylcholine receptors (d) Infection
(c) Acetylcholine vesicles in nerve terminal
(d) Actin-myosin complex of the muscle AUTO IMMUNE AND IMMUNODEFICIENCY DISEASES
TRANSPLANT REJECTION, GVHD 65. Autoimmunity in EBV infection is the result of

(a) Molecular mimicry (AI 2012)
58. Hyperacute rejection is due to (AIIMS Nov 2012) (b) Polyclonal B cell activation
(a) Preformed antibodies (c) Expressing sequestrated antigens
(b) Cytotoxic T-lymphocyte mediated injury (d) Antigenic cross reactivity
(c) Circulating macrophage mediated injury
(d) Endothelitis caused by donor antibodies
66. A 14 yrs. old girl on exposure to cold has pallor of
extremities followed by pain and cyanosis. In later ages
59. All are affected in Graft-Versus host reaction: of life she is prone to develop? (AIIMS May 2011)
(a) Skin (AIIMS May 2007) (a) Systemic lupus eryhtematosis
(b) GIT (b) Scleroderma
(c) Liver (c) Rheumatoid arthritis
(d) Lung (d) Hisiocytosis
60. Preformed antibodies cause: (PGI June 2006) 67. Which is not autoimmune disease? (AI 2011)
(a) Hyperacute rejection (a) Systemic Lupus Erythematosis
(b) Acute rejection (b) Graves Disease
(c) Chronic rejection (c) Myasthenia Gravis
(d) Acute humoral rejection (d) Sickle Cell Disease
Immunity
61. True about graft versus host disease is: (PGI Dec 2005) 68. Which among the following is seen in antiphospholipid
(a) Associated with solid organ transplantation antibody syndrome? (AI 2011)
(b) Graft must contains immunocompetent Tcell (a) Beta 2 microglobulin antibody
(c) It is seen in immunosuppressed persons (b) Anti nuclear antibody
(d) Also called as Runt disease in animals (c) Anti centromere antibody
(d) Anti glycoprotein antibody
62. Acute humoral renal transplant rejection is characterized
by the following, except: (Delhi PG 2009 RP) 69. Necrotizing lymphadenitis is seen in (AI 2011)
(a) Presence of anti-donor antibodies (a) Kimura disease
(b) Interstitial and tubular mononuclear cell infiltrate (b) Kikuchi Fujimoto disease
(c) Necrotizing vasculitis (c) Hodgkin disease
(d) Acute cortical necrosis (d) Castelman disease
63. Transfer of the graft of different species are called as 70. Wire loop lesions are seen in: (DPG 2011)
(a) Isograft (UP 2002) (a) SLE
(b) Allograft (b) Diabetic nephropathy
(c) Homograft (c) Benign nephrosclerosis
(d) Xenograft (d) Wegeners granulomatosis
64. Acute graft versus host disease reaction occurs in all 71. Tissue from rat used for detection of antinuclear
except (UP 2007) antibodies? (AIIMS Nov 2009)
(a) Liver (b) Adrenal (a) Kidney (b) Brain
(c) Gut (d) Skin (c) Stomach (d) Liver
72. Which is not found in CNS in a case of AIDS?
Most Recent Questions (a) Perivascular giant cell (AIIMS May 2009)
(b) Vacuolization
64.1. Preformed antibodies cause: (c) Inclusion bodies
(a) Hyperacute rejection
(d) Microglial nodule
(b) Acute rejection
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Immunity
73. A person present with recurrent swelling on face and

(c) Good pastures syndrome
lips due to emotional stress. Likely cause is:
(d) Wegners granulomatosis
(a) C1 esterase inhibitor deficiency (AIIMS May 2009)
(e) Infective endocarditis.
(b) Allergy
(c) Anaphylaxis 81. Which is seen in Chediak-Higashi syndrome:
(d) None of the above (a) Leucocytosis (PGI Dec 2001)
(b) Neutropenia
74. All of the following statements are true about Wiskott (c) Defective microbial killing
Aldrich syndrome except? (AIIMS Nov 2008)
(d) Presence of large granules in neutrophil
(a) It is an autosomal recessive disorder
(b) There is failure of aggregation of platelets in response (e) Immunodeficiency
to agonists 82. Adenosine deaminase deficiency is seen in:
(c) Thrombocytopenia is seen (a) Severe combined immunodeficiency.
(d) Patient presents with eczema (b) Wiskott Aldrich Syndrome (PGI Dec 2003)
75. Hematoxylin bodies seen in: (AIIMS May 2008) (c) Agammaglobulinemia as HIV
(a) SLE 83. True about alpha-1 antitrypsin deficiency, is/are:
(b) PAN
(a) Autosomal dominant (PGI June 01)
(b) Pulmonary emphysema
(d) Wegeners granulomatosis
(c) Diastase resistant hepatic cells
76. Wire loop lesions are often characteristic for the (d) Hepatic cells are orcein stain positive
following class of lupus nephritis: (AIIMS May 2004) (e) Associated with berry aneurysm
(a) Mesangial proliferative glomerulonephritis (WHO
class II) 84. All are true regarding Hyper IgE syndrome exept:
(b) Focal proliferative glomerulonephritis (WHO class III) (Delhi PG 2009)
(c) Diffuse proliferative glomerulonephritis (WHO class (a) Inheritance is as a single locus autosomal dominant
IV) trait with variable expression
(d) Membranous glomerulonephritis (WHO class V) (b) Coarse facial features
77. A renal biopsy from a 56 year old woman with progressive (c) Recurrent staphylococcal abscesses involving skin,
Immunity
renal failure for the past 3 years shows glomerular and lungs
vascular deposition of pink amorphous material. It (d) High serum IgE with low IgG, IgA and IgM
shows apple-green birefringence under polarized light
after Congo red staining. These deposits are positive for
85. All are true about Wiskott- Aldrich Syndrome except:
(a) Bloody diarrhea during infancy (Delhi PG 2009)
lambda light chains. The person is most likely to suffer (b) Low IgM and elevated IgA and IgE
from:
(c) Large size platelets

(a) Rheumatoid arthritis (AIIMS May 2003)
(d) Atopic dermatitis

(b) Tuberculosis

(c) Systemic lupus erythematosus 86. Diagnosis of X linked Agammaglobulinemia should be

(d) Multiple myeloma suspected if: (Delhi PG 2009)
78. A young lady presented with bilateral nodular lesions (a) Absent tonsils and no palpable lymph nodes on
on shins. She was also found to have bi-lateral hilar physical examination
lymphadenopathy on chest X-ray. Mantoux test reveals (b) Female sex
indurations of 5 mms. Skin biopsy would reveal: (c) High isohemagglutinins titers

(a) Non caseating Granuloma (AIIMS May 2002) (d) Low CD3

(b) Vasculitis
87. Which of the following cell types is not a target for

(c) Caseating Granuloma
initiation and maintenance of HIV infection?

(d) Malignant cells
(a) CD4 T cell (Delhi PG 2009 RP)
79. Anti ds-DNA antibodies are commonly seen in: (b) Macrophage
(a) SLE (PGI June 01) (c) Dendritic cell
(b) Scleroderma (d) Neutrophil
(c) PAN
(d) Dermatomyositis 88. All of the following are found in SLE except:
(e) Rheumatoid arthritis (a) Oral ulcers (Delhi PG-2006)
(b) Psychosis
80. Low complement levels seen in: (PGI Dec 2006)
(c) Discoid rash
(a) PSGN
(b) MPGN (d) Leucocytosis
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89. Which of the following immunoglobulin is absent in 99. Which in not an autoimmune disease (RJ 2001)
Ataxia telangiectasia: (Delhi PG-2005) (a) Syphilis
(a) IgG (b) SLE
(b) IgM (c) Systemic sclerosis
(c) IgA (d) RA
(d) IgD 100. Bilateral parotid gland enlargement is seen in all
90. Scl-70 antibody is characteristic of except. (RJ 2001)
(a) Systemic lupus erythematosus (Karnataka 2007) (a) Sarcoidosis
(b) Scleroderma (b) Sjogrens syndrome
(c) Dermatomyositis (c) SLE
(d) Sjogrens syndrome (d) Viral infections
91. LE cell phenomenon is seen in (Karnataka 2005) 101. Sarcoidosis does not involve (RJ 2004)
(a) Lymphocyte (a) Brain
(b) Neutrophil (b) Heart
(c) Monocyte (c) Lung
(d) Eosinophil (d) Kidney
92. Most sensitive test for screening of Systemic Lupus 102. Characteristic of SLE of kidney is( RJ 2004, Jharkhand 05)
Erythematosus (SLE) is (Karnataka 2005, RJ 2002) (a) Focal sclerosis
(a) LE phenomenon (b) Focal necrosis
(b) Rheumatoid factor (c) Wire loop lesions
(c) Anti nuclear factor (ANF) (d) Diffuse glomerulosclerosis
(d) Double stranded DNA test 103. Libman-Sacks endocarditis is seen in (AP 2001)
93. According to WHO, the feature of class II lupus is (a) Rheumatoid arthritis
(a) Transient proteinuria (UP 2000) (b) SLE
(b) Massive proteinuria (c) Infective endocarditis
(c) Hematuria (d) Nonbacterial thrombotic endocarditis
(d) RBC casts 104. Chediak-Higashi syndrome is due to defect in:
Immunity
94. ANCA antibody with peripheral rim distribution is (a) Opsonisation (Kolkata 2003)
indicative of (UP 2000) (b) Chemotaxis
(a) Antihistone antibody (c) LAD
(b) Anti smith antibody (d) Extracellular microbicidal killing
(c) Anti double stranded DNA antibody 105. Anti-double stranded DNA is highly specific for:
(d) Anti double stranded RNA antibody (a) Systemic sclerosis (Bihar 2004)
95. Basic pathology in cystic fibrosis is (UP 2001) (b) SLE
(a) Defect in the transport of chloride across epithelia (c) Polymyositis
(b) Defect in the transport of sodium across epithelia (d) Rheumatic sclerosis
(c) Defect in the transport of potassium across epithelia 106. Anti-topoisomerase I is marker of: (Bihar 2004)
(d) Defect in the transport of bicarbonate across epithelia (a) Systemic sclerosis
96. Besbuer Boeck Schaumann disease is also called as (b) Classic polyarteritis nodosa
(a) Sarcoidosis (UP 2003) (c) Nephrotic syndrome
(b) Crohns disease (d) Rheumatoid arthritis
(c) Whipples disease 107. An 8-year-old boy presents with sarcoidosis. Which of
(d) Hodgkins disease the following is correct? (Bihar 2005)
97. Most common viral antigen used for diagnosis of HIV (a) Hilar lymphadenopathy with perihilar calcification
in blood before transfusion is (UP 2005) (b) Basal infiltrates
(a) p24 (b) p17 (c) Rubbery lymph nodes
(c) p7 (d) p14 (d) Egg-shell-calcification
98. Most common vascular tumor in AIDS patients is 108. Most common site for lymphoma in AIDS patients is
(a) Kaposi s sarcoma (UP 2000) (UP 2007) (a) CNS (Jharkhand 2004, 05)
(b) Angiosarcoma (b) Spleen
(c) Lymphangioma (c) Thymus
(d) Lymphoma (d) Abdomen
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Immunity
109. All are true about histological features of Kaposis 115. A 7-month-old baby boy Guddu is evaluated because of
sarcoma except: (Jharkhand 2005) repeated episodes of pneumococcal pneumonia. Serum
(a) Microscopically lesion similar to granulation tissue studies demonstrate very low levels of IgM, IgG, and
(b) Dilated and irregular blood vessels with interspersed IgA. This patients condition is thought to be related to
infiltrate of lymphocyte and plasma cells a deficiency of which of the following proteins?
(c) Atypical blood vessels have solid spindle cell (a) Adenosine deaminase
appearance (b) Class III MHC gene
(d) Nodule is the initial lesion of Kaposis sarcoma (c) Gamma chain of the IL-2 receptor
(d) Tyrosine kinase
110. HIV affects which of the following most commonly?
(a) Helper cells (Jharkhand 2006) 116. A patient with systemic lupus erythematosus very much
(b) Suppressor cell wants to become pregnant. What should her physician
(c) RBCs tell her regarding pregnancy in lupus patients?
(d) Platelets (a) There is no increased risk to the baby.
(b) There may be an increase in cardiovascular
111. Which of the following lesions/conditions shows most malformations
specific anatomic changes in HIV infection?
(c) There may be an increase in nervous system
(a) Lymph nodes
malformations.
(b) Opportunistic infections
(d) There may be an increase in spontaneous abortions
(c) CNS lesions
and prematurity
(d) Kaposis sarcoma (blood vessels)
112. A 21-year-old female Pallavi Kumari comes to the 117. and A woman Kamlesh with swelling of the oral mucosa
dry mouth is found to have intense destructive
physician because of migratory arthralgia and a skin
inflammation of the salivary glands and antibodies
rash that is exacerbated by sun exposure. Her urinalysis
against the ribonucleoprotein La. Which of the
shows moderate proteinuria and red blood cell casts.
following clinical findings would most likely be
Serum auto-antibodies with high specificity for this
associated with this syndrome?
patients condition react with

(a) Mitochondrial extract

(a) Conjunctivitis

(b) Fc portion of human lgG

(b) Goiter

(c) Centromere

(c) Hemolytic anemia
Immunity

(d) Double stranded DNA

(d) Proximal muscle weakness
113. A 50-year-old woman, Seeta presents with dry eyes, 118. aA biopsy
female being diagnosed with SLE has undergone
of butterfly rash. Which is most likely to
a dry mouth, and difficulty swallowing solid food.
Physical examination finds enlargement of her parotid demonstrate which of the following?
glands along with marked dryness of her buccal
(a) Fibroblastic-like cells in a storiform pattern
mucosa. Laboratory examination finds the presence of
(b) Granular complement and IgG at the dermal-
both SS-A and SS-B anti bodies. A biopsy of her lip is epidermal junction
likely to show infiltration of minor salivary glands by
(c) Sawtooth dermal/epidermal junction
what type of inflammatory cell?
(d) Pautrier microabscesses

(a) Basophil 119. A terminally ill HIV infected patient develops focal

(b) Eosinophil neurologic signs, dementia, and coma. Amoebic

(c) Epithelioid cell parasites are demonstrated in CSF. Which of the

(d) Lymphocyte
following organisms is most likely to be the causative

(e) Neutrophil
agent?
114. A 16-year-old boy, Raju is being evaluated for failure
(a) Acanthamoeba sp.
to have a growth spurt and the recent development of
(b) Entamoeba histolytica
signs of premature aging. Physical examination finds
(c) Giardia lamblia
the boy to be short with thin skin and muscle autopsy.
(d) Naegleria fowleri
The skin of his face is wrinkled and his lips appear
A 21-year-old male Rohan presents with complaints
atrophic. In the last year, he also has developed bilateral 120.
cataracts and early signs of osteoporosis. None of these of dull lower back pain and morning stiffness. There
signs were present in his first decade of life. Which of is tenderness over the costosternal junctions, spinous
the following is the most likely diagnosis? processes of the vertebrae, and the iliac crests. Which

(a) DiGeorges syndrome of the following tests be helpful in establishing a

(b) Hutchinson-Gilford syndrome diagnosis of ankylosing spondylitis?

(c) Leukocyte adhesion deficiency
(a) serum IgA

(d) Werner syndrome
(b) Erythrocyte sedimentation rate
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(c) HLA typing 121.8. Following is not a feature of AIDS related

(d) Serum alkaline phosphatase lymphadenopathy:
(a) Florid reactive hyperplasia
121. A 27-year-old man Alok Kumar with AIDS develops (b) Follicle lysis
a reddish, slightly raised rash on his face, neck,
(c) Haematoxylin bodies
and mouth, consistent in appearance with Kaposis
(d) Collection of monocytoid B Cells in sinuses
sarcoma. Microscopically, the proliferating cells in
this malignancy most closely resemble which of the 121.9. A false negative tuberculin reaction may be obtained
following? in all of the following situations EXCEPT:

(a) Angiosarcoma (a) Children previously tested with tuberculin test

(b) Carcinosarcoma (b) Post measles test

(c) Lymphoma (c) Corticosteroid therapy

(d) Malignant fibrous histiocytoma (d) Miliary tuberculosis

121.10. Risk of HIV transmission is not seen with
(a) Whole blood
121.1. Which of the following autoantibody is specific for (b) Platelets
SLE? (c) Plasma derived Hepatitis B vaccine
(a) ds DNA (b) Anti RO (d) Leucocytes
(c) Anticentromere (d) Anti topoisomerase 121.11. All of the following methods are used for the diagnosis
1 21.2. Which of the following autoantibody isleast likely of HIV infection in a 2months old child, except
associated with SLE? (a) DNA PCR (b) Viral culture
(a) Anti ds DNA (c) HIV ELISA (d) P 24 antigen assay
(b) Anti Sm 121.12. Mantoux test reading of less than 5 mm indicates:
(c) Anti topoisomerase (a) Tuberculous infections
(d) Anti histone
(b) Disseminated TB
1 21.3. Most common CNS neoplasm in HIV patient is: (c) Susceptibility to TB
(a) Meduloblastoma (d) Immunity to TB
(b) Astrocytoma
Immunity
1 21.13. The poly-arthritic condition that is NOT common in

(c) Primary CNS Iymphoma
males
(d) Ependymoma
(a) Gout
121.4. Regarding severe combined immunodeficiency disease, (b) Psoriatic arthritis
which of the following statement is true? (c) Ankylosing spondylitis
(a) Adenosine deaminase deficiency (d) Systemic lupus erythematosus
(b) Decreased circulating lymphocytes
(c) NADPH oxidase deficiency 121.14. Epitope spreading refers to
(d) C1 esterase deficiency (a) A type of mechanism of spread of malignant tumors
(b) One type of mechanism of HIV dissemination
1 21.5. Which of the following is a finding in lymphoid (c) A mechanism for the persistence and evolution of
tissues in individuals with common variable autoimmune disease
hypogammaglobulinemia? (d) One of the mechanisms of apoptosis

(a) Decreased B cell count

(b) Increased B cell count 121.15. Heerfordts syndrome consists of fever, parotid

(c) Normal B cell count enlargement, facial palsy and

(d) Absent B cells (a) Arthralgia
(b) Bilateral hilar adenopathy
121.6. Thymic hypoplasia is seen in which of the following? (c) Erythema nodosum
(a) Wiskott-Aldrich syndrome
(b) Digeorge syndrome (d) Anterior uveitis
(c) IgA deficiency 1 21.16. HIV affects CD4 cells by which protein
(d) Agammaglobulinemia (a) Gp 120 (b) Gp 41
121.7. Onion peel appearance of splenic capsule is seen in: (c) CCR5 (d) CXCR4
(a) SLE 121.17. Treatment for Asymptomatic HIV is done when CD4
(b) Scleroderma count is below
(c) Rheumatoid arthritis (a) 200 (b) 350
(d) Sjogren syndrome (c) 400 (d) 500
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Immunity
121.18 Hodgkins lymphoma caused for by 131. Which one of the following stains is specific for
(a) EBV (b) CMV Amyloid? (AI 2005)
(c) HHV6 (d) HHV8 (a) Periodic Acid Schiff (PAS)
(b) Alizarin red
AMYLOIDOSIS (c) Congo red
(d) Von-Kossa
122. Secondary amyloidosis is associated with (AI 2012) 132. In amyloidosis Beta pleated sheet will be seen in:
(a) Ab (b) AL (a) X-ray crystallography (AIIMS Nov 2006)
(c) AA (d) APrP (b) Electron microscope
123. A 60 year old female is suffering from renal failure and (c) Spiral electron microscope
is on hemodialysis since last 8 years. She developed (d) Congo red stain
carpal tunnel syndrome. Which of the following finding 133. A 50-year-old presented with signs and symptoms
will be associated? (AIIMS Nov 2011) of restrictive heart disease. A right ventricular endo-

(a) AL
(b) AA myocardial biopsy revealed deposition of extracellular

(c) ATTR
(d) 2 microglobulin eosinophilic hyaline material. On transmission
124. The best investigation for the diagnosis of amyloidosis electron microscopy, this material is most likely to

is (AIIMS May 2010) reveal the presence of: (AIIMS May 2006)
(a) Colonoscopy
(a) Non branching filaments of indefinite length
(b) Rectal biopsy
(b) Cross banded fibers with 67 m periodicity
(c) Upper GI endoscopy
(c) Weibel Palade bodies
(d) CT scan
(d) Concentric whorls of lamellar structures
125. Which type of amyloidosis is caused by mutations in 134. Amyloid deposits stain positively with all of the
transthyretin gene? (DPG 2011, AI 2005) following EXCEPT: (AIIMS May 2006)
(a) Familial Mediterranean fever (a) Congo-red
(b) Familial amyloidosis polyneuropathy (b) Crystal violet
(c) Dialysis associated amyloidosis (c) Methanamine silver
(d) Prion protein associated amyloidosis (d) Thioflavin T
Immunity
126. In Hemodialysis associated amyloidosis, which of the 135. On electron microscopy amyloid characteristically
following is seen: (AI 2008) exhibits: (AIIMS Nov 2005)
(a) Transthyretin (a) Beta-pleated sheat
(b) b2 Microglobulin (b) Hyaline globules
(c) SAA (c) 7.5-10 nm fibrils
(c) a2 Microglobulin (d) 20-25 nm fibrils
127. Bone marrow in AL amyloidosis shows: 136. Familial amyloidotic polyneuropathy is due to
(a) Bone marrow plasmacytosis (AI 2007)
amyloidosis of nerves caused by deposition of:
(b) Granulomatous reaction
(a) Amyloid associated protein (AIIMS Nov 2002)
(c) Fibrosis
(b) Mutant calcitonin
(d) Giant cell formation
(c) Mutant transthyretin
128. A diabetic patient is undergoing dialysis. Aspiration (d) Normal transthyretin
done around the knee joint would show:
(a) A beta 2 microglobulin (AI 2007) 137. Lardaceous spleen is due to deposition of amyloid in:
(b) AA (a) Sinusoids of red pulp (AIIMS Nov 2002)
(c) AL (b) White pulp
(d) Lactoferin (c) Pencillary artery
(d) Splenic trabeculae
129. What is the best method for confirming amyloidosis?
(a) Colonoscopy (AI 2007) 138. What are the stains used for Amyloid? (PGI Dec 2007)
(b) Sigmoidoscopy (a) Thioflavin (b) Congo red
(c) Rectal biopsy (c) Eosin (d) Auramine
(d) Tongue biopsy (e) Rhodamine
130. Neointimal hyperplasia causes vascular graft failure as 139. Gingival biopsy is useful in the diagnosis of:
a result of hypertrophy of: (AI 2006) (a) Sarcoidosis (Delhi PG 2010)
(a) Endothelial cells (b) Amyloidosis
(b) Collagen fibers (c) Histoplasmosis
(c) Smooth muscle cells (d) Scurvy
(d) Elastic fibers
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140. Amyloid is (UP 2000) 145.2. A diabetic patient is undergoing dialysis. Aspiration
(a) Mucopolysaccharide done around the knee joint would show:
(b) Lipoprotein (a) A-2 Microglobulin
(c) Glycoprotein (b) AA
(d) Intermediate filament (c) AL
141. Serum amyloid associated protein is found in (d) Lactoferrin
(a) Alzheimers disease (UP 2007)
(b) Chronic inflammatory states
145.3. Amyloidosis is most commonly seen in:
(a) Maturity onset DM
(c) Chronic renal failure
(d) Malignant hypertension (b) Type 1 DM
(c) Type 2 DM
142. Most common site of biopsy in amyloidosis (RJ 2002) (d) Equally seen with all forms of DM
(a) Liver
(b) Spleen 145.4. Which of the following is the most serious organ
(c) Kidney involvement in amyloidosis?
(d) Lung (a) Cardiac tissue
143. T-lymphocytes from a 6-year-old female Ramya with (b) Renal tissue
severe recurrent respiratory infections are found to lack (c) Splenic tissue
the IL-12 receptor. Supplementation with which of the (d) Hepatic tissue
following substances would be most helpful in treating 1 45.5. Which type of Amyloidosis is caused by mutation of
this patients disease?
the transthyretin protein?
(a) Immunoglobulins
(a) Familial Mediterranean fever
(b) Interferon-g (IFN-g)
(c) Interleukin-2 (IL-2) (b) Familial amyloidotic polyneuropathy
(d) GM-CSF (c) Dialysis associated amyloidosis
(d) Prion protein associated amyloidosis
144. A 43-year-old women Kanata Devi presents with a
several year history of progressive abdominal colic 1 45.6. Cause of death in amyloidosis involving kidney:
and constipation. Colonic biopsy stained with Congo (a) Cardiac failure
Immunity
red reveals the acellular material exhibiting green (b) Renal failure
birefringence. The birefringence is thought to be (c) Sepsis
most closely related to which of the following protein (d) Liver failure
properties?
(a) Ability to bind to oxygen 1 45.7. Secondary amyloidosis complicates which of the
(b) Beta-pleated sheet tertiary structure following:
(c) Electrophoretic mobility (a) Pneumonia
(d) Hydroxyproline content (b) Chronic glomerulonephritis
(c) Irritable bowel syndrome
145. Correctly matched pairs in amyloidosis are: (d) Chronic osteomyelitis
(a) Multiple myeloma - light chain (PGI June 2006)
(b) Chronic inflammation - AA 145.8. On Congo- red staining, amyloid is seen as:
(c) Cardiac - ATTR (a) Dark brown color
(d) Neural Beta-2 microglobulin (b) Blue color
(c) Brilliant pink color
(d) Khaki color
1 45.1. Which of the following is the chemical nature of 1 45.9. Lardaceous spleen is due to deposition of amyloid in:
Hemodialysis associated with amyloid? (a) Sinusoids of red pulp
(a) AA (b) White pulp
(b) AL
(c) Pencillary artery
(c) Beta 2-microglobulin
(d) Splenic trabeculae
(d) ATTR
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Immunity
EXPLANATIONS
1. Ans. (c) Positive selection during development (Ref: Immunology by SK Gupta 1st/142-150, Robbins 8th/209)
This appeared to be a tough question but let us analyze all the options step wise.
Both B cells and T cells have antigen specific receptors. T cells have an antigen specific T cell receptor (TCR) composed
of a and b polypeptide chains in 95% cases to bind with the antigen. B cells have a B cell receptor (BCR) having unique
antigen specificity composed of IgM and IgD on their surface to bind with the antigen.
Since MHC I is expressed on all the nucleated cells, so, it is likely to be present on both B as well as T cells.
As discussed in our accompanying DVD on Immunology, the T cells undergo both negative and positive selection. Both
these are described below:
Positive selection: T cells in the thymic cortex are allowed to survive only if their T cell receptor has affinity for the
MHC molecule. If the T cells do not have any affinity for the MHC molecule, they are programmed to die. This is
important because only if this affinity is present, the T cells can interact with the antigen presenting cells. So, positive
selection is required for self MHC restriction.
Negative selection: T cells come in the thymic medulla after being already positively selected in the thymic cortex.
In the medulla, if a T cell has affinity for self antigens, they are eliminated. This is called as negative selection. It is
therefore required for the self tolerance.
Similar to the negative selection of the T cells, the B cells may also recognize self antigens in the bone marrow. In this
Immunity
situation, the B cell undergoes antigen receptor gene rearrangement so as to express new antigen receptors. These
new receptors are designed as to not recognize self antigens. This process is described as receptor editing. If be-
cause of any reason receptor editing does not take place, the B cells undergo apoptosis. This is the negative selection
of B cells in the bone marrow.
Thus, it can be concluded that both T and B cells undergo negative selection but only the T cells undergo positive selection.
2. Ans. (c) None (Ref: Robbins 8th/194-5, 9/e 198)

It is recommended to go through the chapter review for the best understanding of this question. However, I would try to
summarize the important points as follows;
Option a and d.CD4 is present on helper T cell and is required for antibody production because it is interacts with B
cells for causing activation, conversion into plasma cells and antibody production. The antibody IgG is required for op-
sonisation (making the bacteria coated for preferential killing).
Option b.Helper T cell subtype 1 is responsible for the secretion of cytokines like IFN- and IL-2 which cause nave T
cells to get converted into cytotoxic T cells.
Option c.CD 4 is also important for the following:
B cell mitogenQ
Required for isotype switchingQ.
Affinity maturationQ
Presence of memory in immune cellsQ
So, the answer is none in this question.
3. Ans. (b) Distal domain alfa 1 and 2 (Ref: Robbins 8th/190-191, 9/e 195 see the adjoining diagram below)
The antigen binding cleft is made up a and a chains of MHC I molecule which is structurally the distal domain of these
1 2
chains.Kuby immunology.
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The antigen binding cleft is made up 1and 2Q

chains of MHC I molecule which is structurally
the distal domain of these chains.
The antigen binding cleft is made up distal and

chainsQ (1 and 1chains) of MHC II molecule.
4. Ans. (b) Immunoglobulin production (Ref: Robbins 8th/186-187, 9/e 190-191)

On antigenic stimulation, the nave helper T cells get differentiated into either effector cells or memory cells. The T
helper cells can be of two types (either TH1 or TH2 cells).
The TH1 cells can secrete cytokines like IL-2 and IFN- which cause activation of macrophages and cause activation
of CD8+T cells into cytotoxic T cells.
The TH2 cell can secrete IL-4 and IL-5 which cause B cell proliferation and differentiation into plasma cells which
secrete antibodies or immunoglobulins.
So, we need to understand that the helper T cells is only helping in the production of immunoglobulins by plasma
cells (they themselves dont produce antibodies).
5. Ans. (B) Binds to the beta chain of TCR and MHC class II molecules of APC stimulating T cell activation (Ref: Harrison
Immunity
16th/1920)
Concept of superantigen
*A superantigen, such as staphylococcal enterotoxin,
cross-links the variable domain of the TCR beta chain
to the MHC class II molecule and specifically induces
massive T cell activation. (choice B)
*The superantigen does not bind the B7 and CD28
co-stimulatory molecules (choice A). Instead, the
costimulatory molecules bind to each other to stimulate
the reaction between the antigen-presenting cell and T
cell.
*The superantigen does not bind the CD 4 molecules
(choice C) but instead binds on the other side of the
TCR receptor complex.
*The term superantigen has nothing to do with the
antigen being presented by macrophages to T cells
(choice D).
6. Ans. (d) CD 45 RO (Ref: Harrison 17th/2021)

CD 45 is called as Leukocyte common antigen (LCA) Q
Location of cell Molecular marker

All leucocytes CD45 and CD45RB
Medullary thymocytes (Naive T- cells) CD45 RA and CD45RC
Cortical thymocytes (Memory T-cells) CD45RO
7. Ans. (c) They are MHC restricted cytotoxic cells (Ref: Harrisons 17th/2024-2028, 9/e 192)
NK cells are also called Large granular lymphocytes as they are morphologically larger than both T and B lymphocytes and
contain azurophillic granules (which are absent in both T and B lymphocytes).
218
Immunity
They constitute 5-10% of peripheral blood lymphocytes. These cells express CD16 and CD 56:
CD16 : Surface receptors for Fc portion of IgG
Q
CD56 : Surface receptors for NCAM 1

Q
*NK cells are unique as they are capable of MHC unrestricted direct cell lysis which is not mediated by an immune
Q
response Q
8. Ans. (c) Effective against virus infected cells (Ref: Harrison 17th/2024 2028, 9/e 192)
NK cell activity is non-immune (i.e. effector cells never having had previous contact with the target), MHC unre-
stricted, non-antibody mediated killing of target cells usually malignant cells, transplanted foreign cells or virus-
infected cells.
Cytotoxic T-cells function is to produce antigen specific lysis of target cells (usually virus infected cells and cancer
cells) by direct cell-to-cell contact.
The common feature to both cytotoxic T-cells and NK cells is effectivity against virus-infected cells.
The difference is however that cytotoxic T-cell is MHC- I restricted while NK cell is MHC unrestricted.
9. Ans. (D) Graft rejection (Ref: Robbins 8th/226-230, 9/e 231-233)
CD8+ cytotoxic T lymphocytes (CTLs) recognize cell-bound antigens only in association with class I MHC molecules,
so, CD8+ T cells are said to be class I MHC-restricted.
CD4+ T cells can recognize antigens only in the context of self-class II MHC molecules; they are referred to as class II
MHC-restricted.
So, killing of viruses by cytotoxic cells, killing of bacteria by helper cells and T cell activation in autoimmunity all
require MHC molecules for their normal function.
Talking now about option D i.e. graft rejection;
Rejection is a complex process in which both cell-mediated immunity and circulating antibodies play a role. T cell-mediated graft re-
jection is called cellular rejection, and it is induced by two mechanisms: destruction of graft cells by CD8+ CTLs and delayed
hypersensitivity reactions triggered by activated CD4+ helper cells. Both these as discussed above would require MHC
molecules.
Antibodies evoked against alloantigens in the graft can also mediate rejection. This process is called humoral rejection. It can
Immunity
be of two types

1. Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient

2. In recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens of
the donor may evoke antibodies which are usually formed against graft vasculature. So, in this type of graft rejection,
T cells are not required and so, it becomes the answer here.
10. Ans. (a) Mature Dendritic Cell (Ref: Robbins 7th/199, 8th/187, 9/e 191)
11. Ans. (b) Cells which are not able to express MHC I (Ref: Robbins 7th/201, 8th/188, 9/e 192)
The NK cells express activating and inhibitory receptors. The functional activity of the NK cells is regulated by a
balance between signals from these receptors. Normal cells are not killed because inhibitory signals from normal
MHC class I molecules override activating signals. The ability of NK cells to kill target cells is inversely related to
target cell expression of MHC class I moleculesQ. If virus infection or neoplastic transformation disturbs or reduces
the expression of class I MHC molecules, inhibitory signals delivered to NK cells are interrupted and lysis occurs.
12. Ans. (c) Transcription of nuclear factor mediated by NF- which recruits cytokines (Ref: Robbins 7th/195, 9/e 187)
The Toll-like receptors are membrane proteins that recognize a variety of microbe-derived molecules and stimulate
innate immune responses against the microbes. These derive there name due to homology to a Drosophila protein called
Toll. The Toll-like receptors are expressed on many immune cells of the body. Signaling by Toll-like receptors results in the
activation of transcription factors, notably NF-B and AP-1.
13. Ans. (a) IL-2 (Ref: Robbins 7th/198, 8th/195, 9/e 198)
T-helper cells can be divided in three distinct types on the basis of different cytokines they produce.
T-helper 1 (TH1) secretes: IL-2 and interferon , these cells are important for type IV hypersensitivity
T-helper 2 (TH2) secretes: IL-4, IL-5, these cells are important for type I hypersensitivity reaction.
TH 17 Cells: Secrete IL-17, IL-22, these cells provide defense against extracellular bacteria and fungi.
14. Ans. (a) Apoptosis (Ref: Robbins 8th/29, 7th/29, 9/e 56)
15. Ans. (b) Interleukin IL 8 (Ref: Robbins 8th/62, 7th/71-72, 9/e 87)
16. Ans. (b) IgM (Ref: Harrison, 17th/2036)
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17. Ans. (b) endothelial cells (c) epithelial cells and (d) Langerhans cells (Ref: Robbins Illustrated 7th/204, 9/e 195)
As already discussed in the text also, the antigen presenting cells include macrophages, Dendritic Cells (found in lymphoid
organs) and Langerhans cells (found in epidermis). The question ideally should have been with all except
18. Ans. (a) Langerhans cell; (b) Macrophages; (e) B-lymphocyte (Ref: Robbins 7th/197, 9/e 195)
Antigen presenting cells are:
B-cell
Langerhans cell in skin
Macrophages
19. Ans. (a) Cytotoxic T cells: (Ref: Robbins 7th-218, 8th/208, 9/e p210)
Perforins are hole forming proteins synthesized by cytotoxic T-cells. They can perforate the plasma membrane of the
target cells that are under attack by CD8+ lymphocytes. Granzymes are delivered into the target cells through these
holes formed by perforins. In addition the perforin pores allow water to enter the cells, thus causing osmotic lysis.
20. Ans. (a) B7 and CD28; (Ref: Robbins 7th/225, Harrison 16th/1907, 9/e p213)
Immunological tolerance is a state in which the individual is incapable of developing an immune response to a specific
antigen. It is of two types:
Central: deletion or negative selection of self reactive cell clones during their maturation in bone marrow and thymus.
Peripheral: In peripheral lymphoid organs.
CD28 molecules (co-stimulatory molecule) are constitutively expressed on certain T-cells. These co-stimulatory molecules
bind to their ligands-CD80 (B7-l) and/or CD86 (B7-2) and get activated and deliver upregulating function of T-cell thereby
preventing tolerance and enhancing CD40L expression. If the antigen presented by cell do not bear CD28 ligand, a negative
signal is delivered and cell become tolerant and anergic.
Thus the balance of co-stimulatory signal affects immune homeostasis and self-tolerance
Other mechanism of peripheral tolerance:
Clonal deletion by activation induced cell death (via Fas and Fas L)
Peripheral suppression by regulatory T-cells.
21. Ans. (c) CD19; (d) CD20; (e) CD22 (Ref: Immunology by Roitt, 6th/29, 30, 19 9/e p191)
Immunity
CD19, 20 and 22 are main markers of human B cells. Other B cell markers are CD72 to CD78.
CD33: present in monocyte.
CD34: marker of hematopoetic stem cell
22. Ans. (d) All of the above (Ref: Robbins 7th/71, 9/e p87)
23. Ans. (a) Langerhans cells (Ref: Robbins 7th/1228, 9/e p192)
24. Ans. (b) Helps in the formation of antibody (Ref: Robbins 8th/183-184; 7th/82 , 9/e p191)
25. Ans. (b) 2: 1 (Ref: Robbins 8th/186; 7th/197, 9/e p190-191)
26. Ans. (c) T cells (Ref: Robbins 8th/192, 7th/204, 9/e p191)
27. Ans. (b) T cell (Ref: Robbins 7th/670 , 9/e p191)
28. Ans (c) Memory is seen (Ref: Robbins 8th/184, 9/e p186-188)
Innate immunity Adaptive/Acquired immunity
Present from birthQ AcquiredQ in nature
First line of defenseQ Second lineQ of defense
No prior exposure to antigenQ Prior exposure to antigen is presentQ
Non-specificQ SpecificQ
No memoryQ is seen MemoryQ is seen
29. Ans. (d) Toll like receptor (Ref: Robbins 7th/, 57- 60, 194-196, 9/e p187-188)
Toll-like receptors (TLRs), stimulate one of the immune responses directed against microbes,
TLRs bind to pathogen-associated molecular patterns (PAMPs), which are small molecular sequences found commonly
on pathogens.
Examples of PAMPs include bacterial lipopolysaccharide (LPS), lipoteichoic acid, and peptidoglycan.
LPS is probably the prototypical PAMPQ.
TLRs, in conjunction with CD14, bind to LPS (endotoxin), and activate leukocytes to produce cytokines and reactive
leukocytes to produce cytokines and reactive oxygen intermediates (ROIs).
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Immunity
29.1. Ans. (a)16 (Ref: Robbins 8/e p188, 9/e p192)

Natural Killer cell is identified with the molecules as CD16 and CD56 . Q
CD16 is an Fc receptor for IgG, and it confers on NK cells the ability to lyse IgG-coated target cells. This phenomenon
is known asantibody-dependent cell-mediated cytotoxicity (ADCC) .Q
2 9.2. Ans. (c) NK cells (Ref: Robbins 8/e p188, 9/e p192)
The NK cells are also known as large granular lymphocytes as they have a larger size and contain abundant azurophilic
granules.
NK cells are endowed with the ability to kill a variety of infected and tumor cells, without prior exposure to or ac-
tivation by these microbes or tumors.
2 9.3. Ans. (b) CD 16, CD 56explained earlier (Ref: Robbins 9/e p192)
2 9.4. Ans. (a) T-cells (Ref: Robbins 8/e p186, 9/e p191)
The CD molecules presenton T cells are CD1, CD2, CD3, CD4, CD5, CD7, CD8 and CD28.The T cell having CD4 mol-
ecule is called CD4+ T cell or the Helper T cellQand that having CD8 molecule is called as CD8+ T cell or Cytotoxic/
Killer T cellQ.
B cell associated markers are CD10 (CALLA), CD19 (pan B cell markerQ), CD20, CD21 (EBV receptorQ), CD22, CD23.
29.5. Ans. (a) IL-2 (Ref: Robbins 8/e p195, 9/e p198)
Immunity
After coming in contact with antigen presenting cells, CD4+ helper T cells secrete IL-2 and expresses high-affinity recep-
tors for IL-2. IL-2 is a growth factor that acts on these T lymphocytes and stimulates their proliferation, leading to an
increase in the number of antigen-specific lymphocytes.
2 9.6. Ans. (a)Mature dentritic cells (Ref: Robbins 8/e p187, 9/e p191)
Direct quote.. interdigitating dendritic cells, or just dendritic cells are the most important antigen-presenting cells (APCs) for
initiating primary T-cell responses against protein antigens
2 9.7. Ans. (a) B cells (Ref: Robbins 8/e p187, 7/e p198-199, 9/e p191)
Macroglobulin is the other name for antibodies. So, the answer becomes obvious. i.e. B cells. The activated B cells are called
as plasma cells and are responsible for secretion of antibodies.
2 9.8. Ans. (c) Liverrefer to text for details (Ref: Robbins 8/e p834, 7/e p79, 9/e p102)
2 9.9. Ans. (b) Langerhans cell (Ref: Robbins 9/e p622)
29.10. Ans. (d) IgE... see text table for details
30. Ans. (b) Tumor necrosis factor (Ref: Ananthanarayan 6th/121, Harrison 17th/2047, 9/e p194-195)
*HLA class III contains genes for
Complement components C and C of classical pathway (Not C )
2 4
Q
3
Q
Properdin factor B of alternate pathway

Q
Tumor necrosis factor : Alpha and Beta

Q
Heat shock protein 70 Q
Enzyme tyrosine hydroxylase Q
Genes for MHC (also known as HLA) are located on short arm of chromosome 6 . Q
31. Ans. (b) Governing susceptibility to autoimmune disease (Ref: Ananthanarayan 6th/108, Roilts Essential Immunology
262, Robbins 9/e p215)
*HLA class III region contains genes for early complement components C and C of classical pathway.
2 4
*Deficiency of these early components of the classical pathway viz C , C and C is associated with autoimmune diseases
1 2 4
like SLE and other collagen vascular diseases.
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These genes are thus, important in regulating susceptibility to autoimmune disease

Class III genes do not participate in MHC restriction or graft rejection components.
32. Ans. (c) Short arm of chromosome 6 (Ref: Robbins 8th/190, 7th/203, 9/e p194)
33. Ans. (a) Ankylosing spondylitis (Ref: Robbins 8th/193, Harrison 17th/2051, 9/e p215)
34. Ans. (b) MHC class II antigen (Ref: Harrison 16th/1933, 17th/2047, 9/e p194)
The MHC class II region was originally termed the D-region. The allelic gene products were first detected by their
ability to stimulate lymphocyte proliferation by mixed lymphocyte reaction. So, mixed lymphocyte culture is used
to identify HLA II. It is present on all antigen presenting cells (B cells, dendritic cells and macrophages) and can be
induced on endothelial cells and fibroblasts.
35. Ans. (a) Disputed paternity, (c) Organ transplantation (Ref: Robbins, 9/e p195, 215)
Uses of MHC/HLA typing
Anthropology Transfusion
Paternity Testing Forensic science
Transplantation Disease Correlation
36. Ans. (a) Not involved in innate immunity; (c) Present in nucleated cells; (d) Present in B-cells (Ref: Robbins 7th/203, 9/eP194-195)
Class II MHC Proteins are glycoprotein present on the surface of certain cells including macrophages, B-lympho-
cytes, dendritic cells of the spleen and Langerhans cells of the skin.
Endothelial cells and fibroblasts can be induced to express Class II MHC by IFN-g.
37. Ans. (b) T cells, (d) Platelets; (e) RBCs (Ref: Ananthanarayan 7th/130, Robbins 7th/203, 9/e p194)
38. Ans. (a) Transplantation reaction; (b) Autoimmune disease; (d) Involved in T-cell function (Ref: Harrison 16th-1930,
1934; Robbins 7th-204-205)
The principal physiologic function of Major histocompatibility complex (MHC) is to bind peptide fragments of foreign
proteins for presentation to appropriate antigen specific T-cells. Thus MHC is involved in transplantation reaction, disease
susceptibility (i.e. autoimmune disease, inflammatory disease, infections, etc.), immune response and tolerance.
Immunity
39. Ans. (a) Alpha helices and (c) Alpha and beta1 chain (Ref: Robbins 7th/203-204, 9/e p195)
Friends, the examiner should have specified the type of MHC molecule so that question becomes clear.
a1 and a2 domains form a cleft/groove where the peptides bind to MHC I molecule.
The antigen binding cleft in MHC II is formed by an interaction of a1 and b1 domains of both chains.
3 9.1. Ans. (c) RBCs (Ref: Robbins 8/e p190, 9/e p194)
Class I MHC molecules are expressed on all nucleated cells and platelets
Q Q
3 9.2. Ans. (c) Rheumatoid arthritis (Ref: Robbins 8/e p193, 9/e p215)
HLA B27 is associated with Seronegative spondyloarthropathies. Please revise the following important features about
these.
Seronegative spondyloarthropathies (Mnemonic: PAIR) Salient features of these diseases
P: Psoriatic arthritis * Absence of serum auto-antibodies
A: Ankylosing spondylitis (AS) * Associated with HLA B27 (MC AS)
I: Inflammatory bowel disease arthritis * Onset before the age of 40 years
R: Reactive arthritis (Reiter syndrome) * Presence of uveitis, spine/large peripheral joint arthritis
3 9.3. Ans. (c) Present antigens for recognition by T cell antigen receptors (Ref: Robbin 8/e p191)
The physiologic function of MHC molecules is to display peptide fragments of proteins for recognition by antigen-specific T cells....
(Ref: Robbin 8/e p190)
Also now that:
Class I MHC molecules are required to display antigens to CD8 T cells
Class II MHC molecules are required to display antigens to CD4 T cells.
39.4. Ans. (b) CD4 cell (Ref: Robbins 9/e p195)
39.5. Ans. (d) All blood cells except erythrocytes (Ref: Robbins 9/e p194)
40. Ans. (b) Type 2 hypersensitivity reaction (Ref: Robbins 8th/203, 9/e p206)
Myasthenia gravis is a type 2 hypersensitivity reaction. Other important examples can be remembered from the mnemonic
My blood group is R h positive. For details see text.
222
Immunity
41. Ans. (b) Type 2 hypersensitivity reaction (Ref: Robbins 7th/211, 9/e p206)
42. Ans. (b) Immune complexes (Ref: Internet, 9/e p207)
A Raji cell assay identifies the presence of circulating immune complexes. A positive result suggests the presence of
antigen-nonspecific immune complexes in the circulation. The raji cell assay may be helpful in differentiating diseases.
Additionally, raji cell tests may assist with the assessment of disease activity. A positive raji cell assay that turns negative
may suggest that the disease activity has improved.
43. Ans. (c) Immune complex mediated hypersensitivity (Ref: Robbins 8th/703, 9/e p207)
Hypersensitivity pneumonitis (allergic alveolitis) is ideally an example of type III and type IV hypersensitivity.
Complement and immunoglobulins demonstrated within vessel walls by immunofluorescence as well as presence of
specific antibodies in the serum of affected patients indicate type III (immune complex) hypersensitivity. The presence
of non-caseating granulomas in 2/3rd patients suggest the development of a T cell-mediated (type IV) delayed-type
hypersensitivity against the implicated antigen(s).
However, the single best answer to be marked would be type III hypersensitivity reaction because immune complex for-
mation plays a relatively more important role in hypersensitivity pneumonitis.
44. Ans. (a) IgE (Ref: Robbins 8th/198, 7th/207-208, 9/e p202)
45. Ans. (a) Localized immune complex (Ref: Robbins 8th/205, 7th/215, 9/e p207)
The Arthus reaction is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin.
Revise the mnemonics SHARP from the text.
46. Ans. (d) Type IV (Ref: Robbins 8th/207, 7th/216-217, 9/e p210)
Presence of epitheloid cell granuloma, langhans giant cells and lymphocytes is characteristic of chronic granuloma-
tous inflammation, which is associated with type IV hypersensitivity action.
47. Ans. (b) IgE mediated reaction (Ref: Robbins 7th/210, 8th/197, 9/e p202)
The symptoms of the patient are due to hypersensitivity type I reaction Type I is mediated by IgE and it flairs up
within minutes.
Immunity
The symptoms range form rashes to anaphylactic shock with vasodilation hypotension and bronchiolar spasm.
Type I Type II
The symptoms range form rashes to anaphylactic shock Is characterized by an antigen antibody reaction on the
with vasodilation hypotension and bronchiolar spasm surface of a host cell*
Mediated by IgE Mediated by IgG or IgM
Examples of Type I Examples of Type II
Eczema* Blood transfusion reactions*
Hay Fever* Transplant rejection*
Asthma* Autoimmune hemolytic anemia*
Anaphylactic shock* Good Pastures syndrome*
Urticaria* Graves disease*
Acute dermatitis* Myasthenia gravis*
Theobald Smith Reaction* Pemphigus vulgaris
Pernicious anemia*
Rheumatic fever*
Type III Type IV

Mediated by antigen/antibody complex*
Cell mediated reaction (delayed hypersensitivity)*
Examples of type III Examples of type IV
S: Serum sickness, Post - streptococcal
Tuberculosis
glomerulonephritis, SLE, Schick test
Sarcoidosis*
H: Hypersensitivity pneumonitis
Temporal arteritis
A: Arthus reaction, Acute vira l hepatitis
Contact dermatitis*
R: Reactive arthritis, Rheumatoid arthritis
Lepromin test and PPD (Mantoux test)*
P: Penicillamine toxicity,
Patch test*
Polyarteritis nodosa (PAN)
Type I DM
48. Ans. (b) Contact hypersensitivity (Ref: Robbins 7th/215, 8th/197, 9/e p209)
49. Ans. (a) Blood transfusion reaction (Ref: Robbins 6th/212, 8th/197, 9/e p206)
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50. Ans. (d) Necrotizing vasculitis (Ref: Harrisons 16th/327, 328, Robbins 7th/212, 213, 1253, 9/e p207)
Acute necrotizing vasculitis is the dominant morphological consequences of immune complex injury [Type-III hyper-
sensitivity reaction]. The immune complexes incite an activation of complem ent and produce inflammatory reaction
and necrosis.
Atopic dermatitis and urticaria Type I.
Photoallergy- type IV hypersensitivity or delayed hypersensitivity
Graft versus host disease is mediated by T-cells.
51. Ans. (B) Lymphocytes are the primary cells affected by M. tuberculosis (Ref: Robbins 8th/368, 9/e p371)
Macrophages are the primary cells infected by M. tuberculosis.
52. Ans. (a) IgE mediated response (Ref: Robbins 7th/199-200, 8th/198-200, 9/e p202)
53. Ans. (a) Hard sore (Ref: Robbins 7th/738, 9/e p693)
Granulomas found in sarcoidosis are non-caseating and so, refered to as Hard sore. They contain.
Asteroid Bodies
Schaumann bodies and
Birefringent crystals
54. Ans. (d) All of the above (Ref: Robbins 7th/1344, 9/e p1235-1236; Harrisons 16th/2521 table 366-3)
Myasthenia gravis: revision of key points
Autoimmune mediated neuromuscular disease example of type II hypersensitivity reaction
Distinct finding: ACh receptors (in muscles) and circulating antibodies to ACh receptors
Associations
1. Hyperthyroidism
2. Thymic hyperplasia 65%
3. Thymoma 15%
4. Autoimmune disorders (Hashimotos thyroiditis, Graves disease, RA/SLE, positive family history of autoimmune diseases)
In severe cases muscle biopsy shows type 2 fiber atrophyQ
Immunity
Most sensitive test: Single fiber electromyographyQ

Most specific test: antibodies to ACh receptorsQ
Electrophysiological studies: in motor responseQ on repeated stimulation
Nerve conduction studies: NormalQ
Treatment is done with drugs (neostigmine with atropineQ) and thymectomyQ
55. Ans. (b) Cytotoxic type (Ref: Robbins 8th/198-202; 7th/206, 9/e 205)
56. Ans. (d) Type III (Ref: Robbins 8th/703, 7th/739, 9/e 207)
57. Ans. (c) Good cell mediated immunity (Ref: Robbins 8th/207, 7 th/381, 9/e 210)
5 7.1. Ans. (c) Thymic hyperplasia (Ref: Robbins 8/e p635, 9/e 1235-1236)
Direct quote... Thymic hyperplasia is found in 65% and thymoma in 15% of affected patients.
Myasthenia gravis: revision of key points for NEET/AIIMS!
Autoimmune mediated neuromuscular disease example of type II hypersensitivity reaction
When arising before age 40 years it is most commonly seen in women, but it occurs equally in both sexes in
older patients.
Distinct finding: ACh receptors (in muscles) and circulating antibodies to ACh receptors
Most specific test: antibodies to ACh receptors Q
Electrophysiological studies: in motor response on repeated stimulation

Q
Nerve conduction studies: Normal Q
Treatment is done with drugs (neostigmine with atropine ) and thymectomy

Q Q
Frequently observed associations asked in exams (PGI)!

Hyperthyroidism
Thymic hyperplasia 65%
Thymoma 15%
Autoimmune disorders (Hashimotos thyroiditis, Graves disease, RA/SLE, positive family history of autoim-
224 mune diseases).
Immunity
5 7.2. Ans. (d) Type IV (Ref: Robbins 8/e p197, 9/e 24)
The hypersensitivity reactions have been given the following names:
Immediateor (type I) hypersensitivity
Antibody-mediated or (type II) hypersensitivity
Immune complexmediated or (type III) hypersensitivity
Cell-mediated or (type IV) hypersensitivity
5 7.3. Ans. (b) Acetylcholine receptors (Ref: Robbins 9/e 195)
58. Ans. (a) Preformed antibodies (Ref: Robbins 8th/228, 9/e 233-234)
Direct quote from Robbins. Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of
the recipient. Such antibodies may be present:
In a recipient who has previously rejected a kidney transplant
Multiparous women who develop anti-HLA antibodies against paternal antigens shed from the fetus may have pre-
formed antibodies to grafts taken from their husbands or children
Prior blood transfusions
In recipients not previously sensitized to transplantation antigens, exposure to the class I and class II HLA antigens
of the donor graft may evoke antibodies. The initial target of these antibodies in rejection seems to be the graft vasculature.
Thus, antibody-dependent acute humoral rejection is usually manifested by a vasculitis, sometimes referred to as rejec-
tion vasculitis
Also know that endothelitis is caused by injury to the vascular endothelial cells mediated by CD8+ T cells. This is a
component of acute cellular rejection.
59. Ans. (d) Lung (Ref: Robbin 7th/222-3, 9/e 236, Harrisons 17th/717)
GVHD affects skin (earliest organ), intestine and liver
Lungs are not affected in GVHD. For details see text.
60. Ans. (a) Hyperacute rejection. (Ref: Robbins 7th/219, 220, 8th/197, 9/e 233-234)
Immunity
Hyperacute rejection takes place when there are preformed antibodies in the circulation of the recipient. It can be due to:
Patient who has already rejected a transplant
Multiparous females
Prior blood transfusions
61. Ans. (a) Associated with solid organ transplantation; (b) Graft must contains immunocompetant T cell (c) It is
seen in immunosuppressed persons; (d) Also called as Runt disease in animals (Ref: Robbins 7th/222, 9/e 232-233;
Harrison 16th/670; Ananthanarayan 7th/180)
Graft versus host reaction (GVH) occurs in any situation in which immunologically competent cells or there precursors
are transplanted into immunologically crippled recipient cells and the transferred cells recognize alloantigens in the host.
GVHD occurs most commonly in allogenic bone marrow transplantationQ but may also follow transplantation of solid
organs rich in lymphoid cells.
62. Ans. (b) Interstitial and tubular mononuclear cell infiltrate (Ref: Robbins 8th/228-229 , 9/e 232-233)
63. Ans. (d) Xenograft (Ref: Harsh Mohan 6th/65)
Isograft: Is a graft from a different individual genetically identical with recipient e.g. identical twin
Autograft: Is to self
Allograft: Graft from same species but different genotype (from one human to another human)
Xenograft: Graft from different species (from animal to human)
64. Ans. (b) Adrenal (Ref: Robbins 9/e 236, 8th/230; 7th/125)
6 4.1. Ans. (a) Hyperacute rejection (Ref: Robbins 8/e p201-2, 9/e 233-234)
Hyperacute rejection Acute rejection Chronic rejection

*Takes place in individuals with preformed *Seen days to months after transplantation. *Occurs months to years after transplanta-
antibodiesQ usually within minutes to It can be acute humoral rejection or acute cel- tion
hours of transplantation lular rejection
64.2. Ans. (d) Infection (Ref Cambells Urology, 8/e p346,349)

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Principal causes of death in renal transplant patients (in decreasing order)

Heart disease
Infection
Stroke
65. Ans. (b) Polyclonal B cell activation (Ref: Robbins 8th 212, 9/e 216)
Role of infections in autoimmunity is exemplified by the following:
1. Antigenic cross reactivity: this is due to similarity is the microbial antigenic structure and the self antigens. This is
also known as molecular mimicry. The classical example is rheumatic heart diseaseQ in which streptococcal proteins
cross react with myocardial proteins causing myocarditis.
2. Upregulation of co-stimulatory molecules by infectious organisms.
3. Polyclonal B cell activation: caused by EBVQ and HIVQ resulting in production of autoantibodies
4. Alteration of tissue antigens: infections may alter tissue self antigens so that they activate T cells and loose the property
of self tolerance
Even HIV can cause autoimmune diseases by polyclonal B cell activation
Robbins page 212 also mentions the paradoxical protective effect of infections against some autoimmune diseases
because infections promote low level IL-2 production and this is essential for maintaining regulatory T cells.
66. Ans. (b) Scleroderma (Ref: Robbins 8th/225, 518, Harrison 18th/2096, 9/e 228-229)
The symptoms present in this girl are suggestive of Raynauds phenomenon (pallor and cyanosis of the digits of hands and
feet due to exaggerated vasoconstriction of digital arteries and arterioles). It can either be:
Primary Raynauds phenomenon or
Secondary Raynauds phenomenon (due to SLE, scleroderma, Buergers disease, atherosclerosis). Since, Raynauds
phenomenon may the first manifestation of these diseases, the patient with new symptoms need to be evaluated.
Direct quote Robbins 8 /225.... though systemic sclerosis shares many features with SLE, rheumatoid arthritis and pol-
th
ymyositis, its distinctive features are the striking cutaneous changes, notably skin thickening. Raynaud phenomenon,
manifested as episodic vasoconstriction of the arteries and arterioles of the extremities, is seen in virtually all patients and
precedes other symptoms in 70% of cases. Dysphagia is seen in 50% patients.
Ruling out SLE, the presentation in SLE is.Typically, the patient is a young woman with some of the following features: a but-
Immunity
terfly rash over the face, fever, pain but no deformity in one or more peripheral joints (feet, ankles, knees, hips, fingers, wrists, elbows,
shoulders), pleuritic chest pain, and photosensitivity.
67. Ans. (d) Sickle Cell Disease (Ref: Harrison 17th/2074)
Sickle cell disease is caused by a point mutation in the b chain of hemoglobin. It is not an auto immune disease.
6
68. Ans. (d) Anti glycoprotein antibody (Ref: Robbins 8th/215, Harrison 17th/2073, 9/e 219)
Antiphospholipid antibody syndrome is characterized by antibodies against phospholipid beta 2-glycoprotein 1 com-
plex . For detail, see text under SLE.
Q
69. Ans. (b) Kikuchi Fujimoto disease (Ref: Harrison 17th/1011)

The other name of Kikuchi Fujimoto disease is histiocytic necrotizing lymphadenitis. This will answer our question.
Kikuchi-Fujimoto disease (KFD)/Histiocytic necrotizing lymphadenitis
Benign and self-limited disorder in young individuals characterized by regional cervical lymphadenopathy with
tenderness, usually accompanied with mild fever and night sweats.
May be viral in etiology
Diagnosed on the basis of an excisional biopsy of affected lymph nodes which shows fragmentation, necrosis and
karyorrhexis, presenting with posterior cervical lymphadenopathy.
Patients should be followed-up because of increased chances of development of SLE (systemic lupus erythematosus).
Castleman disease (CD)
Defined by lymph node hypertrophy with angiofollicular lymphoid hyperplasia.
Has localised form or multicentric form (several Lymph nodes are affected).
Clinical features inlcude Peripheral lymphadenopathy, hepatomegaly and/or splenomegaly and POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes)
Human herpes virus 8 (HHV-8) is the etiological agent
Lymph node histological analysis with immunohistochemical staining, shows polyclonal angiofollicular lymphoid
hyperplasia, most often of the hyalinovascular type (especially in localised CD) and more rarely of the plasma-cell
type (particularly in multicentric CD) or mixed/intermediate type.
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Immunity
70. Ans. (a) SLE (Ref: Harrison 17th/2077, Robbins 8th/218, 9/e 224)
Subendothelial deposits create a homogeneous thickening of the capillary wall called wire loop lesion, which can be seen
by means of light microscopy when they are extensive. They usually reflect active disease.
71. Ans. (d) Liver (Ref: Immunofluorescence Methods for Microscopic Analysis in Methods in Nonradioactive Detection,
Lange Publications/247)
Quote from the book. Serum anti-nuclear antibodies (ANA) bind to the corresponding antigens present in rat liver sec-
tions. The antigen-antibody complexes are detected by means of a fluorescein labeled anti-human immunoglobulin, and
visualized with the aid of a fluorescence microscope.
72. Ans. (c) Inclusion bodies (Ref: Robbins 9/e 250-255, 8th/1305, 7th/1375-76)
73. Ans. (a) C1 esterase inhibitor deficiency (Ref: Robbins 8th/235, 9/e 238)
A deficiency of C1 esterase inhibitor gives rise to an autosomal dominant disorder hereditary angioedema. The C1
esterase inhibitor is a protease inhibitor whose target enzymes are C1r and C1s of the complement cascade, factor XII of the
coagulation pathway, and the kallikrein system. So, any individual having the deficiency of C1 esterase inhibitor would
have excessive complement activation.
This causes the release of anaphylatoxins (C3a, C5a) and other inflammatory mediators. These patients therefore have
episodes of edema affecting skin and mucosal surfaces such as the larynx and the gastrointestinal tract. This may result in
life-threatening asphyxia or nausea, vomiting, and diarrhea after minor trauma or emotional stress.
74. Ans. (a) It is an autosomal recessive disorder (Ref: Robbins 9/ p242)
75. Ans. (a) SLE (Ref: Robbins 7th/230, 8th/220, 9/e 218)
In SLE, if antinuclear antibodies (ANAs) can bind to exposed cell nuclei, the nuclei may lose their chromatin pattern, and
become homogeneous to produce lupus erythematosus (LE) bodies. The LE body is also know as hematoxylin body.
76. Ans. (c) Diffuse proliferative Glomerulonephritis (WHO class IV) (Ref: Harrison 17th/2077, Robbins illustrated 8th/218,
9/e p224)
Wire loop lesions are characteristic of type IV or diffuse proliferative glomerulonephritis .
Q Q
It is associated with extensive subendothelial deposits in this type of glomerulonephritis.

It is the most serious of the renal lesions in SLE.
77. Ans. (d) Multiple myeloma (Ref: Robbins 9/e p258-259, 8th/252-254, 7th/261)
Immunity
Pink and amorphous material that shows apple green birefringence under polarized light confirms the diagnosis of Amy-
loidosis. The presence of Lambda light chains is suggestive of multiple myeloma.
78. Ans. (a) Non caseating granulomas (Ref: Robbins 9/e p693, Harrison, 17th/2135)
The presence of bilateral nodules on the shin; bilateral hilar lymphadenopathy and negative Mantoux test in a
female patient point to a probable diagnosis of Sarcoidosis.
The skin lesions characteristically show the presence of non caseating granulomas in sarcoidosis.
Q
79. Ans. (a) SLE: (Ref: Robbins 7th/229, 234, 9/e p218)
Antibodies to ds DNA and the so called Smith (Sm) antigens are virtually diagnostic of SLE. Anti ds-DNA is common in
SLE (40-60%).
Anti nuclear antibody is present in all the mentioned diseases but anti double stranded DNA is very specific for SLE.
80. Ans. (a) PSGN; (b) MPGN; (e) Infective endocarditis (Ref: Harrison 16th-/680)
Causes of hypocomplementemia
Glomerulonephritis
Idiopathic proliferative GN
Cresenteric GN
MPGN
Post-infectious GN
Lupus nephritis
Cryoglobulinemia
Bacterial endocarditis
Shunt nephritis
Atheroembolic renal disease
Sepsis
Acute pancreatitis
Advanced liver disease
81. Ans. (b) Neutropenia; (c) Defective microbial killing; (d) Presence of large granules in neutrophils; (e) Immu-
nodeficiency: (Ref: Harrison 16th/353, 354, Robbins 7th/61, 62, 9/e p238)
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Chediak-Higashi syndrome
Autosomal recessive inheritance
Due to defect in lysosomal transport protein LYST.
Clinical features include: primary immune deficiency, neutropenia, defective microbial killing, impaired chemotaxis,
hypopigmentation of skin, eyes and hair, photophobia and nystagmus
Microscopic examination shows giant peroxidase positive inclusions in the cytoplasm of leukocytes.
82. Ans. (a) Severe combined immune deficiency. (Ref: Robbins 7th/244, 9/e p239)
83. Ans. (b) Pulmonary emphysema; (c) Diastase resistant hepatic cells: (Ref: Robbins 7th/911-912, 9/e p850-851)
a -anti-trypsin deficiency is an autosomal recessive disease having abnormally low levels of a -anti-trypsin
1 1
Deficiency of the enzyme leads to pulmonary panacinar emphysema
Gene located on Chr 14.
Characterized by PAS positive and diastase resistant inclusions in hepatocytes.
84. Ans. (d) High serum IgE, with low IgG, IgA and IgM (Ref: Robbins 9/e p242, Harrison 17th/384, 2061, 2056, 381)
Hyper IgE syndrome is also known as Jobs syndrome
Abnormal chemotaxis is a variable feature.
Patients have characteristic facies with broad nose, kyphoscoliosis, osteoporosis and eczema.
Recurrent abscesses (known as cold abscesses) involving skin, lungs and other organs is a prominent feature
Serum IgE level is significantly elevated whereas IgM, IgG and IgA level are normal.
Note: In Hyper- IgM syndrome, IgM is elevated and IgG, IgA are normal.
85. Ans. (c) Large size platelet (Ref: Robbins 9e/p242, 8th/235, Harrison 17th/2060, OP Ghai pediatrics 6th/326)
86. Ans. (a) Absent tonsils and no palpable lymph nodes on physical examination (Ref: Robbins 9/e p240-241, 8th/231-233)
87. Ans. (d) Neutrophil (Ref: Robbins 8th/238, 9/e p248)
Immunity
88. Ans. (d) Leucocytosis (Ref: Robbins 7th/228, 9/e p218)

89. Ans. (c) IgA (Ref: Harrison 16th/2423, 9/e p242-243)
Patients with ataxia telangiectasia (AT) present in the first decade of life with progressive telangiectatic lesions
associated with deficits in cerebellar function and nystagmus. There is a high incidence of recurrent pulmonary
infections (bronchiectasisQ) and neoplasms of the lymphatic and reticuloendothelial system.
It is caused due to defect in DNA repair genesQ.
Thymic hypoplasia with cellular and humoral (IgAQ and IgG2) immunodeficiencies, premature agingQ and
endocrine disorders such as insulin resistance or type-I DMQ.
The most striking neuropathologic changes include loss of Purkinje, granule and basket cells in the cerebellar
cortex as well as of neurons in the deep cerebellar nuclei.
A poorly developed or absent thymus gland is the most consistent defect of the lymphoid system.
90. Ans. (b) Scleroderma: (Ref: Robbins 7th/229)
91. Ans. (b) Neutrophil (Ref: Robbins 7th/230, 9/e p222)
LE cell or hematoxylin body is a phagocytic leukocyte (neutrophil or macrophage) that has engulfed the denatured
nucleus of an injured cell.
Tart Cell is usually a monocyte which has ingested another cell or nucleus of another cell.
92. Ans. (c) Antinuclear factor (Ref: Robbins 7th/229, 9/e p218-219)
Most sensitive test for SLE antinuclear antibody (ANA)
Most specific test for SLE anti-ds DNA antibody; anti-Smith antibody
93. Ans. (c) Hematuria (Ref: Robbins 9/e p222, 8th/217; 7th/23)
94. Ans. (c) Anti double stranded DNA antibody (Ref: Robbins 9/e p219, 8th/214; 7th/228)
95. Ans. (a) Defect in the transport of chloride across epithelia (Ref: Robbins 9/e p466-467, 8th/465; 7th/489-490)
228
Immunity
96. Ans. (a) Sarcoidosis (Ref: Harsh Mohan 6th/164-165)

97. Ans. (a) P24 (Ref: Robbins 7th/246, 9/e p245)
98. Ans. (a) Kaposis sarcoma (Ref: Robbins 8th/523-524; 7th/256)
99. Ans. (a) Syphilis (Ref: Robbins 9/e p217, 8th/374, 7th/223)
100. Ans. (c) SLE (Ref: Robbins 9/e p225-227, 8th/22, 7th/231,236,239)
101. Ans. (a) Brain (Ref: Robbins 9/e p693, 8th/701-703, 7th/738)
102. Ans. (c) Wire loop lesions (Ref: Robbins 9/e p224 8th/218, 7th/232)
103. Ans. (b) SLE (Ref: Robbins 9/e p224, 8th/215; 7th/233-234, 597-598)
104. Ans. (b) Chemotaxis (Ref: Walter and Israel 7th/150)
The direct quote from the book is Chediak Higashi syndrome is an autosomal recessive condition in which polymorphs exhibit
defective random movements, defective chemotaxis and impaired degranulation on phagocytosing particles.
105. Ans. (b) SLE (Ref: Robbins 9/e p219, 8th/215; 7th/234)
106. Ans. (a) Systemic sclerosis (Ref: Robbins 9/e p228 8th/215,223; 7th/229)
107. Ans. (a) Hilar lymphadenopathy with perihilar calcification (Ref: Robbins 9/e p693, 8th/703, 7th/738)
108. Ans. (a) CNS (Ref: Robbins 9/e p254-255, 8th/247; 7th/257)
109. Ans. (d) Nodule is the initial lesion of Kaposis sarcoma (Ref: Robbins 9/e p254, 8th/529; 7th/549)
110. Ans. (a) Helper cells (Ref: Robbins 9/e p246, 8th/239, 7th/248)
111. Ans. (c) CNS (Ref: Robbins 8th/249, 9/e p254-255)
Direct quote from Robbins. The anatomic changes in the tissues (except of lesions in the brain ) are neither specific nor diag-
Q
nostic.
112. Ans. (d) Double stranded DNA (Ref: Robbins 8th/215, 9/e p219)
Immunity
Explanation:
Skin rash, photosensitivity, arthralgia and renal disease in a young woman are suggestive of systemic lupus erythematosus
(SLE); an autoimmune multisystem vasculitis.
Antibodies against double-stranded DNA (anti-dsDNA) are specific for SLE. However they are only present in 60% of
cases. So absence of anti-dsDNA does not rule out the diagnosis. Antibodies against small nuclear ribonucleoproteins
(anti-snRNPs), also called Anti-Smith antibodies are also specific for SLE.
(Choice A) Anti-mitochondrial antibodies are specific for primary biliary cirrhosisQ, a disease that affects mainly
middle- aged women and presents with jaundice, pruritus, hepatosplenomegaly, and hypercholesterolemia.
(Choice B) Rheumatoid factor is an IgMQ antibody directed against the Fc fragment of self IgGQ found in patients with
rheumatoid arthritis. It is also found in other collagen tissue disorders.
(Choice C) Anti-centromere antibodies are present in the majority of patients with CREST syndromeQ.
113. Ans. (d) Lymphocyte (Ref: Robbins 7th/235-236, 9/e p227)
The combination of dry eyes (keratoconjunctivitis) and dry mouth (xerostomia) in an adult woman is suggestive of
Sjogrens syndrome, an autoimmune disorder characterized by immunologic destruction of the lacrimal and salivary
glands. This disorder is characterized by the presence of SS-A and SS-B auto-antibodies, but the diagnosis of Sjogrens
syndrome is confirmed by finding a lymphocytic infiltrate are characteristic of organs affected by autoimmune diseases.
In addition to enlargement of the salivary glands, the lymph nodes of patients with Sjogrens syndrome may be enlarged
due to a pleomorphic infiltrate of B-lymphocytes.
Patients with Sjogrens syndrome have an increased risk for developing non- Hodgkins lymphoma, especially
marginal zone lymphomaQ.
Biopsy of the lip (to examine minor salivary glands) is essential for making a diagnosis of Sjogren syndromeQ.
114. Ans. (d) Werners syndrome (Ref: Robbins 7th/, 42-43, 8th/39-40, 9/e p66-67)
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Progeria (or Hutchinson-Gilford syndrome) is a disease characterized by symptoms of premature aging; symptoms
begin around the age of 6-12 months of age.
Werners syndrome is a similar appearing disease that first causes symptoms in affected individuals in their late teens.
Werners syndrome is caused by a mutation in the WS gene which results in the production of a defective DNA helicaseQ.
Mnemonic: remember the legendry Amitabh Bachchan as Auro in Paa
115. Ans. is (d) i.e. Tyrosine kinase (Ref: Robbins 8th/231-232, 9/e p240-241)
This patient has X-linkedQ (Brutons) agammaglobulinemia, which is due to a deficiency in a tyrosine kinaseQ, leading
to a B cell maturation arrest at the pre-B cell level.
Selective IgA deficiency has been linked to defective class III MHC genes (option B).
Severe combined immunodeficiency is apparently a heterogeneous disease, and different subgroups have been linked
to abnormalities of adenosine deaminase (option A), the gamma chain of the IL-2 receptorQ (option C), and purine
nucleotide phosphorylase.
116. Ans. is (d) i.e. There may be an increase in spontaneous abortions and prematurity (Ref: Robbins 8th/220, 9/e p222)
Systemic lupus erythematosus (SLE) predominantly affects younger women, and these patients have an increased
incidence of spontaneous abortion, fetal death in utero, and prematurity. The mother may experience an exacerbation
in the activity of her disease in the third trimester or peripartum period.
Congenital malformations (options B and C) are not a complication of pregnancies in patients with SLE.
117. Ans. is (a) i.e. Conjunctivitis (Ref: Robbins 9/e p226-227, 8th/221)
The patient has Sjgrens syndrome, characterized by dry eyes (keratoconjunctivitis) and a dry mouth (xerostomia) due to
destruction of the lacrimal and salivary glands. The most diagnostic autoantibodies are those against ribonucleoproteins
Ro (SS-A) and La (SS-B), although co-existing rheumatoid factor and lupus antibodies are also seen.
118. Ans. is (b) i.e. Granular complement and IgG at the dermal-epidermal junction (Ref: Robbins 8th/219, 9/e p224)
The disease SLE having the characteristic butterfly facial rash of lupus is due to deposition of antibodies and
complement at the dermal/pidermal junction.
Immunity
Cells similar to fibroblasts growing in a storiform (pinwheel) pattern (option A) are characteristic of
dermatofibrosarcoma protuberansQ, a slow-growing type of fibrosarcoma.
A sawtooth dermoepidermal junction (option C) is a feature of the skin condition lichen planusQ.
Pautrier microabscesses (option D) are a feature of a cutaneous T-cell lymphoma called mycosis fungoides.
119. Ans. is (a) i.e. Acanthamoeba sp. (No reference....read explanation below)
Two types of free-living amoeba can infect the brain and meninges: Naegleria fowleri and Acanthamoeba sp.
The former affects healthy adolescent or adult divers, while the latter causes infection in patients with immunosuppres-
sion (diabetes, alcoholism, cancer, or HIV infection).
The brain infection characteristically has a prominent perivascular character, which causes a multifocal hemorrhagic ne-
crotizing meningoencephalitis. Skin ulcers, nasal infection, or pneumonia may also be present. It is thought that the organ-
isms may release a toxin causing host tissue necrosis.
Naegleria fowleri (choice D) is an amoebic cause of meningoencephalitis in previously healthy swimmersQ and divers.
120. Ans. is (c) i.e. HLA typing (Ref: Robbins 8th/193, 9/e p215)
Ankylosing spondylitis is a seronegative spondyloarthropathy primarily affecting the vertebrae and the sacroiliac joints,
usually beginning in late adolescence or early adulthood. Majority 90-100% of these patients are HLA-B27 positive. So,
tests for this HLA type are the most helpful of those given as options in confirming the diagnosis.
Seronegative spondyloarthropathies (Mnemonic: PAIR) Salient features of these diseases
P: Psoriatic arthritis *Absence of serum auto-antibodies
A: Ankylosing spondylitis (AS) *Associated with HLA B27 (most commonly AS)
I: Inflammatory bowel disease arthritis *Onset before the age of 40 years
R: Reactive arthritis (Reiter syndrome) *Presence of uveitis, spine/large peripheral joint arthritis
C-reactive protein and erythrocyte sedimentation rate (choice B) are non-specific markers of inflammation that can be
elevated in active ankylosing spondylitis.
Serum alkaline phosphatase (choice D) and serum IgA (choice E) can also be (usually mildly) elevated, but do not
specifically suggest ankylosing spondylitis.
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Immunity
121. Ans. is. (a) i.e. Angiosarcoma (Ref: Robbins 8th/246, 9/e p254)
Kaposis sarcoma is a spindle cell neoplasm that is highly associated with AIDS (infact, it is the commonestQ malignancy
in AIDS). It is caused due to Herpes simplex virus type 8Q. The tumor has an appearance very similar to that of
angiosarcomaQ-proliferating stromal cells and endothelium creating vascular channels that contain blood cells.
Malignant fibrous histiocytoma (MFH); (choice D) is an extremely poorly differentiated (anaplastic) stromal malignancy.
MFH does not produce any recognizable mesenchymal structures-thus, the production of vascular structures by Kaposis
sarcoma differentiates the two tumors.
1 21.1. Ans. (a) ds DNA (Ref: Robbins 8/e p214-215, 9/e p218-219)
Revise the important features of antibodies in SLE
Anti-double stranded DNA antibody and the antiSmith (Sm) antibody:Highly specific for SLE.
Antinuclear antibody (ANA):Highly sensitive for SLE
Anti-P antibody Associated with lupus psychosis
Anti-SS-A and Anti-SS-B antibody- Associated with congenital heart block and cutaneous lupus
Anticardiolipin antibodies may produce a false positive VDRL test for syphilis
1 21.2. Ans. (c) Anti topoisomerase (Ref: Robbins 8/e p215 , 9/e p219)
Anti topoisomerase is least commonly associated with SLE amongst the given options. The following is a modified table
given for a reference from Robbins.
Nature of Antigen Antibody System % Positive in SLE
Many nuclear antigens (DNA, RNA, proteins) Generic ANA (indirect IF) >95
Native DNA Antidouble-stranded DNA 4060
Histones Antihistone 5070
Core proteins of small nuclear RNP particles (Smith antigen) Anti-Sm 2030
RNP (U1RNP) Nuclear RNP 3040
Immunity
RNP SS-A(Ro) 3050
RNP SS-B(La) 1015
DNA topoisomerase I Scl-70 <5
Centromeric proteins Anticentromere <5
Histidyl-tRNA synthetase Jo-1 <5
121.3. Ans. (c) Primary CNS Iymphoma (Ref: Robbins 8/e p247, 9/e p254-255)
Primary CNS lymphoma is the most common CNS neoplasm in immunosuppressed individuals, including those
Q
with AIDS and immunosuppression after transplantation.

The term primary emphasizes the distinction between these lesions and secondary involvement of the CNS by
lymphoma arising elsewhere in the body.
Primary brain lymphoma is often multifocal within the brain parenchyma
Most primary brain lymphomas are of B-cell origin and most have infection caused by EBV in the setting of
Q Q
immunosuppression.
Histologically, reticulin stains demonstrate that the infiltrating cells are separated from one another by silver-staining
material; this pattern, referred to as hooping, is characteristic of primary brain lymphoma.
In addition to expressing B-cell markers, most of the cells also express BCL-6; when tumors arise in the setting of
immunosuppression,
1 21.4. Ans. (a) Adenosine deaminase deficiency (Ref: Robbins 8/e p234, 9/e p239)
Severe combined immunodeficiency (SCID) represents a constellation of genetically distinct syndromes, all having in
common defects in both humoral and cell-mediated immune responses
The most common form, accounting for 50% to 60% of cases, is X-linked, and hence SCID is more common in boys
than in girls. The genetic defect in the X-linked form is a mutation in the common -chain (c) subunit of cytokine
receptors
The remaining cases of SCID are inherited as autosomal recessive. The most common cause of autosomal recessive
SCID is a deficiency of the enzyme adenosine deaminase (ADA).
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1 21.5. Ans. (c) Normal B cell count (Ref: Robbins 8/e p233, 9/e p241)
Common Variable Immunodeficiency
Rare disease characterised by hypogammaglobulinemia, generally affecting all the antibody classes but sometimes
only IgG.
The diagnosis of common variable immunodeficiency is based on exclusion of other well-defined causes of decreased
antibody production.
In contrast to X-linked agammaglobulinemia, most individuals with common variable immunodeficiency have normal
or near-normal numbers of B cells in the blood and lymphoid tissues. These B cells, however, are not able to
differentiate into plasma cells.
Clinicalmanifestations include recurrent sinopulmonary pyogenic infections. The patients with the disease are prone to
the development of persistent diarrhea caused by G. lambliaQ.
It affects both sexes equally (In contrast to X-linked agammaglobulinemia)
Histologically the B-cell areas of the lymphoid tissues (i.e., lymphoid follicles in nodes, spleen, and gut) are
hyperplastic.
Associated with high frequency of autoimmune diseases like rheumatoid arthritis and malignancies (lymphoid can-
cer and gastric cancer)
1 21.6. Ans. (b) Digeorge syndrome (Ref: Robbins 8/e p234, 9/e p241)
Digeorge syndrome/ Thymic hypoplasia/Velocardiofacial syndrome
DiGeorge syndrome is a T-cell deficiency that results from failure of development of the third and fourth pharyngeal pouches.
Individualswith this syndrome have a variable loss of T cellmediated immunity (resulting from hypoplasia or
lack of the thymus), tetany (resulting from lack of the parathyroids), and congenital defects of the heart and great vessels.
The T-cell zones of lymphoid organs (paracortical areas of the lymph nodes and the periarteriolar sheaths of the
spleen) are depleted.
DiGeorge syndrome results from the deletion of a gene mapped to chromosomes 22q11.
Mnemonic: (CATCH 22)
C Cardiac abnormalities (especially tetralogy of Fallot)
Immunity
A Abnormal facies
T Thymic aplasia
C Cleft palate
H Hypocalcemia (due to hypoplasia or lack of parathyroids)
22 22q11 deletion
1 21.7. Ans. (a) SLE (Ref: Robbins 9/e p224, 8/e p220, 7/e p234)
In the splenic tissue involvement in SLE, splenomegaly, capsular thickening, and follicular hyperplasia are common
features. Central penicilliary arteries may show concentric intimal and smooth muscle cell hyperplasia, producing so-
called onion-skin lesionsQ.
121.8. Ans. (c) Haematoxylin bodies (Ref: Robbins 9/e p256)
Biopsy specimens from enlarged lymph nodes in the early stages of HIV infection reveal a marked follicular hyper-
plasia
Monocytoid cells along the blood vessels can be seen in acute lymphadenitis.
With disease progression, the frenzy of B-cell proliferation subsides and gives way to a pattern of severe follicular
involution. The follicles are depleted of cells, and the organized network of follicular dendritic cells is disrupted.
The germinal centers may even become hyalinized.
During this advanced stage viral burden in the nodes is reduced, in part because of the disruption of the follicular
dendritic cells. These burnt-out lymph nodesQ are atrophic and small
1 21.9. Ans. (a) Children previously tested with tuberculin test (Ref: Robbins 9/e p371)
Children previously tested with tuberculin test may show a FALSE POSITIVE TUBERULIN TEST.
False-negative Mantoux test False-positive Mantoux test
SarcoidosisQ Infection by atypical mycobacteriaQ
MalnutritionQ Previous vaccination with BCGQ
Hodgkin diseaseQ
ImmunosuppressionQ
Fulminant tuberculosisQ
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Immunity
121.10. Ans. (c) Plasma derived Hepatitis B vaccine

Blood products which can transmit HIV Blood products which can NOT transmit HIV
Whole blood Hyperimmune gamma globulin
Packed red blood cells Hepatitis B immune globulin
Platelets Plasma-derived hepatitis B vaccine
Leukocytes
Rho immune globulin
Plasma The procedures involved in processing these products either
All are capable of transmitting HIV infection. inactivate or remove the virus.
1 21.11. Ans. (c) HIV ELISA

Excellent question testing your basics buddies!
HIV ELISA is required for detection of antibodies against the virus. The antibodies may be present in the infant
because of maternal infection also because IgG antibodies can cross the placental barrier. So,the presence of anti HIV
antibodies is not reliable for diagnosis of HIV in a 2 month old child.
Please dont get foxed by the option viral culture friends. There is indeed a HIV culture method being used which is
called as peripheral blood mononuclear cells (PBMC) using the virus microculture in macrophages concept. PBMC
are drawn in high concentration from centrifugation of freshly drawn anticoagulated venous blood.
Viral DNA detection using DNA-PCR andp24 antigen assay are standard techniques used for viral detection.
121.12. Ans. (b) Disseminated TB (Ref: Robbins 9/e p371)
Mantoux test is simply able to predict the presence or absence of cell mediated immunity against the tubercular
antigens. It CANNOT differentiate between infection and disease.
Negative Mantoux test just indicates that the individual has never been exposed to tubercle bacilli earlier; it cant
indicate the susceptibility to the disease.
1 21.13. Ans. (d) Systemic lupus erythematosus (Ref: Robbins 9/e p218)
Similar to many autoimmune diseases, SLE predominantly affects women. A female-to-male ratio of 9:1 is seen during the
reproductive age group. By comparison, the female-to-male ratio is only 2:1 for disease developing during childhood or
after the age of 65.
121.14. Ans. (d) A mechanism for the persistence and evolution of autoimmune disease (Ref: Robbins 9/e p217)
Immunity
Epitope spreading is a phenomenon in which an immune response against one self antigen causes tissue damage, releasing
other antigens, and resulting in the activation of lymphocytes by these newly encountered epitopes. This is responsible for
the persistence and progression of autoimmune diseases.
121.15. Ans. (d) Anterior uveitis (Ref: Harrison 18th/2806)
Lfgrens syndrome consists of erythema nodosum, hilar adenopathy on chest X ray and uveitis.
Heerfordts syndrome: fever, parotid enlargement, facial palsy and uveitis.
121.16. Ans. (a) Gp 120 (Ref: Robbins 8th/246-7)
HIV-1 uses CD4 to gain entry into host T-cells and achieves this through its viral envelope protein known as gp120.
121.17. Ans. (b) 350
Under the revised guidelines the treatment of AIDS patients with respect to opportunistic infections has undergone a
change with H.A.A.R.T being initiated at a threshold of CD4 count <350 cells/cu.mm instead of previous 200 cells/cu.mm.
121.18. Ans. (a) EBV (Ref: Robbins 9th/607)
122. Ans. (c) AA (Ref: Robbins 8th/252-3, 9/e p257)
123. Ans. (d) microglobulin (Ref: Robbins 8th/254, 9/e p258)
2
Hemodialysis associated amyloidosis is caused by the deposition of the b microglobulin which is a component of MHC
2
class I molecule and cannot be filtered through the cuprophane dialysis membrane. It gets deposited in the synovium,
joints and the tendon sheaths.
Deposition of the amyloid in long term hemodialysis takes place in joints and in the carpal ligament of the wrist, the
latter leading to development of carpal tunnel syndrome
124. Ans. (b) Rectal biopsy (Ref: Harrison 17th/2145-6; Robbins 8th/255, 9/e p262, Harsh Mohan 6th/88)
The histological examination of the biopsy material is the commonest and confirmatory method for the diagnosis in a sus-
pected case of amyloidosis. The sites for the biopsy can be the renal tissue, rectum, abdominal fat aspiration and gingiva. The
rectumQ is the best site for taking the biopsy in the options provided.
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Note: Congo red staining of aspirated abdominal fat is initial test of choice in most cases. If it is found to be negative, more invasive
biopsy of other affected organ can be taken. The staining of abdominal fat aspirate is quite specific but has low sensitivity.

125. Ans. (b) Familial amyloidosis polyneuropathy (Ref: Robbins 8th/252-253, 9/e p259)
Transthyretin is a normal serum protein that binds and transports thyroxine and retinol (transthyretin). A mutant form
of transthyretin is deposited in a group of genetically determined disorders referred to as familial amyloid polyneu-
ropathies.
Inherited amyloidosis due to ATTR is autosomal dominant
Even normal transthyretin (pre-albumin) can form fibrils and lead to senile systemic amyloidosis.
126. Ans. (b) b2 microglobulin (Ref: Robbins 7th/159-160, 9/e p258)
b2 microglobulin, a component of MHC-1 molecule complicates the course of patients on long term hemodialysis. It is similar to the
normal b2 microglobulin protein which is retained in circulation of patients with renal failure because it cannot be filtered through the
cuprophane dialysis membrane.
127. Ans. (a) Bone marrow plasmacytosis (Ref: Robbins 7th/pg 260, 8th/252, 9/e p257)
AL (Amyloid Light chain) protein is produced by immunoglobulin secreting plasma cells and their deposition is associated with some
form of monoclonal B cell proliferation. These patients have a modest increase in the number of plasma cells in the bone mar-
row (plasmacytosis) which presumably secrete the precursors of AL protein.
128. Ans. (a) A beta 2 Microglobulin (Ref: Robbins 7th/260, 261, 8th/253, 9/e p258)
129. Ans. (c) Rectal biopsy (Ref: Harrison 16th/2028, 17th/2145 Robbins 9/e p262)
130. Ans. (c) Smooth muscle cells (Ref: Robbins 7th/515)
The proliferation of smooth muscle cells is a critical event in the neointimal hyperplastic response. Several studies have
clearly demonstrated that blockade of smooth muscle cell proliferation resulted in preservation of normal vessel pheno-
type and function, causing the reduction of neointimal hyperplasia and graft failure.
131. Ans. (c) Congo red (Ref: Robbins 7th/259, 8th/255, 9/e p257 Harrison 17th/2145)
132. Ans. (a) X-ray crystallography (Ref: Robbin 7th/259, 8th/250, 9/e p257)
Immunity
b Pleated structure is seen on X-ray crystallography

Electro Microscope shows non branching fibrils of indefinite length.
133. Ans. (a) Nonbranching filaments of indefinite length (Ref: Robbins 7th/259, 9/e p257)
134. Ans. (c) Methanamine silver (Ref: Harsh Mohan 5th/89, 6th/87, Robbins 9/e p262)
135. Ans. (c) 7.5-10 nm fibrils (Ref: Robbins 6th/259, 8th/249, 9/e p257)
Remember b-pleated structure of amyloid is seen on X-ray crystallography, whereas it is seen as a non-branching fibril of
7.5-10 nm diameter and infinite length on electron microscopy.
136. Ans. (c) Mutant transthyretin (Ref: Robbins 7th/260, 9/e p259)
137. Ans. (a) Sinusoids of red pulp (Ref: Robbins 7th/263, 9/e p261)
Amyloidosis of spleen
Sago spleen Lardaceous spleen
Amyloid deposition is largely limited to splenic Amyloid deposition spares the follicles and involve the walls of
follicles the splenic sinuses in red pulp
Mnemonic: Red is lal in hindi, so, similar sounding lardaceous.

138. Ans. (a) Thioflavin; (b) Congo red. (Ref: Robbins 7th/254, 9/e p262)
139. Ans. is b i.e. Amyloidosis (Ref: Harrison 17th/2146; Robbins 7th/264, 9/e p262)
140. Ans. (c) Glycoprotein (Ref: Robbins 9/e p256, 8th/250, 7th/259)
141. Ans. (b) Chronic inflammatory states (Ref: Robbins 9/e p257, 8th/251-252; 7th/159)
142. Ans. (c) Kidney (Ref: Robbins 8th/254, 9/e p261)
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Immunity
143. Ans. (b) Interferon- (IFN- g) (Ref: Robbins 8th/195, 206-8)

IL-12 stimulates differentiation of naive T-helper cells into the T 1 subpopulation. Patients with IL-12 receptor deficien-
H
cysuffer from severe mycobacterial infections due to the inability to mount a strong cell-mediated granulomatous immune
response. They are treated with IFN-.
The differences between the TH1 andTH2 subpopulations of helper T-cells are presented below:
TH1 TH2
Type of immunity Cell mediated Humoral/antibody mediated
Function Activate macrophages and cytotoxic T cells Activated B cells
Cytokines secreted IL-2, IFN-g IL-4, 5
Result Cytotoxicity, Delayed hypersensitivity Secretion of antibodies
(Choice A) B-cell differentiation into plasma cells and secretion of immunoglobulins is dependent on the T 2 subpopula- H
tion of helper T-cells.
(Choice C) Synthesis of IL-2 is diminished in patients with IL-12 receptor deficiency. This interleukin activates both T and
B-lymphocytes but does not activate macrophages. It is not directly responsible for delayed hypersensitivity reactions.
144. Ans. (b) i.e. Beta-pleated sheet tertiary structure (Ref: Robbins 8th/250, 9/e p257)
The patient has amyloidosis and this protein has a beta-pleated sheet tertiary structure that apparently is reflected in the
apple-green birefringence. Other mentioned properties do not contribute to birefringence.
The ability to bind oxygen (option A) is important to hemoglobin.

Electrophoretic mobility (option C) is used to separate serum proteins.
Hydroxyproline content (option D) is important to collagen structure.
145. Ans. (a) Multiple myeloma-Light chain; (b) Chronic inflammation- AA; (c) Cardiac-ATTR (Ref: Harsh Mohan 5th/87,
Robbins 7th/260, 8th/252, 9/e p259)
1 45.1. Ans (c) Beta 2-microglobulin (Ref: Robbins 8/e p252, 9/e p258)
Hemodialysis associated Amyloidosis
It is caused by the deposition of the 2 microglobulin which is a component of MHC class I molecule and cannot be
Immunity
filtered through the cuprophane dialysis membrane. It gets deposited in the synovium, joints and the tendon sheaths.
The chemical nature of the amyloid is A2Q.
Patients often present with carpal tunnel syndrome because of 2-microglobulin deposition.
1 45.2. Ans. (a) A- Microglobulin..See earlier explanation (Ref: Robbins 9/e p258)
2
1 45.3. Ans. (c) Type 2 DM (Ref: Robbins 8/e p253, 9/e p259)
Amyloid replacement of islets is a characteristic finding in individuals with long-standing type 2 diabetes . It is believed
Q
that the islet amyloid protein is directly cytotoxic to islets, analogous to the role played by amyloid plaques implicated in
the pathogenesis of Alzheimer disease
1 45.4. Ans. (b) Renal tissue (Ref: Robbins 8/e p254, 9/e p261)
Amyloidosis of the kidney is the most common and potentially the most serious form of organ involvement
1 45.5. Ans. (b) Familial amyloidotic polyneuropathy (Ref: Robbins 8/e p253, 9/e p259)
Clinical conditions and the chemical nature of amyloid
S.No. Amylold protein Precursor Disease
1. AL lg light chain Multtiple myeloma (primary amyloidosis)
2. AA SAA Secondary or reactive amyloidosis
3. Ab2m b2microglobulin Hemodialysis Associated amyloidosis
4. Ab Ab precursor protein Senile cerebral Alzhemimers
5. ATTR Mutant Transthyretin Familial amyloidotic neuropathy
Normal Transthyretin Systemic senile amyloidosis
6. ACal Calcitionin Medullary carcinoma of thyroid
7. AIAPP Islet amyloid polypeptide Type II diabetes
8. AANF ANP Isolated atrial amyloidosis
Misfolded prion protein (PrPsc) disease
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9. Aa Fibrinogen Familial renal amyloidosis
1 45.6. Ans. (b)Renal failure (Ref: Robbins 8/e p254, 9/e p261)
Amyloidosis of the kidney is the most common and potentially the most serious form of organ involvement..direct
lines from Robbins.
Renal involvement gives rise to proteinuria that may be severe enough to cause the nephrotic syndrome. Progressive obliteration
of glomeruli in advanced cases ultimately leads to renal failure and uremia. Renal failure is a common cause of death.
1 45.7. Ans. (d) Chronic osteomyelitis (Ref: Robbins 9/e p257, 8/e p253, 7/e p261)
Direct quote tuberculosis, bronchiectasis, and chronic osteomyelitis were the most important underlying conditions,
but with the advent of effective antimicrobial chemotherapy the connective tissue disorders such as rheumatoid arthritisQ
(most common), ankylosing spondylitis, and inflammatory bowel disease, particularly Crohn disease and ulcerative
colitis. Among these the most frequent associated condition is.
1 45.8. Ans. (c) Brilliant pink color (Ref: Robbins 9/e p257, 8/e p253, 7/e p263)
Congo red under ordinary light imparts a pink or red color to amyloid deposits. Under polarized light, the Congo redstained
amyloid shows a green birefringence.
1 45.9. Ans. (a) Sinusoids of red pulp (Ref: Robbins 9/e p261, 8/e p254, 7/e p263)
Spleen involvement in amyloidosis
Red pulp like splenic sinuses: Lardaceous spleen
White pulp like splenic follicles : Sago spleen
(IMMUNITY)
Pattern Recognition Receptors (Page 187 of Robbins)

Cells that participate in innate immunity are capable of recognizing certain microbial components that are shared among related
microbes and are often essential for infectivity. These microbial structures are called pathogen-associated molecular patterns.
Immunity
Pattern recognition receptors are the cellular receptors that recognize these molecules and include:

a. Toll-Like Receptors: The TLRs are present in the plasma membrane and endosomal vesicles. All these receptors
activates either NF-B (stimulating the synthesis and secretion of cytokines) or interferon regulatory factors (IRFs;
stimulate the production of the antiviral cytokines)

b. NOD-Like Receptors and the Inflammasome. NOD-like receptors (NLRs) are cytosolic receptors which recognize a
wide variety of substances like products of necrotic cells (e.g., uric acid and released ATP), ion disturbances (e.g., loss
of K+), and some microbial products. Some NLRs signal via a cytosolic multiprotein complex called the inflammasome
to produce the biologically active form of IL-1.
The NLR-inflammasome pathway may also play a role in many common conditions like gout, atherosclerosis and type 2 diabetes.
c. RIG-like receptors (RLRs): they are located in the cytosol of most cell types and detect nucleic acids of viruses that
replicate in the cytoplasm of infected cells. These receptors stimulate the production of antiviral cytokines.
Innate Lymphoid Cells (ILCs); (Page 193)

ILCs belong to a population of lymphocytes that lack TCRs but produce cytokines similar to those that are made by T cells. NK
cells are considered the first defined ILC. Different subsets of ILCs produce IFN-, IL-5, IL-17, and IL-22. Their functions include:
Early defense against infections
Recognition and elimination of stressed cells (so-called stress surveillance)
Shaping the later adaptive immune response, by providing cytokines that influence the differentiation of T
lymphocytes.
Immunologic Tolerance and Autoimmunity (Page 213)

Tolerance (unresponsiveness) to self antigens is a fundamental property of the immune system, and breakdown of tolerance is
the basis of autoimmune diseases. It can be of the following subtypes:
236
Immunity
Central tolerance: immature lymphocytes that recognize self antigens in the central (generative) lymphoid
organs are killed by apoptosis. Similarly in the B-cell lineage, some of the self-reactive lymphocytes switch to
new antigen receptors that are not self-reactive. This is called as receptor editing.
Peripheral tolerance: mature lymphocytes that recognize self antigens in peripheral tissues become function-
ally inactive (anergic), or are suppressed by regulatory T lymphocytes, or die by apoptosis.
The factors that lead to a failure of self-tolerance and the development of autoimmunity include
Inheritance of susceptibility genes that may disrupt different tolerance pathways, and
Infections and tissue injury that may expose self antigens and activate APCs and lymphocytes in the tissues.
Autoimmune diseases are usually chronic and progressive, and the type of tissue injury is determined by the nature of the
dominant immune response.
Non HLA genes associated with autoimmune diseases.Robbins 9th/ 216

Putative Gene Involved Diseases Postulated Function of Encoded Protein and Role of Mutation/
Polymorphism in Disease
Genes involved in immune regulation:
PTPN22 RA, T1 D, Protein tyrosine phosphatase, may affect signalling in lymphocytes and may after
IBD negative selection or activation of self-reactive T cells
IL23R IBD, PS, AS Receptor for the T117-includeing cytokine IL-23; may after differentiation of CD4+
T cells into pathogenic T1 17 effector cells
CTLA4 T1D, RA Inhibits T cell responses by terminating activation and promoting activity of
regulatory T cells; may interfere with self-tolerance
IL2RA MS, T1D a chain of the receptor for IL-2, which is a growth and survival factor for activated
and regulatory T cells; may affect development of effector cells and/or regulation
of immune responses
Genes involved in immune responses to microbes:
Immunity
NOD2 IBD Cytoplasmic sensor of bacteria expressed in Paneth and other intestinal epithelial
cells; may control resistance to gut commensal bacteria
AT616 IBD Involved in autophagy; possible role in defense against microbes and
maintenance of epithelial barrier function
IRF5, IFIH1 SLE Role in type 1 interferon production; type I IFN is involved the pathogenesis of
SLE (See text)
AUTOANTIBODIES IN AUTOIMMUNE DISORDERS.Robbins 9th/ 219

Disease Specificity of Autoanti Body Association with specific Disease Features
Systemic lupus erythernatosus Double-stranded DNA Nephritis; specific for SLE
(SLE) U1-RNP
Smith (Sm) antigen (Core protein of small RNP Specific for SLE
particles)
Ro (SS-A)/La (SS-B) nucleoproteins Congenital heart block; neonatal lupus
Phospholipid-protein complexes (anti-PL) Antiphospholipid syndrome (in~10% of SLE patients)
Multiple nuclear antigen (generic ANAs) Found in other autoimmune diseases, not specific.
Systemic scleroids DNA topoisornerase 1 Diffuse skin disease, lung disease; specific for
systemic sclerosis
Centromeric proteins (CENPs) A, B, C Limited skin disease, ischemic digital loss,
putomonery hypertension
RNA polymerase III Acute onse, aclerodema renal crisis, cancer
Sjgren syndrome Ro/SS-A
La/SS-B
Autoimmune myositis Histidyl-tRNA synthetase, Jo1 Interstitial lung disease, Raynaud phenomenon
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Mi-2 nuclear antigen Dermatomyositis, skin rash

MDAS (cytoplasmic receptor for viral RNA) Vascular skin lesions, interstitial lung disease
TF1y nuclear protein Dermatomyositis, cancer
Rheumetold arthritis CCP (cyclic citrullinated peptides); various Specific for rheumatoid arthritis
citrullinated proteins
Rheumatoid factor (not specific)
For Special Attention...Potential Future AIIMS Question
Anti RNA polymerase III antibody is associated with Acute onset, scleroderma renal crisis and cancer.
Autoimmune myositis is associated with antibody against Histidyl aminoacyl-tRNA synthetase, Jo1 25, Mi-2
nuclear antigen, MDA5 (cytoplasmic receptor for viral RNA) and TIF1 nuclear protein
IgG4-RELATED DISEASE.Robbins 9th/ 231
IgG4-related disease (IgG4-RD) is an idiopathic newly recognized constellation of disorders affecting middle
aged to old men characterized by tissue infiltrates dominated by IgG4 antibody-producing plasma cells and
T lymphocytes, storiform fibrosis, obliterative phlebitis, and usually increased serum IgG4.Autoimmune
myositis is associated with antibody against Histidyl aminoacyl-tRNA synthetase, Jo1 25, Mi-2 nuclear
antigen, MDA5 (cytoplasmic receptor for viral RNA) and TIF1 nuclear protein.
It includes disorders like Mikulicz syndrome (enlargement and fibrosis of salivary and lacrimal glands), Rie-
del thyroiditis, idiopathic retroperitoneal fibrosis, autoimmune pancreatitis, and inflammatory pseudotu-
mors of the orbit, lungs, and kidneys.
X-linked Lymphoproliferative Disease.. Robbins 9th/242

It is characterized by an inability to eliminate Epstein-Barr virus (EBV), eventually leading to fulminant infectious
Immunity
mononucleosis and the development of B-cell tumors.

In most of the cases it is caused by mutations in the gene for SLAM-associated protein (SAP) that are associated with the
activation of NK cells and T and B lymphocytes. This leads to attenuated NK and T cell activation and result in increased
susceptibility to viral infections. SAP is also required for the development of follicular helper T cells, and so, XLP patients are
unable to form germinal centers or produce high affinity antibodies.
238
CHAPTER 7 Anemia and Red Blood Cells

Hematology is the study of the various cells and components of the blood. Hematopoeisis is
the process of production of blood cells which primarily takes place in the following organs: Sites of Hematopoeisis
Till 3rd week of intrauterine life:
Yolk sac.
SALIENT FEATURES OF BONE MARROW
By 3rd month of intrauterine life:

The ratio of the fat cells and the hematopoeitic cells in an adult is 1:1. The number of Liver is the main site of blood
formation.
the myeloid cells is more than the number of the erythroid cells (normal M:E ratio
is 3 to 15:1). At 4th month of intrauterine life:

The investigations for the information about bone marrow are bone marrow Bone marrow is the main site of
hematopoiesis.
aspiration and bone marrow biopsy.
Hematopoietic stem cells are pluripotent stem cells which are CD34+ cells. They give rise to Finally by birth, the bone
marrow in whole of the skeleton
the trilineage myeloid cells, lymphoblasts and monoblasts. The trilineage myeloid cell gives
is hematopoietically active and is
rise to the following three cells: the chief source of blood cells and

Normoblast (Gives rise to RBCs) it remains so till puberty.

Myeloblast (Gives rise to neutrophils, eosinophils and basophils) After puberty, the red marrow

Megakaryocyte (Gives rise to platelets). is present in vertebrae, ribs,
Monoblast gives rise to monocytes whereas lymphoblast gives rise to lymphocytes. sternum, skull, pelvis and proximal
epiphyseal regions of humerus
Stages of Erythropoiesis and femur.
Hemoglobinization takes place

during the stage of intermediate
normoblast.
General Information About RBCs The normal reticulocyte count

is 0.2-2%.
The normal red cell is biconcave in shape and has a diameter of 7-8 mm. The cytoskeleton
of the RBC is made up of proteins like spectrin, ankyrin, band 2.1, band 3, band 4.1, etc.
that provide deformability to the RBCs so that they can cross through tiny blood vessels
like capillaries. Importance of these proteins can be appreciated in disorders like hereditary
spherocytosis. When the RBCs are of unequal size, this is referred to as anisocytosis and when
Spectrin is the chief protein
of different shapes, it is called poikilocytosis. responsible for biconcave shape
of normal red blood cell.
Reticulocytes are nonnucleated spherical cells bigger than normal RBCs and are polychromatic
(having a blue color) due to the presence of free ribosomes and RNA.
Reticulocyte count: Percentage of reticulocytes among the red cells present in the peripheral
blood is called reticulocyte count. Normal value is around 1.5% in adults and 1.7% in the cord
blood cells.
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Absolute reticulocyte count (ARC): Number of reticulocytes present in 1 mm3 of blood.

The reticulocyte count is an ARC = (Reticulocyte %) X Erythrocyte Count/100.
indicator of erythropoetic activity Reticulocyte Index (RI): It adjusts reticulocyte count for hematocrit. It reflects bone marrow
of the bone marrow. activity and is also known as Poor mans Bone Marrow Aspirate. Normal reticulocyte index is
1-3%.
RI = Reticulocyte Count X (Hb/Age and sex adjusted normal Hb level).
Reticulocytosis (Increased RBC production) Reticulocytopenia (Decreased RBC production)

*Criteria *Criteria
Reticulocyte Index > 3% Reticulocyte Index < 1%
Reticulocyte Index: Reflects Reticulocyte Count > 1.5% Reticulocyte Count < 0.5%
bone marrow activity and is also
known as Poor mans Bone Conditions Conditions
Marrow Aspirate. Acute blood loss or hemorrhage
Aplastic anemia
Postsplenectomy
Bone marrow infiltration
Microangiopathic Anemia
Bone marrow suppression (Sepsis/Chemotherapy
Autoimmune Hemolytic Anemia radiotherapy)
Hemoglobinopathy (Sickle cell anemia and
Blood transfusion
Thalassemia)
Liver disease
Reticulocytes are stained in

Post anemia Treatment like Folate Supplementa-
Disordered RBC maturation (Iron, B12, Folate
tion, Iron Supplementation and vitamin B12 Deficiency, Hypothyroidism, Sideroblastic Anemia
living state in vitro so staining Supplementation. or Anemia of Chronic Disease)
with dyes like brilliant cresyl
blue and new methylene blue is ANEMIAS
referred to as supravital stai
ning. Anemia is defined as any reduction below normal limits of the total circulating red cell
mass which is characterized by the clinical features of pallor of skin and nails, dizziness,
Anemia and Red Blood Cells
palpitations, lethargy and fatigue.

Some of the important terms used in context of anemias are as follows:
MCV (Mean cell volume): It is the average volume (in femtolitres) of a red blood cell (normal
value is 82-96 fl). If the value of MCV is less than 80 fl, RBCs are called microcytic and if the MCV
is more than 100 fl, RBCs are called macrocytic.
MCH (Mean corpuscular hemoglobin): Average mass of hemoglobin (in picograms) per red
blood cell is MCH. Normal value is 27-33 pg.
MCHC (Mean corpuscular hemoglobin concentration): MCHC is average concentration of
hemoglobin in a given volume of packed red blood cells. Normal value is 33-37g/dl.
RDW (Red cell distribution width): It is the coefficient of variation of size of RBCs. Normal value
is 11.5-14.5. The important point to be kept in mind is that RDW is an indicator of anisocytosis.
Normal RBCs have central pallor of around a third of the diameter (normochromic). If the color is
RDW (Red cell distribution decreased which means pallor more than one-third, the RBCs are called hypochromic and if color
width): is an indicator of aniso is increased (central pallor is lost), the RBCs are called hyperchromic.
cytosis.
240
Microcytic
Hypochromic
Anemia: Causes
S - Sideroblastic anemia
I - Iron deficiency
T - Thalaesemia
A - Anemia of chronic disease
Macrocytic
Anemia: Causes
L - Liver disease (As in alcoholics)
H - Hypothyroidism
M - Megaloblastic anemia (Folic
acid and vitamin B12 deficiency)
C - Cytotoxic drugs like metho-
trexate and other drugs like phe-
nytoin.
A. BLOOD LOSS
Blood loss causes decrease in hematocrit resulting in compensatory increased release of
erythropoietin from the renal juxtaglomerular cells. Erythropoietin stimulates increased

bone marrow activity. However, the earliest change in the peripheral blood is leucocytosis
(caused by increased mobilization from the marginal pools) followed by reticulocytosis
and thrombocytosis. Chronic blood loss is usually due to GIT lesions and gynecological
disturbances.
B. IMPAIRED RBC PRODUCTION
1. DUE TO DECREASED ERYTHROPOIESIS

This category of anemias may result from the defective DNA synthesis due to vitamin B12 or
folic acid deficiency (called megaloblastic anemia) or impaired heme synthesis due to iron
deficiency.
a. Megaloblastic Anemia
The chief feature in this anemia is impaired DNA synthesis resulting in delayed mitosis Earliest change in the
while RNA and protein synthesis is not impaired. This leads to nuclear/cytoplasmic asynchrony peripheral blood after acute
which affects all proliferating cell lines particularly cells of bone marrow and GIT cells. The blood loss is leucocytosis
chief findings are a hypercellular bone marrow with megaloblasts in the bone marrow along followed by reticulocytosis and
thrombocytosis.
with presence of abnormal granulocytic precursors (giant metamyelocyte and band forms) and
large megakaryocytes with bizarre multilobated nuclei. The presence of ineffective erythropoiesis
can result in pancytopenia associated with features of hemolytic anemia including jaundice
and increased levels of serum bilirubin and LDH enzyme. In the peripheral smear, there
is pancytopenia with presence of macrocytes (RBCs having MCV >100 fl) lacking a central
pallor. There is characteristically presence of large and hypersegmented neutrophils
(neutrophils having > 5 lobes). The earliest manifestation of megaloblastic anemia is presence of
hypersegmented neutrophils. Diagnosis is made if even a single neutrophil with 6 lobes is
seen or > 5% neutrophils with 5 lobes are seen.
Note:
Triad of megaloblastic anemia includes oval macrocytes, Howell Jolly bodies and hyperseg-
mented neutrophils.
MCHC is not elevated because hemoglobin increases proportionately to the increased volume
of the RBCs.
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The two main causes of this anemia are vitamin B12 and folic acid deficiency.
Earliest manifestation of mega
(i) Vitamin B12 deficiency
loblastic anemia is presence of Normal vitamin B12 metabolism
hypersegmented neutrophils. The vitamin B12 (or cobalamin) is present in the bound form (bound with dietary
proteins) in the diet. It is freed by the action of pepsin in stomach and then binds with
salivary proteins called R-binders (also known as cobalaphilins). In the duodenum,
this cobalamin-cobalaphilin complex is broken by the action of pancreatic proteases.
Free cobalamin now binds with the intrinsic factor (Castles factor) secreted from the
parietal cells of the stomach. Vitamin B12-intrinsic factor complex is taken by the ileal
enterocytes. Within the intestinal cells, the cobalamin gets bound with a transport
protein called transcobalamin II which delivers it to the rapidly proliferating cells of
the body (bone marrow and GIT cells). So, the causes of vitamin B12 deficiency can
be:
MCHC is not elevated in mega

loblastic anemia because hemo-
globin increases proportionately
to the increased volume of the
RBCs.
Biochemical functions of vitamin B 12

It is required for the conversion of homocysteine to methionine
It is also involved in the conversion of methylmalonyl CoA to succinyl CoA which
is required for the formation of normal neuronal lipids. So, any deficiency of
vitamin B12 results in neurological features. Also, there are increased levels of
methylmalonic acid in the serum and urine of the patient with deficiency of this
vitamin.
Vitamin B12-intrinsic factor

complex is taken by the ileal
Pernicious anemia
enterocytes. It is an autoimmune disorder against parietal cells of the stomach by auto-reactive T cells
resulting in chronic atrophic gastritis and parietal cells loss (responsible for decreased
intrinsic factor production). The antibodies which are present in the patients are:
Concept
Type I antibodies (most common): Block binding of vitamin B12 to IF (in 75% patients).
Vitamin B12
Type II antibodies: Prevent cobalamin-IF binding with ileal receptors.
It is required for the conver Type III antibodies: formed against the a and b subunits of gastric proton pump (seen in 90%
sion of homocysteine to patients but not specific as it also seen in idiopathic chronic gastritis).
methionine.

It is also involved in the con It is also associated with other autoimmune disorders like autoimmune thyroiditis and
version of methylmalonyl adrenalitis.
CoA to succinyl CoA which
is required for the formation Morphology
of normal neuronal lipids. So,
any deficiency of vitamin B12 The principal organs affected are the bone marrow, GIT and CNS which show the following
results in neurological fea features:
tures.
Bone marrow
Megaloblasts, hypersegmented neutrophils and precursors of granulocytes along with megakaryocytes
are seen.
242
GIT
There is presence of shiny and beefy tongue due to atrophic glossitis, almost complete loss of parietal
cells and replacement of gastric mucosa by mucus secreting goblet cells (intestinalization).
CNS
There is principally demyelination of the dorsal and lateral spinal cord tracts which can also be
associated with degenerative changes in the posterior root ganglia and peripheral nerves in severe
deficiency cases. Latter can result in involvement of both motor and sensory pathways. The combined The combined involvement of
involvement of the axons in the ascending tracts of posterior column and the descending pyramidal the axons in the ascending
tract is a characteristic feature of vitamin B12 deficiency giving the term as subacute combined tracts of posterior column
degeneration of the spinal cord. and the descending pyramidal
tract is a characteristic feature of
Clinical Features vitamin B12 deficiency giving the
term as subacute combined
They are as follows: degeneration of the spinal

Megaloblastic anemia cord.

Pancytopenia (Leucopenia with hypersegmented neutrophils, thrombocytopenia)

Jaundice due to ineffective hematopoiesis and peripheral hemolysis

Neurological features due to posterolateral spinal tract involvement.
Laboratory tests
Schilling test: It is performed
Serum antibodies against intrinsic factor are present. to distinguish between different

causes of vitamin B12 deficiency.
Achlorhydria even after histamine stimulation.
It is NOT USED for the diagnosis
Increased serum levels of methylmalonic acid and homocysteine. of vitamin B12 deficiency.


Schilling test: It is performed to distinguish between different causes of vitamin B12 deficiency.
(ii) Folic acid deficiency

Megaloblastic anemia caused due to folic acid deficiency is clinically indistinguishable
from vitamin B12 deficiency anemia. However, folic acid deficiency is NOT associated
with neurological abnormalities. Diphyllobothrium latum is

b. Due to Defective Hemoglobin Synthesis associated with megaloblastic

(i) Iron deficiency anemiaQ

It is the commonest cause of anemia worldwide.
Normal iron metabolism
The metabolism of iron can be divided in the following headings:
Absorption Ankylostoma duodenale is
Iron is present in two forms in the food: heme and nonheme iron. The iron is associated with iron deficiency
anemiaQ.
absorbed more completely from the heme form (present in the nonvegetarian food)
as compared to nonheme form. The factors affecting absorption of iron include:
Factors increasing absorption Factors decreasing absorption Megaloblastic anemia caused

Ferrous form (Fe ) 2+
Ferric form (Fe3+) due to folic acid deficiency is
NOT associated with neuro-
Acid (HCl) in the stomach Achlorhydria (absence of HCl secretion) logical abnormalities.
Ascorbic acid Alkaline food (pancreatic secretions)
Amino acid and sugars in the food Phytates, tannates and phosphates in diet
Iron deficiency Iron overload
Physiological conditions (pregnancy and hypoxia) Tetracyclines and EDTA
Inflammatory disorders
Concept
Iron is absorbed primarily from the duodenum in the ferrous form. It is transported inside the
Pernicious anemia is
enterocytes by an apical transporter called DMT1 (Divalent Metal Transporter 1) and from associated with increased risk
here, it enters the plasma by two basal membrane transporters (ferroportin and hephaestin). of gastric cancer and increased
A fraction of ferrous iron gets converted into ferric state by intracellular oxidation. Most chances of atherosclerosis
of the iron absorbed from the gut is lost because of mucosal lining shedding whereas in
and thrombosis (because of
increased requirements it is absorbed in a greater percentage. elevated homocysteine levels).
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CONCEPT
A regulatory protein called hepcidin regulates the absorption of iron from the gut. In
case of iron depletion the level of this negative regulatory protein is decreased thereby
increasing the absorption of iron and vice versa. Mutation of the gene coding for hepcidin
Iron is absorbed primarily from is implicated in the causation of hemochromatosis.
the duodenum in the ferrous
form. Transport and storage of iron
From the enterocytes, the absorbed iron is transferred to a plasma protein called transferrin
that delivers it to different cells of the body expressing high levels of transferrin receptors
on their surface. These cells include hepatocytes and the developing erythroblasts in the bone
marrow. The serum transferrin saturation is an indicator of serum iron concentration.
Absorbed iron is transferred Normally, transferrin is 33% saturated (one-third saturation) with iron. Since, the serum
to a plasma protein called transferrin concentration is nearly 300-350 g/dl (also called as total iron binding capacity
transferrin. or TIBC), the normal serum iron levels are in the range of 100-120 g/dl. The iron which is
not immediately required by the cells is stored in the form of ferritin which is a protein iron
complex present in all the tissues especially liver, spleen and bone marrow. It is the ferric
form of iron which is present in ferritin. A small amount of ferritin is also present in the plasma
which is derived from the storage pools of the body iron; so, serum ferritin is an indicator
Each molecule of transferrin of body iron stores. Intracellular iron is converted into hemosiderin which stains positively
can transport two molecules of with potassium ferrocyanide giving a positive Prussian blue stain.
iron to the desired areas.
The normal requirement of iron in the diet is nearly 1 mg/d. The causes of iron deficiency
anemia include the following:
Dietary lack Impaired Increased Chronic blood loss

Iron is stored in ferritin in the absorption requirement
ferric form.
Infants Steatorrhea Growing infants GIT (peptic ulcer, gas-
Children Sprue and children tric cancer, hemorrhoids,
Low socio- Chronic diarrhea Pregnant females hookworm disease)
economic status Gastrectomy Premenopausal Urinary tract (renal, pelvic
Elderly women or bladder cancers)
Most of the bodys iron is Genital tract (uterine can-
contained in hemoglobin and cer, menorrhagia)
not ferritin.
Features of Iron Deficiency Anemia
It is characterized by the following stages:
Serum ferritin is an indicator of Stage I or stage of negative iron balance
body iron stores. This is a stage characterized by decreased amount of storage iron manifesting as decreased serum
ferritin concentration and reduced amount of bone marrow iron staining with Prussian blue stain.
The serum iron and red cell protoporphyrin levels are absolutely normal. Though TIBC is marginally
increased, the red cell indices and morphology are normal.
Stage II or stage of iron deficient erythropoeisis
This is a stage of reduced circulating iron in addition to decrease storage form of iron. So, this stage
is characterized by deficient iron stores, reduced serum ferritin, decreased % saturation of serum
transferrin and increased TIBC. The red cell morphology is normal.
Stage III or stage of iron deficiency anemia
It is characterized by all features of stage II and in addition abnormal morphology of the red cells, i.e.
the presence of microcytic and hypochromic cells.
Clinical features include fatigue, impaired growth and development, pica (eating
noedible substances like mud, etc. in children), koilonychia (angular or spoon shaped nails),
angular stomatitis (ulceration at the angle of mouth), dysphagia (as in Plummer Vinson
syndrome) and palpitations (because of hyperdynamic circulation which can even precipitate
congestive heart failure).
244
Peripheral blood
Microcytic and hypochromic red cells with slight reticulocytosis whereas TLC is normal. Usually,
microcytosis is seen before appearance of hypochromia. Poikilocytosis is seen in form of small and The normal requirement of iron
in the diet is nearly 1 mg/d.
elongated red cells called pencil cells. It is also characteristic feature of this disease. There is increased
red cell distribution width also.
Bone marrow
Hypercellular bone marrow (having increased erythroid progenitors) with depleted bone marrow iron
stores.

Serum ferritin and serum iron are decreased whereas serum transferrin and TIBC are increased.

Red cell protoporphyrin levels are increased because there is decrease in the availability of
heme (due to reduced iron availability) resulting in elevated free erythrocytic protoporphyrin levels.
RBC free protoporphyrin is normally 30-50 g/dl whereas its value reaches > 200 g/dl in iron
deficiency anemia.
The treatment of anemia is with the help of either oral or parenteral iron therapy the
response of which is clinically assessed with the reticulocyte count on about 8th - 9th day
which demonstrates reticulocytosis.
Differential diagnosis of microcytic hypochromic anemia In iron deficiency anemia,
microcytosis is seen before
Tests Iron Inflammation Thalassemia Sideroblastic appearance of hypochromia.
deficiency anemia
Peripheral Micro/hypo Normal Micro/hypo Variable
smear micro/hypo with targeting
SI < 30 < 50 Normal to high Normal to high

TIBC > 360 < 300 Normal Normal
Percent TS < 10 10-20 30-80 30-80
TIBC levels at
Ferritin(mcg/L) < 15 30-200 50-300 50-300 Top = Iron deficiency (In iron
Hemoglobin pattern Normal Normal Abnormal Normal deficiency anemia, TIBC is
raised)
SI, serum iron; TIBC, total iron-binding capacity; TS, transferrin saturation. Bottom = Chronic disease (In

(ii) Thalassemia Anemia of Chronic Disease,
It is discussed in detail with other hemolytic diseases.
TIBC is low).
There are many indices to differentiate between iron deficiency anemia (IDA) and
beta-thalassemia (BT):
Index Formula Value for Value
Iron deficiency for beta-
anemia thalassemia
Mentzer index MCV/RBC count > 13 < 13
Shine and Lal index MCV X MCH X 0.01

2
> 1530 < 1530
England and Fraser index MCV RBC (5 X Hb) 5.19 >0 <0
Srivastava index MCH/RBC > 3.8 < 3.8
Green and king index MCV2 X RDW X Hb/100 > 65 < 65
Red Cell Distribution Width MCV X RDW/RBC > 220 < 220
index
a. Miscellaneous

i. Anemia of Chronic Disease (AOCD)
It is characterized by the decreased utilization of iron from the storage from of iron, i.e.
ferritin. In chronic inflammatory conditions, there is increased secretion of cytokines
like IL-1, TNF, IFN-g, etc. that cause release of the protein hepcidin because of which
Anemia of chronic disease is
release of iron from the storage pool is inhibited. This result in the high serum caused by hepcidin.
ferritin levels, reduced TIBC, reduced % transferrin saturation and decreased serum
iron levels.
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In the peripheral blood smear there is presence of microcytic and hypochromic

red cells.
In the bone marrow there is absence of hypercellularity because of inhibition of
erythropoetin secretion by renal cells due to the action of cytokines like IL-1, etc.
Common clinical conditions having AOCD include diseases like rheumatoid
arthritis, regional enteritis, osteomyelitis, lung abscess and cancers like
Hodgkins lymphoma, carcinomas of breast and lung.
Mnemonic: During a chronic inflammation (microbial or RA) the microbes want iron, so our
body reacts by locking all of its iron within the macrophages and loosing the key
The good news is that the microbe does not get any iron However, the bad news is that our
Concept body doesnt get iron either, which reduces the amount of heme (no iron, no heme), which re-
duces the amount of hemoglobin. hence, microcytic anemia.
Anemia of chronic disease is
differentiated from iron deficiency
(ii) Anemia due to marrow infiltration
anemia morphologically by the
fact that microcytosis follows
This type of anemia is caused due to infiltration of the bone marrow resulting in
myelophthisic anemia. It is characterized by presence of immature erythroid and
hypochromia (microcytosis
precedes hypochromia in IDA).
myeloid precursors in the blood (this is called as leukoerythroblastosis). Metastasis
from cancers like breast, lung and prostate are the most common cause of marrow
infiltration.

(iii) Sideroblastic anemia
Sideroblastic anemia is char-
Sideroblastic anemia is characterized by the presence of ringed sideroblasts. These are
normoblasts having pin point iron granules (easily demonstrable with the help of
acterized by the presence of
ringed sideroblasts. Prussian blue dye) in the cytoplasm or perinuclear region. Sideroblastic anemia
can be hereditary (due to decreased ALA synthase activity) or acquired (secondary
to leukemias, myelodysplastic syndrome, alcoholism, copper deficiency, pyridoxine

deficiency or lead poisoning). The pathogenesis of the diseases involves defective
heme synthesis resulting in ineffective erythropoiesis which thereby contributes to
There is increase in serum iron overload.
iron, serum ferritin, % transferrin
saturation and free erythrocyte

Peripheral smear is characterized by presence of microcytic hypochromic cells
which also demonstrate the presence of anisopoikilocytosis. There is increase
porphyrin whereas TIBC is
in serum iron, serum ferritin, % transferrin saturation and free erythrocyte porphyrin
decreased.
whereas TIBC is decreased.
Note: Abnormal sideroblasts are also seen in thalassemia, megaloblastic anemia and hemolytic ane-
mias.
2. DUE TO DECREASED STEM CELLS PROLIFERATION

a. Aplastic anemia
This is a disorder characterized by marrow failure associated with pancytopenia
(anemia, thrombocytopenia and leukopenia). The causes are:
Acquired Inherited
Primary stem cell defect Fanconi anemia
Irradiation
Viral infections [hepatitis (non A, non B , non C, non G), CMV, EBV,
varicella zoster virus]
Chemical agents (alkylating agents, antimetabolites, benzene,
chloramphenicol, phenylbutazone, arsenicals, insecticides like DDT,
parathion)
It has been postulated that the etiological agents cause alteration in the stem cells thereby
activating the T cells of the body against them resulting in destruction of the stem cells
contributing to the pancytopenia.
Bone marrow aspiration in The bone marrow biopsy shows it is characteristically hypocellular being replaced by fat cells (in
aplastic anemia reveals dry contrast to aleukemic leukemia and myelodysplastic syndrome in which we have pancytopenia as-
tap. sociated with hypercellular marrow) whereas bone marrow aspiration reveals dry tap.
246
Clinical features are caused because of anemia (pallor, weakness and dyspnea), thrombo
cytopenia (petechiae) and neutropenia (recurrent infections). Red cells are normocytic and
normochromic.
Characteristically, splenomegaly is absent and reticulocytopenia is the rule.
It is treated with either bone marrow transplantation (in young patients) or antithymocyte
globulin (in old patients).

b. Anemia of chronic disease (has been discussed above) Features of Shwachman

c. Anemia of renal failure Diamond syndrome are exocrine
It is characterized by inadequate release of erythropoetin resulting in development pancreatic insufficiency, bone
marrow dysfunction, skeletal
of anemia. The other contributory factors are:
abnormalities, neutropenia and

Iron deficiency secondary to increased bleeding tendency (seen in uremia)
short stature.

Extracorpuscular defect induced hemolysis
The severity of anemia is proportional to uremia and is usually managed with
recombinant erythropoetin.
C. HEMOLYTIC ANEMIA
This type of anemia can be due to intracorpuscular or extracorpuscular defects.

Hemolysis can result due to destruction of RBCs inside the circulation (intravascular) or
outside the blood vessels (extravascular).
Haptoglobin followed by hemo-

pexin form the defense against
free heme in the plasma.
Note: Serum haptoglobin decrease but not as much as in intravascular hemolysis.

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1. Hereditary Spherocytosis
Hereditary spherocytosis (HS), an autosomal dominantQ disorder, is an important cause of
hemolytic anemia.
Normal RBC membrane skeleton

Normally, RBC membrane consists of a protein spectrin, which has two subunits a and b.
This spectrin is attached to cell membrane at two sites. At head region, spectrin binds to ion
transporter, band 3 of membrane with the help of ankyrin and band 4.2 whereas at the tail
region, spectrin binds to glycophorin A of the membrane by protein 4.1 and actin.
Mostly the mutations in HS

are seen in head region most
commonly in ankyrinQ.
Maximum amount of H antigen:

O blood group
Mutations in these proteins can result in HS. Mostly the mutations are seen in head
region most commonly in ankyrinQ [Robbins 8th/e pg 642] and the next common mutation is
in band 3 (Anion channel). Rarely, the mutations can be seen in band 4.2 (Palladin), spectrin
and glycophorin A.
Minimum amount of H antigen: Pathogenesis

AB blood group HS is characterized by reduced life span of RBC [10-20 days as compared to 120 days] and has
increased osmotic fragility (the pathogenesis is explained above). The main clinical findings
are jaundice, splenomegaly and gallstones. A characteristic feature of HS is increase in MCHCQ
due to dehydration caused by loss of K+ and water. It is almost the only condition where high
MCHC is seen.
248

A characteristic feature of HS
is increase in MCHCQ due to
dehydration caused by loss of K+
and water.
Note:

Mutations in a spectrin are most common cause of hereditary elliptocytosis [65% cases] and b
spectrin mutation is responsible for another 30% cases. Some of the cases of HE occur due to
mutation in band 4.1.

Please note that spherocytosis on peripheral smear is not pathognomic of HS because autoim-
Osmotic fragility is increased in
HS.
mune hemolytic anemias, infections/burns, ABO hemolytic disease (NOT with Rh hemo-
lytic disease) of new born and G6PD deficiency can also result in formation of spherocytes.

Unlike hereditary spherocytosis, Autohemolysis in ABO HDN is not corrected by addition of glu-
coseQ
Pink testQ is done to measure the osmotic fragility. SplenectomyQ is almost always
beneficial in HS. After splenectomy anemia is corrected but spherocytes will remain in blood.
The vaccination against encapsulated organisms like pneumococccus and H. influenza is also
must.
Most common mutation in HS
2. Glucose 6-Phosphate Dehydrogenase Deficiency (G-6PD Deficiency)
is in ankyrin and in HE is in a
Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from spectrin.
deficient or impaired enzyme function reduce the ability of red cells to protect themselves To rememeber: S is not for
against oxidative injuries. This results in hemolytic disease. The most important of these is S means spectrin is not in
spherocytosis.
G6PD deficiency. Normal G6PD functioning is required to decrease oxidative damage to
RBCs.
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G6PD deficiency manifests in several distinct clinical patterns. Most common is

The episode is self-limited, as hemolysis after exposure to oxidant stress. This can occur due to ingestion of certain drugs
hemolysis stops when only the or foods (consumption of fava beans), or more commonly, exposure to oxidant free radicals
younger red cells remain (even generated by leukocytes in the course of infections. The oxidant drugs include antimalarials
if administration of an offending
(e.g., primaquine and chloroquine), sulfonamides, nitrofurantoin, etc.
drug continues).
G6PD deficiency causes both episodic intravascular and extravascular hemolysis. When
G6PD-deficient red cells are exposed to high levels of oxidants, there is oxidation of globin
chains, which become denatured and form membrane-bound precipitates known as Heinz
bodies. These can damage the membrane sufficiently to cause intravascular hemolysis. Less
severe membrane damage results in decreased red cell deformability leading to formation
of spherocytes or removal of membrane by the macrophages leading to the presence of bite
cells. Both bite cells and spherocytes are trapped in splenic circulation resulting in their
removal by erythrophagocytosis.
Features of chronic hemolytic

anemias like splenomegaly
and cholelithiasis are absent
because the hemolytic episodes
occur intermittently.
Acute intravascular hemolysis with anemia, hemoglobinemia, and hemoglobinuria usually

begins 2 to 3 days following exposure of G6PD-deficient individuals to oxidants. Since only
older red cells are at risk for lysis, the episode is self-limited, as hemolysis stops when only
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the younger red cells remain. Reticulocytosis is seen in the recovery phase. The features of
chronic hemolytic anemias like splenomegaly and cholelithiasis are absent because the
hemolytic episodes occur intermittently.
3. Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is the only hemolytic anemia caused by an
acquired intrinsic defect in the cell membrane. The stem cells of the bone marrow acquire PNH is the only hemolytic
mutations in Phosphatidyl inositol glycan A (PIGA) gene, which is essential for the synthesis of the anemia caused by an acquired
glycosylphosphatidyl inositol (GPI) anchor. GPI is responsible for providing an anchor for cell intrinsic defect in the cell
membrane attachment of some proteins. These proteins are also required for inactivating the membrane.
complement. The examples of these proteins include:
Decay-accelerating factor or CD55

Membrane inhibitor of reactive lysis, or CD59 The stem cells of the bone
C8 binding protein marrow acquire mutations in
Phosphatidyl inositol glycan A
Out of the above mentioned proteins, CD 59 is most important. It is a potent inhibitor of
(PIGA) gene.
C3 convertase, and thereby prevents spontaneous activation of the alternative complement
pathway in vivo. These defects are not limited to red blood cells, as deficient platelets and
granulocytes are also more sensitive to lysis by complement.
Clinical features include intravascular hemolysis with hemoglobinuria. The complement The triad of hemolysis, pan-
system is activated by acidotic conditions like exercise (accumulation of lactic acid) or sleep cytopenia and thrombosis is
(due to decreased respiratory rate). Since the respiration decreases at night, so, patient unique to PNH.
experiences intermittent attacks (paroxysmal) of hemolysis at night (nocturnal) resulting in
passage of red urine (hemoglobinuria) in the morning. The dysfunction of the GPI linked

proteins on the platelets is responsible for the prothrombotic state. Thrombosis is the leading Thrombosis is the leading cause
cause of disease related death in PNH patients as it can affect cerebral, hepatic or portal veins. of disease related death in
PNH.
Diagnosis
It is best made with flow cytometry in which there is presence of bimodal distribution of the red
cells i.e. cells which are deficient in CD55/CD59 as well normal cells which are CD55+/CD59+. PNH is best diagnosed with flow
Other tests demonstrating increased susceptibility to the complement system which can be used cytometry in which there is pres-
for diagnosis include: ence of bimodal distribution of
1. Hams acidified serum test: lysis of erythrocytes on addition of acidified serum. the red cells.
2. Sucrose lysis test: complement system is increased by the presence of sucrose.
4. Immune Hemolytic Anemias

Immune hemolytic anemias are caused because of the formation of anti-RBC antibodies.
Types of Immune Hemolytic Anemia
Warm antibody type Cold antibody type
Mostly IgGQ; rarely IgA Mostly IgMQ, rarely IgG
Causes Causes
Primary (Idiopathic) Primary (Idiopathic)
SLEQ , rheumatoid arthritis Mycoplasma infection,
B cell lymphoid neoplasms Infectious Mononucleosis
Drugs (-methyldopa, penicillin) Lymphoid neoplasms
Paroxysmal cold hemoglobinuria (IgG)
Mechanism of hemolysis Mechanism of hemolysis
Extravascular hemolysis (in spleen) Extravascular hemolysis in cold agglutinin
Intravascular hemolysis in cold hemolysins
The antibody does not usually fix Antibodies reacts at 4-6C, dissociate at 30C or
complement, and is active at 37C. above
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Cold-antibody autoimmune hemolytic anemia (cold AIHA) is subdivided into two

clinical categories based on the type of antibodies involved. These two types of cold antibodies
are:

1. Cold agglutinins: these are monoclonal IgM antibodies that react at 4 to 6C. They
Cold agglutinins: Are are called agglutinins because the IgM directed against the I antigen present on
associated with Mycoplasma the RBCs can agglutinate red cells due to its large size (pentamer). In addition IgM
pneumonitits and infectious
mononucleosis.
can activate complement resulting in the cells being coated with C3b followed by
extravascular hemolysis. Examples include Mycoplasma pneumonitits and infec
tious monoucleosis. Vascular obstruction by the red cell agglutination can produce
Raynauds pheonomenon, which is characterized by ischemia in the fingers when
expose to the cold.
Paroxysmal cold hemolglobinuria

2. Cold hemolysins: these are seen in patients with paroxysmal cold hemolglobinuria
(PCH). They are unique because they are biphasic antierythrocyte autoantibodies. These
(PCM) has the presence of
Donath-Landsteiner antibody. antibodies are IgG that is directed against the P blood group antigen. They are
called biphasic because they attach to red cells and bind complement at 4C but
the complement activation takes place when the temperature is increased. This is
followed by intravascular hemolysis. The antibody is called the Donath-Landsteiner
antibody (previously associated with syphilis, but also with mycoplasma pneumonia
measles, mumps, and ill defined viral and flu syndromesQ.
Microangiopathic hemolytic

3. Microangiopathic hemolytic anemia (MAHA)
anemia (MAHA) is identified
MAHA is a microangiopathic subgroup of hemolytic anemia (anemia, loss of red blood cells
by the finding of anemia and
schistocytes, burr cells, through destruction) caused by factors in the small blood vessels. The endothelial layer of
helmet cells, and triangle small vessels is damaged with resulting fibrin deposition and platelet aggregation. As red
cells on microscopy. blood cells travel through these damaged vessels, they are fragmented resulting in intra-
vascular hemolysis. It is identified by the finding of anemia and schistocytes, burr cells,

helmet cells, and triangle cellson microscopy (should be > 3/5000 cells) and these
should have 1-3 sharp spicules. It is associated with conditions like DICQ (most common-
ly), malignant hypertension, SLE, thrombotic thrombocytopenic purpura (TTP), hemolytic-
uremic syndrome (HUS), and disseminated cancer.
4. Hemoglobinopathies
HbA is a2b2 (95-96%) The normal hemoglobin is composed of heme (consisting of iron and protoporphyrin)
HbA2 is a2b2 (3-3.5%) and globin (having two pairs of polypeptide chains).
HbF is a2g2 (present in the The adult hemoglobin (HbA) forms about 95-96% of total hemoglobin and is
fetal life). As gestational age composed of two identical a and two b chains.
increases, the g chains are
replaced by the b chains,
The other hemoglobin seen in the adults is HbA2 (normally less than 3.5% of total
resulting in formation of adult hemoglobin) consisting of two identical and two chains.
hemoglobin, HbA. The hemoglobin in the fetal life is HbF consisting of two identical a and two g chains.
A. Sickle cell anemia

This is characterized by the presence of an abnormal type of hemoglobin called HbS. It results
from a point mutation that causes the glutamic acid to be replaced by valine at the b6 position
of the globin chain. If the individual is homozygous, it is represented as HbSS (1 gene each
from both the parents) whereas the heterozygous is HbAS (1 gene from one parent is for HbS
and the other gene is for HbA). Heterozygotes are protected against falciparum malaria.
Mnemonic: Glutamic acid can Go and Valine is Welcome
Pathogenesis
When deoxygenated, HbS molecules becomes insoluble, undergoes aggregation and
polymerization producing a sickle cell or holly leaf shape of the RBCs. Initially, this process is
reversible (on getting oxygenated, the cells attain there normal shape) but repeated attacks of
aggregation can cause irreversible sickling of the RBCs which also causes oxidative damage
to the red cells.
252
Reversible sickled cells exhibit increased adhesiveness within the microcirculation of

organs with sluggish blood flow thereby causing episodes of hypoxia and infarction called
as vasoocclusive crisis or pain crisis. Hemoglobin released from the lysed red cells causes
inactivation of NO thereby increasing the severity of ischemia.
Irreversible sickled cells get sequestrated in the spleen thereby contributing to extravascular
hemolysis.
Factors Affecting Sickling of the Hemoglobin Sickling of hemoglobin affects

its solubility and NOT its
Amount of HbS (most important factor) and its interaction with other hemoglobins function/stability/affinity.
The presence of relatively low concentration of HbS (25-40%) and the presence of HbA in heterozygotes
prevents efficient HbS sickling thereby contributing to decreased severity of the disease in them. In
comparison, the homozygotes have full blown disease.
Other hemoglobins like fetal hemoglobin (HbF) and HbC (having a substitution of lysine for glutamic Sequestration crisis is the
acid at 6 position) have inhibitory effect on the disease. HbF inhibits the polymerization of HbS, so, most dangerous crisis in sickle
newborns do not manifest the disease till 5-6 months of age when their HbF levels fall. This finding cell anemia because it can
is utilized in the management of the disease with hydroxyurea which actually increases the HbF cause heart failure.
concentration. HbC has increased tendency to aggregate than HbS so the disease is milder in patients
with HbSC disease.
Hemoglobin concentration of the red cell
Hb concentration of the cell,i.e. MCHC affects polymerization to a great extent. Hence, intracellular
dehydration which increases MCHC facilitates sickling and vaso-occlusion. On the other hand, in Vaso occlusive crisis are the
patients with thalassemia, there is reduced severity of the disease because these patients usually most common type of crisis in
have low Hb concentration (due to reduced globin chain formation) in their RBCs. sickle cell disease.

Decrease in pH
Acidosis decreases the affinity of hemoglobin for oxygen, so, there is more deoxygenated hemoglobin
and increased chances of sickling.
Duration of time red cells are exposed to decreased oxygen tension Sickle cell anemia shows
splenomegaly and later auto-
Normal transit time for RBCs is not sufficient for significant aggregation of deoxygenated HbS to occur
splenectomy because it can
but in organs having slow or sluggish circulation, there is an increased chance of sickling. This is
cause heart failure.
particularly important in organs like bone and spleen.
Clinical features
Severe anemia results in jaundice and pigment gallstone formation and is associated
with reticulocytosis. Vaso-occlusive crisis clinically manifests as painful episodes in In most other causes of anemia,
affected organs of the body. In the bone, it presents as dactylitis or inflammation ESR is high except in sickle cell
of the bones of hands and feet, so called Hand foot syndrome, increased chances of disease. ESR is less is sickle
Salmonella osteomyelitis, avascular necrosis of femoral head, fish mouth appearance of cell disease.
vertebra (due to occlusion of vertebral arteries) and prominent cheek bones and crew
cut appearance of skull (both because of extramedullary hematopoeisis).
Other organs of the body may also be affected, e.g. lungs (acute chest syndrome
characterized by cough, fever and chest pain), brain (seizures or stroke), skin (leg
ulcers), penis (stagnation in corpora cavernosa leads to priapism) or spleen. In the
initial stages, there is splenomegaly due to congestion and trapping of red cells in
the vascular sinusoids (Gamma gandy bodies; consisting of foci of fibrosis having iron
or calcium salts deposited in connective tissue are seen).
In the later stages, hypoxia and infarction induced progressive shrinkage of the
spleen results in reduced splenic mass that may be replaced by fibrous tissue called
Management of sickle cell
autosplenectomy. This also increases susceptibility to infection with capsulated anemia is done by ensuring that
organisms like Hemophilus influenzae, Pneumococcus, etc. the patient should be properly
Parvovirus infection can precipitate an attack of aplastic crisis also. Chronic anemia hydrated and with the help
can cause hyperdynamic circulation resulting in cardiomegaly. of drugs like hydroxyurea (it
increases HbF and NO and acts
Peripheral smear shows anisopoikilocytosis, presence of sickle cells, target cells, as an anti-inflammatory agent),
polychromatophilia and ovalocytes. Howell Jolly bodies (composed of chromatin aggregates 5azacytidine, etc.
in red cells) are seen particularly after autosplenectomy. ESR is low because roleaux formation
is not seen with sickle cells.
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Diagnosis is done with the help of the following:

Sickling test: Sickling is induced by a reducing agent like 2% metabisulfite or dithionite to
blood. However, this test cannot differentiate between sickle cell disease and sickle cell trait.
Hb electrophoresis: It is carried out on a cellulose acetate membrane (pH 8.6). HbS is slower
moving as compared to normal HbA, so, heterozygotes show 2 bands of hemoglobin.
HbF estimation (by alkali denaturation method) shows HbF to be 10-30% in homozygotes.
Prenatal genetic testing can be done using the enzyme MstII endonuclease. Chorionic villus
sampling at 10-12 weeks of gestation is used to estimate fetal DNA abnormality.
B. Thalassemia
Thalassemia is the most common It is a group of autosomal recessive inherited disorders characterized by decreased synthesis
type of hemoglobinopathy in the of either or globin chain of HbA. It is the most common type of hemoglobinopathy in the
world.
world. and thalassemia is caused by deficient synthesis of and chains respectively.
The globin chain is coded by a gene on chromosome 16 and the gene for globin chain is located
on chromosome 11. The clinical features therefore result from deficiency of one chain and the
relative excess of the other chain.
Pathogenesis of thalassemia
254
thalassemia syndromes
i.
This type of thalassemia is caused by point mutations. These are of two types:
1. thalassemia Characterized by total absence of chains in the homozygous
0
state.
2. thalassemia Characterized by reduced synthesis of chains in the homozygous
+
state.
Mutations can be caused due to the following mechanisms:
a. Promoter region mutation: Causes reduced transcription of the chains leading to
thalassemia.
+
b. Chain terminator mutations: Either creation of a stop codon in exon or frameshift

mutation inducing a downstream stop codon leads to premature chain
termination resulting in thalassemia. Splicing mutations: Are the

c. Splicing mutation: They are the most common cause of thalassemia resulting in most common cause of b
thalassemia.
unspliced mRNA being degraded in the nucleus leading to the development of
either + thalassemia or thalassemia.
Clinical features
Clinically , thalassemia is of three types: thalassemia major, thalassemia intermedia and
thalassemia minor.

a. Thalassemia major (also called Cooley anemia): It is seen in individuals homo Thalassemia major (also called
Cooley anemia): is a severe
zygous for the thalassemia genes (+/+or /); these individuals have a severe
transfusion dependent anemia in
transfusion dependent anemia which manifests at usually 6 to 9 months after birth.
this condition HbF is markedly
There is presence of prominent frontal and cheek bones, hepatosplenomegaly increased.
(due to extramedullary hemopoiesis), jaundice, increased risk of pigment stones

and endocrinological manifestations as delayed puberty (due to GH deficiency),
bone fractures (hypoparathyroidism) and/or diabetes mellitus (iron in islet of
Langerhans).
Peripheral smear shows moderate to severe anemia, anisocytosis, microcytic hypochromic
red cells, target cells, nucleated red cells, basophilic stippling, Howell Jolly bodies, etc. There
is reticulocytosis and left shift in the leukocytes. Since chains are not produced
but chains are synthesized normally, HbF is markedly increased and is the major
constituent of red cells (90%). MCH, MCV and MCHC are reduced.
Bone marrow is hypercellular with erythroid hyperplasia causing reversal of
normal M:E ratio (it becomes 1:3 in thalassemia). Pink inclusions are seen in the
normoblasts (caused by chain accumulation). Widening of the diploe gives rise to
crew cut appearance on skull X-ray.

b. Thalassemia minor or trait: It is seen in individuals heterozygous with one
thalassemia gene and one normal gene (+/ or 0/). It is more common clinically Thalassemia minor (also called
than the major variant and offers resistance against falciparum malaria. These Thalassemia trait): HbA2 is
patients are usually asymptomatic with only mild anemia. characteristically elevated.
Peripheral smear shows microcytic, hypochromic cells with basophilic stippling and
presence of target cells. MCH, MCV and MCHC are reduced. The levels of HbA2 are
characteristically elevated (It is normally 3-3.5% but in thalassemia trait, the level is
3.6-8%; this is a diagnostic feature of this disease). HbF is mildly increased (5%).
NESTROF Test
A Screening test used for this condition is Naked Eye Single Tube Red cell Osmotic Fragility
(NESTROF) test. In this test 2 blood samples (1of a normal person serving as control and 1 of patient) Naked Eye Single Tube Red cell
are added to 2 tubes with 0.35% saline. After 30 min a white paper with a black line is placed behind Osmotic Fragility (NESTROF)
both the tubes. The RBCs in control sample undergo hemolysis so the black line is visible whereas is a Screening test and NOT
cells in thalassemia trait are resistant so black line is not clearly visible. a diagnostic test used for this
condition.
c. Thalassemia intermedia: The patients show anemia but do not require transfusions.
The features of the disease are intermediate between the two other types of thalas
semia discussed above.
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Important Investigations
Apart from the above mentioned investigations, the thalassemia patients must
undergo Hb electrophoresis to determine the nature of the hemoglobin present.
HbA2Q is characteristically elevated in a patient of thalassemia minorQ.
Globin chain synthesis can be studied by calculating a: ratio. It is normally 1:1 but
in thalassemia, it is 5-30:1.
Alkali denaturation methodQ is done to determine the concentration of HbF which is
HbF is shown by acid elution
relatively resistant to denaturation by strong alkali like NaOH/KOH as compared to
method (Kleihauers cytochemical
methodQ). HbA. In the RBCs, HbF is shown by acid elution method (Kleihauers cytochemical
methodQ).
Concept
Qualitative estimation of HbF is done by Apt testQ

Quantitive estimation of HbF is done by Kleihauer testQ
Management of these patients is done with blood transfusions (to maintain hemoglobin
concentration), iron chelators like desferrioxamine, deferiprone and defrasirox (to chelate
excessive iron) and bone marrow transplantation (if HLA matched donor is available).
Preventive measures include marriage counseling and chorionic villus sampling at 9-10
weeks followed by PCR analysis. All antenatal females with Hb <11 gm% should undergo
NESTROF test.

ii. a thalassemia syndromes
This type of thalassemia is caused by gene deletionQ. These are of four types.
In the silent carrier state, the patients are clinically asymptomatic. The clinical picture in
-thalassemia trait is similar to that discussed in -thalassemia minor which means there is
presence of microcytosis, minimal or no anemia, and no abnormal physical signs. HbHQ is a
major cause of anemia, as precipitates of oxidized HbH form in older red cells, which are then
removed by splenic macrophages. This produces a moderately severe anemia resembling
-thalassemia intermedia. Hydrops fetalis is the most dangerous form of -thalassemia and severe
tissue anoxia leads to intrauterine fetal death. The fetus shows severe pallor, generalized
edema, and massive hepatosplenomegaly.
256

SPECIAL TOPICS FOR EXAMS
Massive Blood Transfusion
Massive Transfusion is defined as the need to transfuse from one to two times the patients
normal blood volume. In a normal adult, this is equivalent to 10-20 units.
Complications of massive blood transfusion are:

Coagulopathy: Most common cause of bleeding after massive transfusion is dilutional
thrombocytopenia.
Citrate toxicity: Citrate in the transfused blood may bind calcium. Clinically,
significant hypocalcemia usually do not develop because citrate is metabolized by
liver to bicarbonate. In hepatic dysfunction, this effect can be pronounced.
Hypothermia: Massive transfusion is an absolute indication for warming of all blood
and fluids to body temperature to avoid hypothermia.
Acid Base Imbalance: Most common abnormality is metabolic alkalosis. It results
from conversion of citrate (present in stored blood) and lactate (accumulated due to
hypoperfusion) to bicarbonate.
Serum potassium can rise because K+ concentration in stored blood increases steadily
with time.
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Anticoagulants
Agents Trisodium EDTA 3.2% Trisodium Citrate Heparin Potassium Oxalate

Mechanism of Remove calcium Remove calcium Activation of antithrombin III Binds calcium
action

Preferred Uses Blood cell counts
Platelet studiesQ
Osmotic fragility testQ
Anticoagulant (not
and morphologyQ
Coagulation stud-
WBC Functional or immunopheno- preferred because labile
iesQ typingQ factors are

ESRQ
Red cell testingQ unstable in oxalate)
Advantages Complete anticoagula- Preserves the labile Does not affect shape and size Cheap
tion with minimal mor- coagulation factors Easily available
phologic and physical
effects on the cell
Disadvantages
Not suitable for blood counts because Distorts cell morphology

it cannot inhibit platelet and leucocyte Shrinks red cell size, so,
clumping not used for hematocrit

Bluish discoloration to blood smear estimation
slide on applying Wright Giemsa stain.
Anticoagulated blood may be stored at 4CQ for 24 hour period without significantly altering
cell counts or cellular morphology but hematologic analysis should be done as soon as possible.
Any anticoagulantQ can be used for collecting blood for Flow cytometryQ.
Splenectomy

Indications of splenectomy include traumatic or iatrogenic splenic rupture (most

common), symptom control in patient with massive splenomegaly, correction of
cytopenias in patients with hypersplenism, staging of patients with Hodgkins
disease, treatment of hairy cell leukemia and prolymphocytic leukemia.

The only contraindication to splenectomy is the presence of marrow failure, in
which the enlarged spleen is the only source of hematopoietic tissue.

Most serious consequence of splenectomy is increased susceptibility to capsulated
bacterial infections like Streptococcus. Pneumoniae, H. influenzae and some gram-nega
tive enteric organisms.

Increased susceptibility to Babesisis (intra-RBC parasite) is also noted in splenec
tomized patients

Pneumococcal vaccine and vaccine against Neisseria meningitides are recommended
for patients in whom elective splenectomy is planned. H. influenza type B vaccine
may also be given.
Acute manifestations of splenectomy include leukocytosis (up to 25000/l) and

thrombocytosis (up to 1 106/l) but return back to normal levels within 2-3 weeks.
Chronic Manifestations of splenectomy include:

Anisocytosis and poikilocytosis

Howell-Jolly bodies (nuclear remnants)

Heinz bodies (denatured hemoglobin)

Basophilic stippling

Target cells

Pappenheimer bodies (contain sideroblastic granules)

Irregular contracted red cells. (WBC count usually normal but there may be mild
lymphocytosis and monocytosis. Thrombocytosis persists in about 30% of cases.

Occasional nucleated erythrocyte in peripheral blood.
When such erythrocyte abnormalities are seen without splenectomy, splenic infiltration by tumor
should be suspected.
SPLENOSIS: It is the presence of multiple rests of spleen tissue not connected to portal
circulation it occur in patients with splenic rupture causing peritoneal seeding of splenic
fragments. This condition is similar to endometriosis (presence of endometrial tissue at non-
endometrial sites).
258

RBC: GENERAL ASPECTS 9. Anemia which is associated with pancytopenia is
(a) Hemolytic (RJ 2002)
1. Which of the following is associated with an intrinsic (b) Iron deficiency
defect in the RBC membrane? (AIIMS May 2012) (c) Megaloblastic
(a) Autoimmune hemolytic anemia (d) All
(b) Hereditary spherocytosis 10. Hematuria with dysmorphic RBCs are seen in:
(c) Microangiopathic haemolytic anemia
(a) Acute glomerulonephritis (RJ 2002)
(d) Thermal injury causing anemia
(b) Renal TB
2. Which of the following is not a stem cell of the bone (c) Renal calculi
marrow? (AI 2012) (d) Chronic renal failure
(a) Lymphoblast (b) Myeloblast
(c) Myoblast (d) Normoblast
11. MCHC is increased in: (RJ 2005)
(a) Iron deficiency anemia
3. Which of the following surface glycoproteins is most (b) Spherocytosis
often expressed in human hematopoietic stem cell? (c) Thalassemia
(a) CD 22 (AIIMS May 2008) (d) All
(b) CD 40
(c) CD 15 12. In polycythemia vera, all are raised except:

(d) CD 34 (a) Hematocrit (RJ 2006)
(b) Platelet count
4. Reticulocytosis is seen in all except: (c) RBCs
(a) P.N.H. (AIIMS May 2007) (d) Erythropoietin
(b) Hemolysis
(c) Nutritional anemia 13. The type of anemia seen in chronic renal failure is:
(d) Dyserythropoietic syndrome (a) Microcytic (AP 2008)
(b) Normocytic
5. Which of these are seen on Romanowsky stain: (c) Macrocytic
(a) Reticulocytes (PGI Dec 2004) (d) All of the above
(b) Basophilic stippling
(c) Heinz bodies 14. Burr cell is seen in: (Jharkhand 2003)
(d) Howell-Jolly bodies (a) Uremia
(e) Cabot ring (b) Hepatocellular carcinoma
(c) Gastric carcinoma
6. Which of the following surface glycoproteins is most (d) Ovarian carcinoma
often expressed in human hematopoietic stem cell?
(a) CD22 (Delhi PG 2010) 15. Acanthocytes are seen in: (Jharkhand 2003)
(b) CD40 (a) Abetalipoproteinemia
(c) CD15 (b) Hartnup disease
(d) CD34 (c) Whipple disease
(d) None
7. Inappropriate erythropoietin level is found in all
except (UP 2001) 16. A 74 year-old female Lajo Devi with renal failure
(a) Renal cell carcinoma presents for hemodialysis. She complains of weakness
(b) Lung disease and palpitations for about a month. On further
(c) High altitude investigations, she is found to be anemic and is given a
(d) Benign liver tumor dose of erythropoietin. Erythropoietin stimulates which
8. The size of the red blood cells is measured by: of the following intermediates in hematopoiesis?
(a) MCV (UP 2007)
(a) Basophilic erythroblasts
(b) MCHC
(b) Colony forming units-erythroid
(c) ESR
(c) Proerythroblasts
(d) MCH
(d) Reticulocytes
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(c) Cyanmethemoglobin method

(d) Any of the above

16.1. Progenitor hematopoetic stem cells originate in which

16.11. The number of Fe2+ atoms in one Hb molecule
of the following?

(a) Bone marrow (a) 1
(b) Thymus (b) 2

(c) Lymph node (c) 4
(d) Spleen (d) 8

16.2. The anaemia associated with leukaemia is ?
16.12. Hb is a good buffer because of:

(a) Iron deficiency
(a) Histidine residues

(b) Megaloblastic type
(b) Protein nature

(c) Myelophthisic type
(c) Acidic nature

(d) Iron molecule
16.3. Linzenmeyer is used to measure: 16.13. Serum contains all the clotting factors except
(a) Plasma thromboplastin
(a) Bleeding time
(b) Labile factor
(b) Clotting time
(c) Hageman factor
(c) Prothrombin time (d) Christmas factor
(d) ESR
1 6.14. Reticulocytes are stained with
1 6.4. Normal platelet count is found in: (a) Methyl violet
(a) Wiskott Aldrich syndrome (b) Brilliant Cresyl blue
(b) Henoch Schonlein purpura (c) Sudan black
(c) Immune thrombocytopenia (d) Indigo carmine
(d) Dengue fever
1 6.15. Haematocrit is the ratio of:
1 6.5. Thrombosthenin is: (a) WBC to whole blood

(a) Coagulation protein (b) Platelets to whole blood
(b) Contractile protein (c) RBCs to whole blood
(c) Thrombus inhibiting protein (d) Total blood cells to plasma
(d) Protein for platelet production 1 6.16. Storage form of iron
1 6.6. The longest living WBC is which one of the following (a) Ferritin
(a) Lymphocyte (b) Transferrin
(b) Eosinophil (c) Hepcidin
(c) Neutrophil (d) Ferroportin
(d) Monocyte 1 6.17. Reticulocytes are stained with which of the following
1 6.7. Freezing point of normal human plasma is: stains?
(a) 4 C (a) Brilliant cresyl blue
(b) 0 C (b) Sudan black
(c) 0.54 C (c) Warthin starry
(d) 1.54 C (d) Hemotoxylin-eosin stain
1 6.8. The normal albumin: globulin (A/G) ratio blood is

MEGALOBLASTIC ANEMIA, APLASTIC ANEMIA
(a) 5:1
(b) 2:1
(c) 1:2 17. Which of these does not indicate megaloblastic anemia?
(d) 1:1 (a) Increased reticulocyte count (AIIMS Nov 2012)
(b) Raised Bilirubin
1 6.9. In an adult man, there is about how much grams of (c) Mild splenomegaly
hemoglobin in the circulating blood? (d) Nucleated RBC
(a) 350
(b) 500 18. A patient with Hb-6 gm%, TLC 1200, platelet-60,000,
(c) 900 MCV 12fl, what is the diagnosis?
(d) 1000 (a) Aplastic anemia (AIIMS May 2008)
(b) Megaloblastic anemia
1 6.10. The best method for estimation of hemoglobin (c) PNH
concentration in blood is (d) Myelofibrosis
(a) Acid hematin method
(b) Alkali hematin method
260
19. Macrocytosis in complete blood count can be diagnosed 28. Cause of macrocytic anemia is: (UP 2002)
by: (PGI Dec 2006) (a) Sideroblastic anemia
(a) MCV (b) Iron deficiency
(b) MCHC (c) Thalassemia
(c) Hematocrit (d) Hypothyroidism
(d) Red cell distribution width
20. Which is the true statement regarding megaloblastic 29. Pure red cell aplasia is associated with:
(a) Thymoma (UP 2004)
anemia: (PGI Dec 01) (b) Renal cell carcinoma
(a) Megaloblastic precursors are present in bone mar-
row
(d) Prostate carcinoma
(b) Mean corpuscular volume is increased
(c) Serum LDH is increased 30. Vitamin B malabsorption is caused by:
(d) Thrombocytosis occurs
12
(a) Ankylostoma duodenale (UP 2005)
(e) Target cells are found (b) Diphyllobothrium latum
21. Macrocytic anemia may be seen in all of these except: (c) Giardiasis
(a) Liver disease (PGI June 2002) (d) Taenia solium
(b) Copper deficiency 31. Maturation failure in poor absorption of the vitamin B
(c) Thiamine deficiency is associated with (UP 2006)
12
(d) Vitamin B deficiency

(a) Microcytic hypochromic anemia
(e) Orotic aciduria
12
(b) Sickle cell anemia

22. Causes of vitamin B12 deficiency megaloblastic anemia (c) Anemia occurs after 3-4 months of poor absorption
are: (PGI June 2005) (d) Causes polycythemia
(a) Fish tap worm infestation
(b) Dilantin therapy 32. FIGLU test is done for: (UP 2008)
(c) Gastrectomy (a) Cyanocobalamin deficiency

(d) Ileal resection (b) Folic acid deficiency
(e) Methotrexate (c) Thiamine deficiency
(d) Riboflavin deficiency
23. Aplastic anemia can progress to all except:
(a) AML (Delhi PG 2010) 33. Hypersegmented neutrophils are present in which of
(b) Myelodysplastic anemia the following anemia? (RJ 2000)
(c) Pure red cell aplasia (a) Hemolytic
(d) Paroxysmal nocturnal hemoglobinuria (b) Iron deficiency
24. Serum vitamin B level is increased in all except: (c) Megaloblastic
(a) Hepatitis (d) Aplastic
12
(UP 2000)
(b) Cirrhosis of liver 34. Hypersegmented neutrophils are seen in:
(c) Hepatocellular carcinoma (a) Thalassemia (RJ 2002)
(d) Cholestatic jaundice
(b) Iron deficiency
25. Normocytic normochromic anemia is seen in all (c) Megaloblastic anemia
except: (UP 2000) (d) All
(a) Aplastic anemia
(b) Chronic renal disease 35. Howell-Jolly bodies are seen in: (RJ 2002)
(c) Pure red cell aplasia (a) Alcoholics
(d) Thalassemia (b) Cirrhosis
(c) Nephrotic syndrome
26. A 76 years old male presented with anemia with (d) Postsplenectomy
splenomegaly. PBS shows tear drop shaped cells and
bone marrow examination was normal. The diagnosis 36. Macrocytic anemia is caused by: (AP 2004)
is: (UP 2000) (a) Hookworm infestation

(a) Myelofibrosis (b) Iron deficiency

(b) Iron deficiency anemia (c) Diphyllobothrium latum infestation

(c) Folic acid deficiency (d) All of the above

(d) CML
37. An adult who develops pure red cell aplasia should be
27. TRUE about Schilling test is all except: explicitly evaluated for which of the following?
(a) B deficiency (UP 2001)
(a) Gastric adenocarcinoma
(b) Folic acid deficiency
12
(b) Pancreatic adenocarcinoma

(c) Ileal disease
(c) Papillary thyroid cancer
(d) Bacterial overgrowth
(d) Thymoma
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38. A 50-year-old female Ramya with megaloblastic anemia 39.4. All of the following can cause reticulocytosis except
and ataxia is given radiolabeled cobalamin by mouth (a) Aplastic anemia
followed by an intramuscular injection of unlabeled (b) Thalassemia
cobalamin. The urine radioactivity level measured (c) Sickle cell anemia
afterwards is determined to be normal. Which of the (d) Chronic blood loss
following is the most likely cause of this patients
3 9.5. Reticulocytosis is not seen in which of the following
symptoms?
conditions?
(a) Dietary cobalamin deficiency
(a) Thalassemia
(b) Atrophic gastritis
(b) Hereditary spherocytosis
(c) Nontropical sprue
(d) Fish tapeworm infestation
39. A 50-year-old male Pandey undergoing evaluation 39.6 Which of following viruses causes hemolysis of red
for fatigue and exertional dyspnea is diagnosed with
blood cells?
macrocytic anemia. Upper gastrointestinal endoscopy is
(a) Rubella (b) Human parvo virus B19
consistent with atrophic gastritis. Some blood parameter
(c) Measles (d) Dengue virus
changes after the first dose of cyanocobalamin are
shown in the graph on the left side of the page. The first
curve most likely corresponds to which of the following MICROCYTIC ANEMIA: IDA, AOCD, SIDEROBLASTIC ANEMIA
parameters?

(a) RBC count
(b) Reticulocyte count 40. A 60-year old male patient with history of rheumatoid

(c) Haptoglobin
(d) Gastrin arthritis presents with the following: Hb:4.5g/dL.
platelet count is 2 lakh/mm3. TLC: 6000/mL, serum
ferritin is 200g/dL, serum iron 30mg/dL and TIBC
280ng/L. Which of the following is the most likely
diagnosis?

(a) Anaemia of chronic disease (AIIMS Nov 2011)

(b) Thalassemia minor

(c) Iron deficiency anemia

(d) Autoimmune haemolytic anemia
41. A 20 year old female presents with the following
laboratory values: hemoglobin 9gm%, MCV is 55%,
RBC is 4.5 million/mm3. There is no history of blood
transfusion. What is the most likely diagnosis out of the
following? (AIIMS Nov 2011)

(a) Thalassemia major

(b) Thalassemia minor

(d) Anemia of chronic disease
39.1. Hb A2 is raised in which of the following conditions? 42. A 13 yr girl with fatigue and weakness was found to be
(a) Beta thalassemia trait having reduced hemoglobin. Her MCV 70fl, MCH 22pg
(b) Sickle cell anemia and RDW was 28. What is her most likely diagnosis?
(c) Hereditory spherocytosis (a) Iron deficiency anemia (AI 2010)
(d) G6 PD deficiency (b) Thalassemia minor
(c) Sideroblastic anemia
3 9.2. Schilling test is used for identification of which of the
(d) Thalassemia major
following?
(a) Fat absorption 43. Ringed sideroblasts are seen in: (AI 2008)
(b) Vit K absorption (a) Iron deficiency anemia
(c) Vitamin B12 absorption (b) Myelodysplastic syndrome
(d) Vitamin D absorption (c) Thalassemia
(d) Anemia of chronic disease
3 9.3. Which of the does not indicate megaloblastic anemia?
(a) Raised bilirubin 44. A 30 years old female, RBC count 4.5 million, MCV 55fl,
(b) Mild splenomegaly TLC 8000/mm3. There is no history of blood transfusion.
(c) Increased reticulocyte count What is the likely diagnosis?
(d) Nucleated red cells (a) Iron deficiency anemia (AIIMS May 2008)
(b) Thalassemia major
262

(c) Thalassemia minor (a) Beta-Heterozygous thalassemia (Delhi PG-2008)

(d) Megaloblastic anemia (b) Beta-Homozygous thalassemia
45. The pathogenesis of hypochromic anemia in lead (c) Intermediate thalassemia
poisoning is due to: (AIIMS Nov 2002)
(d) Persistently raised HbF
(a) Inhibition of enzymes involved in heme biosynthesis 54. The condition which does not cause microcytic hypo
(b) Binding of lead to transferrin, inhibiting the trans- chromic anemia is: (Karnataka 2008)
port of iron (a) Iron deficiency
(c) Binding of lead to cell membrane of erythroid pre- (b) Hookworm infestation
cursors. (c) Absence of intrinsic factor
(d) Binding of lead to ferritin inhibiting their breakdown (d) Prolonged bleeding episodes
into hemosiderin
55. Hypochromic microcytic blood picture is seen in all of
46. A patient presents with increased serum ferritin, the following conditions except:
decreased TIBC, increased serum iron, % saturation (a) Iron deficiency anemia (Karnataka 2007)
increased. Most probable diagnosis is: (b) Lead poisoning

(a) Anemia of chronic disease (AIIMS Nov 2006) (c) Rheumatoid arthritis

(b) Sideroblastic anemia (d) Sideroblastic anemia

56. Lead poisoning is associated with:

(d) Thalassemia minor
(a) Microcytic hypochromic anemia
47. Anemia in CRF is due to: (PGI Dec 2006) (b) Macrocytic anemia (Karnataka 2005)
(a) erythropoietin (c) Decreased levels of zinc protoporphyrin
(b) RBC survival (d) Howell-Jolly bodies
(c) folate
(d) Bone marrow hypoplasia
57. Microspherocytes in peripheral blood smear are seen
in: (Karnataka 2005)
(e) Iron deficiency

(a) Congenital spherocytosis
48. Iron deficiency anemia is seen in: (PGI Dec 2006) (b) Autoimmune acquired hemolytic anemia
(a) Chronic renal failure (c) Thalassemia
(b) Billroth II operation (d) All of the above
(c) Hookworm infection
(d) Celiac sprue
58. Macropolycytes in peripheral smear is a feature of:
(a) Hereditary spherocytosis (Karnataka 2004)
(e) Carcinoma cecum (b) Iron deficiency anemia
49. Bone marrow iron is increased in: (PGI Dec 2003) (c) Sickle cell anemia
(a) Thalassemi(a) (d) Megaloblastic anemia
(b) Iron deficiency anemi(a) 59. Anemia of chronic disease is characterized by of all
(c) Anemia in chronic disease. except: (UP 2000)
(d) PNH (a) Serum iron level
(e) Megaloblastic anemi(a) (b) TIBC
50. Microcytosis is seen in: (PGI June 2004) (c) Serum ferritin level
(a) Thalassemia (b) Hb Lepore (d) Increased macrophages iron in marrow
(c) Hb Barts (d) Gastrectomy 60. Most common cause of anemia is: (UP 2003)
(e) Systemic sclerosis (a) Iron deficiency
51. True about iron deficiency anemia is: (PGI June 2005) (b) Folic acid deficiency
(a) Microcytic hypochromic anemia (c) Sideroblastic anemia
(d) Pernicious anemia
(b) Decreased TIBC
(c) Increased ferritin 61. A patient of anemia due to chronic inflammation, the
(d) Bone marrow iron decreased earlier than serum iron positive finding is
(a) Serum iron is increased (UP-2000) (UP 2004)
52. In Anemia of chronic disease, what is seen? (b) S. ferritin is decreased
(a) TIBC (Delhi PG-2008)
(c) TIBC is decreased
(b) S. Iron (d) Presence of normal iron in blasts
(c) BM iron
(d) S. ferritin 62. Which of the following glycoproteins is transported in
plasma in iron metabolism: (UP 2006)
53. A 30 years old female asymptomatic not requiring blood (a) Spectrin (b) Transferrin
transfusion has Hb-13 gm%, HbF-95%, HbA2 1.5%. (c) Ferritin (d) Hemosiderin
Which of the following is the most likely diagnosis?
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63. All are laboratory finding in iron deficiency anemia

(c) Thalassemia
except: (UP 2006)
(d) G6PD deficiency
(a) Decreased serum iron
(b) Increased total iron binding capacity
69.4. Response of iron therapy in a patient with iron
deficiency anemia is denoted by:
(c) Decreased serum ferritin
(a) Restoration of enzymes
(d) Increased mean corpuscular volume
(b) Reticulocytosis
64. Best parameter for assessment of body iron stores is (c) Increase in iron binding capacity
(a) Serum iron (RJ 2002) (d) Increase in hemoglobin
(b) Serum TIBC
6 9.5. Sideroblastic anemia is seen in chronic poisoning with:
(c) Serum ferritin
(a) Lead (b) Arsenic
(d) Serum transferin
(c) Copper (d) Mercury
65. Hemochromatosis affects all of the following organs 6 9.6. Echinocytes are types of:
except: (RJ 2002)
(a) Liver (b) Pancreas (a) RBCs (b) Lymphocytes
(c) Heart (d) Salivary gland (c) Monocytes (d) Platelets
66. Skin pigmentation in hemochromatosis occurs due to: 6 9.7. Anemia in humans can be caused by which of the fol-
(a) Melanin (RJ 2002) lowing worm?
(b) Ferritin (a) Roundworm (b) Hookworm
(c) Hemosiderin (c) Strongyloides (d) Tapeworm
(d) All
6 9.8. Earliest feature of correction of iron deficiency anemia
67. Storage form of iron in body is: (RJ 2005) is:
(a) Ferritin (b) Transferrin (a) Reticulocytosis
(c) Ceruloplasmin (d) Ferriportin
(b) Increase in serum ferritin
68. Microcytic hypochromic anemia is seen in: (c) Increase in RBC count
(a) Hereditary spherocytosis (AP 2001) (d) Increase in serum iron level immediately
(b) Thalassemia major
6 9.9. Rate of iron uptake is regulated by which one of the fol-
lowing:
(d) Pernicious anemia
(a) Mucosal cell iron stores
69. A 68 year-old man Babu Rao Apte presents with skin (b) Route of administration
pigmentation, cirrhosis and diabetes mellitus. Which (c) Preparation administered
pattern for serum iron and total iron-binding capacity (d) Age of the patient
(TIBC) is most consistent with the familial illness
suggested by these findings? 6 9.10. Low iron and low TIBC is seen in

(a) Increased Serum iron, Increased TIBC (a) Anaemia of chronic disease

(b) Increased Serum iron, Decreased TIBC (b) Sideroblasticanaemia

(c) Decreased Serum iron, Decreased TIBC (c) Iron deficiency anaemia

(d) Decreased Serum iron, Increased TIBC (d) Aplastic anemia
Most Recent Questions HEMOLYTIC ANEMIA: PNH, HS, G6PD, IMMUNE HEMOLYTIC
ANEMIA
69.1. Sideroblastic anemia is caused by all except:
(a) Collagen vascular disease
(b) Erythropoetic porphyria
70. A 23-year-old female presented with jaundice and
pallor for 2 months. Her peripheral blood smear
(c) Lead poisoning
(d) Cutaneous porphyria shows the presence of spherocytes. The most relevant
investigation to arrive at a diagnosis is which of the
6 9.2. Lead causes following except: following? (AIIMS May 2012)
(a) Uroporphyrinuria (a) Tests for PNH
(b) Sideroblastic anemia (b) Osmotic fragility test
(c) Basophilic stippling (c) Coombs test
(d) Macrocytic anemia (d) Reticulocyte count
6 9.3. All of the following if present provide protection 71. An abnormal Ham test is most likely associated with
against malaria except: which of the following? (AIIMS Nov 2011)
(a) Duffy blood group
(a) Spectrin
(b) Sickle cell anemia
(b) Defect in complement activating proteins
264

(c) Defective GPI anchor 81. Intravascular hemolysis occurs in:

(d) Mannose-binding residue effect (a) Hereditary spherocytosis (PGI Dec 2000)
(b) Acute G6PD deficiency
72. A 5 year old male child presents with episodic anemia (c) Sickle cell disease
and jaundice since birth. He is least likely to have
(d) Thalassemia
which of the following? (AIIMS Nov 2011)
(e) PNH
(a) Hereditary spherocytosis
(b) Sickle cell disease 82. Microangiopathic hemolytic anemia is seen in:
(c) G6PD deficiency (a) HUS (PGI June 01)
(d) Paroxysmal nocturnal hemoglobinuria (b) ITP
(c) Malignant hypertension
73. Thrombotic event is seen in all of following except: (d) Prosthetic valves
(AIIMS May 2011) (e) TTP
(a) Paroxysmal nocturnal hemogloninuria
(b) Disseminated intravascular coagulation 83. Spherocytosis in blood smear is seen in:
(c) Idiopathic thrombocytopenic purpura (a) Hemoglobin C (PGI June 2004)
(d) Heparin induced thrombocytopenia (b) Mechanical trauma
(c) Hereditary spherocytosis
74. PNH associated with somatic mutation affecting: (d) Hereditary elliptosis
(a) Decay accelerating factor (DAF) (AI 2010)
(b) Membrane inhibitor of reactive lysis (MIRL) 84. Cause of fragmented RBC in peripheral blood:
(c) Glycosylphosphatidylinositol (GPI) (a) Microangiopathic hemolytic anemia
(d) C8 binding protein (b) DIC (PGI June 2005)
(c) Hemophilia-A
75. Cold hemagglutinin is associated with: (AI 2008) (d) Malignant hypertension
(a) Anti IgM (e) HELLP syndrome
(b) Anti IgG

(c) Anti IgA
85. Intravascular hemolysis is seen in: (PGI June 2005)
(a) Glucose-6 phosphate dehydrogenase deficiency
(d) Donath-Landsteiner antibody
(b) Thalassemia
76. The following protein defects can cause hereditary (c) Sickle cell anemia
spherocytosis except: (AI 2007) (d) Hemophilia
(a) Ankyrin (b) Palladin
(c) Glycophorin C (d) Anion transport protein
86. The peripheral smear of hereditary spherocytosis will
show spherocytes: (PGI Dec 2006)
77. Autoimmune hemolytic anemia is seen in: (AI 2001) (a) Usually of same size
(a) ALL (b) AML (b) Reticulocytosis seen
(c) CLL (d) CML (c) Smaller size
(d) Anemia is negligible
78. Microangiopathic hemolytic anemia is seen in all of the (e) Always associated with MCHC
following diseases except (AIIMS Nov 2008)
(a) Antiphospholipid antibody syndrome 87. Microangiopathic hemolytic anemia seen in:
(b) Thrombotic thrombocytopenic purpura (a) Thrombotic thrombocytopenic purpura
(c) Microscopic polyangiitis (b) Hemolytic uremic syndrome (PGI Dec 2003)
(d) Metallic cardiac valves (c) Henoch-Schonlein purpura
(d) DIC
79. An Rh -ve woman became pregnant with Rh +ve fetus. (e) IgA nephropathy
Within few days after birth, the infant developed
jaundice, ascites, hepatomegaly and edema. The likely 88. Donath-Landsteiner antibodies are seen in:
substance(s) deposited in skin and sclera in jaundice is/ (a) Warm agglutination (Delhi PG 2010)
are given below. Which is the best possible answer? (b) Cold agglutination

(a) Biliverdin (AIIMS Nov 2003) (c) Paroxysmal nocturnal hemoglobinuria

(b) Conjugated and unconjugated bilirubin (d) ITP

(c) Unconjugated bilirubin 89. In hereditary spherocytosis an inherited abnormality is

(d) Conjugated bilirubin seen in which of the following red blood cell compo
80. Features seen in hemolytic anemia are all except: nent: (Delhi PG 2009)
(a) Teardrop and Burr cells (a) a-globin chain
(b) b-globin chain
(b) Haptoglobin
(c) Phosphatidyl inositol glycan A
(c) Reticulocytosis
(d) Spectrin
(d) Hemoglobinuria
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90. Hereditary spherocytosis is due to: (UP 2001) (c) Hereditary erythrocyte enzyme deficiency
(a) Acquired membrane defect (d) Microangiopathic hemolytic anemia
(b) Ankyrin deficiency 97. A young male photographer Alok Nath from Bangalore
(c) Defective hemoglobin synthesis is evaluated for recurrent episodes of jaundice. He
(d) Mechanical trauma to red cells has no history of recent travel. Past medical history is
91. Not seen in paroxysmal nocturnal hemoglobinuria is: insignificant and the person is not on any medication.
(a) LDH levels are raised (AP 2000) He does admit to unprotected sex with multiple sexual
(b) Increased hemosiderin in urine partners. His blood pressure is 120/80 mmHg, pulse is
(c) Decreased leukocyte alkaline phosphatase 72/mm, temperature is 36.7C (98F) and respiratory rate
(d) Increased platelets is 14/min. Physical examination shows pallor, icterus
and mild splenomegaly. There is no lymphadenopathy
92. Warm autoantibodies are seen in: (AP 2003) or hepatomegaly. Laboratory studies are shown below
(a) SLE Hemoglobin 9.1 g/L
(b) Mycoplasma Platelets 188,000/mm3
(c) Syphilis Leukocyte count 6,400/mm3
(d) Varicella LDH Increased
93. Hot agglutinin is found in all except: Total bilirubin 3.5 mg/dL
(a) Mycoplasma infection (Bihar 2006) Direct bilirubin 1.1 mg/dL
(b) SLE Aspartate aminotransferase (AST) 27 U/L
(c) Methyl dopa Alanine aminotransferase (ALT) 32 U/L
(d) Rheumatoid arthritis When red blood cells are incubated in hypotonic saline,
hemoglobin is released. The control sample does not
94. A 20-year-old man John Abraham is transported to the release hemoglobin. This patient is at highest risk of
emergency department within 20 minutes of sustain-
ing a road traffic accident on his bike. The patient is developing which of the following?
poorly responsive. If it is presumed that he may have (a) Cirrhosis and hepatocellular carcinoma
lost about 1.5 liters of blood at the scene, which of the (b) Pigmented gallstones
following is the most likely finding in this patient? (c) Avascular necrosis of the femur

(a) Increased mean corpuscular hemoglobin concentra-
(d) Episodic venous thrombosis
tion

(b) Decreased hematocrit
98. A 16-year-old female Gitika notices that her urine
becomes red after she is given sulfonamides for

(c) Decreased blood pressure
treatment of a urinary tract infection. Both urine and

(d) Decreased red blood cell count
serum test positive for free hemoglobin, and the urine
95. Rahul Singh migrates from UP to Bihar to work under red cell count is 1.2 million/mm3. A peripheral blood
the NREGA scheme as a daily wage labourer. The dis- smear shows normocytic and normochromic red cells
trict has high endemicity of malaria. So, his physician and a few bite cells. Deficiency of which of the
Dr. Dubey gives him primaquine chemoprophylaxis following substances is most likely responsible for
for Plasmodium vivax malaria. Several days after be- these symptoms?
ginning such a regimen, Mr. Singh develops anemia,
hemoglobinemia, and hemoglobinuria. Special studies

(a) Alpha-chain of hemoglobin
will likely reveal an abnormality in which of the fol-

(b) Beta-chain of hemoglobin
lowing?
(c) Glucose-6-phosphate dehydrogenase

(a) Duffy antigen
(d) Glycoprotein IIb/IIIa

(b) Glucose-6-phospate dehydrogenase 99. An infant presents with mild anemia, jaundice, and

(c) Intrinsic factor splenomegaly. A complete blood count with differential

(d) PIG-A reveals spherocytosis; with elevated reticulocyte count.
96. A 38-year-old male Kritesh presents to his physician The parents state that several relatives have also
with the complaints of sudden onset of fever, chills suffered from a similar illness. The infants condition
and dysuria. He has no significant past medical history. is most likely caused by defective
A per-rectal examination reveals tenderness. The
(a) Clathrin
(b) Connexon
prostatic secretions are collected and on microscopic
examination, it demonstrates >15 WBCs/hpf. A

(c) Ankyrin
(d) Spectrin
diagnosis of acute prostatitis is made. He was started 100. A 30-year-old woman A. Jolie with SLE and chronic
on treatment with trimethoprim-sulfamethoxazole, but renal failure manifests rapidly progressive weakness.
subsequently developed dark urine and anemia with a She appears pale and has slightly yellow sclerae and
high reticulocyte count. Which of the following is the an enlarged spleen. Blood tests reveal severe anemia
best explanation for the observed findings? and mild, mostly unconjugated, hyperbilirubinemia.

(a) Anti body-mediated erythrocyte destruction Coombs test is positive at 37C but negative at 0-4C.

(b) Hereditary erythrocyte membrane defect
266
This patient developed anemia because of 100.10. G6PD help in maintaining the integrity of RBC by?

(a) Bone marrow aplasia (a) Controlling reduction stress on RBC

(b) IgG directed against red blood cells (b) Controlling oxidative stress on RBC

(c) IgM directed against red blood cells (c) Maintaining flexibility of cell membrane

(d) Spleen sequestration (d) Component of electron transport chain
Most Recent Questions HEMOGLOBINOPATHIES: SICKLE CELL ANEMIA,

THALASSEMIA
100.1. In DIC, following are seen except
(a) Fibrinogen decreased
(b) Thrombocytopenia 101. Person having heterozygous sickle cell trait are
(c) Normal APTT protected from infection of? (AIIMS Nov 2012)
(d) PT elevation (a) P. falciparum (b) P. vivax
(c) Pneumococcous (d) Salmonella
1 00.2. D.I.C is seen in:
(a) Acute promyelocytic leukemia 102. A 6yrs old child belonging to Punjabi family with
(b) Acute myelomonocytic leukemia past history of blood transfusions presented with
(c) CML hemoglobin 3.5 g/dl, MCV 30 fl, MCHC 20. Peripheral
smear findings of microcytic hypochromic anemia with
(d) Autoimmune haemolytic anemia
target cell and reduced osmotic fragility. What is the he
1 00.3. Intravascular hemolysis occurs in: probable diagnosis of patient? (AIIMS Nov 2012)
(a) Hereditary spherocytosis
(a) Alpha thalassemia
(b) Autoimmune haemolytic anemia
(b) Beta thalassemia
(c) Paroxysmal nocturnal hemoglobinuria
(c) Sickle cell anemia
(d) Thalassemia
(d) G6PD deficiency
1 00.4. Bite cells are seen in: 103. NESTROF test is a screening test for which of the

(a) G6PD deficiency following conditions? (AIIMS Nov 2011)
(b) Sickle cell anemia (a) - thalassemia
(c) Hereditary spherocytosis (b) Hereditary spherocytosis
(d) Trauma (c) Autoimmune haemolytic anaemia
(d) Megaloblastic anaemia
1 00.5. Cold agglutinin is:
(a) IgG 104. Which of the following is the cause of alpha thalassemia?
(b) IgM (a) Deletion of alpha genes (AIIMS May 2011)
(c) IgA (b) Deletion of beta genes
(d) IgD (c) Excess of alpha genes
(d) Single amino acid substitution in alpha chain
1 00.6. Helmet cells are characteristic of anemia of:
(a) Hemolytic uremic syndrome
105. HbH is formed due to which of the following?
(a) Deletion of 4 alpha chains (AI 2011)
(b) Polysplenia
(b) Deletion of 3 alpha chains
(c) Spherocytosis
(c) Deletion of 2 alpha chains
(d) Acanthocytosis (d) Deletion of 1 alpha chain
1 00.7. Schistocyte is/are found in: 106. Mutation causing sickle cell anemia is protective for
(a) TTP which of the following? (AI 2010)
(b) March hemoglobinuria (a) Malaria (b) Filaria
(c) Severe iron deficiency (c) Leishmania (d) None of the above
107. What is affected in HbS (Hemoglobin S)? (AI 2009)
1 00.8. PNH due to defect in: (a) Stability (b) Function
(a) CD 59 (c) Affinity (d) Solubility
(b) CD 15
(c) CD 100
108. A couple, with a family history of beta thalassemia
major in a distant relative, has come for counseling. The
(d) CD 20 husband has HbA2 of 4.8% and the wife has HbA2 of
100.9. All are the features of hemolytic anemia except: 2.3%. The risk of having a child with beta thalassemia
(a) Hemoglobinuria major is: (AI 2003)
(b) Jaundice
(a) 50%
(c) Increased haptoglobin
(b) 25%
(d) Hemosiderinuria

(c) 5%

(d) 0%
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109. The primary defect which leads to sickle cell anemia 117. Sickle cell anemia is due to: (UP 2001)
is: (AI 2003) (a) Presence of a structurally abnormal Hb
(a) An abnormality in porphyrin part of hemoglobin (b) Red cell enzyme deficiency
(b) Replacement of glutamate by valine in b-chain of (c) Unknown multiple mechanisms
HbA (d) Disturbance of proliferation and differentiation of
(c) A nonsense mutation in the b-chain of HbA stem cells
(d) Substitution of valine by glutamate in the a-chain of
HbA 118. In sickle cell disease, the defect is in: (AP 2000)
(a) a-chain (Jipmer 1997, TN 1989),
110. Which one of the following statements about (b) b-chain
hemoglobin S (HbS) is not true: (AIIMS Nov 2004) (c) g-chain
(a) Hemoglobin HbS differs from hemoglobin HbA by (d) Hb formation
the substitution of Val for Glu in position 6 of the
beta chain 119. A 14-year-old male Kaalu is brought to the emergency
(b) One altered peptide of HbS migrates faster towards room with high grade fever, chest pain, and dyspnea.
the cathode () than the corresponding peptide of His past medical history is significant for two prior
HbA hospitalizations for abdominal pain, which resolved

(c) Binding of HbS to the deoxygenated HbA can extend with analgesics and hydration. Evaluation today
the polymer and cause sickling of the red blood cells reveals a hematocrit of 23% and reticulocyte count of

(d) Lowering the concentration of deoxygenated HbS 9%. Several hours after being admitted, the patient dies
can prevent sickling in the hospital. At autopsy, the patients spleen is firm
and brown; this finding is most likely related to:
111. Sickle cell trait patient do not have manifest-tations of

sickle cell disease, because: (AIIMS Nov 2001)

(a) Work hypertrophy
(a) 50% HbS is required for occurrence of sickling

(b) Follicular hyperplasia
(b) HbA prevents sickling

(c) Vascular occlusion
(c) 50% sickles

(d) Pressure atrophy
(d) HbA prevents polymerization of HbS

120. A 23-year-old male Subhas Raj presents to the medicine

112. True about Sickle cell anemia are all except: OPD with complaint of hematuria. There is no burning
(a) Commonly seen in blacks (PGI June 2004) sensation during urination. He also has no history
(b) R.(b)(c) size is altered suggestive of respiratory tract infection. He gives a
(c) Valine is substituted for glutamic acid in beta chain history of two of his relatives suffering from some
of globin. blood disease. His coagulation studies are within
(d) Deletion of gene normal limits. The hemoglobin electrophoresis shows
(e) Target cell are present the following: Hb A 60% and Hb S 40%. Which of the
following is most likely true about this patient?

113. True about beta-thalassemia trait is:
(a) Irreversible sickle cells are present on the peripheral
(a) Increased HbF (PGI June 2004) smear.
(b) Increased HbA2
(b) Reticulocyte count is elevate(d)
(c) Microcytosis
(c) He is protected from Plasmodium falciparum.
(d) Severe anemia
(d) MCHC is decrease(d)
(e) Target cell

121. Which of the following manifestations is common to

114. Sickle cell anemia is the clinical manifestation of sickle cell anemia and thalassemia major?
homozygous genes for an abnormal haemoglobin
(a) Autosplenectomy
molecule. The event responsible for the mutation in the
(b) Bone marrow expansion in the calvarium
b chain is (Delhi PG 2010)
(c) Ineffective erythropoiesis

(a) Insertion
(b) Deletion

(d) Predisposition to Hemophilus influenzae infections

(c) Non- disjunction (d) Point mutation
115. Hemoglobin H disease is caused by deletion of: Most Recent Questions
(a) A single a globin gene (Karnataka 2009)
(b) Two a globin genes 1 21.1 The primary defect which lead to stickle cell anemia is ?
(c) Three a globin genes (a) An abnormality in porphyrin part of haemoglobin
(d) All four a globin genes (b) Substitution of valine by glutamate in the -chain of
116. All of the following aggravate sickling phenomenon in HbA
sickle cell disease EXCEPT: (Karnataka 2008) (c) Replacement of glutamate by valine in -chain of
(a) Higher concentration of HbS HbA
(b) Higher concentration of HbF (d) A nonsense mutation in the -chain of HbA
(c) Lower concentration of HbC
(d) A fall in blood pH
268
121.2. In -thalassemia, which of the following is a finding? BLOOD GROUPING, BLOOD TRANSFUSION, ANTI
(a) No -chain COAGULANTS
(b) Excess -chain
(c) No -chain 122. Which of the following regarding Bombay blood group
(d) Relative excess of , , and chains is false? (AIIMS May 2012)
(a) Lack of H, A and B antigen on RBCs
121.3. In sickle cell anemia defect is in which chain: (b) Lack of H, A and B substance in saliva
(a) Alpha chain (b) Beta chain (c) Lack of antigens of several blood group systems
(c) Both the chains (d) None of these (d) H, A and B antibody will always be present in serum
121.4. Sickle cell red blood cells have: 123. Which of the following is the genotype of a person with
(a) Altered stability blood group A? (AI 2012)
(b) Altered functions (a) BO (b) AO
(c) Decreased oxygen carrying capacity (c) AB (d) OO
(d) Protective action against adult malaria
124. Secondary hemochromatosis is associated with all
121.5. Bone infarcts are seen in: except: (AI 2012)
(a) Iron deficiency anemia (a) Thalassemia
(b) Thalassemia (b) Sideroblastic anemia
(c) Sickle cell anemia (c) Multiple drug transfusions
(d) Hereditary spherocytosis (d) Paroxysmal nocturnal hemoglobinuria
121.6. Ideally children with thalassemia should be transfused 125. (a)

The anticoagulant of choice for anticoagulation testing
Heparin (AIIMS Nov 2011)
with
(a) Packed RBC (b) EDTA
(c) Sodium oxalate
(b) Platelet rich plasma
(d) 3.2% trisodium citrate

(c) Saline washed packed RBC
(d) Whole blood 126. You are working in a PHC and have to send a sample
for blood glucose estimation. Which of the following
121.7 . A 18 year old Afro American boy presenting with a non anticoagulant will you use for sending your sample?
healing ulcer of the foot, with recurrent pneumonia (a) EDTA (AIIMS Nov 2011)
and chronic hemolytic anemia. The peripheral blood (b) Heparin
erythrocytes showed some peculiar appearance. Most (c) Potassium oxalate + sodium fluoride
likely cause is: (d) Tri Sodium citrate
(a) Trinucleotide repeat
(b) Genomic imprinting
127. A newborn with ABO incompatibility, the characteristic
feature on peripheral smear is the presence of
(c) Single amino acid base substitution
(a) Microspherocytes (AIIMS Nov. 2010)
(d) Antibody to red cell membrane
(b) Fragmented RBC
1 21.8. Molecular pathogenesis of thalassemia involves (c) Polychromasia
(a) Mutation in transcription sequence (d) Elliptocytosis
(b) Gene deletion 128. Most common blood transfusion reaction is:
(c) Codon termination mutation (a) Febrile non-hemolytic transfusion reaction
(d) mRNA splicing defect (b) Hemolysis (AI 2008)
121.9. One of the common variants of sickle cell anemia (c) Transmission of infections
(d) Electrolyte imbalance
frequently marked by lesser degree of haemolytic
anemia and greater propensity for the development of 129. Rh antigen is a/an: (AI 2008)
retinopathy and aseptic necrosis of bones is (a) Antibody
(a) Sickle cell trait (b) Mucopolysaccharide
(b) Haemoglobin SC disease (c) Protein
(c) Sickle thalassaemia (d) Fatty acid
(d) Sickle Hb E disease 130. A 40 years old male had undergone splenectomy 20
years ago. Peripheral blood smear examination would
1 21.10. All are seen in Thalasemia major except-
show the presence of: (AI 2003)
(a) Transfusion dependency (a) Dohle bodies
(b) Splenoheptatomegaly (b) Hypersegmented neutrophils
(c) Ineffective erythropoiesis (c) Spherocytes
(d) Macrocytic anaemia (d) Howell-Jolly bodies
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131.
Which of the following complications is likely to result 139.
Spur cell anemia is caused by: (UP 2003)
after several units of blood have been transferred?
(a) Chronic liver disease

(a) Metabolic alkalosis (AI 2001)
(b) Acute blood loss

(b) Metabolic acidosis
(c) Chronic blood loss

(c) Respiratory alkalosis
(d) None

(d) Respiratory acidosis Hypersplenism is characterized by all except: (UP 2006)
140.
132. ABO incompatibility not seen with: (a) Leukemoid reaction
(b) Thrombocytopenia
(a) Fresh frozen plasma (AIIMS Nov 2009)
(c) Splenomegaly
(b) Platelet rich plasma
(d) Responds to splenectomy
(c) Single donor platelets
(d) Cryoprecipitate 141. The antigen lacking in Rh negative person is:(UP 2006)
(a) C b) D
133. A 55 years old male accident victim in casualty urgently (c) d (d) E
needs blood. The blood bank is unable to determine his
ABO group, as his red cell group and plasma group do Most Recent Questions
not match. Emergency transfusion of the patient should
be with:
(AIIMS Nov 2002) 141.1. Hemophilia is associated with :

(a) RBC corresponding to his red cell group and
(a) X chromosome (b) Y Chromosome
colloids/crystalloid

(b) Whole blood corresponding to his plasma group

(c) Chromosome 3 (d) Chromosome 16

(c) O positive RBC and colloids/crystalloid
141.2. Hemophilia B is due to deficiency of:

(d) AB negative whole blood
(a) Factor VIII
(b) Factor VII

134. Although more than 400 blood groups have been
(c) Factor IX
(d) Factor X
identified, the ABO blood system re-mains the most

141.3. All are true about polycythemia vera except:
important in clinical medicine because:

(a) It was the first blood group system to be discovered
(a) Increased LAP score

(b) It has four different blood group A, B, AB, O (H)
(b) Increased erythropoietin level

(c) ABO (H) antigens are present in most body tissues
(c) Splenomegaly
and fluids (AIIMS Nov 2002)
(d) May cause Budd-Chiari syndrome

(d) ABO (H) antibodies are invariably present in plasma

when persons RBC lack the corres-ponding antigen 141.4. Elevated ESR is seen in following conditions except:

135. Which of the following is seen in peripheral smear of a

(a) Polymyositis rheumatica
patient who has underwent splenectomy:
(b) Multiple myeloma

(a) Howell-Jolly bodies (PGI Dec 2001)
(c) Temporal arteritis

(b) Eosinophilia
(d) Polycythemia rubra

(c) Macrocytosis

141.5. True about von Willebrand factor are all except

(d) Thrombocytopenia

(a) Component of factor VIII

(e) Neutrophilia

(b) Synthesized by hepatocytes
136. Blood component products are all except?

(a) Whole blood (PGI Dec 2005)

(c) Facilitate the adhesion of platelets

(b) Platelets
(d) None
(c) Fresh frozen plasma 141.6. Patient with hemophilia A have bleeding disorder
(d) Packed red blood cells because of:
(e) Leukocyte reduced RBC
(a) Lack of platelet aggregation
137. The anticoagulant of choice for performing coagulation (b) Lack of reaction accelerator during activation of fac-
studies is: (Delhi PG 2010) tor X in coagulation cascade
(a) EDTA
(c) Neutralization of antithrombin III
(b) Heparin
(d) Release of Thromboxane A2
(c) Trisodium citrate
(d) Double oxalate 141.7. A 7-year-old girl presents with bleeding in joints. She
138. Howell Jolly bodies are seen in: (Karnataka 2009) has prolonged aPTT, normal PT and platelet counts.
(a) Liver disease What could be the deficiency?
(b) Postsplenectomy
(a) Factor IX
(b) Factor VIII
(c) Hemolysis
(c) Factor VII
(d) von Willebrand Factor
(d) DIC
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141.8. Hemophilia A is characterized by: 141.13. Platelets growth factor are synthesized by:
(a) Prolonged PTT (a) Glial cells
(b) Prolonged PT (b) Endothelium
(c) Low platelet count (c) Fibroblasts
(d) Abnormal BT (d) All of the above
141.9. True about hemophilia is: 141.14. Blood group antigens are
(a) If the male is affected, it will transmit to male (a) Carried by sex chromosomes
(b) Normal PT (b) Attached to plasma proteins
(c) Low PT (c) Attached to hemoglobin molecule
(d) Low aPTT (d) Sometimes found in saliva
1 41.10. The major hemoglobin present in an adult is 141.15. Stored plasma is deficient in
(a) HbA2 (b) HbA (a) Factors 7 and 8
(b) Factors 5 and 7
1
(c) HbA (d) HbA
(c) Factors 5 and 8
1c 1b
1 41.11. Bence Jones protein in urine are due to the presence of (d) Factors 5, 7 and 8
(a) Light chain of monoclonal immunoglobulins
(b) Heavy chain of monoclonal immunoglobulins 141.16. Carbohydrate present in blood group substance is
(c) Light chain of polyclonal immunoglobulins (a) Fucose (b) Deoxyribose
(d) Heavy chain of polyclonal immunoglobulins (c) Ribulose (d) Ribose
1 41.12. Starry Sky pattern is seen in all of these except: 141.17. All cause pseudohyperkalemia, except
(a) Burkitts lymphoma (a) Thrombocytopenia
(b) Large B cell lymphoma (b) Leucocytosis
(c) Small cleaved cell lymphoma (c) Clenching of fists
(d) Lymphoblast lymphoma (d) Hemolysis
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EXPLANATIONS
1. Ans. (b) Hereditary spherocytosis (Ref: Robbins 8th/640-2, 9/e p632)
Regarding Hereditary spherocytosis;
Direct quote from Robbins....this inherited disorder is caused by intrinsic defects in the red cell membrane that render red cells
spheroid, less deformable, and vulnerab le to splenic sequestration and destruction
Other disorders with intrinsic defect in red cell membrane are hereditary elliptocytosis and abetalipoproteinemia.
2. Ans. (c) Myoblast (Ref: Robbins 8th/85, 9/e p580)
Bone marrow cells include
Hematopoietic stem cells include lymphoblast, myeloblast and normoblast.
Marrow stromal cell/multipotent stem cells (MSC) including myoblast, osteoblasts, chondrocytes, adipocytes and endothelial
cell precursors. Myoblast is an example of MSC giving rise to muscle cells or myocytes.

3. Ans. (d) CD 34 (Ref: Robbins 7th/670, 9th/590)
CD34 is expressed on pluripotent hematopoietic stem cells and progenitor cells of many lineages

4. Ans. (c) Nutritional anemia (Ref: Harrison 18th/454, 17th/359-361 and Ghai 6th/306)
Reticulocytes are nonnucleated spherical cells bigger than normal RBCs and are polychromatic (having a blue color) due to the pres-
ence of free ribosomes and RNA.

Reticulocytosis (Increased RBC production) Reticulocytopenia (Decreased RBC production)
*Conditions *Conditions

Acute blood loss or hemorrhage
Aplastic anemia

Postsplenectomy
Bone marrow infiltration

Microangiopathic Anemia
Bone marrow suppression (Sepsis/Chemo/radiotherapy)

Autoimmune Hemolytic Anemia
Blood transfusion

Hemoglobinopathy (Sickle cell anemia and Thalassemia)
Liver disease

Post anemia treatment like folate supplementation, iron
Disordered RBC maturation (Iron, B12, Folate Deficiency,
supplementation & vitamin B12 supplementation. Hypothyroidism, Sideroblastic Anemia or Anemia of Chronic
Disease)
5. Ans. (b) Basophilic stippling; (d) Howell-Jolly bodies; (e) Cabot ring. (Ref: PJ Mehta 16th/372, T. Singh 1st/34)
Romanowsky dyes are used for staining blood films. They are made up of combination of acid and basic dyes. The
nucleus and neutrophilic granules are basophilic and stains blue. Hemoglobin is acidophilic and stains red.
Various modifications available are Leishmans stain, Wrights stain, Giemsa and Jenners stain.
Basophilic stippling, Howell-Jolly body and Cabot rings are seen by Romanowsky stain.
Basophilic stippling: These are small blue or black granules in red cells seen in megaloblastic anemia, heavy metal poisonings,
etc.
Howell-Jolly Body: These are remnants of the nucleus seen as small, round dark blue particles near the periphery of the cells;
found in postsplenectomy, asplenia and severe hemolytic anemia.
Cabot ring: These are pale staining nuclear remnants in the form of rings or figure of eight seen in hemolytic anemia, megaloblastic
anemia, leukemia and after splenectomy. These are arginine rich and acidophilic.
Heinz bodies are denatured hemoglobin which does not stained with Romanowsky stain. It is demonstrated by supravital stains
such as crystal violets. Reticulocytes also require Supravital staining.

6. Ans. (d) CD 34 (Ref: Robbins 7th/670, 9/e p590)
7. Ans. (d) Benign liver tumor (Ref: Robbins 7th/334, 649 9/e p331)
8. Ans. (a) MCV (Ref: Robbins 9/e p630, 8th/289, 7th/623 9/e p630)
9. Ans. (c) Megaloblastic (Ref: Robbins 9/e p645, 8th/655, 7th/638)
272
10. Ans. (a) Acute glomerulonephritis (Ref: Robbins 9/e p898, 8th/941, 7th/973-974)
11. Ans. (b) Spherocytosis (Ref: Robbins 9/e p633, 8th/642-644, 7th/627)
12. Ans. (d) Erythropoietin (Ref: Robbins 9/e p656, 8th/628, 7th/699)
13. Ans. (b) All of the above (Ref: Robbins 8th/665; 7th/960, Harrison 18 Table 280 (5))
14. Ans. (a) Uremia (Ref: Tejinder Singh 1st/38)
15. Ans. (a) Abetalipoproteinemia (Ref: Tejinder Singh 1st/38)
16. Ans. (b) Colony forming units-erythroid (Ref: Robbins 9/e p580, 8th/641)
The colony forming unit-erythroid (CFU-E) is a unipotential stem cell that develops from a burst forming unit-erythroid
(BFU-E), which develops eventually from the multipotential stem cell. The CFU-E is completely dependent on erythropoi-
etin. Erythropoietin is normally released from the kidney in response to hypoxic or anemic conditions.
The basophilic erythroblast (option a) differentiates from the proerythroblast. It has a dark basophilic staining due to
hemoglobin synthesis. The proerythroblast (option c) is the first recognizable cell in the red cell lineage. It develops from
the CFU-E cell. The basophilic erythroblast and the proerythroblast are not affected directly by erythropoietin, but instead
increases in number from the increased CFU-E cells.
The reticulocyte (option d) is the enucleated cell just before the mature red blood cell. It is not directly stimulated by
erythropoietin, but increases in number as a result of the increase in precursors.
16.1. Ans. (a) Bone marrow (Ref: Robbins 8/e p590, 9/e p580)
By birth, marrow throughout the skeleton is hematopoietically active and hepatic hematopoiesis dwindles to a trickle,
persisting only in widely scattered foci that become inactive soon after birth.
1 6.2. Ans. (c) Myelophthisic type (Ref: Robbins 8/e p665, 9/e p655)
Myelophthisic anemia describes a form of marrow failure in which space-occupying lesions replace normal marrow
elements. The commonest cause is metastatic cancer, most often carcinomas arising in the breast, lung, and prostate.
There is presence of leukoerythroblastosis (nucleated erythroid precursors) and the appearance of teardrop-shaped red

cells. This is due to disturbance of mechanisms regulating the egress of red cells and granulocytes from the marrow.
1 6.3. Ans. (d) ESR .(Ref: A Textbook of Hematology p133)
1 6.4. Ans. (b) Henoch Schonlein purpura (Ref: Robbins, 9/e p526-527 8/e p666; 7/e p986-987)
All other options have decreased platelet count except Henoch Schonlein purpura. Though it has the name purpura, but
the platelet count in this condition is normal. The skin manifestations in HSP are due to small vessel vasculitis.
1 6.5. Ans. (b) Contractile protein (Ref: Harsh Mohan 5th/ 177, The Circulating Platelet/ 215-8)
Thrombosthenin is a contractile protein in platelets that is active in the formation of blood clots.
1 6.6. Ans. (a) Lymphocyte (Read below)
Lymphocyte is the longest living white blood cell.
Q
Neutrophil is the most numerous white blood cell.

Q
1 6.7. Ans. (c) 0.54 C (See below)

The freezing point of normal human plasma averages -0.54 C , which corresponds to an osmolal concentration in plasma
Q
of 290 mOsm/L .
Q
The term tonicity is used to describe the osmolality of a solution relative to plasma
A 0.9% saline solution and 5% glucose solution is isotonic when initially infused intravenously.
Also know how to calculate osmolality: medicine link!

Osmolality (mOsm/L) = 2[Na+] (mEq/L) + 0.055[Glucose] (mg/dL) + 0.36[BUN] (mg/dL)
16.8. Ans. (b) 2:1 (Read below)

Normal albumin-globulin ratiois 1.8 : 1 to 2 : 1 . Q
Synthesis of albumin exclusively occurs in liver but many globulins (immunoglobulins) are synthesized by
B-lymphocyte.
Conditions with altered albumin globulin ratio
High Albumin Globulin Ratio Low Albumin Globulin Ratio

Hypothyroidism Overproduction of globulins in conditions like multiple myeloma, chronic infections and
Hypogammaglobulinemia in some autoimmune diseases.
Leukemia Under production of albumin in conditions like liver cirrhosis, malnutrition and
Glucocorticoid excess nephrotic syndrome.
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1 6.9. Ans. (c) 900 (Read below)

About 900 g of hemoglobin is present in the circulating blood of an adult man
Q
Also know:
The erythrocytes carry hemoglobin in the circulation. They are biconcave disks because of the protein
called as spectrin .
Q
In humans, the RBCs survive in the circulation for an average of 120 days. Q
The average normal red blood cell count is 5.4 million/ L in men and 4.8 million/ L in women.
1 g of hemoglobin yields 35 mg of bilirubin . Q
16.10. Ans. (c) Cyanmethemoglobin method (Read below)

Hemoglobin estimation
Visual Colorimetric method Sahlis (acid hematin method) Most popular method
Alkali hematin method
Photocolorimetric method Cyanmethemoglobin method Most accurate and currently used
1 6.11. Ans. (c) 4

Hemoglobin is a globular molecule made up of four subunits. Each subunit contains a heme moiety conjugated to a poly-
peptide. Heme is an iron-containing porphyrin derivative. So, hemoglobin = 4 globins + 4 heme groups
Since each heme molecule contains an iron, so total iron atoms present in hemoglobin are 4 in number.
70% of the iron in the body is in hemoglobin, 3% in myoglobin, and the rest in ferritin, which is present not only in
enterocytes, but also in many other cells.
1 6.12. Ans. (a) Histidine residues
Harper mentions Hemoglobin also functions in CO and proton transport from tissues to lungs. Release of O from oxy
2 2
Hb at the tissues is accompanied by uptake of protons due to lowering of the pKa of histidine residues.
Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase Q
Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine
16.13. Ans. (b) labile factor.

If whole blood is allowed to clot and the clot is removed, the remaining fluid is called serum. Serum has essentially the
same composition as plasma, except that:
Fibrinogen (factor I) and clotting factors II, V, and VIII have been removed and
Has higher serotonin content because of the breakdown of platelets during clotting.
Also know that factor 5 is called as labile factor .Q
1 6.14. Ans. (b) Brilliant Cresyl blue (Ref: Robbins, 9/e 635)
Reticulocytes are stained in living state in vitro so staining with dyes like brilliant cresyl blue and new methylene
blue is referred to as supravital staining.
1 6.15. Ans. (c) RBCs to whole blood (Ref: Robbins, 9/e 631)
Haematocrit (also known as packed cell volume) is the volume percentage (%) of red blood cells in blood.
16.16. Ans. (a) Ferritin (Ref: Robbins, 9/e 650)
Ferritin is the storage and transferring the transport form of iron.
Ferroportin is a transmembrane protein that transports iron from the inside of a cell to the outside of it.
Hepcidin is released by liver in setting of anaemia of chronic disease. It is the master regulator of human iron metabo-
lism.
16.17. Ans. (a) Brilliant cresyl blue (Ref: Robbins, 9/e)
The most common supravital stain is performed on reticulocytes using new methylene blue or brilliant cresyl blue. It
makes it possible to see the reticulofilamentous pattern of ribosomes characteristically precipitated in these live immature
red blood cells.
17. Ans. (a) Increased reticulocyte Count (Ref: Robbins 9/e 645, 8th/655, Wintrobes 12th/1151-3)
Direct quote from Robbins The reticulocyte count is low.
Please be clear of the concept friends that the reticulocyte count is increased when the megaloblastic anemia is being
treated with vitamin B12 and folate supplementation i.e. after the initiation of the treatment in these patients.
274
The marrow is usually markedly hypercellular as a result of increased hematopoietic precursors, which often completely replace
the fatty marrow. Certain peripheral blood findings are shared by all megaloblastic anemias. The presence of red cells that are
macrocytic and oval (macro-ovalocytes) is highly characteristic. There is presence of marked variation in the size (anisocytosis) and
shape (poikilocytosis) of red cells. The reticulocyte count is low. Nucleated red cell progenitors occasionally appear in the circulating
blood when anemia is severe. Granulocytic precursors also display dysmaturation in the form of giant metamyelocytes and band
forms. Neutrophils are also larger than normal and are hypersegmented (having five or more nuclear lobules instead of the normal
three to four). Megakaryocytes, too, can be abnormally large and have bizarre, multilobate nuclei.
The derangement in DNA synthesis causes most precursors to undergo apoptosis in the marrow (ineffective hematopoiesis) and
leads to pancytopenia. The anemia is further exacerbated by a mild degree of red cell hemolysis. This leads to raised bilirubin.
Wintrobe mentions Mild reversible splenomegaly is present in megaloblastic anemia.
18. Ans. (d) Myelofibrosis (Ref: Harrison 17th/661, 674, 646)

The findings in the given question are:
Anemia (Hb = 6g)
Reduced leukocyte count (TLC= 1200)
Reduced platelet count (60000)
Reduced MCV (12fL)
Normal value of MCV is 80-100 fL. It is the measure of size of RBC. Reduced MCV means microcytic and increased
MCV means macrocytic RBCs. Normal TLC is 4000-11000, normal platelet count is 1,50,000 to 4,50,000 and normal
Hb is above 12 g/dL.
Now, considering the options one by one:
Aplastic anemia has reduced RBC, WBC as well as platelet counts. Anemia is normocytic normochromic, thus it
can be easily ruled out.
Paroxysomal nocturnal hemoglobinuria (PNH) typically presents with anemia which is usually normomacrocytic.

If MCV is high, it is due to reticulocytosis. Neutropenia and thrombocytopenia may or may not be present.
Therefore, this option also cannot be the answer.
Megaloblastic anemia presents with raised MCV. There may be leukopenia as well as thrombocytopenia. Severity
of these changes parallels the degree of anemia.
Myelofibrosis usually presents with anemia, leukopenia and thrombocytopenia. Mostly anemia is normocytic but
in 30% cases microcytic anemia can be present.
Based on the above discussion, the most probable answer is Myelofibrosis.
However, the value of MCV given is 12 fL which is practically not possible. Normal value of MCV is 80-100 fL. MCV < 50
fL is considered to be extremely low. Therefore, one possibility is that it may be 112 fL and due to typographical error in
the question, written as 12 fL. If this is the case, then the answer will become megaloblastic anemia.
As we cannot say for sure that it is a printing mistake, so we will go for Myelofibrosis.
19. Ans. (a) MCV. (Ref: T. Singh 1st/35, Harrison 17th/357, Robbins 9/e 629-630)
MCV > 100fL indicates macrocytosis.
20. Ans. (a) Megaloblastic precursors are present in bone marrow; (b) Mean corpuscular volume is increased; (c) Serum
LDH is increased: (Ref: Robbins 9/e 645, Harrison 17th/645-646)
Megaloblastic anemia is a maturation disorder of red cells
Cells are macrocytic and hyperchromic. Anisocytosis and hypersegmented neutrophils are also seen.
Bone marrow shows hypercellularity, erythrocyte precursors at different stages of development is found. Increased
megaloblast causes ineffective erythropoiesis.
In severe anemia as many as 90% of RBC precursors may be destroyed before their release into the circulation (Nor-
mal 10-15%). Thereby increased unconjugated bilirubin and lactic acid dehydrogenase.
Target cells result due to increased ratio of RBC surface area to volume, seen in hemoglobin disorders, thalassemia, liver
disease. Reticulocytes, platelet count and leukocyte count decreased.
21. Ans. (b) Copper deficiency: (Ref: Harrison 17th/449)
Copper deficiency is manifested by hypochromic normocytic anemia, osteopenia, depigmentation, mental retardation and psychomotor
abnormalities.

Thiamine, pyridoxine and Bl2 deficiency leads to megaloblastic anemia.
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Classification of megaloblastic anemia

Drugs Diseases Unknown etiology
Cobalamin deficiency Purine and Pyrimidine antagonists Hereditary orotic aciduria Refractory megaloblastic anemia.
Folic acid deficiency Others-procarbazine, zidovudine Lesch-Nyhan syndrome Di-Gueglielmo syndrome
hydroxyurea, acyclovir Congenital dyserythropoietic anemia
Causes of anemia in Liver diseases are gastrointestinal bleeding, folate deficiency and hypersplenism.
22. Ans. (a) Fish tapeworm infestation; (c) Gastrectomy; (d) Ileal resection. (Ref: Robbins 7th/640, 9/e 645)
The other two cause megaloblastic anemia by interfering with folic acid metabolism.
23. Ans. (c) Pure Red Cell Aplasia (Ref: T. Singh 1st/140; Robbins 7th/648, 636, 9/e 642)
PNH is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane. PNH arises in the setting
of aplastic anemia and these patients are at increased risk of developing acute myelogenous leukemia.
Aplastic anemia may progress to PNH and MDS.
24. Ans. (d) Cholestatic jaundice (Ref: Robbins 7th/640, 9/e 645)
25. Ans. (d) Thalassemia (Ref: Robbins 9/e 639, 8th/649, 7th/635)
26. Ans. (a) Myelofibrosis (Ref: Robbins 9/e 620-621, 8th/630-631; 7th/700-701)
27. Ans. (b) Folic acid deficiency (Ref: Robbins 9/e 648, 8th/659; 7th/642)
28. Ans. (d) Hypothyroidism (Ref: Tejinder Singh 1st/66, Robbins 9/e 645)
29. Ans. (a) Thymoma (Ref: Robbins 9/e 627, 8th/636-637; 7th/707-708)
30. Ans. (b) Diphyllobothrium latum (Ref: Robbins 9/e 648, 8th/655, 7th/640)
31. Ans. (c) Anemia occurs after 3-4 months of poor absorption (Ref: Robbins 9/e 648, 8th/657; 7th/682)
32. Ans. (b) Folic acid deficiency (Ref: Harsh Mohan 6th/308, Robbins 9/e 647)
33. Ans. (c) Megaloblastic (Ref: Robbins Robbins 9/e 645, 8th/655, 7th/638)
34. Ans. (c) Megaloblastic anemia (Ref: Robbins 9/e 645, 8th/655, 7th/638)
35. Ans. (d) Postsplenectomy (Ref: Robbins 9/e 627, 633, 8th/646, 7th/627, Harrison 17th/375)
36. Ans. (c) Diphyllobothrium latum infestation (Ref: Robbins 9/e 648, 8th/655)
37. Ans. (d) Thymoma (Ref: Robbins 9/e 627, 8th/664)
In the rare pure red cell aplasia, the erythroid marrow elements are absent or nearly absent, while granulopoiesis and
thrombopoiesis remain unaltered. This condition occurs in both primary and secondary forms, both of which are thought
to be related to autoimmune destruction of erythroid precursors. There is a specific association between thymic tumors
(thymoma) and autoimmune hematologic diseases, specifically including pure red cell aplasia.
38. Ans. (a) Dietary cobalamin deficiency (Ref: Robbins 9/e 648, 8th/656-8)
Vitamin B deficiency may occur due to low dietary intake of this vitamin, the presence of antibodies against intrinsic fac-
12
tor (pernicious anemia) or malabsorption.
The Schilling test helps to differentiate between different causes of vitamin B12 deficiency. The patient is first given a dose of radiola-
beled oral vitamin B12 and an intramuscular injection of unlabeled Vitamin B12. The urinary excretion of radioactive B12 is then measured.
Normal urinary excretion of radiolabeled vitamin B12 suggests normal absorption, and B12 deficiency in this setting is most likely due to
poor intake of Vitamin B12 in the diet (choice A).

Diminished urinary excretion of radiolabeled vitamin B12 is a sign of impaired intestinal absorption. To differentiate between pernicious
anemia and malabsorption, the next dose of radiolabeled B12 is given with intrinsic factor. Normal excretion after the addition of intrinsic
factor is diagnostic of pernicious anemia. Low excretion of B12 after administration of intrinsic factor rules out pernicious anemia and
suggests a malabsorption syndrome such as pancreatic insufficiency, bacterial overgrowth, or short gut syndrome.

(Choice B) Pernicious anemia is associated with atrophic gastritis and the presence of antibodies against gastric parietal
cells and intrinsic factor. Administration of vitamin B12 without intrinsic factor will show low urinary radioactive vitamin
B12 excretion on the Schilling test.
(Choices C and D) Nontropical sprue (celiac disease) and Diphyllobothrium latum infestation are examples of malabsorption
syndromes. They are characterized by impaired absorption of vitamin B12 on the Schilling test that is not corrected by oral
intrinsic factor supplementation.
39. Ans. (b) Reticulocyte count (Ref: Robbins 8th/641)
276
The graph describes the treatment response to vitamin B12 (cyanocobalamin) in a patient with vitamin B12-deficiency ane-
mia secondary to atrophic gastritis. Once vitamin B12 replacement therapy is begun the rate of effective erythropoiesis
increases immediately. Immature erythrocytes are released from the bone marrow into the bloodstream. The peripheral
count of these reticulocytes may rise within one week as indicated by the Gaussian curve on the graph. The anemia typi-
cally takes as long as six weeks to correct as indicated by the exponential curve on the graph.
(Choice A) The RBC count curve would be expected to follow the contour of the total hemoglobin curve.
(Choice C) Since this patient is suffering from a vitamin B12-deficiency anemia (which is non-hemolytic in nature) we
would not expect serum haptoglobin levels to be affected by the anemia or its treatment.
(Choice D) In chronic atrophic gastritis, parietal cell loss results in profound hypochlorhydria, increased serum gastrin
levels (antral G cell gastrin secretion is inhibited by the presence of hydrochloric acid) and inadequate intrinsic factor pro-
duction. The vitamin B12 deficiency in this patient is a consequence not a cause of his parietal cell atrophy.
Atrophic gastritis can result in profound hypochlorhydria inadequate intrinsic factor production, vitamin B12 deficiency, megaloblastic
anemia and elevated serum gastrin and methylmalonic acid (MMA) levels. Once vitamin B12 replacement therapy is initiated in an
individual with atrophic gastritis the reticulocyte count increases dramatically. Hemoglobin and RBC count levels gradually rise while
the methylmalonic acid level decreases.
3 9.1. Ans. (a) Beta thalassemia trait (Ref: Robbins 9/e 641, 8/e p649)
Hemoglobin electrophoresis usually reveals an increase in HbA ( ) to 4% to 8% of the total hemoglobin (normal, 2.5%
2 2 2
0.3%), which is a reflection of an elevated ratio of -chain to -chain synthesis. HbF levels are generally normal or occasionally
slightly increased.
3 9.2. Ans. (c) Vitamin B absorption (Ref: Robbins 9/e 648, 8/e p657-8)
12
The Schilling test is performed to determine the cause for cobalamin malabsorption. Since cobalamin absorption requires
multiple steps, including gastric, pancreatic, and ileal processes, the Schilling test also can be used to assess the integrity
of those other organs.
Differential Results of Schilling Test in Several Diseases with Cobalamin (Cbl) Malabsorption

58
Co-Cbl With Intrinsic Factor With Pancreatic Enzymes After 5 Days of Antibiotics
Pernicious anemia Reduced Normal Reduced Reduced
Chronic pancreatitis Reduced Reduced Normal Reduced
Bacterialovergrowth Reduced Reduced Reduced Normal
Ileal disease Reduced Reduced Reduced Reduced
39.3. Ans. (c) Increased reticulocyte count..(Ref: Robbin 8/e p655, Wintrobes 12/e p1151-3)
Repeat from AIIMS Nov 12 see earlier explanation
39.4. Ans. (a) Aplastic anemia..(Ref: Robbin 9/e p653)
Aplastic anemia refers to a syndrome of chronic primary hematopoietic failure and attendant pancytopenia (anemia,
neutropenia, and thrombocytopenia).
39.5. Ans. (c) Chronic renal failure.. read below
The same question was asked in different sets with different choices. Choices a,b,d are examples of hemolytic anemias and
hence the answer by exclusion is chronic renal failure. CRF has low erythropoietin levels due to less production and has
normocytic normochromic anaemia.

39.6. Ans. (b) Human parvo virus B19 (Ref: Robbin 9/e p460)
Parvovirus B19 causes erythema infectiosum or fifth disease of childhood in immunocompetent older children. Parvovi-
rus B19 has a particular tropism for erythroid cells, and diagnostic viral inclusions can be seen in early erythroid progeni-
tors in infected infants.
Parvovirus infection in pregnant women is associated with hydrops fetalis due to severe fetal anemia, sometimes leading to miscarriage or
stillbirth.
40. Ans. (a) Anaemia of chronic disease (Ref: Robbins 9/e 652-653, Wintrobe 12th/1221-2)
Looking at the data one by one friends, we infer that:
We have an old patient with chronic inflammatory condition. In addition,
Parameter with value in question Normal range Inference in our patient
Hemoglobin 4.5gm/dl 13-17g/dl Decreased
Platelet count 2 lakh/ml 1.5-4.5lakh/ml Normal
TLC 6000/mm3 4000-11000/mm3 Normal
Contd...
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Contd...
Parameter with value in question Normal range Inference in our patient
Serum ferritin 200 g/L 15-300 g/L Normal
Serum iron 30 mg/L 50-150 g/L Reduced
TIBC 280 ng/L 300-400 mg/L Reduced
Final conclusion, decreased serum iron, increased storage iron i.e. serum ferritin, decreased serum transferring and decreased total
iron binding capacity suggest the diagnosis of anaemia of chronic disease.
41. Ans. (b) Thalassemia minor (Ref: Hematology by Renu Saxena 1st/174)
Thalassemia major patient presents with severe anemia and cannot survive without blood transfusion, so this option can be
easily ruled out. For other options, Mentzer index is useful for differentiating between thalassemia minor and iron defi-
ciency anemia.
Mentzer index is calculated as MCV/RBC count. Its value is >13 in iron deficiency anemia and <13 in thalassemia minor.
For our given question, the value on calculation comes out to be 55/4.5 = 12.22.
As the value is < 13, so it is a case of thalassemia minor.
42. Ans. (a) Iron deficiency anemia (Ref: Robbins 8th/651, 9/e 652, T.Singh 1st/34)
Decreased hemoglobin with the clinical features of fatigue and weakness is diagnostic of anemia
MCV is 70 fl, so, microcytosis is present (normal MCV is 82-96fl)
MCH is 22pg, so, decreased MCH is suggestive of hypochromic anemia (normal MCH is 27-33pg)
Red cell distribution width (RDW) is the coefficient of variation of size of RBCs. Normal value is 11.5-14.5. It is an
indicator of anisocytosis which may present in IDA as well as hemolytic anemias.
In early iron deficiency anemia, RDW increases along with low MCV while in beta thalassemia trait, RDW is normal
with low MCV, thus distinguishing from each other.
Increased reticulocytosis is a feature of iron deficiency anemia.

43. Ans. (b) Myelodysplastic syndrome (Ref: Robbins 9/e 615, Wintrobes 10th/1022-25)
Sideroblastic anemia can be hereditary (due to decreased ALA synthase activity) or acquired (secondary to leukemias,
myelodysplastic syndrome, alcoholism, copper deficiency, pyridoxine deficiency or lead poisoning).
44. Ans. (c) Thalassemia minor (Ref: Robbins 9/e 641, 8th/651, 7th/633-634)
Thalassemia major patient presents with severe anemia and cannot survive without blood transfusion, so this option
can be easily ruled out.
This cannot be a case of megaloblastic anemia because in megaloblastic anemia, M.C.V. is increased (> 100 fL)
So, we are left with two options, i.e. Iron deficiency anemia and thalassemia minor. Both of these presents with mi-
crocytic hypochromic anemia.
The key point in the differential diagnosis of these two conditions is the RBC count.
In thalassemia minor, the RBC count is near normal and only the hemoglobin is reduced. In this condition the R.B.C.
count is not reduced as much as the hemoglobin and hematocrit in fact it is usually normal. This due to the fact that the mar-
row can keep on producing the cell at normal rate but it cannot fill them with hemoglobin. Hence, the hemoglobin is
low and the empty cells occupy less space thus lowering the hematocrit relative to the erythrocyte count.
On the other hand, in Iron deficiency anemia, the RBC production is also impaired.
There are many indices to differentiate between iron deficiency anemia (IDA) and beta-thalassemia (BT):
Index Formula Value for iron Deficiency anemia Value for beta-thalassemia
Mentzer index MCV/RBC count > 13 < 13
Shine and Lal Index MCV2 X MCH X 0.01 > 1530 < 1530
England and fraser index MCV RBC (5 X Hb) 5.19 > 0 <0
Srivastava Index MCH/RBC > 3.8 < 3.8
Green and King index MCV X RDW X Hb/100
2
> 65 < 65
Red Cell Distribution Width index MCV X RDW/RBC > 220 < 220
In the given question, only the value of MCV and RBC are given, so we can utilize Mentzer index. The Mentzer index in
the given question is 55/4.5 = 12.22
As the value is < 13, so it is a case of thalassemia minor.
45. Ans. (a) Inhibition of enzymes involved in heme biosynthesis (Ref: Robbins 9/e 411, Tejinder Singh 1st/147)
278
Lead inhibits the enzymes aminolevulinic acid dehydrase, red cell pyrimidine 5 nucleotidase and ferrochelatase
which are involved in the synthesis of heme.
Deficiency of heme causes microcytic hypochromic anemia because heme is an integral part of hemoglobin and
hemoglobin deficiency causes microcytic hypochromic anemia.
46. Ans. (b) Sideroblastic anemia (Ref: Harrison 17th/631-32 (t) 98-4)
The hematological findings suggest the diagnosis of sideroblastic anemia.
Differential diagnosis of microcytic hypochromic anemia (Very Important for exams)
Tests Iron deficiency Inflammation Thalassemia Sideroblastic anemia
Peripheral smear Micro/hypo Normal micro/hypo Micro/hypo with targeting Variable
SI Normal to high Normal to high
TIBC Normal Normal
Percent TS
Ferritin (mcg/L)
Hemoglobin pattern Normal Normal Abnormal Normal
SI, serum iron; TIBC, total iron-binding capacity; TS, transferrin saturation.
47. Ans. (a) Erythropoietin; (b) RBC survival; (c) folate; (d) Bone marrow hypoplasia; (e) Iron deficiency. (Ref: Harrison
17th/633-634, 18th/e (t) 280 (5))
48. Ans. All. (Ref: Robbins 9th/651, Harrison 17th/631; (t) 98(2))
49. Ans. (a) Thalassemia; (c) Anemia in chronic disease (e) Megaloblastic anemia (Ref: Harsh Mohan 6th/302, 307)
Increased bone marrow iron is seen in:
Sideroblastic anemia
Anemia of chronic disease

Megaloblastic anemia
Pernicious anemia
Thalassemia.
50. Ans. (a) Thalassemia; (b) Hb Lepore; (c) Hb Barts. (Ref: Harsh Mohan 6th/323-324)
Causes of microcytosis (MCV < 80fl)
Iron deficiency anemia
Thalassemia
Sideroblastic anemia
Anemia of chronic disease
In Hb Barts, all the four a chain genes are deleted resulting in formation of Barts Hb.
In Hb Lepore, there is nonhomologus fusion of b and d genes and forms an abnormal hemoglobin with total absence of normal b chain.
It is one of the form of b thalassemia minor.

51. Ans. (a) Microcytic hypochromic anemia; (d) Bone marrow iron decrease earlier than serum iron. (Ref: Robbins 7th/645,
de Gruchys 5th/42)
52. Ans. (d) S. ferritin (Ref: Harrison 17th/632-4, Robbins 9/e 625-653, 8th/662)
53. Ans. (d) Persistently raised HbF (Ref: Wintrobes 11th/1326; Nelson 17th/1630)
It is a case of persistently raised HbF.
Characteristics
There is persistence of fetal Hb in adult life so that almost whole of the Hb of patient is HbF.
Patient remains asymptomatic even without blood transfusion.
No anemia or splenomegaly seen.
Beta-globin genes HbA HbA2 HbF
Normal Homozygous b 97-99% 1-3% < 1%
Homozygous b0 0% 4-10% 90-96%
Thalassemia major
Homozygous b+(mild) 0-30% 0-10% 60-100%
Thalassemia intermedia Homozygous b (mild)
+
0-30% 0-10% 60-100%
Homozygous b0 80-95% 4-8% 1-5%
Thalassemia minor
Homozygous b+ 80-95% 4-89% 1-5%
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From the values given in question it can be thalassemia major or thalassemia intermedia.
In thalassemia major patient presents with severe hemolytic anemia at the age of 6 months and cannot survive with-
out blood transfusions.
In thalassemia intermedia patient can survive without transfusion but they are not asymptomatic.
54. Ans. (c) Absence of intrinsic factor (Ref: Robbins 9/e 645, 7th/639-640)
Absence of IF causes Pernicious anemia which is an example of megaloblastic anemia.
55. Ans. (c) Rheumatoid arthritis (Ref: Robbins 7th/639-640)
Hypochromic/microcytic blood picture is seen in: (mnemonic: SITA)
S - Sideroblastic anemia shows presence of ringed sideroblasts (Lead poisoning has basophilic stippling), I - Iron deficiency
anemia, T - Thalassemia major, A - Anemia of chronic disease
Note: In anemia of chronic disease (of Rheumatoid Arthritis, TB, UTI, etc), the red cells are mainly normocytic; normochromic red cells.
In some cases, red cells may be hypochromic. So, we would go with RA as the best answer in this question.

How to differentiate feature between IDA and AOCD is:
In IDA microcytosis precedes development of hypochromia.
In Anemia of chronic disease hypochromia precedes microcytosis.
56. Ans. (a) Microcytic hypochromic anemia (Ref: Hematology by Tejinder Singh/83)
Explained in text.
57. Ans. (a) Congenital spherocytosis (Ref: Robbins 7th/625)
Hereditary spherocytosis Small RBCs are seen without central pallor (normal RBCs have central 1/3 pallor). It is also rd
seen conditions where spherocytes are present in peripheral blood like:

Hereditary spherocytosis Burns
Autoimmune hemolytic anemia G6PD deficiency
Cirrhosis ABO incompatibility

Clostridial sepsis
58. Ans. (d) Megaloblastic anemia (Ref: Robbins 9/e 645, 7th/639/643/626/629)
Megaloblastic anemia: Two principal types
Pathology: Defective DNA synthesis and diminished erythropoiesis
Morphology - Anisocytosis (various size + shape), Macrocytosis (MCV > 100 fl), MCHC is normal and, Macropoly-
morphonuclear (hyper segmented) neutrophils
59. Ans. (c) Serum ferritin level (Ref: Robbins 9/e 652-653, 8th/662, 7th/646)
60. Ans. (a) Iron deficiency (Ref: Robbins 9/e 652-653, 8th/659; 7th/643)
61. Ans. (c) TIBC is decreased (Ref: Robbins 9/e 652-653, 8th/662; Harrison 17th/632)
62. Ans. (b) Transferrin (Ref: Robbins 9/e 650, 8th/659; 7th/644)
63. Ans. (d) Increased mean corpuscular volume (Ref: Robbins 9/e 652, 8th/660-661, 7th/645)
64. Ans. (c) Serum Ferritin (Ref: Robbins 9/e 652, 8th/659-660)
65. Ans. (d) Salivary gland (Ref: Robbins 9/e 848-849, 8th/660, 7th/909)
66. Ans. (a) Melanin (Ref: Robbins 9/e 849, 8th/660-661, 7th/910)
67. Ans. (a) Ferritin (Ref: Robbins 9/e 650, 8th/659-660, 7th/644)
68. Ans. (c) Iron deficiency anemia (Ref: Robbins 9/e 652, 8th/659-662; 7 th/634, 646)
69. Ans. (b) Serum iron increased, TIBC decreased (Ref: Robbins 9/e 849, 8th/862-3)
The stem of the question is suggestive of long-standing, late stage hereditary hemochromatosis, and the expected findings
would include markedly increased serum iron and moderately reduced TIBC. This combination often results in almost
100% saturation of iron-binding capacity.
6 9.1. Ans. (d) Cutaneous porphyria (Ref: Hematology: Diagnosis and Treatment p467)
Sideroblastic anemia is associated with the following
Hereditary: X linked, autosomal recessive, autosomal dominant
Acquired: previous chemotherapy, irradiation, myelodysplasia, myelproliferative disorders
280
Drugs: alcohol isoanizid, choramphenicol, pyridoxine deficiency, lead poisoning

Rare causes: copper deficiency, zinc overload, hypothermia, erythropoetic porphyria
Hereditary syndromic: Pearson syndrome, thiamine responsive megaloblastic anemia,
69.2. Ans. (d) Macrocytic anemia (Ref: Robbins 9/e 411, 8/e p406-7)
Lead inhibits the activity of enzymes involved in heme synthesis; -aminolevulinic acid dehydratase and Q
ferrochelatase (BIOCHEMISTRY NEET QUESTION INFO)

Q
Ferrochelatase catalyzes the incorporation of iron into protoporphyrin, and its inhibition causes a rise in
protoporphyrin levels as well as appearance of scattered ringed sideroblastsQ. The elevated levels of protoporphyrin
may appear in the urine of an individual.
There is a distinctive punctate basophilic stipplingQ of the red cells and the presence of microcytic, hypochromic
anemiaQ.
Also know that in lead poisoning is associated with reduction in uric acid excretion which can lead to gout (saturnine
gout Q)
6 9.3. Ans. (a) Duffy blood group (Ref: Robbins 9/e 391, 8/e p387)
Conditions providing protection against malaria with the reasons
Sickle cell disease: P falciparum can not multiply properly in the presence of HbS
and thalassemia:
Absence of duffy blood group: duffy antigen is required for parasite to enter the RBCs
G6 PD deficiency: G6PD is required for respiration of plasmodium
6 9.4. Ans. (b) Reticulocytosis (Ref: Robbins 9/e 652, 8/e p662, 7/e p624)

In uncomplicated cases, oral iron supplementation produces an increase in reticulocytosis in about 5-7 days that is fol-
lowed by a steady increase in blood counts and normalization of red cell indices.
6 9.5. Ans. (a) Lead (Ref: Robbins 9/e 411, 8/e p406-407, 7/e p432-433)
Lead is associated with sideroblastic anemia..details are discussed in a separate question.
6 9.6. Ans. (a) RBCs (Ref: Harrison 17/e p77)
You must know: Different type of red blood cells are:
Echinocytes/Burr cells : Regular spine-like projections on cell surface; in Megaloblastic anemia/burns/hemolytic
anemia
Acanthocytes/Spur cells : irregular thorn-like projections; in liver disease, abetalipoproteinemia
Stomatocytes : Slit-like (mouth like) area of pallor
Schistocytes : Fragmented RBCs; triangular, comma-shaped or helmet shaped
Leptocytes : Thin flat cells
Codocytes : Mexican hat cells
Dacrocytes : Tear drop cells or Target cells (red cells with central dark area; in liver disease, anemia of chronic disease)
Drepanocytes : Sickle cells
Elliptocytes : Pencil cells or cigar cells
Keratocytes : Helmet cells
Knizocytes : Cells with more than one concavities
6 9.7. Ans. (b) Hookworm (Ref: Robbins 9/e 651, 8/e p336, 7/e p623)
Hookworm infestation can cause chronic blood loss and therefore may cause iron deficiency anemia.
6 9.8. Ans. (a) Reticulocytosisexplained earlier (Ref: Robbins 9/e 652, 8/e p641, 7/e p624)
6 9.9. Ans. (a) Mucosal cell iron stores (Ref: Robbins 9/e 650)
Rate of iron uptake is dependent on the levels of a protein called hepcidin. This protein functions to regulate (inhibit) iron
transport across the gut mucosa, thereby preventing excess iron absorption and maintaining normal iron levels within the
body. Hepcidin also inhibits transport of iron out of macrophages (where iron is stored).
Mutation of the gene coding for hepcidin is implicated in the causation of hemochromatosis.
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69.10. Ans. (a) Anaemia of chronic disease.... see text for details
Revision of iron profile table
Parameter Iron deficiency Sideroblastic Anemia of
anemia anaemia chronic disease
Serum iron Low High Low
Serum ferritin Low High High
T.I.B.C Increased decreased Low
Homozygous b+ (mild) 0-30% 0-10% 60-100%
70. Ans. (c) Coombs test (Ref: Robbins 9/e 643, 8th/653)
The presence of spherocytes can be seen in the following conditions:
Hereditary spherocytosis
Autoimmune hemlolytic anemia
G6PD deficiency
Infections
Burns
Hemolytic disease of new born
PNH is not a cause for the presence of spherocytes; so, no test for this condition is required.
Osmotic fragility is increased with spherocytes. So, it does not add anything to our existing information about the
disease causing spherocyte formation.
Reticulocyte count is expected to be elevated in the setting of haemolytic anemia (suggested by jaundice and pallor).
Coombs test is done for detection of the antibodies formed against the normal antigens present on the surface of cells like platelets
and red blood cells. So, it is going to be positive in autoimmune hemolytic anemia whereas negative in hereditary spherocytosis. Thus,

a differentiation between these conditions can be done.

71. Ans. (b) Defective GPI anchor (Ref: Robbins 9/e 642, 8th/65, Harrison 17th/660)
Hams acidified serum test is the lysis of erythrocytes on addition of acidified serum. It demonstrates increased susceptibility
to the complement system and is seen in paroxysmal nocturnal hemoglobinuria (PNH).
PNH is caused due to acquired mutations in Phosphatidyl inositol glycan A (PIGA) gene. Normally, this gene is essential for the
synthesis of the glycosylphosphatidyl inositol (GPI) molecule which provides an anchor for cell membrane attachment of some
proteins. These proteins are also required for inactivating the complement (not for activating complement as was given
in the option). The examples of these proteins include:
Decay-accelerating factor or CD55
Membrane inhibitor of reactive lysis, or CD59
C8 binding protein
Thus it is easy for us to understand that in PNH, the defective GPI anchor prevents the attachment of the above mentioned
proteins.
72. Ans. (d) Paroxysmal nocturnal hemoglobinuria (Ref Wintrobes 12th/1007, 1044-5, Nathan and Oskis Hematology of
infancy and childhood 7th/45, Guhas NEONATOLOGY Principles and Practice vol 2, 3rd/910)
G6PD and Hereditary spherocytosis can cause anemia and jaundice since birth and are causes of haemolytic anemias.
So, they are easily ruled out.
Friends I got some worthy information after spending few days and multiple book searching which should bring a
smile on your face.
These are the lines from Oskis Hematology chain mutations generally produce no clinical symptomatology in
the newborn period. This does not mean that chain variants are never a problem in the neonate. Sickle cell hemoglo
binopathies are the most commmonly encountered chain variants in the newborn period. Several cases of homozy
gous sickle cell disease have been seen in neoanates. In infants in whom sickle cell anemia has been diagnosed in first
days of life because of some specific symptoms specifcally jaundice, fever, pallor, respiratory distress and abdominal
distension.
Hyperbilirubinemia appears to be more common in newborns with sickle cell anemia... Nathan and Oski 7th/45
chain defects do not manifest in newborn. An important exception is sickle cell disease which can manifest in new-
born as up to 30% of hemoglobin at birth may be adult hemoglobin. Sickling and hemolytic jaundice may result and is best
treated with exchange transfusion. Guha 3rd/910, Jaypee
Therefore the answer of exclusion is option d .. paroxysmal nocturnal hemogloninuria. Its mean age of presentation is in
the 30s. Even after extensive search, I could not get hold of any material which supports presence of symptomatic PNH in
infancy.
282
73. Ans. (c) Idiopathic thrombocytopenic purpura (Ref: Robbins 9/e 658-659, 8th/668, Harrison 17th/367)
Primary or idiopathic ITP has two clinical subtypes: acute and chronic. Both of them are autoimmune disorders in which
platelet destruction results from the formation of antiplatelet autoantibodies. The opsonized platelets are rendered
susceptible to phagocytosis by the cells of the mononuclear phagocyte system.
Option a: The triad of hemolysis, pancytopenia and thrombosis is unique to this condition. Thrombosis is the leading cause of
death in individuals with PNH.Robbins 8th/653
Option b: DIC is an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of
diseases. It is characterized by activation of the coagulation sequence that leads to the formation of microthrombi throughout the
microcirculation of the body.. Robbins 8th/673
Option d: Heparin Induced Thrombocytopenia can be two types; type I thrombocytopenia which occurs rapidly after
onset of therapy, is moderately severe, clinically insignificant and may resolve despite continuation of heparin therapy.
Type II thrombocytopenia is more severe and occurs 5 to 14 days after initiation of therapy. It can, paradoxically, lead to
life-threatening venous and arterial thrombosis.
Why do we have paradoxical thrombosis in HIT type II?
It is caused by an immune reaction against a complex of heparin and platelet factor 4 (a normal component of platelet
granules). The attachment of antibody to platelet factor 4 produces immune complexes that activate platelets,
promoting thrombosis even in the setting of marked thrombocytopenia.
Additional important features of Heparin Induced Thrombocytopenia
Platelet count < 100,000/L or decreased by > 50%.

Starts 5-10 days after starting heparin.
More common with unfractionated heparin (than LMW heparin), Surgical patients (than medical patients) and females (than males)


Venous thrombosis is more common than arterial.

74. Ans. (c) Glycosylphosphatidylinositol (GPI) (Ref: Robbins 9/e 642, 8th/65, Harrison 17th/660)
Paroxysmal nocturnal hemoglobinuria (PNH) results from acquired mutations in Phosphatidyl inositol glycan A (PIGA) gene,
which is essential for the synthesis of the glycosylphosphatidyl inositol (GPI) anchor. GPI is responsible for providing an anchor
for cell membrane attachment of some proteins like CD59 (most important), CD55 and C8 binding protein which are also
required for inactivating the complement.
It is the only hemolytic anemia caused by an acquired intrinsic defect in the cell membrane. The triad of hemolysis, pancytopenia
and thrombosis is unique to this condition.

75. Ans. (d) Donath-Landsteiner antibody (Ref: Robbins 9/e 644, 7th/407-408; Harrison 16th/611-614)
Cold hemagglutinin is associated with more commonly IgM or rarely IgG antibodies. These are not to be confused with
anti-IgM or anti-IgG antibodies given as other options in the question. An important example of cold hemagglutinin dis-
ease is paroxysmal cold hemoglobinuria. For details, see text
76. Ans. (c) Glycophorin C (Ref: Harrison 17th/653-655, Robbins 9/e 632, 8th/642-644, 7th/625)
Normally, RBC membrane consists of a protein spectrin, ion transporter called band 3 of membrane with the help of
ankyrin and band 4.2.
Mutations in glycophorin A has not been reported.
Mutations in a-spectrin are most common cause of hereditary elliptocytosis [65% cases] and b-spectrin mutation is responsible for
another 30% cases. Some of the cases of HE occur due to mutation in band 4.1.
77. Ans. (c) CLL (Ref: Harrison 17th/693, Robbins 9/e 643)
Leukemias especially of the CLL type are associated with warm autoimmune hemolytic anemia.
78. Ans. (d) Metallic cardiac valves (Ref: Rubins pathology 5th/878, Nathan and Oski hematology 7th/643, Goljan pathology
edn 2013/ 314)
Microangiopathic hemolytic anemia is associated with fragmentation of the red cells in the microcirculation. It is associated with
antiphospholopid antibody syndrome... NMS Medicine 5th/348
Pathologically, macroangiopathic hemolytic anemia is associated with prosthetic cardiac valves.

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Macroangiopathic hemolytic anemia may be caused by:

Direct red cell trauma from abnormal valvular surface: prosthetic valve grafts, tight aortic stenosis and synthetic vascular grafts.
Large vessel disorders that may cause shearing of red cells: cavernous hemangioma (Kasabach Merrit syndrome),
Other causes include coarctation of aorta, ruptured sinus of valsalva, ruptured chordae tendinae and aortic aneurysm.
Causes of Microangiopathic hemolytic anemia
Vasculitis like microscopic polyangiitis

1. Scleroderma
5.
Malignant hypertension
2. Thrombotic thrombocytopenic purpura (TTP) and Hemolytic uremic Syndrome (HUS)
6.
Eclampsia
3. DIC
7.
Renal graft rejection
4. March hemoglobinuria
8.
79. Ans. (b) Conjugated and unconjugated bilirubin (Ref: Robbins illustrated, 9/e 853, 8th/840-841, 7th/886-887)
It is a case of erythroblastosis fetalis. (type II Hypersensitivity reaction)
In erythroblastosis fetalis there is excessive breakdown of RBCs leading to increased production of bilirubin in the
blood. This increased bilirubin is predominantly unconjugated but the level of conjugated bilirubin will also increase
because of compensatory increase in bilirubin conjugation process by the liver. So, both unconjugated bilirubin and
bilirubin glucuronides may accumulate systemically and deposit in tissues, giving rise to the yellow discoloration of
jaundice. This is particularly seen in yellowing of the sclera (because of presence of elastin fibers).
80. Ans. (a) Teardrop and Burr cells (Ref: Robbins 7th/766, 687, 9/e 620)
Teardrop cells also known as dacryocytes are seen in myelofibrosis. Rest of the features are seen in hemolytic anemia.
81. Ans. (b) Acute G6PD deficiency; (e) PNH (Ref: Robbins 7th/624, 625, 9/e 631-632)
Intravascular hemolysis occurs due to disruption of red cell membrane in circulation. The RBCs are damaged mechanically,
by complement fixation, malaria, toxins and drugs. It is seen in: Acute G6PD deficiency and PNH
In Sickle cell disease and hereditary spherocytosis, RBC destruction occurs in spleen (extravascular hemolysis)
Thalassemia is a hemoglobinopathy.
82. Ans. (a) HUS; (c) Malignant hypertension; (d) Prosthetic valves; (e) TTP: (Ref: Robbins 7th/638, 9/e 630)
83. Ans. (a) Hemoglobin C; (c) Hereditary spherocytosis (Ref: de Gruchys 5th/184, Robbins 9/e 632)
Spherocytosis is the anomaly due to abnormal ion permeability of the red cell membrane.
This results in higher level of Na and low level of K in the cell, thus making the cell hyperosmotic. Interior of the cell takes
+ +
up water and the cell becomes macrocytic and hypochromic and thus osmotic fragility is increased.
Acquired causes of spherocytosis:
Autoimmune acquired hemolytic anemia.
Infections/burnchemicals
Water dilution hemolytic anemia
Hemolytic disease of the newborn (ABO incompatibility)
Heinz body hemolytic anemia.
Hb C disease associated with compensated hemolysis with normal hemoglobin level or mild anemia. In this disease in
peripheral smear, target cells and microspherocytes are seen.
84. Ans. (a) Microangiopathic hemolytic anemia; (b) DIC; (d) Malignant hypertension; (e) HELLP syndrome
(Ref: de Gruchys 5th/209 , Wintrobes 11th/1236, Robbins 9/e 630)
Schistocytosis or fragmented RBCs are found in
Thalassemia Severe burn DIC
Hereditary elliptocytosis Microangiopathic hemolytic anemia Malignant hypertension
Megaloblastic anemia Iron deficiency anemia HUS
HELLP syndrome
85. Ans. (a) Glucose-6 phosphate dehydrogenase deficiency: (Ref: Robbins 7th/624, 628, 9/e 631)
86. Ans. (b) Reticulocytosis seen; (c) Smaller size; (d) Always associated with MCHC. (Ref: Robbins 7th/626, 9/e 633)
Hereditary spherocytosis is an usually autosomal dominant condition in which the ratio of surface area to volume decreases
and hence the RBC becomes rounded. Spherocytes are small densely staining RBC without central pallor. Mean cell Hb
concentration (MCHC) is always increased in this disease because the size is decreased. Reticulocytosis would be seen
because HS is an important cause of hemolytic anemia.
284
RBCs are macrocytic; hyperchromic and show anisocytosis. Hypersegmented neutrophils are also seen.
87. Ans. (a) Thrombotic Thrombocytopenic purpura; (b) Hemolytic uremic syndrome; (d) DIC (Ref: Robbins 7th/638, 9/e 630)
In Henoch-Schonlein purpura, there is hematuria and palpable purpura.
DIC is the commonest cause of Microangiopathic hemolytic anemia.

88. Ans. (b) Cold agglutination (Ref: Harrison 17th/660, Robbins 7th/657, Robbins 9/e 644)
Paroxysomal cold hemoglobinuria is characterized by the presence of Donath-Landsteiner antibody. It has anti-P specificity
and bind to red cells only at low temperature (Optimally at 4C)
89. Ans. (D) Spectrin (Ref: Robbins 9/e 632, 8th/642)
Ideal answer is ankyrin (most commonly) but in the given options, spectrin is the best option.
90. Ans. (b) Ankyrin deficiency (Ref: Robbins 9/e 632, 8th/642; 7th/625)
91. Ans. (d) Increased platelets (Ref: Robbins 9/e 642, 8th/654; 7 th/636)
92. Ans. (a) SLE (Ref: Robbins 9/e 642-644, 8th/653-654; 7 th/230)
93. Ans. (a) Mycoplasma infection (Ref: Robbins 9/e 643-644, 8th/653-654; 7th/637)
94. Ans. (c) Decreased blood pressure
Read explanation below:
Within the first few hours of acute blood loss, findings of hypovolemia predominate, especially with signs of hypovolemic
shock, such as decreased blood pressure. It is likely that red cell indices (red blood cell counts, hemoglobin, and hematocrit)
eventually decrease as a result of hemodilution.
Increased mean corpuscular hemoglobin concentration (MCHC) is a rare finding but is seen in hereditary spherocytosis.
95. Ans. (b) Glucose-6-phospate dehydrogenase (Ref: Robbins 8th/643-4, 9/e 634-635)

Explanation
Drugs that cause oxidative stress (e.g., primaquine, sulfa-containing drugs) result in intravascular hemolytic anemia in
individuals (most often male) with glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Duffy antigen is a minor red blood cell antigen, the absence of which provides resistance to malarial infection. Intrinsic
factor may be absent in pernicious anemia. PIG-A deficiency results in paroxysmal nocturnal hemoglobinuria.
96. Ans. (c) Hereditary erythrocyte enzyme deficiency (Ref: Robbins 9/e 634-635, 8th/644)
The patient has signs of hemolysis induced by trimethoprim-sulfamethoxazole. It is a common scenario for glucose-
6-phosphate dehydrogenase (G6PD) deficiency to present.
Glucose-6-phosphate dehydrogenase deficiency is an X-linked disorder of the hexose monophosphate (pentose phos-
Q
phate) pathway. In affected individuals, the amount of NADPH produced in RBCs is low, which impairs glutathione-
mediated inactivation of free radicals. Hemolytic episodes are induced by infectionsQ, medicationsQ (e.g. TMP-SMX,
dapsone, antimalarials, nitrofurantoin), and other oxidantsQ (e.g. fava beans).
Hemolytic episodes manifest with symptoms of anemia such as malaise and pallor, indirect bilirubinemia (jaundice),
hemoglobinemia and hemoglobinuria (dark-red urine). The level of serum haptoglobin decreases and a reticulocytosis
develops to compensate for the increased destruction of RBCs. Patients are generally asymptomatic between episodes.
(Choice A) Autoimmune hemolytic anemias result from extrinsic antibody-mediated hemolysis and are associated with a positive
Coombs testQ. These anemias often accompany SLE, Hodgkin and non-Hodgkin lymphomas, mycoplasma infections (cold agglutinins)
and infectious mononucleosis.
(Choice B) Hereditary spherocytosis is an autosomal dominantQ defect in RBC structural proteins (spectrin, ankyrin, or protein 4.1)
characterized by increased erythrocyte osmotic fragilityQ and MCHCQ > 36 g/dL.
(Choice D) Microangiopathic hemolytic anemia (MAHA) occurs when there is destruction of RBCs within small vessels due to
widespread thrombosis. MAHA is associated with disseminated intravascular coagulationQ (DIC), thrombotic thrombocytopenic
purpuraQ (TTP) and hemolytic-uremic syndromeQ (HUS).
97. Ans. (b) Pigmented gallstones (Ref: Robbins 8th/644, 9/e 632-633)
The patient has anemia, an elevated LDH, and indirect bilirubinemia, suggesting hemolytic anemia. The lysing of blood
cells when incubated in hypotonic saline describes a positive osmotic fragility test, the diagnostic test for spherocytosis.
Here, the sexual history is deliberately given just to confuse you friends, it is not related to the cause of this patients
anemia. You may find such questions in NEET-PG more frequently.
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Pigmented gallstones are a complication of any hemolytic anemia. In chronic hemolysis, the increased bilirubin from lysed
red blood cells precipitates as calcium bilirubinate, forming pigmented stones in gallbladder.
(Choice A) Cirrhosis of the liver may result from chronic alcohol use, hepatitis B or C infection, hemochromatosis, Wilson
disease, and alpa-1 antitrypsin deficiency. The sexual history of this patient might make you suspect blood-borne hepatitis,
but then the AST/ALT would have been abnormal.
(Choices C and D) The abnormal adhesion of sickle-cell red blood cells to the endothelium may cause episodic venous
thrombosis and avascular necrosis of the femur. The unique anatomy of the femoral head makes it exceptionally susceptible
to avascular necrosis from a range of causes, including sickle cell anemia.
Hereditary spherocytosis is an autosomal dominantQ defect in RBC structural proteins (ankyrinQ most commonly) characterized by
increased erythrocyte osmotic fragilityQ and MCHCQ

98. Ans. (c) Glucose-6-phosphate dehydrogenase (Ref: Robbins 9/e 634, 8th/644)
The presence of free hemoglobin in the serum and urine, and bite cells due to splenic removal of Heinz bodies (oxidized
hemoglobin) all point to hemolysis. Hemolysis following oxidant injury by drugs (sulfonamides, for example) or infection
suggests glucose-6-phosphate dehydrogenase deficiency or the related deficiencies of glutathione synthetase, pyruvate
kinase, and hexokinase. These conditions are typically asymptomatic between episodes of hemolysis.
Deficiencies of glycoprotein IIb/IIIa (choice D) produce thrombasthenia, a platelet aggregation defect.
99. Ans. (c) Ankyrin (Ref: Harrison 17th/653-655, Robbins 9/e 632)
100. Ans. (b) IgG directed against red blood cells (Ref: Robbins 8th/653, 9/e 643-644)
1 00.1. Ans. (c) Normal APTT (Ref: Robbins 8/e p673-4, 9/e 665, Harrison 18/e p)
DIC is an acute, subacute, or chronic thrombohemorrhagic disorder characterized by the excessive activation of coagulation, which
leads to the formation of thrombi in the microvasculature of the body.
Harrison 18/e pmentions Common findings include the prolongation of PT and/or aPTT; platelet counts 100,000/
L3, or a rapid decline in platelet numbers; the presence of schistocytes (fragmented red cells) in the blood smear; and
elevated levels of FDP.
The D-dimer test is more specific for detection of fibrinbut not fibrinogendegradation products and indicates
that the cross-linked fibrin has been digested by plasmin. Because fibrinogen has a prolonged half-life, plasma levels
diminish acutely only in severe cases of DIC.
The most sensitive test for DIC is the FDP levelQ. DIC is an unlikely diagnosis in the presence of normal levels of FDP.
100.2. Ans. (a) Acute promyelocytic leukemia (Ref: Robbins 9/e 664, 8/e p673-4, Harrison 18/e p)
The most common causes are bacterial sepsis, malignant disorders such as solid tumors or acute promyelocytic leukemia , Q
and obstetric causes (pregnant women with abruptio placentae, or with amniotic fluid embolism).
100.3. Ans. (c) Paroxysmal nocturnal hemoglobinuria (PNH) (Ref: Robbins 9/e 642, 8/e p652)
PNH is a disease that results from acquired mutations in the phosphatidylinositol glycan complementation group
Q
A gene (PIGA ), an enzyme that is essential for the synthesis of certain cell surface proteins.
Q
Red cells, platelets, and granulocytes deficient in these GPI-linked factors are abnormally susceptible to lysis by
complement. In red cells this manifests as intravascular hemolysis , caused by the C5b-C9 membrane attack complex.
Q
Also revise
The triad of hemolysis, pancytopenia and thrombosis is unique to PNH.
Thrombosis is the leading cause of disease related death in PNH.
PNH is best made with flow cytometry in which there is presence of bimodal distribution of the red cells
100.4. Ans. (a) G6PD deficiency (Ref: Robbins 9/e 634, 8/e p645)
Direct lines Oxidants cause both intravascular and extravascular hemolysis in G6PD-deficient individuals. Exposure of
G6PD-deficient red cells to high levels of oxidants causes the globin chains to get denatured and form membrane-bound
precipitates known as Heinz bodies. These can damage the membrane sufficiently to cause intravascular hemolysis.
As inclusion-bearing red cells pass through the splenic cords, macrophages pluck out the Heinz bodies. As a result of
membrane damage, some of these partially devoured cells retain an abnormal shape, appearing to have a bite taken out of
them. These bite cells and spherocytes are trapped in splenic cords and removed rapidly by phagocytes.
1 00.5. Ans. (b) IgM (Ref: Robbins 9/e 644, 8/e p653)
Cold agglutinins are monoclonal IgM antibodies that react at 4 to 6C. They are called agglutinins because the IgM directed
against the I antigen present on the RBCs can agglutinate red cells due to its large size (pentamer).
1 00.6. Ans. (a) Hemolytic uremic syndrome (Ref: Robbins 9/e 660, 8/e p952)
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Schistocytes are typically irregularly shaped, jagged, and have two pointed ends. A true schistocyte does not have central pallor.
Helmet cells are also known as schistocytes/triangle cells/burr cells are a feature of microangiopathic diseasesincluding
disseminated intravascular coagulation (DIC), thrombotic microangiopathies (TTP), mechanical artificial heart valves
and hemolytic uremic syndrome (HUS).
1 00.7. Ans. (d) All of the above (Ref: Robbins 8/e p952)
Yes friends, only additional important thing that you need to be aware of is that schistocytes can also be seen in severe iron
deficiency anemia.
Echinocytes/Burr cells Regular spine-like projections on cell surface; Megaloblastic anemia/ hemolytic
Acanthocytes/Spur cells irregular thorn-like projections; anemia /burns
Stomatocytes Slit-like (mouth like) area of pallor in liver disease,
Schistocytes Fragmented RBCs; triangular, comma-shaped or helmet abetalipoproteinemia
Leptocytes shaped in liver disease, anemia of chronic
Codocytes Thin flat cells disease)
Dacrocytes Mexican hat cells
Drepanocytes Tear drop cells or Target cells (red cells with central dark area;
Elliptocytes Sickle cells
Keratocytes Pencil cells or cigar cells
Helmet cells
Knizocytes
100.8. Ans. (a) CD 59 (Ref: Robbins 9/e 642, 8/e p652)

PNH blood cells are deficient in three GPI-linked proteins that regulate complement activity:
Decay accelerating factor, or CD55;
Membrane inhibitor of reactive lysis, or CD59; and
C8 binding protein.
Of these factors, the most important is CD59, a potent inhibitor of C3 convertase that prevents the spontaneous activation of

the alternative complement pathway.
1 00.9. Ans. (c) Increased haptoglobin (Ref: Robbins 9/e 631, 8/e p641-642, 7/e p624)
Hemolytic anemia is characterized by a reduction in the free haptoglobin levels because the hemoglobin released by de-
struction of red cells binds to the serum haptoglobin decreasing its levels.
100.10. Ans. (b) Controlling oxidative stress on RBC (Ref: Robbins 9/e 634)
G6PD helps in neutralizing the effect of oxidative stress on the RBC. Oxidative stress is induced by drugs like primaquine
and hence in patients of G6PD there is accelerated hemolysis (intravascular during the hemolytic episode) resulting in
hemoglobinuria and passage of shockingly black urine by the patient.
101. Ans. (a) P. Falciparum (Ref: Robbins 9/e 391, 8th/387, 645)
People who are heterozygous for the sickle cell trait (HbS) become infected with P. falciparum, but they are less likely
to die from infection. The HbS trait causes the parasites to grow poorly or die because of the low oxygen concentrations.
HbC, another common hemoglobin mutation, also protects against severe malaria by reducing parasite proliferation.
People can also be resistant to malaria due to the absence of proteins to which the parasites bind. P. vivax enters red
cells by binding to the Duffy blood group antigen. Many individuals (usually Africans), are not susceptible to infec-
tion by P. vivax because they do not have the Duffy antigen.
102. Ans. (b) Beta Thalassemia (Ref: Robbind 9/e 640-641, 8th/648-652, Textbook of Hematology 1st/89)
Friends, lets get the answer of this question in a methodical manner. The clues in the question:
Reduced values of MCV and MCHC: microcytic hypochromic anemia (G6PD deficiency is ruled out)
Age of presentation and ethnicity: 6 year old and Punjabi ethnicity
History of repeated blood transfusion: in favour of thalassemia
Osmotic fragility is reduced: in favour of thalassemia again though it may be seen in sickle cell also
If we compare the above mentioned points, we can deduce that the stem talks about a patient suffering from thalassemia.
Now comparing the incidence of alpha and beta thalassemia, it is clear that beta thalassemia is far more common than
alpha thalassemia. Hence, it is a better option than alpha thalassemia.
Also, the hemoglobin is the question is more suggestive of severe anemia with positive history of multiple blood
transfusions both being important pointers towards thalassemia major.
Please note that apart from Punjabis, other ethnic groups having high prevalence of thalassemia are Sindhis, Gujaratis,
Parsis, Begalis and Lohanas. The clinical importance of knowing this fact is the application of screening test like Naked
Eye Single Tube Red cell Osmotic Fragility (NESTROF) in these groups before marriage so as to avoid complications like
having kids with thalassemia major/intermedia later on.
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103. Ans. (a) - thalassemia (Ref Recent Advances in Hematology -3, 1st/173)
104. Ans. (a) Deletion of alpha genes (Ref: Robbins 8th/651, T. Singh 2nd/95)
105. Ans. (b) Deletion of 3 alpha chains (Ref: Robbins 8th/652, 9/e 642)
a thalassemia is caused by gene deletion.when there is deletion of 3 a chains, it results in the formation of tetramers of b
chain called as HbH. Note that g chain tetramers are responsible for the formation of barts hemoglobin.
106. Ans. (a) Malaria (Ref: Robbins 9/e 638, 8th/645, T. singh 1st/270)
Sickle cell trait patients are protected against falciparum malaria because the sickled RBCs with parasites inside them are
sequestered in the reticuloendothelial cells of the spleen providing protection against malaria.
A similar protection against malaria is also seen in patients having G6PD deficiency as the parasites needs G6PD enzyme for survival.
Protection against malaria is also seen in conditions like Thalassemia, pyruvate kinase deficiency; HbC and duffy negative RBcs.

107. Ans. (d) Solubility (Ref: Robbins 9/e 635-636, 8th/645-648)
108. Ans. (d) 0% (Ref: Robbins 7e/632-33, Harrison 17th/641)
Normal percentage of HbA2 ranges from 1.5 to 3%.
In thalassemia trait ( thalassemia minor), HbA2 level may be elevated (3.5-7.5%).
Thus, wife in this question has normal genotype (bb) whereas husband has thalassemia trait (+).
-Thalassemia is an autosomal recessive disease
None of the offsprings thus will have thalassemia major ( ), thus, the risk of having a child with thalassemia major
+ +
is therefore 0%.
50% of the offspring (b b) will be carriers like father.
+
109. Ans. (b) Replacement of glutamate by valine in chain of HbA (Ref: Robbins 9/e 635, Harrison 17th/637)
Sickle cell anemia results due to a missense point mutation.
Normally, glutamic acid is present at 6 position of chain. It is replaced by valine due to missense mutation.
th
Valine is Welcome and Glutamic acid can Go

110. Ans. (c) Binding to HbS to the deoxygenated HbA can extend the polymer and cause sickling of the red blood cells
(Ref: Harper 25th/71, Robbins 7th/628, 630, 8th/645-646, 9/e 636)
Sickle cell anemia is caused by a point mutation is which there is replacement of glutamine by valine at position 6 of the
beta chain generating a sticky patch on the surface of HbS.
The sticky patch on the surface of adjacent HbS molecules cause their polymerization resulting in formation of long
fibrous precipitates.
HbA molecule can complementarily bind with the sticky patch by HbS but cannot promote the formation of long fib-
ers because it does not have a patch itself. So, the option c is false in the given question.
Other hemoglobins which also weakly interact with HbS and prevent its polymerization include HbF and HbC.
111. Ans. (a) 50% HbS is required for occurrence of sickling (Ref: Robbins 7th/628-629, 9/e 635-636)
Sickle cell disease is a hemoglobinopathy in which HbS due to point mutation. If an individual is homozygous for
sickle mutation almost all the Hb in erythrocyte is HbS, if he is heterozygote only 40% is HbS the remainder being
normal.
In addition, Nelson also mentions that persons with sickle cell trait have totally benign clinical course because the
low level of HbS present in them (35-40% of total) is insufficient to produce sickling manifestation. So, option a
is a better answer than option b.
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112. Ans. (d) Deletion of gene (Ref: Robbin 9/e 635, 7th/628-629)
113. Ans. (a) Increased HbF; (b) Increased HbA ; (c) Microcytosis; (e) Target cell (Ref: Harrison 17th/641, Robbins
2
7th/634-635, 9/e 641)
Characteristics of thalassemia minor (trait):
Microcytosis and hypochromia
Target cells
Mild to moderate anemia (MCV > 75 fL and Hematocrit < 30 to 33%).
Hemoglobin electrophoresis classically reveals increased HbA2 (3.5-7.5%) and HbF is normal or elevated.
Patients with beta thalassemia trait are resistant against falciparum malaria, making it more prevalent disease in areas
where malaria is endemic.
114. Ans. (d) Point Mutation (Ref: Harrison 17th/637 Robbins 7th/628, 9/e 635)
115. Ans. (c) Three globin genes (Ref: Robbins 7th/636, 9/e 642)
116. Ans. (b) Higher concentration of HbF (Ref: Robbins 7th/629, 9/e 642)
117. Ans. (a) Presence of a structurally abnormal Hb (Ref: Robbins 8th/645; 7th/628)
118. Ans. (b) b-chain (Ref: Robbins 8th/645; 7 th/628, 9/e 635)
119. Ans. (c) Vascular occlusion (Ref: Robbins 8th/645-8, 9/e 637-638)
In a patient with the hematologic findings described above and recurrent episodes of abdominal pain that resolve with
hydration, sickle cell anemia is the most likely diagnosis. The patient has presented with symptoms of acute chest
syndrome (ACS), which is vaso-occlusive crisis localized to the pulmonary vasculature that can occur in patients with
sickle cell anemia. ACS is commonly precipitated by pulmonary infection..
In patients with homozygous hemoglobin S disease vaso-occlusive crises can also cause splenic infarctions. Repeated
infarctions produce a spleen that is shrunken, discolored, and fibrotic. By the time they reach adulthood, most patients
with sickle cell anemia have undergone autosplenectomyQ as a result of these infarcts and are left with only a small,

scarred splenic remnant. The spleen may demonstrate brownish discoloration (hemosiderosis) due to extensive ingestion
of sickled RBCs by splenic macrophages (extravascular hemolysis).
(Choices A and B) There may be hyperplasia and hypertrophy of normal splenic elements (especially macrophages and lymphoid
cells) in systemic infections and various other disease states.
(Choice D) Pressure atrophy of the splenic parenchyma can be seen when there is a tumor infiltrating the spleen.
AutonephrectomyQ is seen with tubercular infection of the urinary tract.

120. Ans. (c) He is protected from Plasmodium falciparum (Ref: Robbins 8th/645, 9/e 638)
Patients who are heterozygous for the sickle cell trait (Hb AS) have hemoglobin composed of 35 to 40% hemoglobin S
(HbS); they are generally protected from sickle cell crisis, aplastic crisis and sequestration crisis by the presence of > 50%
normal hemoglobin (Hb A).
Amount of HbSQ is the most important factor affecting sickling of the RBCs
The alteration of the hemoglobin (from HbA to HbS) reduces its solubility.
Patients with sickle cell trait are usually asymptomatic, although they may develop hematuria and a limited ability to
concentrate urine. A high incidence of UTI and splenic infarction at high altitude may be seen. The heterozygotes enjoy
relative protection from Plasmodium falciparum (malaria) because of increased sickling of parasitized sickle-cell trait red
blood cells and accelerated removal of these cells by the splenic monocyte macrophage system.
(Choices A, B and D) Peripheral smears are usually normal in sickle cell trait patients; irreversibly sickled cells are not
seen. Furthermore, red cell indices and red cell morphology are normal; the reticulate count is not elevated. However, the
sickling test will be positive (RBCs will sickle when sodium metabisulfite is added). Increased MCHC, which represents
intracellular dehydration, is seen only with homozygous SS (i.e. full-blown sickle cell anemia).
Sickling test: Sickling is induced by a reducing agent like 2% metabisulfite or dithionite to blood.
Hb electrophoresis is the best investigation for diagnosis of sickle cell disease and trait.

121. Ans. (b) Bone marrow expansion in the calvarium (Ref: Robbins 8th/646-651, 9/e 636-638)
Sickle cell anemia is caused by a point mutation leading to substitution of valine for glutamate at the 6th position of
the b-globin chain. Thalassemia major refers to the clinical picture of patients with homozygous b-thalassemia, leading
to severely deficient or absent synthesis of b globin chains. Sickle cell anemia results in shortening of erythrocyte life
by causing hemolysis of irreversibly sickled cells. b-thalassemia causes formation of excess free a-globin chains, which
precipitate within the normoblasts, resulting in premature apoptosis of red cell precursors (ineffective erythropoiesis).
Compensatory increases of erythroid precursors occur in both conditions, leading to expansion of bone marrow with
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resultant bone deformities. The radiologic crew haircut appearance of the skull is due to bone marrow expansion in the
calvarium and is seen in both sickle cell anemia and thalassemia major patients.
Autosplenectomy (choice A) and increased predisposition for infections by capsulated organisms (H. influenzae and
Streptococcus pneumoniae) is characteristic of sickle cell anemia.
121.1. Ans. (c) Replacement of glutamate by valine in -chain of HbA (Ref: Robbins 8/e p645, 9/e 635)
Direct lines from Robbins... Sickle cell disease is caused by a point mutation in the sixth codon of -globin that leads to
the replacement of a glutamate residue with a valine residue.
1 21.2. Ans. (d) Relative excess of , , and chains (Ref: Robbins 8/e p651, 9/e 635-636)
The -thalassemias are caused by inherited deletions that result in reduced or absent synthesis of -globin chains.
As in -thalassemias, the anemia stems both from a lack of adequate hemoglobin and the effects of excess unpaired
non- chains (, , and ), which vary in type at different ages.
In newborns with -thalassemia, excess unpaired -globin chains form tetramers known as hemoglobin Barts,
4
whereas in older children and adults excess -globin chains form tetramers known as HbH.
4
Since free and chains are more soluble than free chains and form fairly stable homotetramers, hemolysis and
ineffective erythropoiesis are less severe than in -thalassemias.
Also, remember that gene deletion is the most common cause of reduced -chain synthesis.
The options which created confusion were options c and d.
Total absence of -chains is a feature of most severe form of -thalassemia resulting in hydrops fetalis.
Every patient having -thalassemia would not be having total absence of - chains but all patients would be having relative
excess of , , and chains as per their age of presentation. Hence, we prefer option d as the answer for this question.
1 21.3. Ans. (b) Beta chain.too obvious friends (Ref: Robbins 9/e 635, 8/e p645, 7/e p628)
1 21.4. Ans. (d) Protective action against adult malaria (Ref: Robbins 9/e 638, 8/e p645-648, 7/e p629)
1 21.5. Ans. (c) Sickle cell anemia (Ref: Robbins 9/e 635, 8/e p645-648, 7/e p402)
Sickled cells can cause microvascular occlusion affecting bones, brain, kidney, liver, retina and pulmonary vessels.
1 21.6. Ans. (c) Saline washed packed RBC Ref: Choudhary p80
Saline washed RBCs are specially indicated in conditions requiring repeated transfusion when the chances of urticar-
ial reactions due to plasma is high. These have negligible plasma proteins and just 10% leucocytes. It is also preferred
in the management of babies suffering from thalassemia and paroxysmal nocturnal hemoglobinuria.
1 21.7. Ans. (c) Single amino acid base substitution (Ref: Robbin 8/e p645-6)
Afro American male presenting with the mentioned features is suggestive of sickle cell anemia is due to vaso-occlusion
caused by sickled cells. Sickle cell anemia can cause chronic hemolytic anemia, recurrent pneumonia and non haling
painful ulcer.
Sickle cell anemia is caused by a point mutation in the sixth codon of -globin that leads to the replacement of a glutamate residue with
a valine residue (Ref: Robbind 8/e p645)
1 21.8. Ans. (b) Gene deletion (Ref: Robbin 9/e p641)
The -thalassemias are caused by inherited deletions that result in reduced or absent synthesis of -globin chains.
1 21.9. Ans. (c) Sickle thalassemia (Ref: Robbin 9/e and Harrison chapter 104, disorders of hemoglobin synthesis)
Condition Clinical Abnormalities Hemogblobin Level g/l (g/dL) MCV. fL Hemoglobin Electrophoresis
Sickle cell trait Non: rare painless Normal Normal Hb S/A: 40/60
hematunia
Sickle cell anemia Vasooclusive crises; aseptic 70-100 (7-10) 80-100 Hb S/A: 100/0
necrosis of bone Hb F:2-25%
S/ B0 thalassemia Vasoocclusive crises: 70-100 (7-10) 60-80 Hb S/A: 100/0
aseptic necrosis of bone Hb F;1-10%
S/B+ thalassemia Rare crises and aseptic 100-140 (10-14) 70-80 Hb S/A: 60/40
necrosis
Hemoglobin SC Rare crises and aseptic 100-140 (10-14) 80-100 Hb S/A:50/0
necrosis; painless hematuria
1 21.10. Ans. (d) Macrocytic Anaemia (Ref: Robbin 9/e)

Thalassemia major presents before 1 yr of age with severe anemia which necessitates packed RBC transfusions every 2-3
months. The child is said to be transfusion dependent as survival is decided by RBC being transfused.
The ineffective erythropoiesis in bone marrow results in shift of hematopoiesis to liver and the bone marrow. Hence
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the liver and spleen enlarge in size. But the net result is defective microcytes being produced. The type of anaemia is
microcytic hypochromic anaemia.
Mnemonic to remember causes of macrocytic anemia: ABCDEF
Alcohol + liver disease
B12 deficiency
Compensatory reticulocytosis (blood loss and hemolysis)
Drug (cytotoxic and AZT)/ Dysplasia (marrow problems)
Endocrine (hypothyroidism)
Folate deficieny/ Fetus (pregnancy)
122. Ans. (c) Lack of antigens of several blood group systems (Ref: Wintrobes hematology 12th/635-6 ; Harrison 18th/951)
Red cells of group O individuals lack A and B antigens but carry H substance
The enzyme in group A individuals is N-acetylgalactosaminosyl transferase
The enzyme in group B individuals is D-galactosyltransferase
People with Bombay phenotype (rarest blood group in the world) express no A, B or H antigens on the red blood cells. These are
homozygous for the silent h allele (being represented hh). So, these antigens are not present in the saliva also. As the antigens are
not expressed, so, the H, A and B antibody will always be present in serum.
ABO antigens are present not only on the red blood cells abut also on the other blood cells, in most body fluids (except CSF), cell
membrane of tissues such as intestine, urothelium and vascular endothelium.
Clinical significance of knowing about Bombay blood group is that in case of requirement of blood transfusion, these
people would be compatible only with Bombay blood from another individual.
123. Ans. (b) AO
Too obvious to explain friends.
124. Ans. (d) Paroxysmal nocturnal hemoglobinuria (Ref: Robbins 8th/861 (table 18-6, 9/e 847)

I. Hereditary Hemochromatosis
Mutation in the gene coding for HFE, transferring receptor 2 or hepcidin
Mutation in the gene coding for hemojuvilin:juvenile hemochromatosis
II. Secondary Hemochromatosis
A.Parenteral iron overload: Transfusions, Long-term hemodialysis, Aplastic anemia, Sickle cell disease, Leukemias,
Myelodysplastic syndromes Iron-dextran injections
B.Ineffective erythropoiesis with increased erythroid activity

-Thalassemia, Sideroblastic anemia and Pyruvate kinase deficiency
C.Increased oral intake of iron: African iron overload (Bantu siderosis)
D. Congenital atransferrinemia
E. Chronic liver disease: Chronic alcoholic liver disease and Porphyria cutanea tarda.
125. Ans. (d) Trisodium citrate 3.2% (Ref: Henrys Clinical Diagnosis and Management by Laboratory Methods 21st/188,
Clinical Chemistry Theory, Analysis and Correlation (Mosby) 4th/23-4, 71,Wintrobe 12th/1, Dacie and Lewis practical
hematology 10th/7, 391)
See text.
126. Ans. (c) Potassium oxalate + sodium fluoride (Ref: Henrys Clinical Diagnosis and Management by Laboratory Methods
21st/188, Clinical Chemistry Theory, Analysis and Correlation (Mosby) 4th/23-4, 71, Harper 27th/152)
Direct quote from Harper. enolase enzyme in the glycolysis is inhibited by fluoride, and when blood samples are taken for
measurement of glucose, it is collected in tubes containing fluoride to inhibit glycolysis.
The standard clinical sample for glucose estimation is venous plasma glucose. Glucose is metabolized at room temperature.
The rate of metabolism is higher with leucocytosis. To inhibit the glycolysis, sodium fluoride is added. Henry 21 /188 st
Biochemistry concept: Source Clinical Chemistry

Lithium IodoacetateQ is another anticoagulant which can be used for blood glucose estimation. However, it acts by inhibiting the en-
zyme glyceraldehyde 3 phosphate dehydrogenaseQ. It inhibits glycolysis for 24 hours in contrast to sodium fluoride which inhibits
glycolysis for 3 days.
127. Ans. (a) Microspherocytes (Ref: Wintrobes 12th/982-3, T. Singh Hematology 2nd/32-3, Handbook of pediatric transfusion
medicine by Hillyer 1st/198)
Wintrobes mentions spherocytes predominate in the peripheral blood smear of infants with ABO hemolytic disease
of newborn. Peripheral blood smear shows numerous spherocytes, occasional nucleated red cells, anisocytosis and
polychromasia.
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The blood film in ABO hemolytic disease of the newborn (ABO HDN) is marked by the presence of microspherocytes
(a feature not usually seen in Rh hemolytic disease of the newborn). The spherocytosis is attributed to loss of
membrane surface area when the spleen removes antigen-antibody complexes from the affected cell.
Handbook of pediatric transfusion medicine writes clearly The peripheral blod smear in ABO hemolytic disease
of new born is marked by the presence of microspherocytes. Increased osmotic fragility and autohemolysis may be
demonstrated just like hereditary spherocytosis.
Concept: potential future question
Unlike hereditary spherocytosis, Autohemolysis in ABO HDN is not corrected by addition of glucoseQ.

Other options
Option BFragmented RBC or schistocytes are feature of microangiopathic hemolytic anemia, DIC and cardiac hemolytic
anemia.
Option Cpolychromasia is the term used for red cells staining bluish red with Roamnowsky stains. These cells are larger
than normal and show fine reticulin network in supravital staining. They are commonly observed in response to therapy
in deficiency anemias and hemolytic anemia. So, is not specific for ABO incompatibility.
Option DElliptocytosis is a feature of hereditary elliptocytosis and macrocytic anemias.
128. Ans. (a) Febrile nonhemolytic transfusion reaction (Ref: Harrison 16th/665-666, Robbin 9/e 665)
The most frequent reaction associated with the transfusion of cellular blood components is a febrile non-hemolytic
transfusion reaction.
FNHTR is characterized by chills and rigor and > 1C rise in temperature.

129. Ans. (c) Protein (Ref: Wintrobes hematology, 11th/797; Harrison 17th/708)
Unlike other red cell antigens, Rh antigens do not contain any sugar. The Rh proteins are multipass membrane proteins
that traverse the RBC membrane 12 times. The Rh proteins form a complex with other membrane glycoproteins.
Red cells of group O individuals lack A and B antigens but carry H substance
The enzyme in group A individuals is N-acetylgalactosaminosyl transferase
The enzyme in group B individuals is D-galactosyltransferase
People with Bombay phenotype (rarest blood group in the world) express no A, B or H antigens
Please remember friends that the Rh antigen should not be confused with Rh factor which is an antibody (Ig) against the
Fc portion of IgG seen in patients of rheumatoid arthritis.
130. Ans. (d) Howell-Jolly bodies (Ref: Harrisons 17th/374-375, 9/e 623, 636)
Howell-Jolly bodies are spherical or ovoid eccentrically located granules in stroma of erythrocytes in stained prepara-
tions. These represent nuclear remnants and these occur most frequently after:
1. Splenectomy 2. Megaloblastic anemia 3. Severe hemolytic anemia

Acute manifestations of splenectomy include leukocytosis (up to 25000/l) and thrombocytosis (up to 1 106/l) but these
return back to baseline levels within 2-3 weeks.
Chronic Manifestations of splenectomy include:
Anisocytosis and poikilocytosis
Howell-Jolly bodies (nuclear remnants)
Occasional nucleated erythrocyte in peripheral blood
When such erythrocyte abnormalities are seen without splenectomy, splenic infiltration by tumor should be suspected.

Other options

Dohle bodies are discrete round or oval bodies. These represent rough ER and glycogen granules and are found in
neutrophils. These may be seen in patients with infections, burns, trauma, pregnancy or cancer.

Hypersegmented neutrophills are seen in megaloblastic anemia.

Spherocyte result from acquired or inherited defect in erythrocyte membrane. It may be seen in hypersplenism and not
following splenectomy.
131. Ans. (a) Metabolic Alkalosis (Ref: Harrison 17th/293, 9/e 666)
Massive Transfusion is defined as the need to transfuse from one to two times the patients normal blood volume. In a
normal adult, this is equivalent to 10-20 units. Most common abnormality is metabolic alkalosis. It results from conversion
of citrate (present in stored blood) and lactate (accumulated due to hypoperfusion) to bicarbonate
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132. Ans. (d) Cryoprecipitate: (Ref: Harrison 17th/708-710, Wintrobes 11th/846-8)

Donated blood is processed into components: PRBCs, platelets, and fresh-frozen plasma (FFP) or cryoprecipitate. Whole
blood is first separated into PRBCs and platelet-rich plasma by slow centrifugation. The platelet-rich plasma is then
centrifuged at high speed to yield one unit of random donor (RD) platelets and one unit of FFP. Cryoprecipitate is produced
by thawing FFP to precipitate the plasma proteins, and then separated by centrifugation.
Wintrobes clearly mentions that ABO incompatible plasma carries high risk of transfusion reactions, therefore, plasma
transfusions should always be ABO incompatible. So, option a and b are ruled out.
The platelets bear the intrinsic ABO antigens. So, platelet rich plasma and single donor platelets also should be preferably
ABO compatible. So, answer of exclusion is cryoprecipitate. It is not carrying ABO antigens but should preferably be ABO
compatible to avoid even the minimal risk of hemolytic reaction.
Apheresis technology is used for the collection of multiple units of platelets from a single donor. These single-donor
apheresis platelets (SDAP) contain the equivalent of at least six units of RD platelets and have fewer contaminating
leukocytes than pooled RD platelets. Still the risk of severe hemolytic reactions is much more with single donor
incompatible platelets than pooled plasma because the dose of incompatible plasma is also increased.
FFP is an acellular component and does not transmit intracellular infections, e.g. CMV

133. Ans. (c) O positive RBC and colloids/crystalloids (Ref: Wintrobes Clinical Hematology vol.I, 10th/833, CMDT 2010/477)
Selection of blood for emergency transfusion
If patients blood group is known, unmatched blood group of the same group may be used.
If the patients blood cannot be determined, Group O red blood cells should be chosen. The use of such unmatched blood
should be Rh (ve) when used in woman of child-bearing age in whom we do not want sensitization to Rh antigen. As Rh negative
blood is often in limited supply, Rh positive blood is used in the emergency transfusion of older females and males of unknown
blood group. In such cases sensitization may occur but the risk of an immediate hemolytic reaction is low. O blood group is the
universal donor and therefore, should be given to this patient.


134. Ans. (d) ABO (H) antibodies are invariably present in plasma when persons RBC lacks the corresponding antigen.
(Ref: Harrison 17th/708, CMDT 2010/477)
In clinical transfusion practice the ABO blood groups are the most important and can never be ignored in red cell
transfusion, because individuals, who genetically lack any antigen, have antibodies against the red cell types that
they have not inherited. These antibodies can destroy red cells rapidly in circulation.
The same is not the case with other blood groups where antibodies are formed only after exposure to the sensitive
antigen (Preformed antibodies are absent).
135. Ans. (a) Howell-Jolly bodies; (c) Macrocytosis: (Ref: Harrison 17th/374-375, 9/e 623-636)
Chronic manifestations of splenectomy (Postsplenectomy hematological features) are:
Red cells: Marked variation in size and shape (anisocytosis, poikilocytosis)
Macrocytosis
Presence of Howell-Jolly bodies (nuclear remnants)
Occasional nucleated red cells in the peripheral blood
Target cells
Pappenheimer bodies (contain sideroblastic granules)
Irregular contracted red cells.
WBC count usually normal but there may be mild lymphocytosis and monocytosis.
Thrombocytosis persists in about 30% of cases.
136. Ans. (a) Whole blood. (Ref: Harrison 17th/709)
Whole blood is processed into its components intended for transfusion. The blood component products are:
Packed RBC FFP
Platelets Cryoprecipitate
Plasma derivatives, e.g. albumin, antithrombin, coagulation factors Leukocyte reduced RBC
137. Ans. is c i.e. Trisodium citrate (Ref: Wintrobes Clinical Hematology 11th/4)
138. Ans. (b) Postsplenectomy >> (c) hemolysis (Ref: Tejinder singhs 1st/38-39, internet)
Friends, in hemolytic anemia Howell Jolly body is seen only if anemia is very severe. So, the preferred answer is post
splenectomyQ
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Howell-Jolly bodies are nuclear remnants seen in red cells, intermediate or late normoblasts. They are seen in:
Normally in neonates (spleen is immature)

Megaloblastic anemia is due to dyserythropoiesis
Post splenectomy due to absence of pitting function of the spleen
Acute severe hemolytic anemias
Hyposplenia (radiation exposure, splenic trauma, autosplenectomy due to sickle cells disease)
Myelodysplastic syndrome
139. Ans. (a) Chronic liver disease (Ref: Harrison 17th/359, T. Singh 1st/86)
140. Ans. (a) Leukemoid reaction (Ref: Robbins 8th/633; 7th/704, 9/e 719)
141. Ans. (b) D (Ref: Robbins 8th/460, 7th/485)
141.1. Ans. (a) X chromosome (Ref: Robbins 8/e p672, 9/e 662)
Hemophilia A is caused by mutations in factor VIII, which is an essential cofactor for factor IX in the coagulation cascade.
It is inherited as an X-linked recessive trait and thus affects mainly males and homozygous females.
Q
Read the following lines carefully for a future NEET question!

Hemophilia A is the most common hereditary disease associated with life-threatening bleeding.
Von Willebrand disease is the most common inherited bleeding disorder of humans
141.2. Ans. (c) Factor IX (Ref: Robbins 8/e p672, 9/e 662-663)
Disorder Deficiency
Hemophilia A Factor 8
Hemophilia B (Christmas disease) Factor 9 (Christmas factor)
Hemophilia C Factor 11
Parahemophilia Factor 5 (labile factor)
1 41.3. Ans. (b) Increased erythropoietin level (Ref: Robbins 9/e 656, 8/e p628, 7/e p699)
Polycythemia vera progenitor cells have markedly decreased requirements for erythropoietin and other hematopoietic
growth factors. Accordingly, serum erythropoietin levels in polycythemia vera are very low, whereas almost all other
forms of absolute polycythemia are caused by elevated erythropoietin levels.
1 41.4. Ans. (d) Polycythemia rubra (Ref: Robbins 9/e 619, 656, 8/e p665, 7/e p699)
Lab manifestations in polycythemia rubra (CMDT)
Elevated hemoglobin level and hematocrit: due to increased number of red blood cells
Platelet count or white blood cell count may also be increased.
Erythrocyte sedimentation rate (ESR) is decreased due to an increase in zeta potential.
Low erythropoietin (EPO) levels.
1 41.5. Ans. (b) Synthesized by hepatocytes (Ref: Robbins 9/e 661, 8/e p878; 7/e p654-655)
von Willebrand factor is synthesized by endothelial cells and megakaryocytes. It has the following functions:
It facilitates platelet adhesion by linking platelet membrane receptors to vascular endothelium (most important
function).
It serves as the plasma carrier for the factor VIII, the anti-hemophilic factor and increases its shelf life in circulation.
1 41.6. Ans. (b) Lack of reaction accelerator during activation of factor X in coagulation cascade. (Ref: Robbins 9/e 662, 8/e p672)
Hemophilia A is caused by the deficiency of clotting factor 8.
The chief role of the extrinsic pathway in hemostasis is to initiate a limited burst of thrombin activation upon tissue
injury. This initial procoagulant stimulus is reinforced and amplified by a critical feedback loop in which thrombin
activates factors XI and IX of the intrinsic pathway. In the absence of factor VIII, this feedback loop is inactive and
insufficient thrombin (and fibrin) is generated to create a stable clot.
1 41.7. Ans. (d) von Willebrand Factor (Ref: Robbins 9/e 661-662, 8/e p671, 672)
The clues given in the stem of the question are:
Female patient
Bleeding tendency
Prolonged aPTT
Normal PT
Normal platelet count
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As platelet count is normal, thrombocytopenia as a cause of bleeding can be easily ruled out.
PT is prolonged in defects of extrinsic pathway of coagulation whereas aPTT increases in defective intrinsic
pathway. Therefore, deficiency of factor VII can be ruled out, because it is involved in extrinsic pathway and its
deficiency will prolong PT.
Factor VIII and IX are involved in intrinsic coagulation pathway and vWF stabilizes factor VIII. Therefore,
deficiency of any of these will prolong aPTT with PT remaining normal. However, both Hemophilia A (factor
VIII deficiency) and Hemophilia B (Christmas disease; factor IX deficiency) are X-linked recessive diseases and
commonly affect males. Females are affected only in homozygous state, which is rare.
So, the answer is vWF deficiency which is mostly inherited as autosomal dominant disorder.
141.8. Ans. (a) Prolonged PTT (Ref: Robbins 9/e 662, 8/e p672; 7/e p 655)
aPTT is prolonged by deficiency of factors XII, XI, IX, III, X, V, prothrombin and fibrinogen and drugs like heparin
Q Q
Hemophilia A is characterized by the deficiency of factor 8 and decreased activity of intrinsic pathway. This is
associated with prolongation of partial thromboplastin timeQ.
141.9. Ans. (b) Normal PT (Ref: Robbins 9/e 662, 8/e p672; 7/e p656)
As discussed earlier, hemophilia A is an X linked disorder, so, if a male is affected, he cannot transmit it to his son
(option a is false). In this sdiorder, there is an increase in the activated partial thrombolastin time and normal values of
prothrombin time.
141.10. Ans. (b) HbA (Read below)
1
HbA is (95-96%)
2 2
HbA is (3-3.5%)
2 2 2
HbF is (present in the fetal life). As gestational age increases, the chains are replaced by the chains, resulting
2 2
in formation of adult hemoglobin, HbA.
HbA1c is glycated hemoglobin and is used for both diagnosis and checking the compliance of a patient having diabetes

mellitus.
1 41.11. Ans. (a) Light chain of monoclonal immunoglobulins (Ref: Robbins 9/e p600)
Bence Jones proteins are made up of light chains of the immunoglobulin and are monoclonal in nature.
141.12. Ans. (c) Small cleaved cell lymphoma (Ref : Pattern Approach to Lymph Node Diagnosis by Anthony S-Y Leong)
Friends, I know people would require reference for this question for believing the answer! JJ The tumor cells, which are
large with minimal cytoplasm, are closely apposed to each other, forming a dark blue background (the sky). These cells
have a very high turnover rate, so the macrophages that happen to be hanging around get stuffed with cellular debris (they
are at this point called tingible body macrophages), and upon fixation, the cytoplasm falls away, leaving round white
spaces filled with debris (the stars). This pattern can be seen on both bone marrow or lymph node sections. It is seen
with:
Burkitts lymphoma (earlier called as small non cleaved lymphoma)
Mantle cell lymphoma
Large B cell lymphoma (including plasmablastic lymphoma)
T lymphoblastic lymphoma
141.13. Ans. (b) endothelium (Ref: Robbins 8/e p434, 9/e p19-20)
Platelet-derived growth factor (PDGF) is present in the following:
The alpha granules of the platelets
Macrophages
Endothelial cells
Keratinocytes and
Smooth muscle cells.
141.14. Ans. (d) Sometimes found in saliva (Read below)
The A and B antigens are inherited as mendelian allelomorphs, A and B being dominants and they are located on
chromosome 9.
They are located on the membranes of human red cells
Antigens very similar to A and B are common in intestinal bacteria and possibly in foods to which newborn individuals
are exposed. Therefore, infants rapidly develop antibodies against the antigens not present in their own cells. Thus,
type A individuals develop anti-B antibodies, type B individuals develop anti-A antibodies, type O individuals
develop both, and type AB individuals develop neither
Secretors are individuals who secrete ABH antigens in body fluids like saliva and plasma.
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141.15. Ans (c) Factor 5 and 8 (Ref: Internet)

FFP contains an average of 1 IU/mL of each coagulation factor, including the labile factors V and VIII. In the question it
was asked regarding stored plasma.
By day 5 of storage the amount of factor VIII (8) is reduced by up to 40% and factors V (5) and VII (7) may be reduced by
up to 20%
141.16. Ans (a) Fucose (Ref: Harrison 18th/ 951)
The first blood group antigen system was ABO and is the most important in transfusion medicine. The major blood groups
of this system are A, B, AB, and O. H substance is the immediate precursor on which the A and B antigens are added. This
H substance is formed by the addition of fucose to the glycolipid or glycoprotein backbone. The subsequent addition of
N-acetylgalactosamine creates the A antigen, while the addition of galactose produces the B antigen.
141.17. Ans (d) Hemolysis (Ref: Hematology manual)

Conditions with pseudohyperkalemia
Excessive muscle activity during venipuncture (fist clenching),
Thrombocytosis, leukocytosis, and/or erythrocytosis
Acute anxiety
Cooling of blood after venipuncture
Gene defects leading to hereditary pseudohyperkalemia
Hemolysis causes real hyperkalemia.
(ANEMIA AND RED BLOOD CELLS)
Complications of Blood Transfusion ..Page 665

Blood products are often responsible for saving lives of individuals but may be associated with the development of the
complications. These include:
Febrile nonhemolytic reaction: this is the most common complication leading to fever and chills, sometimes with
mild dyspnea, within 6 hours of a transfusion of red cells or platelets. It is caused by the release of inflammatory
chemicals from the donor leukocytes. It is treated symptomatically with antipyretics.
Allergic Reactions: Severe, potentially fatal allergic reactions may occur when blood products containing certain
antigens are given to previously sensitized recipients. These occur more commonly in patients with IgA deficiency.
Urticarial allergic reactions may be triggered by the presence an allergen in the donated blood product that is
recognized by IgE antibodies in the recipient. This is more common. The condition is managed with antihistaminic
drugs.
Hemolytic Reactions: Acute hemolytic reactions are usually caused by preformed IgM antibodies against donor
red cells that fix complement. They occur due to improper labeling in the blood bank (ABO incompatibility).
Clinical features include fever with chills, flank pain, intravascular hemolysis, and hemoglobinuria. It is diagnosed
with a positive direct Coombs test. It may be fatal in rare cases.
Delayed hemolytic reactions: they are caused by antibodies that recognize red cell antigens that the recipient
was sensitized to previously, for example, through a prior blood transfusion. These are typically caused by IgG
antibodies to foreign protein antigens and are associated with a positive direct Coombs test.
Transfusion-Related Acute Lung Injury: TRALI is a severe, frequently fatal complication in which factors in a
transfused blood product trigger the activation of neutrophils in the lung microvasculature. It is associated with
a two hit hypothesis (priming event that leads to increased neutrophils in the lung microvasculature followed
by activation of the primed neutrophils). TRALI is associated with antibodies that bind major histocompatibility
complex (MHC) antigens, particularly MHC class I antigens. It is more common in multiparous women receiving
plasma derived blood products. Clinically, there is a sudden onset of respiratory failure, fever, hypotension and
hypoxemia. The treatment is largely supportive.
Infectious Complications: though any infection can be transmitted through blood products, but bacterial and viral
infections are relatively more commonly seen. It is also more common with platelet preparations. Donor screening
and infectious disease testing have reduced the incidence of viral transmission by blood products.
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White Blood Cells

CHAPTER
HEMATOGENOUS NEOPLASMS
8 and Platelets
Leukemia is a term used to describe the widespread involvement of the bone marrow
accompanied with large number of cancer cells in the peripheral blood whereas lymphoma According to WHO classification,
is a term used for proliferation of lymphoid cells arising as discrete tissue masses. blasts should be >20% in bone
marrow for diagnosis of acute
WHO Classification of the Lymphoid Neoplasms leukemia.
I. Precursor II. Peripheral B-Cell III. Precursor T-Cell IV. Peripheral T-Cell
B-Cell Neoplasms Neoplasms Neoplasms Neoplasms
* Precursor-B Chronic lymphocytic *Precursor-T Angioimmunoblastic
lymphoblastic leukemia/small lymphocytic lymphoblastic T-cell lymphoma
leukemia or lymphoma leukemia or
lymphoma B-cell prolymphocytic lymphoma Large granular
leukemia lymphocytic leukemia
Lymphoplasmacytic T-cell prolymphocytic
lymphoma leukemia
Splenic and nodal marginal Peripheral T-cell
zone lymphomas lymphoma, unspecified
Extranodal marginal zone Anaplastic large cell
lymphoma lymphoma
Mantle cell lymphoma Mycosis fungoides/
Sezary syndrome
Follicular lymphoma Enteropathy-
associated T-cell
lymphoma
Marginal zone lymphoma Panniculitis-like T-cell
lymphoma
Hairy cell leukemia Hepatosplenic
T-cell lymphoma
Plasmacytoma/plasma cell Adult T-cell leukemia/
myeloma lymphoma
Diffuse large B-cell lymphoma NK/T-cell lymphoma,
nasal type
Burkitt lymphoma NK-cell leukemia
V. HOdGkiN LyMPHOMA
Classic subtypes Non classical
Nodular sclerosis Lymphocyte predominant
Mixed cellularity
Lymphocyte-rich
Lymphocyte depletion
The FAB (French-American-British Classification) diagnostic criteria for acute leukemia is the
presence of >30% blasts in the bone marrow (normally, they are <5%) and increased number of
cells in the blood.
Note that according to WHO classification, blasts should be >20% in bone marrow for diagnosis
of acute leukemia.
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For broad understanding, WBC neoplasms can be classified as:
Acute leukemias have a high rate of proliferation without differentiation and their clinical
ALL is the commonest leukemia course is rapid.
seen in childhoodQ. Chronic leukemias have a low rate of proliferation of tumor cells with good differentiation and
their clinical course is slow.
LEUkEMiAS
White Blood Cells and Platelets
1. Acute Lymphoblastic Leukemia (ALL)
It is the commonest leukemia seen in childhoodQ having slight predilection for males. The
etiological agents include exposure to ionizing radiations as X rays, chemical like benzene,
genetic disorders like Down syndrome, ataxia telangiectasia and acquire disorders like
paroxysmal nocturnal hemoglobinuria and aplastic anemia.
LymphoblastQ staining positively The predominant cell seen in this leukemia is lymphoblastQ characterized by coarse nuclear
with PAS and (TdT). chromatin, 1-2 nucleoli, high N:C (nuclear:cytoplasmic) ratio and staining positively with PAS
(block positivity) and terminal deoxynucleotidyltransferase (TdT).
FAB (French-American-British) classification of ALL (Older classification)
L1 ALL L2 ALL L3 ALL
L1 ALL is the CommonestQ
type of ALL having the best CommonestQ type of ALL Next common type having Rarest type of ALL with the worstQ
prognosis. having the best prognosis. worse prognosis. prognosis.
Small homogenous blast, Large, heterogenous blast, Large homogenous blast, abundant
scanty cytoplasm, indistinct indented nuclei, one or basophilic cytoplasm with prominent
nucleoli more nucleoli, moderately cytoplasmic vacoulation staining
L3 ALL is the rarest type of ALL
abundant cytoplasm, minimal positive with Oil Red O.
having the worst prognosis.
cytoplasmic vacoulation
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Clinical features
ALL is characterized by sudden onset of symptoms that arise due to replacement of
the normal bone marrow cells with blast cells, thereby causing features/symptoms Aleukemic leukemia is diagnosed
due to decreased number of RBC, WBC and platelets (anemia, infections and increased by the presence of >20% blasts
bleeding tendency respectively). The leukemic cells also infiltrate the organs of the in the bone marrow.
body like spleen, liver and lymph nodes causing splenomegaly, hepatomegaly and
lymphadenopathy.
Bone marrow expansion is responsible for bone pain and tenderness (usually sternal
tenderness) in these patients. Testicular involvement and CNS features like headache, Testicular involvement and
vomiting and nerve palsies are also seen in these patients. This leukemia can is seen with T type ALL and is
associated with bad prognosis.
either be a precursor B-cell or T-cell type (these are the two predominant types of
lymphocytes). In the pre-T-cell type, there is presence of mediastinal mass due to
thymus involvement which can compress either the vessels or airways in the region.
Investigations
Blood findings
They include markedly elevated WBC count. Uncommonly, some patients may show pancytopenia with
few or no blast cells in peripheral blood which is called as aleukemic leukemia. However, diagnosis
is made in this condition by the presence of >20% blasts in the bone marrow. Blast cells with Periodic
Acid Schiff (PAS) positivity are seen. There is presence of anemia, neutropenia and thrombocytopenia.
Bone marrow
It is hypercellular with blast cells >20% of the marrow cells.

Biochemical investigations
It include elevated serum uric acid and phosphate levels accompanied by hypocalcemia (because of
hyperphoshatemia). Serum LDH is also increased as a result of increased turnover of the cancer cells.
Prognostic factors in ALL

Good Prognosis Bad Prognosis
Age 2-10 years Age <1 year or > 10 years
Female sex Male sex
L1 cell L2 or L3 cell
Peripheral blast count <1,00,000 Peripheral blast count >1,00,000
Pre B-cell phenotype Pre T-cell phenotype
Absence of mediastinal mass Mediastinal mass
Hyperdiploidy (>50 chromosomes) or Pseudodiploidy or t (9;22) (Philadelphia
t(12;21) chromosome) or t (8;14) or t (4;11)
Trisomy 4,7 and 10
Genetic associations of ALL

T cell ALL is associated with gain of function mutation in NOTCH 1 gene (normally required for Treatment of choice for ALL is
T cell development) allogenic bone marrow trans-
B cell ALL is associated with loss of function mutation in PAX5, E2A and EBF or balanced t (12; plantation and cancer drug re-
21) affecting TEL and AML1 genes (normally required for B cell development). gime used for induction is VAPD
(vincristine + asparaginase +
Treatment of choice for ALL is allogenic bone marrow transplantation and cancer drug prednisolone + daunoribicin) with
regime used for induction is VAPD (vincristine + asparaginase + prednisolone +daunoribicin) intrathecal methotrexate.
with intrathecal methotrexate.
2. Acute Myelogenous Leukemia (AML)
It is the leukemia affecting adults seen most commonly between the ages of 15-39 years. Myeloblast stains positively
The etiological agents include exposure to ionizing radiations such as X-rays, chemicals like with Sudan black B, myeloper-
benzene, secondary to myelodysplastic syndrome, drugs like anti-cancer drugs and genetic oxidase (MPO) and Non Specific
disorders like Downs syndrome and Fanconis anemia. Esterase (NSE).
The predominant cell seen in this leukemia is myeloblast characterized by fine nuclear
chromatin, 3-5 nucleoli, high N: C (nuclear: cytoplasmic) ratio, presence of Auer rods (these
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are abnormal azurophilic granules) and staining positively with Sudan black B, myeloperoxidase
(MPO) and Non Specific Esterase (NSE).
FAB (French-American-British) classification of AML
Class Salient Features
M0: Minimally differentiated AML Myeloid lineage blasts
M1: AM L without maturation Myeloblasts without maturation (> 3% blasts MPO or
SBB positive)
M2: AML with maturation t (8;21)Q is present, maximum incidence of chloromaQ,
M2: AML is the CommonestQ
Auer rods are seen
type of AML.
M3: Acute (Hypergranular) promyelocytic t (15;17)Q seen, Associated with disseminated
leukemia intravascular coagulation (DIC)Q, Auer rods are seen
M4: Acute myelomonocytic leukemia Inversion 16Q present, Presence of both myeloblasts
(Naegli type) and monoblasts (blasts > 20%; neutrophil and its
precursors > 20%; monocyte and precursors > 20%)
M5: Acute monocytic leukemia (Schilling t (9;11) seen, Highest incidence of tissue infiltrationQ,
type) organomegaly, and lymphadenopathy
M3: AML is associated with dis-
seminated intravascular coagu- M6: Acute erythroleukemia (Di Gugliemo Abnormal erythroid precursors are seen
lation (DIC). disease)
M7: Acute megakaryocytic leukemia Least common type of AML, Megakaryocytes are seen,
Release of platelet derived growth factor (PDGF) causes
myelofibrosis
MPO: Myeloperoxidase; SBB: Sudan black B

M7: AML is the CommonestQ

AddiTiONAL SALiENT POiNTS
type of AML in Down syndrome.
Generally AML following myelodysplastic syndrome (MDS) is associated with monosomy involving
chromosomes 5 and 7 and lack chromosomal translocation except AML following treatment with
topoisomerase II inhibitors (which is associated with translocation on chromosome 11 involving
MLL gene).
Cells with multiple Auer rods are called faggot cells and are seen in M3- AML.
Some authorities mention AML-M8 as acute basophilic leukemia.
Clinical features
They are similar to ALL i.e. fatigue due to anemia, bleeding and infections in oral cavity,
lungs etc. Patients may develop bleeding diathesis due to DIC which results from release of
Cells with multiple Auer rods are thromboplastic substances in the granules (most common with M3 AML). Infiltration of these
called faggot cells and are
seen in M3- AML.
cells into the organs is relatively less common as compared to ALL resulting in only mild
hepatosplenomegaly and lymphadenopathy.
However, gum hypertrophy and infiltration in the skin (called as leukemia cutis) is common
with particularly M5 AML. Less frequently, patients may present with localized masses in
absence of marrow or peripheral blood involvement called myeloblastoma, granulocytic
sarcoma or chloroma (most commonly with M2 AML and so named as they turn green in
Therapy in M3 AML specifically
can be done with all trans presence of dilute acid due to the presence of MPO). Lysozyme, CD43, CD45, CD117 and
retinoic acidQ (ATRA) or arsenic MPO are positive markers of granulocytic sarcoma. These manifest as proptosisQ (due to
oxideQ. orbital involvement) most commonly or may present as bone or periosteal masses.
iNVESTiGATiONS
Blood findings
It includes markedly elevated WBC count. Findings are similar to that in ALL except that the blast
cells show positivity with MPO, NSE or Sudan black. There is presence of anemia, neutropenia and
thrombocytopenia.
Bone marrow
It is hypercellular with blast cells >20% of the marrow cells.
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Biochemical investigations
These show elevated serum uric acid and phosphate levels accompanied by hypocalcemia (because
of hyperphosphatemia). Serum Muramidase levels is also increased in M4 and M5 AML. The fibrin
degradation products (FDPs) are elevated in M3 AML due to DIC.
PrOGNOSTic fAcTOrS iN AML

Good prognosis Bad prognosis
Age <40 years Age <2 years or >55 years
M2,M3,M4 forms of AML M0,M6,M7 forms of AML
Blast cell with Auer rods Complex karyotypes
TLC < 25 X 109/L TLC > 100 X109/L
t(15;17), t (8;21), inv 16 Deletions 5q, 7q
Rapid response to therapy Delayed response to therapy
Leukemia without preceding MDS AML with preceding MDS or anticancer drug exposure
Therapy in M3 AML specifically can be done with all trans retinoic acidQ (ATRA) or
arsenic oxideQ. In M3 AML or Acute promyelocytic leukemia, the translocation between
chromosomes 15 and 17 results in fusion of a gene encoding retinoic acid receptor (RAR )
with another protein PML and this fusion gene blocks the differentiation of the myeloid cells.
So, trans retinoic acid provided from external source is beneficial in these patients. For other
types of AML, the drugs used are cytarabine with daunorubicin.
However, treatment of choice of AML is allogenic bone marrow transplantation.

LEUkEMOid rEAcTiON
It is defined as the presence of leucocytes in the peripheral blood resembling leukemia in an

individual who actually does not have leukemia.
Myeloid leukemoid reaction Lymphoid leukemoid reaction
Seen in conditions like: Seen in conditions like:
Infections (sepsis, TB, endocarditis) Infections (usually viral like measles,
Severe hemorrhage and hemolysis chicken pox, CMV, infectious
Malignancies (Hodgkins, multiple myeloma, mononucleosis or bacterial like TB,
metastasis, myelofibrosis) pertussis)
Miscellaneous (burns, eclampsia, mercury Rare with malignancies.
poisoning).
cONcEPT
Leukemoid reaction is differentiated from leukemia by:
Absence of hepatosplenomegaly, lymphadenopathy and hemorrhage
Presence of immature cells/blasts to <5% (in leukemia, blasts are >20%)
Presence of increased leukocyte alkaline phosphatase score (in leukemia, LAP score is
decreased)
Presence of toxic granulations and Dohle bodies (cytoplasmic small round bodies) in neutrophils
{in leukemia, Dohle bodies are absent}
MyELOdySPLASTic SyNdrOMES (MdS)

Deletions in the long arm of
Myelodysplastic syndromes refer to a clonal stem cell disorder resulting in ineffective hematopoiesis chromosome 5 are the most
frequent cytogenetic changes in
and increased risk of development into acute myelogenous leukemia (AML). The bone marrow
MDS in adultsQ.
is replaced with multipotent stem cells which can differentiate but in an unorganized and
ineffective manner only.
It has been linked to the exposure to radiation, benzene, alkylating agents and some
chromosomal abnormalities. MDS can be classified into:
1. Primary MDS Develops slowly usually after 50 years of age.
Monosomy 7 is the most
2. Secondary or Therapy related MDS (t-MDS) Usually 2 to 8 years after toxic drug frequent cytogenetic change in
or radiation exposure. The secondary MDS gets transformed to AML most frequently MDS in childrenQ.
and so has a poorer prognosis.
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The bone marrow is usually hypercellular in this condition but the myelodysplastic precursor
cells undergo apoptosis at a fast rate resulting in ineffective hematopoiesis. MDS is frequently
associated with chromosomal abnormalities including monosomy 5 and 7, deletion of 5q and
7q, trisomy 8 and deletion of 20 q.
Juvenile myelomonocytic leu- Bone marrow findings
kemiaQ is a childhood myelo-
dysplastic syndrome. It is the Cells affected Features seen
commonest leukemia seen in Erythroid cells Ringed sideroblastsQ (Iron laden mitochondria in erythroblasts) with increased
children suffering from neurofi- iron stores
bromatosis-1Q. Megaloblasts, nuclear budding, intranuclear bridging, irregular nuclei
Megakaryocytes Pawn ball megakaryocytesQ (Megakaryocytes with multiple separate nuclei)
Neutrophils Dohle bodiesQ (toxic granulations) are seen,
Pseudo-Pelger-Huet cellsQ (Neutrophils with two nuclear lobes) are also seen
Peripheral blood shows the presence of Pseudo-Pelger-Huet cells, giant platelets,
macrocytes, poikilocytes and monocytosis.
Clinical features are seen in only 50% patients including weakness, infection and
hemorrhage due to pancytopenia. Usually patients are of an old age (mean age of onset is
>60 years). The prognosis is poor.
3. chronic Myelogenous Leukemia (cML)
It is a type of myeloproliferative disorder characterized by the increased number of immature

leukocytes, basophilia and splenomegaly seen in adults between the ages of 25-60 years.
An increased risk of CML is seen in people exposed to ionizing radiation (survivors of
nuclear bombs). There is presence of ABL gene (a proto-oncogene) on chromosome 9 and

BCR (break point cluster) gene on chromosome 22. A reciprocal translocation between these
two chromosomes causes formation of BCR-ABL fusion gene on chromosome 22 (called
Philadelphia chromosomeQ or Ph). This fused gene causes synthesis of a 210 kDa fusion
protein.
CML is associated with (t

9;22) resulting in formation of
Philadelphia chromosomeQ.
Clinical features
CML has a gradual onset with fatigue, anorexia and weight loss as the initial complaints.
Characteristically, there is presence of splenomegalyQ caused by infiltration of leukemic cells
as well as extramedullary hematopoiesis. Hepatomegaly is also seen but lymphadenopathy
is uncommon in these patients. Leukocytic infiltration and hypercellularity can cause
sternal tenderness whereas leukostasis can cause priapism, venous thrombosis and visual
disturbances.
Bone marrow
It is 100% cellular in these patients (in normal individuals, the marrow is 50% cellular and 50%
fat is present). The erythroid precursors are decreased (due to replacement by myeloid precursors)
The Neutrophil Alkaline Phos- whereas abnormal megakaryocytes are commonly seen. The presence of scattered histiocytes with
phate (NAP or LAP) is decreased
blue granules (sea-blue histiocytes or pseudo-Gaucher cellsQ) is characteristically seen. There
(in chronic phase) in CML.
is also increased deposition of reticulin fibres.
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PEriPHErAL SMEAr
It shows the presence of thrombocytosis and marked leukocytosis with presence of immature
white cells, eosinophilia and basophilia. The Neutrophil Alkaline Phosphate (NAP or LAP)
is decreased (in chronic phase) in these patients.
BiOcHEMicALLy
There are increased levels of uric acid, serum B12 levels (due to increased transcobalamin)
serum LDH and serum alkaline phosphatase.
PHASES Of cML
1. Chronic phase
Lasting for about 3-6 years having <10% blasts in the blood or bone marrow.
2. Accelerated phase
Aggressive phase lasting for few months showing increased anemia and
thrombocytopenia.
Number of blasts are >10% but <20%.
Cytogenetic abnormalities like trisomy 8, isochromosome 17q, duplication of Ph
chromosome may develop.
3. Blast phase
Resembles AML

Characterized by the presence of >20% blasts in the blood/bone marrow.
Two third of the blasts are of myeloid lineage whereas the remaining 1/3rd are of lymphoid
lineage (expressing CD10 & CD19; TdT).
Management
Drug as well as treatment of choice for CML is a tyrosine kinase inhibitor Imatinib
mesylate.
concept
LAP score is reduced in CML but it often increases when CML transforms to a blast crisis or
accelerated phase.
A variant of CML is seen in children called as juvenile CML. It is characterized by presence of
skin rash, absence of Philadelphia chromosome, increased levels of HbF and a poor prognosis.
4. chronic Lymphocytic Leukemia (cLL)/Small Lymphocytic Lymphoma (SLL)

Drug of choice as well as
It is a proliferation of mature lymphocytes seen in the old patients (mean age is 60 years) treatment of choice for CML
having a chronic course of onset which means that in this cancer, replacement of the bone is a tyrosine kinase inhibitor
Imatinib mesylate.
marrow hematopoietic cells occurs after a period of few years. So, anemia, thrombocytopenia
and granulocytopenia occur late in this disease.
The exact cause of this cancer is unknown but the role of TNF-a and TGF-b is
demonstrable which are produced by the cancer cells. These are responsible for suppression
of the proliferation of normal lymphocytes and bone marrow cells.
The chromosomal defects are rare in CLL but the ones still seen include deletion of 13qQ (commonest
and has good prognosis) and 11q trisomy 12q and deletion of 17p (have poor prognosis). (Ref
Wintrobes 12th edn 2222). Mean age of patients having
CLL is 60 years.
cLiNicAL fEATUrES
The cancer is more commonly seen in males and is asymptomatic in a large number of cases.
FatigueQ is the commonest presenting complaint associated with lymphadenopathy (initially,
cervical followed by a generalized lymphadenopathy). There is also presence of pallor, mild
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hepatosplenomegaly, skin rash and petechiae. However, sternal tenderness is absent (it is seen
in acute leukemia). These cells are not able to produce normal immunoglobulins resulting in
CLL is the only blood cancer
NOT associated with radiation the increased susceptibility to infections. As already discussed above, the presence of anemia,
exposure. thrombocytopenia and granulocytopenia signify the late stage of the disease.
Investigations
The diagnostic criteria for CLL are:
Peripheral blood lymphocyte count >5000 cells/mm3with <55% cells being atypical.
Bone marrow aspirate showing >30 % lymphocytes.
Blood investigation
It reveals low Hb, elevated TLC with lymphocytosis being the hallmark of the disease.
Peripheral smear shows increased number of lymphocytes with scanty cytoplasm. These cells
are fragile, so they get disrupted while making a smear and are called as smudge cells or
basket cells or parachute cells.
Bone marrow
CLL is also associated with
Autoimmune Hemolytic anemia It is hypercellular with >30% of the nucleated cells being lymphocytes as the diagnostic feature of
(so, Coombs test is positive in the leukemia. The aggregation of small lymphocytes and larger cells called prolymphocytes
this condition.
is called proliferation center which is a characteristic finding of CLL.
Immunophenotyping
The cancer cells are positive for CD19, CD20, CD23 and CD5. There is also low level
expression of surface immunoglobulin heavy and light chains.
Additional points
The distinguishing feature of CLL and SLL is that in the former blood involvement is predominant
presenting feature whereas in SLL the patients usually have lymph node findings.
NON-HOdGkiN LyMPHOMA (NHL)
1. follicular Lymphoma
It is the commonest NHL in the US (otherwise the commonest NHL is Diffuse large B
cell lymphoma) derived from the B-lymphocytes usually presenting in the middle age. It
shows the presence of translocation t(14;18)Q. Normally chromosome 14 has immunoglobulin
heavy chain gene whereas the chromosome 18 has bcl-2 gene. The translocation results in the
increased expression of bcl-2Q. The bcl-2 being the inhibitor of apoptosis causes promotion of
the follicular lymphoma cells resulting in the cancer.
Clinical features
The cancer presents usually as painless generalized lymphadenopathy with less commonly
Follicular lymphoma has the the involvement of CNS, GIT or testes. The median survival is for 7-9 years. In almost 50% of
presence of translocation t(14;18)Q. patients, this cancer gets transformed to diffuse large B-cell lymphoma.
Investigations
Immunophenotyping
The cells expressing bcl-2 protein, surface Ig, CD19, CD20 and CD10 (CALLA). CD5 is negative in
The cells in follicular lymphoma these cells (differentiating feature from mantle cell lymphoma and CLL).
express bcl-2 protein, surface Lymph node biopsy
Ig, CD19, CD20 and CD10
(CALLA). CD5 is negative in There is presence of centrocytes (small cell with cleaved nucleus and scant cytoplasm) and centroblasts
these cells. (large cell with open nuclear chromatin and multiple nucleoli).
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Peripheral blood
Presence of lymphocytosis.
Bone marrow
It shows the presence of characteristic para-trabecular lymphoid aggregates.
2. Mantle cell Lymphoma
It is a neoplasm in which the tumor cells resemble the normal mantle zone B-cells which
surround germinal centers. These have the translocation t(11; 14)Q. Normally chromosome
11 has cyclin D1 (bcl-1) locus whereas the chromosome 14 has immunoglobulin heavy chain
gene. This translocation leads to in the increased expression of cyclin D1Q which promotes
the G1 to S phase progression in the cell cycle resulting in development of neoplasia.
Clinical features
The cancer usually presents as painless generalized lymphadenopathy, splenomegaly or
involvement of the GIT. Uncommonly, multifocal mucosal involvement of the small bowel
and colon produces lymphomatoid polyposis. Mantle cell lymphoma has
the presence of translocation
Investigations t(11;14)Q.
Immunophenotyping reveals the cells expressing cyclin D1, surface Ig and CD 5. CD23 is
negative in these cells. Lymph node biopsy reveals typically the presence of small cleaved
cells with diffuse effacement of lymph nodes.

Centroblasts are absentQ (differentiating feature from mantle cell lymphoma and CLL).
CD23 is negativeQ in these cells (differentiating feature from CLL)
3. Burkitts Lymphoma/Small Non cleaved Lymphoma
It is a cancer of the germinal center B cell origin characterized by the presence of hallmark
translocation t(8;14)Q. The other translocations which may be present include t (2;8) or t (8;22).
Normally chromosome 8 has c-MYC gene whereas the chromosome 14 has immunoglobulin
heavy chain gene. The translocation results in the increased expression of c-MYC resulting in
development of neoplasia. It has the following 3 categories:
Burkitts lymphoma has the

presence of translocation t(8;14)Q.
Burkitts lymphoma has the

presence of starry sky pattern
Investigations in the lymph node biopsy.
Immunophenotyping reveals the cells expressing bcl-6Q protein, surface Ig, CD19, CD20 and
CD10 (CALLA).
Lymph node biopsy reveals typically the presence of a high mitotic index of lymphoid
cells associated with apoptotic cell death. The presence of tissue macrophages with clear
cytoplasm distributed with tumor cells creates the typical starry skyQ pattern.
Unlike the other tumors arising from the germinal centre, there is failure of expression of the anti-
apoptotic gene bcl-2 in Burkitts lymphoma.
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4. MArGiNAL ZONE LyMPHOMA (MALToma)
It is a group of B-cell tumors arising within the lymph nodes, spleen or extranodal tissues in
Marginal zone lymphoma has which the tumor cells resemble the normal marginal zone B cells. They are associated with
the presence of translocation mucosa associated lymphoid tissue, so, are called maltoma. Their salient features include:
t(11;18)Q. It is associated with H. Begin as polyclonal activation associated with autoimmune disorders, chronic
pylori infection.
inflammatory conditions or having infectious etiology.
Remain localized for a long duration of time.
May regress if causative agent is removed.
Splenic marginal zone lymphomas are TRAP +ve (like hairy cell leukemia)
The extranodal lymphomas can occur in stomach (H. pylori), orbit (Chlamydia), skin
(Borrelia), lung, salivary gland, intestine, etc. Tumors may respond to antibiotic therapy. If
they have cytogenetic abnormality t (11;18)Q as in extranodal marginal zone lymphoma, they
are refractory to antibiotic therapy.
5. Hairy cell Leukemia
Most cases of Hairy cell leukemia It is a misnomer because it is not a leukemia but a B cell NHL of the old age predominantly
are caused by activating affecting males (M:F ratio is 4:1) characterized by the presence of hairy cells in the peripheral
mutations in BRAF (Serine/ blood, splenomegaly and pancytopenia. The exact cause of this cancer is unknown but the
threonine kinase)
role of TNF- is postulated which is responsible for proliferation of hairy cells and are
responsible for the suppression of the proliferation of the normal bone marrow cells resulting
in pancytopenia. The chromosomal abnormalities associated with this leukemia like trisomy
5 etc have been detected.
Clinical features are massive splenomegaly and less commonly there is presence of
hepatomegaly (note that lymphadenopathy is distinctly rare in this disorder). Marrow failure
contributes to pancytopenia resulting in increased chances of infection, fatigue and easy
bruisability in these patients.
Cytochemistry reveals the
diagnostic feature of presence of Investigations
TRAP (Tartarate resistant acid
phosphate) cells in Hairy cell Blood
leukemia.
There is presence of pancytopenia with the presence of atypical lymphoid cells despite the presence
of neutropenia. Characteristic cells are hairy cells which are leukemic cells having hair-like projections
due to fine cytoplasmic processes seen best under phase contrast microscope. Electron microscope
shows the presence of ribosomal lamellar complexes in the cytoplasm.
Peripheral blood shows hairy cells with nuclei of different shapes.
All NHLs involve white pulp
of the spleen except Hairy cell Bone marrow aspirate
leukemia and hepatosplenic There is presence of dry tapQ due to presence of reticulin fibrils along with the leukemic cells.
lymphoma which involve red
pulp of the spleen. In hairy cell Bone marrow biopsy
leukemia, the white pulp is It reveals infiltration by the cancer cells called as honeycomb appearanceQ and leukemic cells have
atrophic. nucleus surrounded by cytoplasmic halo called as fried egg appearanceQ which is diagnostic of hairy
cell leukemia.
Immunophenotyping
Drug of choice for Hairy cell Tumor cells have the presence of pan B cell markers like positivity for surface Ig, CD19, CD20, CD11c,
leukemia is cladribine.
CD25 and CD103. Presence of CD11c, CD25 and CD103 positivity is characteristic of hairy cell
leukemia.
Cytochemistry reveals the diagnostic feature of presence of TRAP+Q (Tartarate resistant acid
phosphate) cells in Hairy cell leukemia.
cONcEPT
TRAP is also positive in some cases of splenic marginal zone lymphoma.
Hairy cell leukemia appears benign even though it is malignant because it is having less mitotic
rate resulting in reduced N:C ratio (normally malignant cells have increased N:C ratio) and there
is ample space between tumor cells (normally malignant cells are overcrowded).
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Characteristic Immunophenotypes of Major Subtypes of Lymphoma

Lymphoma Immunophenotype
Follicular CD20+, CD3, CD10+, CD5
Small lymphocytic CD20+, CD3, CD10, CD5+, CD23+
Marginal zone/MALT CD20+, CD3, CD10, CD5, CD23
Mantle cell CD20+, CD3, CD10, CD5+, CD23, CD43+, PRADI+
Diffuse large B-cell CD20+, CD3, CD5, CD45+
Burkitt CD20+, CD3, CD10+, CD5; Tdt
Lymphoblastic CD20, CD3+, Tdt+
Anaplastic large cell CD20, CD3+, CD30+, CD15, EMA+, ALK+
Peripheral T-cell CD20, CD3+
Hodgkin CD30+, CD15+
CD135 is an important cell surface marker used to identify hematopoietic progenitors in the bone
marrow. Specifically, multipotent progenitors (MPP) and common lymphoid progenitors (CLP) express
high surface levels of CD135. This marker is therefore used to differentiate hematopoietic stem cells
(HSC), which are CD135 negative, from MPPs, which are CD135 positive. HSC are CD 34 positive.
HOdGkiNS LyMPHOMA (HL)
It is a group of lymphoid neoplasms arising in a single node and spreads from the nodes

to spleen, then liver and finally bone marrow. Clinical importance of this predictable route
of spread is highlighted by the importance of staging which determines prognosis as well
guides the choice of therapy of HL.
It is differentiated from non- Hodgkins lymphoma by the following features:
Hodgkins Lymphoma Non-Hodgkins Lymphoma
More often localized to a single axial group of More frequent involvement of multiple
nodes (cervical, mediastinal, para-aortic) peripheral nodes
Orderly spread by contiguity Non contiguous spread
Mesenteric nodes and Waldeyer ring rarely Waldeyer ring and mesenteric nodes
involved commonly involved
Extra nodal involvement uncommon Extranodal involvement common
There is presence of neoplastic giant cell called Reed-Sternberg cell (derived from the
germinal center B cell) which induces the accumulation of reactive lymphocytes, macrophages
and granulocytes.
The cause for the development of HL is inappropriate activation of NF-B usually
induced by the latent membrane protein-1 of Ebstein Barr virus (EBV) in majority of the cases.
The malignant cell is Reed Sternberg (RS) cell which is having an owl-eye appearance
due to the presence of symmetric (mirror image) bilobed nucleus with prominent nucleoli
surrounded by clear space. The RS cells are positive for CD15 and CD30 for most subtypes
except in lymphocyte predominant HL in which the neoplastic cells stain for CD20 and BCL-6
and are negative for CD15 and CD30.
Important points about Reed Sternberg cell The malignant cell in Hodgkins
lymphoma is a Reed Sternberg
Lacunar cell is a variant of RS cell having a clear space surrounding the cell. (RS) cell which is having an
Popcorn cell is a lymphohistiocytic (L-H) variant of RS cell having a multilobed nucleus resembling owl-eye appearance
a popcorn kernel.
CD 30 is the most sensitive marker of Reed Sternberg cell.
Cells similar or identical in appearance to Reed-Sternberg cells are also seen in other conditions
like infectious mononucleosis, solid tissue cancers, and NHL (Immunoblastic lymphoma).
Thus, although Reed-Sternberg cells are requisite for the diagnosis, they must be present in
an appropriate background of non-neoplastic inflammatory cells (lymphocytes, plasma cells,
eosinophils).
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cLiNicAL fEATUrES
Lymphocyte predominant Hodg- Presence of painless enlargement of lymph nodes is the common presenting symptom and is
kins lymphoma is also called as
associated with fever (Pel Ebstein fever) and night sweats in disseminated disease. A strange
Non classical Hodgkins lym-
phoma. paraneoplastic syndrome in HL is pain in the affected lymph nodes on consumption of alcohol. The
prognosis is directly related to the number of RS cells present.
cHrONic MyELOPrOLifErATiVE diSOrdErS

PAX 5 is the most specific
marker of Reed Sternberg cell. The common pathogenic feature of the myeloproliferative disorders is the presence of
mutated, constitutively activated tyrosine kinases which lead to growth factor independent
proliferation and survival of marrow progenitor cells. These arise from the clonal proliferation
of multipotent stem cells which proliferate along the three cell lines (erythroid, megakaryocytic
Treatment of Hodgkins lympho- and granulocytic) except in CML in which with the pluripotent cell gives rise to myeloid cells.
ma is done with ABVD (Adria- Depending on the predominant cell in the myeloproliferative disorder, following
mycine, Bleomycin, Vinblastine disorders can be seen:
and Dacarbazine.
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1. chronic Myelogenous Leukemia (cML)
It has been discussed earlier with other leukemias.
2. Polycythemia Vera
This is a myeloproliferative disorder characterized by the increased number of erythroid,

granulocytic and megakaryocytic cells. The presence of erythrocytosis or polycythemia is
responsible for the development of the symptoms. Polycythemia vera progenitor cells have
markedly decreased requirements for erythropoietin and other hematopoietic growth factors.
Accordingly, serum erythropoietin levels in polycythemia vera are very low, whereas almost
all other forms of absolute polycythemia are caused by elevated erythropoietin levels.
Clinical features are primarily caused by increase in hematocrit and red cell mass
contributing to sluggish blood flow and even increased chances of thrombosis. These manifest in the
form of dusky cyanosis, visual disturbances, headache, dizziness, venous thrombosis (causes
Budd Chiari syndrome due to hepatic vein thrombosis), bowel infarction and stroke. The
increased basophils in the circulation (release histamine) are responsible for the development
of intense itching and increased incidence of peptic ulcer in these patients. Hyperuricemia is seen
due to increased cell turnover. The patients also have splenomegaly due to extramedullary Polycythemia Vera is strongly
hematopoiesis. associated with activating point
mutation in the tyrosine kinase
Investigations JAK2.
Blood shows elevated hemoglobin (Hb > 18 g %) and red cell count (> 6 million/
mm3; normal is 3.5-5.0 million/mm3), increased hematocrit with decreased levels

of erythropoietin. The last differentiate it from secondary polycythemia in which
serum erythropoietin is elevated.
Peripheral blood shows increased basophils and abnormal platelets.
Bone marrow is hypercellular having increased number of erythroid, granulocytic
Transformation to AML is un-
and megakaryocytic cells. In later stage, there is presence of myelofibrosis. common in polycythemia vera.
recent info in exams
Proposed Revised WHO Criteria for Diagnosis of Polycythemia Vera*
Major criteria 1. Hemoglobin > 18.5 g/dL in men or > 16.5 g/dL in women or evidence of
increased red cell volume
2. Presence of JAK2 mutation
Minor criteria 1. Hypercellular bone marrow biopsy with panmyelosis with prominent erythroid,
granulocytic, and megakaryocytic hyperplasia
2. Low serum erythropoietin level
3. Endogenous erythroid colony formation in vitro
Management of polycythemia
Polycythemia vera is the most common of the chronic myeloproliferative disorders. Its vera is done with venesection
diagnosis requires presence of both the major criteria and one minor criterion or the presence or alpha interferon.
of the first major criterion plus 2 minor criteria.
3. Essential Thrombocytosis
It is associated with activating mutation in JAK2 (more commonly) or MPL, a receptor

tyrosine kinase normally activated by thrombopoietin. This is the stem cell disorder having
increased proliferation of the megakaryocytes in bone marrow and high platelet count in the
blood (> 6 lakh/mm3; normal level is 1.5-4.5 lakh/mm3). It is usually a diagnosis of exclusion.
It is strongly associated with activating point mutation in the tyrosine kinase JAK2 or MPL, the latter is
receptor tyrosine kinase activated by thrombopoietin.
Clinical features arise because of non-functioning platelets resulting in bleeding (mucosal

bleeding, skin bleeding or spontaneous bleeding following trauma) and occlusion by these
dysfunctional platelets can result in thrombotic manifestations (arterial thrombosis occurs
more commonly as compared to deep venous thrombosis resulting in headache, dizziness
or ischemia of the digits).
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Investigations
Bone marrow is hypercellular with increase in number of giant megakaryocytes along with
dysmegakaryopoeisis. Erythroid and myeloid cell show only mild hyperplasia, if at all.
Erythromelalgia is a character- Blood shows elevated platelet count in the blood (diagnostic criteria is > 6 lakh/mm3), normal Hb
istic symptom caused by throb- levels and elevated LAP scores.
bing pain and burning of hands
and feet due to occlusion of Management is done with aspirin or hydroxyurea or anagrelide.
small arterioles by platelet ag-
gregates. 4. idiOPATHic Or PriMAry MyELOfiBrOSiS
It is characterized by the presence of marrow fibrosis associated with extramedullary

hemopoeisis in the spleen in old patients (usually more than 60 years of age). It is associated
with activating mutation in JAK2 (more commonly) or MPL. There is presence of neoplastic
megakaryocytes which are responsible for the release of fibrogenic factors like PDGF (platelet derived
growth factor) and TGF-. These factors cause progression of marrow fibrosis. This results in:
Replacement of normal hematopoietic stem cells by fibrous tissue.
Movement of hematopoietic stem cells to spleen and liver (responsible for
hepatosplenomegaly).
Both the above contribute to development of decreased cell count resulting in the
symptoms of fatigue, weight loss or bleeding episodes along with hepatosplenomegaly.
Hyperuricemia is seen due to increased cell turnover.
Bone marrow aspiration reveals dry tap due to fibrosis of the bone marrow.
So, bone marrow biopsy is the investigation of choice for the diagnosis which shows
the presence of hypocellularity with increased deposition of reticulin inside the marrow,
Concept abnormal megakaryocytes and the characteristic finding of dilated marrow sinusoids.
The fibrosis of the bone marrow
can occur as a primary hema- Peripheral blood findings include presence of nucleated red cells and immature white cells (called as
tological process (called pri- leukoerythroblastosis).
mary myelofibrosis or myeloid
metaplasia). There is also presence of abnormal red cells called dacryocytes (or tear drop RBC) formed
due to damage to red cell membrane caused by fibrous tissue in the marrow. Blood shows
mild leukocytosis, decreased Hb and hematocrit levels and elevated LAP scores.
PLASMA cELL dyScrASiAS
These are characterized by proliferation of B-cell clone which synthesizes and secretes a single
homogenous immunoglobulin or its fragments. The entity includes the following conditions:
Myelophthisis ia a term used
for secondary myelofibrosis due
Multiple myeloma (Plasma cell myeloma) presents as multiple masses in the
to tumors (breast/lung/prostate skeletal system. Smoldering myeloma is an asymptomatic subtype with high plasma
cancers or neuroblastoma) M component.
or granulomatous processes Waldenstroms macroglobulinemia Caused by blood hyperviscosity due to high
(infections like TB/fungi/HIV) or level of IgM. It is seen in adults with lymphoplasmacytic lymphoma.
radiation therapy.
Heavy chain disease Characterized by synthesis and secretion of free heavy chain
fragments and is seen in association with CLL/SLL, Mediterranean lymphoma,
lymphoplasmacytic lymphoma.
Primary or immunocyte associated amyloidosis Results from a monoclonal
proliferation of plasma cell secreting free light chains (most commonly isotype).
Monoclonal Gammopathy of Undetermined Significance (MGUS) It is the most
common symptomatic monoclonal gammopathy.Usually asymptomatic disease seen
in elderly patients. Rarely, it may progress to symptomatic monoclonal gammopathy
(most often multiple myeloma).
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*Hyperviscosity is defined on the basis of the relative viscosity of serum as compared with
water. Multiple Myeloma is a mono-
clonal plasma cell disorderQ.
*Normal relative viscosity of serum is 1.8
*Hyperviscosity is seen in
Multiple myeloma
Waldenstroms macroglobulinemia
Cryoglobulinemia
1. Multiple Myeloma
It is a plasma cell cancer having skeletal involvement at multiple sites. The most common
IL-6 is the most important
karyotypic abnormalities in this condition are deletions of 13q and translocation involving
cytokine for the proliferation of
Ig heavy chain locus on 14q. the plasma cells.

Infections are the commonest
cause of death.
Serum b2 microglobulin is the

most important prognostic
marker.
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Note: Commonest cause of Death in Multiple Myeloma is infectionsQ.
diAGNOSiS
In 2008 WHO diagnostic criteria for diagnosis of plasma cell myeloma are
Symptomatic plasma cell myeloma
M-protein in serum or urine (No level is included). M-protein in most cases is > 30 g/L if IgG, >
25g/L for IgA or 1g/dL urine light chain.
Bone marrow clonal plasma cell or plasmacytoma (monoclonal plasma cell usually exceed 10%
of nucleated cells in the marrow).
Related organ or tissue impairment (CRAB: hypercalcemia, renal failure, anemia and bone
lesions).
The diagnosis can be made on the basis of blood, bone marrow and urine findings as
described the following flowchart:
X-ray shows the presence of

punched out lytic lesions in
flat bones like skull, ribs, pelvis
and vertebra.
Note:
Definitive diagnosis is by Bone marrow examinationQ.
Treatment is done with melphalan, bortezomib and lenalidomideQ (refer to Review of Pharma-
cology for details)
MGUS is the commonest cause

of monoclonal gammopathy. 2. Monoclonal Gammopathy of Undetermined Significance (MGUS)
It is characterized by the presence of M spike without associated disease of the B cells. MGUS is the
commonest cause of monoclonal gammopathy. Around 1% of the patients with MGUS progress to
develop multiple myeloma per year. It is usually a diagnosis of exclusion. Patients of MGUS
have less than 3 g/dL of monoclonal protein in the serum and no Bence Jones proteinuria.
In Waldenstrom Macroglobu-
3. Waldenstrom Macroglobulinemia/Lymphoplasmacytic Lymphoma
linemia, there is presence of
a M or monoclonal spike It is a B cell neoplasm presenting in 6th or 7th decade of life having features similar to CLL/
caused due to IgM.
SLL and multiple myeloma.
312
Like MM, there is presence of a M or monoclonal spike (caused due to IgM whereas in MM, it is
caused by IgG)
Like SLL (unlike MM), the neoplastic cell infiltrates into organs like spleen, lymph node and bone
marrow.
Unlike multiple myeloma, there is absence of lytic lesions and serum calcium levels are normal.
Unlike multiple myeloma, there is balanced production of light and heavy chains thereby
decreasing the development of renal failure and amyloidosis.
Clinical features
These include non specific symptoms like fatigue, weakness, weight loss, hepatosplenomegaly
and cervical lymphadenopathy. The immunoglobulin increases viscosity of the blood
resulting in hyperviscosity syndrome affecting CNS and retina characterized by the headache,
dizziness, visual disturbances etc. Abnormal globulins may interfere with platelet function
resulting in bleeding and cryoglobulins may lead to acrocyanosis and cold urticaria.
Investigations
Bone marrow reveals the presence of plasmacytoid lymphocytes infiltration. PAS + inclusions
containing immunoglobulins are seen in the cytoplasm (called Russell bodies) or in the nucleus
(called Dutcher bodies) of the plasmacytoid cells. Deletion involving chromo-
Blood investigations show anemia with atypical plasmacytoid lymphocytes. ESR is elevated and some 6q is the commonest
rouleaux formation is seen. Immunoelectrophoresis reveals the presence of M spike composed abnormality in Waldendtroms
macroglobulinemia.
of IgM.
Immunophenotyping reveals the lymphocytic cells expressing B-cell markers like CD20. These
cells are negative for CD5 and CD10. The plasma cell secretes a monoclonal immunoglobulin.

Langerhans cell Histiocytosis (LcH)
The term histiocytosis is a broad term for a variety of proliferative disorders of dendritic
cells (DCs) or macrophages. Langerhans cell is a special type of dendritic cell in the skin
functioning as antigen presenting cell. Langerhans cell histiocytosis (LCH) has the following
entities:
1. Letterer-Siwe syndrome (multifocal multisystem LCH)
2. Pulmonary Langerhans cell histiocytosis: seen in adult smokers and may regress on cessation
of smoking.
3. Eosinophilic granuloma.
These three conditions are now considered different expressions of the same basic
disorder. The tumor cells in each are derived from dendritic cells and express The presence of Birbecks
HLA-DR, S-100, and CD1a. They have abundant, often vacuolated cytoplasm and granules in the cytoplasm is
vesicular nuclei containing linear grooves or folds. characteristic.
The presence of Birbecks granules in the cytoplasm is characteristic. These granules, under
the electron microscope, have a pentalaminar, rod like, tubular appearance and a
dilated terminal end (tennis-racket appearance) which contains the protein langerin.
The reason for the involvement of the organs like skin, bone, lymph node is that
while normal epidermal cells express CCR6, their neoplastic counterparts co-express
Hand-Schuller-Christian triad
CCR6 and CCR7, and this allows the abnormal DCs to migrate into tissues that is composed of calavrial bone
express the relevant chemokinesCCL20 in skin and bone (the ligand for CCR6) defects, diabetes insipidus
and CCL19 and 21 in lymphoid organs (ligands for CCR7). and exophthalmos.
PLATELETS
Platelets are enucleated cells in the circulation released from the megakaryocyte, likely under
the influence of flow in the capillary sinuses. The normal blood platelet count is 1.5- 4.5 lakhs/
mm3. The production of the platelets is regulated by the hormone thrombopoietin produced
in the liver.
The platelet synthesis is also specifically increased by interleukin 6. The average life span
of the platelets is 710 days.
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Normal hemostasis is a process that maintains blood in a fluid, clot-free state in normal
vessels while inducing the rapid formation of a localized hemostatic plug at the site of vascular
injury. After initial injury a brief period of arteriolar vasoconstriction occurs followed by the
formation of a temporary hemostatic plug due to platelets. This platelet plug formation
requires the following steps:
1. Platelet adhesion
On vascular injury, platelets adhere to the site of injury and this is mediated primarily
by two collagen receptors glycoprotein (Gp) Ia/IIa, and GpVI. This interaction with
collagen is stabilized by the von Willebrand factor (vWF) which is an adhesive
glycoprotein helping in the attachment of the platelets to the vessel wall. The vWF
forms a link between a platelet receptor site on Gp Ib/IX and collagen fibrils.
2. Platelet activation
A defect in the glycoprotein Ib
factor results in defective platelet The adherent platelets get activated, undergo a shape change and degranulate. The
adhesion known as Bernard- granules in the platelets can be
Soulier syndrome a. Alpha granules having P-selectin, fibrinogen, fibronectin, factors V and VIII,
platelet factor 4, platelet-derived growth factor, and transforming growth
A deficiency of Gp IIb-IIIa lead to
Glanzmann thrombasthenia,
factor-.
a disorder having defective b. Delta granules or delta bodies having ADP, ATP, ionized calcium, histamine,
platelet aggregation. serotonin, and epinephrine.
3. Platelet aggregation
The release of mediators in granule result in release of calcium (required in the
coagulation cascade), ADP and the surface expression of phospholipid complexes,
which provide the platform for the coagulation cascade. The platelets also synthesize
thromboxane A2 (TXA2) which is a potent vasoconstrictor and is also responsible for

platelet aggregation. The released ADP binds to platelet-specific purinergic receptor
Glanzmann is a defect in platelet P2Y12 which result in change in the conformation of the GpIIb/IIIa complex so that
aggregation (both have g in
it binds fibrinogen, linking adjacent platelets into a hemostatic plug. During platelet
them).
Bernard Soulier syndrome is a aggregation (platelet-platelet interaction), additional platelets are recruited from the
defect in platelet adhesion (both circulation to the site of vascular injury, leading to the formation of an occlusive
haved in them). platelet thrombus. The platelet plug is anchored and stabilized by the developing
fibrin mesh.
A deficiency of vWF results in

von Willebrands disease.
Ristocetin is an antibiotic which

increase the interaction between
VWF and GpIb receptor on
platelets.
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Classification of functional platelet disorders

Disorders of adhesion
Inherited Acquired
Bernard-Soulier syndrome Uremia
von Willebrand disease Acquired vWD
Disorders of aggregation
Inherited Acquired
Glanzmann thrombasthenia FDP inhibition
Afibrinogenemia Dysproteinemias
Drugs-Ticlopidine, GpIIb/IIIa inhibitors
Disorders of granule release
Inherited Acquired
Oculocutaneous albinism Cardiopulmonary bypass
Chediak-Higashi syndrome Myeloproliferative disease
Isolated dense granule deficiency Drugs- NSAIDs Thrombocytopenia is defined
Gray platelet syndrome (combined a and b granule as a platelet count of 1 lakh
deficiency) cells/L or less though
spontaneous bleeding is seen
Bleeding time represents the time taken for a standardized skin puncture to stop bleeding usually when the count falls
and it gives an in vivo assessment of platelet response to limited vascular injury. The value below 20000 cells/L.
varies from 2 to 9 minutes. It is abnormal when there is a defect in platelet numbers or
function. Currently, quantitative measures of platelet function are being introduced by using
an electronic particle counter.

Thrombocytopenia is characterized by spontaneous bleeding a prolonged bleeding time and a normal
PT and PTT.
immune Thrombocytopenic Purpura (iTP)
ITP can be either primary (idiopathic) or secondary (SLE, AIDS, viral infections and drug
induced). The primary ITP can be dependent on the duration of the disease, acute (less than
6 months) or chronic (> 6 months). The platelet destruction in both of them results from the
formation of antiplatelet autoantibodies (type II hypersensitivity reaction).
Pathogenesis
Chronic ITP is caused by the formation of autoantibodies mostly of the IgG class against
platelet membrane glycoproteins, most often IIb-IIIa or Ib-IX. The opsonized platelets are
rendered susceptible to phagocytosis by the cells of the mononuclear phagocyte system. The
spleen is the major site of removal of sensitized platelets.
Clinical features Immune Thrombocytopenic Pur-

pura (ITP) is a type II hypersen-
Chronic ITP occurs most commonly in adult women younger than age 40 years. The sitivity reaction.
female-to-male ratio is 3:1. This disorder is often insidious in onset and is characterized by
bleeding into the skin (pinpoint hemorrhages called petechiae, especially in the dependent
areas where the capillary pressure is higher or ecchymoses), mucosal surfaces (nose bleed,
post brushing gum bleeds and hematuria), menorrhagia (menstrual bleeding in females)
and intracranial bleeds. Splenomegaly and lymphadenopathy are uncommon in primary ITP, and
their presence should make one consider other possible diagnoses.
Findings: The blood smear shows abnormally large platelets (megathrombocytes). The
spleen is normal in size and sinusoidal congestion with prominent germinal centers. Bone
marrow is hypercellular and shows megakaryocytic hyperplasia. The bone marrow should
be examined to rule out thrombocytopenias resulting from marrow failure. A decrease in
the number of megakaryocytes argues against the diagnosis of ITP. The bleeding time is
prolonged, but PT and PTT are normal.
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The management is done with immunosuppressive therapy like glucocorticoids and

intravenous immunoglobulins. Splenectomy is beneficial because it is the site of destruction
of the platelets and is also an important site of autoantibody synthesis which are reduced
after its removal.
Acute immune Thrombocytopenic Purpura

Concept It is similar to chronic ITP (caused by anti platelet antibodies) but is differentiated from the
Splenectomy is beneficial in same by the following:
ITP because it is the site of
Seen in children
destruction of the platelets
Less duration (2-6 weeks)
and is also an important site of
autoantibody synthesis which Occurs with equal frequency in both sexes
are reduced after its removal. Abrupt onset of thrombocytopenia
Preceded by a viral illness and is
Self-limiting (resolving spontaneously within 6 months). Steroids may be required in few cases
only.
The diagnosis of Idiopathic Thrombocytopenic Purpura should be made only after exclusion of other
known causes of thrombocytopenia.
Thrombotic Thrombocytopenic Purpura (TTP)/Moschcowitz disease
It is a rare disorder of the blood-coagulation system, causing extensive microscopic blood

clots to form in the small blood vessels throughout the body. It arises from deficiency of the
vWF metalloprotease enzyme ADAMTS13 which is responsible for cleaving large multimers
of von Willebrand factor (vWF). In the absence of this enzyme, very high molecular weight
multimers of vWF accumulate in plasma and promote platelet aggregation. This is also
associated with activation of coagulation in the small blood vessels. Platelets are consumed in
the coagulation process, and bind fibrin, the end product of the coagulation pathway. These
platelet-fibrin complexes form microthrombi which circulate in the vasculature and cause
shearing of red blood cells, resulting in hemolysis. Any additional endothelial cell injury
further increases microaggregate formation. Reduced blood flow and cellular injury result in
end organ damage.
Classically, the following five features (pentad) are indicative of TTP:
Fluctuating neurological symptoms, such as bizarre behavior, altered mental

status, stroke or headaches
Kidney failure
Fever
Thrombocytopenia (low platelet count), leading to bruising or purpura
Microangiopathic hemolytic anemia (anemia, jaundice and a characteristic blood
film)
If coagulation tests indicate a major consumption of procoagulants, the diagnosis of TTP is
doubtful .The inherited inherited deficiency of ADAMTS13, known as the Upshaw-Schulman
syndrome. The management of these patients is done with plasmapheresis (plasma exchange)
and sometimes additional immunosuppressive therapy.
The combination of hemolytic anemia with fragmented RBCs, thrombocytopenia, normal
coagulation tests, fever, neurological disorders and renal dysfunction is virtually pathognomic
of TTP.
Hemolytic Uremic Syndrome (HUS)
HUS is also associated with microangiopathic hemolytic anemia and thrombocytopenia but
is distinguished from TTP by
Normal ADAMTS13 levels
Absence of neurological symptoms
Dominance of acute renal failure
Childhood onset of disease
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It can be of the following types:

1. Epidemic or typical HUS: It is associated with infectious gastroenteritis caused by E.
coli strain O157: H7. This bacterium releases a Shiga-like toxin damaging endothelial
cells followed by platelet activation and aggregation. The patients presents with Concept
bloody diarrhea followed by HUS after few days. In HUS, microthrombi mainly
2. Non-epidemic or atypical HUS: It is associated with mutations in the gene encoding contain fibrin whereas in TTP
complement regulatory proteins like factor H, factor I or membrane cofactor protein these are composed of platelet
CD46. These proteins normally prevent excessive activation of alternate pathway aggregates, fibrin and VWF.
of the complement system. So, their deficiency is associated leads to uncontrolled
complement activation after minor endothelial injury, resulting in thrombosis. The
patients have a relapsing remitting course.
HUS can also be seen due to other factors (e.g., certain drugs, radiation therapy) that
damage endothelial cells.
Activation of the coagulation cascade is not of primary importance in HUS and TTP and so, the
laboratory tests of coagulation (such as the PT and the PTT) are usually normal.
Von Willebrand disease
The von-Willebrand factor (vWF) is a heterogenous multimeric plasma glycoprotein

produced by endothelial cells (Weibel Palade bodies) and megakaryocytes (can be shown inside
platelet -granules) with two major functions:
1. It facilitates platelet adhesion under conditions of high shear stress by linking

platelet membrane receptors to vascular endothelium (most important function).

2. It serves as the plasma carrier for the factor VIII, the anti-hemophilic factor
and increases its shelf life in circulation. Factor VIII is synthesized tissues like
sinusoidal endothelial cells and Kupffer cells in the liver and glomerular and
tubular epithelial cells in the kidney.
von Willebrand disease which
The disease can have the following variants: is the most common inherited
disorder of bleeding in humans.
1. Type 1 and type 3 von Willebrand disease are associated with a reduced quantity
of circulating vWF. Type 1 (commonest variant) is an autosomal dominant disorder
and is mild clinically. Type 3 (an autosomal recessive disorder) is associated with
extremely low levels of functional vWF, and severe clinical manifestations. Type 1
disease is associated with missense mutations whereas Type 3 disease is associated
with deletions or frameshift mutations
2. Type 2 von Willebrand disease is characterized by qualitative defects in vWF. The
type 2A variant is the most common. It is inherited as an autosomal dominant
disorder and is associated with missense mutations. It is associated with mild to
moderate bleeding.
Clinical features in von Willebrand disease are due to
Platelet Adhesion defects
Deficiency of vWF results in defect in the adhesion of platelets to collagen preventing the formation
of haemostatic plug. It leads to mucus and cutaneous bleeding in the form of epistaxis, menorrhagia
and GI bleeding.
Coagulation defect
There is reduced half life of factor VIII leading to its deficiency resulting in hemorrhages and
intramuscular hematoma.
LABOrATOry fiNdiNGS
1. A prolonged bleeding time in the presence of a normal platelet count.
2. The defective platelet adhesion also results in a positive tourniquet test (Hess test).
3. In deficiency of vWF, ristocetin induced platelet aggregation does not take place.
So, ristocetin induced aggregation is defective and is diagnostic of this disease.
However, platelet aggregation with ADP, collagen and thrombin is normal.
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4. Though the synthesis of factor VIII remains normal but half life of VIII in plasma
decreases due to reduced vWF (carrier) levels. This leads to secondary VIIIC deficiency in
plasma. So, intrinsic pathway of coagulation is affected and thus, aPTT is increased in these
patients.
Hemophilia A (factor Viii deficiency)

The management of these patients
is done with desmopressin and Hemophilia A is the most common hereditary disease associated with serious bleeding. This X
cryoprecipitate. linked disorder is caused by a reduction in the amount or activity of factor VIII which is a
cofactor for factor IX in the activation of factor X in the coagulation cascade. The disease can
have the following variants:
1. Mild disease levels of factor VIII activity between 6% and 50% of normal
2. Moderate disease - levels between 2% and 5% of normal
3. Severe disease- the levels less than 1% of normal activity.
The severe variant of hemophilia A is caused due to an inversion of the intron 22 sequence involving
the X chromosome that completely abolishes the synthesis of factor VIII.
Clinical features: it includes easy bruising and massive hemorrhage after trauma
or operative procedures. The disease is evident early in life when there is bleeding after
circumcision or when the child begins to walk or crawl. The hemorrhages occur frequently
in the joints (hemarthroses) and recurrent bleeding may lead to progressive deformities. Acute
hemarthroses is painful and to avoid pain, the patient may adopt a fixed position leading to
muscle contractures. It mainly affect knees, elbows, ankles, shoulders, and hips Petechiae
are characteristically absent. Muscle hematoma can also be seen leading to a compartment
syndrome. Fascial hemorrhages can result in the formation of blood filled cysts with
calcification and proliferation of fibroblasts giving the appearance of a tumor (pseudotumor
Petechiae are characteristically
absent in hemophilia. syndrome). Self limiting episodes of hematuria in the absence of genitourinary pathology are
frequent in the patients.
LABOrATOry fiNdiNGS
1. Patients with hemophilia A typically have a normal bleeding time, platelet count,
and PT
2. There is a prolongation of aPTT due to an abnormality of the intrinsic coagulation
The management is done with pathway.
the drug desmopressin, cryo- 3. Factor VIII-specific assays are required for diagnosis.
precipitate and recombinant
factor VIII.
Hemophilia B (christmas disease, factor iX deficiency)
The factor IX deficiency produces a disorder similar to hemophilia A. It is inherited as an

X-linked recessive trait and the PTT is prolonged and the PT is normal, as is the bleeding
time. The diagnosis is done only by assay of the factor IX levels.
SUMMARy OF LABORATORy FINDINGS IN HEMOSTATIC DISORDERS

Diseases Platelet count Bleeding time PT APTT FDP
Hemophilia A N N N Absent
Fresh frozen plasma or recombi- Hemophilia B N N N Absent
nant factor IX is useful for the
management of Chrismas disease. vWD N N Absent
Liver failure Absent
DIC Present
Vascular purpura N N N N Absent
Aspirin N N N Absent
Warfarin N N (Even in (In high Absent
low dose) dose)
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Multiple ChoiCe Questions

LEUkEMiA: ALL, AML, cLL, cML (c) Mediastinal rich B cell lymphoma
(d) T cell Lymphoblastic ALL
1. Flow cytometry is done in: (AIIMS Nov 2012) 8. Which of the following is the least likely to be a pre-
(a) Polycythemia leukaemic condition? (AIIMS Nov 2011)
(b) Thrombocytosis (a) Paroxysmal nocturnal haemoglobinuria
(c) Neutrophilia (b) Aplastic anaemia
(d) Lymphocytosis (c) Paroxysmal cold haemoglobinuria
2. Myelofibrosis leading to a dry tap on bone marrow (d) Myelodysplastic syndrome
aspiration is seen with which of the following 9. A 6 year old child presents with pallor that required two
conditions? (AIIMS Nov 2012) blood transfusions previously. He has now developed
(a) Burkitts lymphoma fever and petechial haemorrhages. His hemoglobin is is
(b) Acute erythroblastic leukemia 9 g/dL, platelet count is 20,000/mm3 and TLC is 60,000/
(c) Acute megakaryocytic leukemia mm3. Flow cytometry reveals the cells to be CD10+ve,
(d) Acute undifferentiated leukemia MPO+ ve, CD 19 + ve, CD 33 ve, CD 117 + ve, and
3. Marker of myeloid cancers: (AIIMS Nov 2012) CD3 ve. Which of the following is the most likely
(a) S100 diagnosis? (AIIMS Nov 2011)

(b) HMB45 (a) ALL
(c) Common leukocyte antigen (b) AML
(d) Cyto-keratin (c) Mixed phenotypic leukaemia
(d) Undifferentiated leukaemia
4. Adult patient presents with generalized lymphadenop-
athy and blood film shows 70% immature looking lym- 10. Poor prognostic factor for ALL is (AI 2011)
phocytes. What should be the next best investigation? (a) Hyperdiploidy
(a) Genotyping/karyotyping (AIIMS Nov 2012) (b) t(9;22) t(4;11)
(b) Immunophenotyping (c) Age at presentation is 2-8 yrs
(c) Bone marrow (d) Total Leucocyte count <50000
(d) Peripheral smear study 11. All the following are poor prognostic indicators in
5. Which of the following statements in context of AML except (AIIMS Nov. 2010)
leukemias is true? (AIIMS May 2012) (a) Inv 16
(a) Chronic myeloid leukemia occurs beyond 50 years of (b) Complex karyotype
age (c) AML M7
(b) Hairy cell leukemic in less than 50 years has a good (d) Deletion 7q
prognosis 12. Most specific marker for myeloid series is
(c) Acute lymphoid leukemic in less than 1 year has a (a) CD 34 (AIIMS May 2010)
poor prognosis (b) CD 45
(d) Chronic lymphocytic leukemia occurs in less than 50 (c) CD 99
years of age (d) CD 117
6. In an ablated animal, myeloid series cells are injected.
13. t (2,8) is associated with: (AI 2010)
Which of following is seen after incubation period?
(a) T cell ALL
(a) Fibroblast (AIIMS May 2012)
(b) B cell ALL
(b) T lymphocytes
(c) CML
(c) RBC
(d) CLL
(d) Hematopoetic stem cell
7. A young boy came with dyspnea and was found to have 14. ALL L3 morphology is a malignancy arising from which
a mediastinal mass. Which of the following is known to cell lineage? (AI 2007)
produce mediastinal lymphadenopathy? (AI 2012) (a) Mature B-cell
(a) Diffuse large B cell Lymphoma (b) Precursor B-cell
(b) B cell rich T cell lymphoma (c) Immature T-cell
(d) Mixed B cell and T-cell
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15. Non-specific esterase is positive in all the categories of 23. Marker for granulocytic sarcoma: (AIIMS May 2008)
AML except (AI 2007) (a) CD33
(a) M3 (b) CD38
(b) M4 (c) CD117
(c) M5 (d) CD137
(d) M6 24. Pancytopenia with a cellular marrow is seen in all
16. Which of the following statements pertaining to except (AIIMS Nov 2007)
(a) PNH
leukemia is correct? (AI 2005)
(b) Megaloblastic anemia
(a) Blasts of acute myeloid leukemia are typically Sudan
(c) Myelodysplastic syndrome
black negative
(d) Congenital dyserythropoietic anemia
(b) Blasts of acute lymphoblastic leukemia are typically
myeloperoxidase positive 25. All are B-cell marker except: (AIIMS May 2007)
(c) Low leucocyte alkaline phosphatase score is charac- (a) CD-15 (b) CD-19
teristically seen in blastic phase of chronic myeloid (c) CD-21 (d) CD-24
leukemia 26. Acid phosphatase is specific to which of the following
(d) Tartarate resistant acid phosphatase positivity is typ- cells (AIIMS Nov 2006)
ically seen in hairy cell leukemia (a) Monocyte
(b) T-lymphocyte
17. Which is the most common cytogenetic abnormality in (c) B-lymphocyte
adult myelodysplastic syndrome (MDS)? (AI 2004) (d) Myelocytes
(a) Trisomy 8
(b) 20q 27. A peripheral smear with increased neutrophils,
basophils, eosinophils, and platelets is highly
(c) 5 q
suggestive of: (AIIMS May 2006)

(d) Monosomy 7
(a) Acute myeloid leukemia
18. Which of the following is a pan-T lymphocyte marker? (b) Acute lymphoblastic leukemia
(a) CD2 (AI 2003) (c) Chronic myelogenous leukemia
(b) CD3 (d) Myelodysplastic syndrome
(c) CD19 28. A 17-year-old boy presented with TLC of 138
(d) CD25 109/L with 80% blasts on the peripheral smear.
19. B cell marker are all except: (AIIMS Nov 09) Chest X-ray demonstrated a large mediastinal mass.
(a) CD 19 Immunophenotyping of this patients blasts would
most likely demonstrate: (AIIMS May 2006)
(b) CD 20
(c) CD 10 (a) No surface antigens (null phenotype)
(d) CD135 (b) An immature T-cell phenotype (Tdt/CD34/CD7
positive)
20. Which of the following is having poor prognosis in (c) Myeloid markers, such as CD13, CD33 and CD15
ALL:
(d) B cell markers, such as CD19, CD20 and CD22
(a) TLC 4000-10000 (AIIMS Nov 09)
(b) Age < 2 yrs 29. A 15-year-old boy presented with one day history of
(c) Presence of testicular involvement at presentation bleeding gums, subconjunctival bleed and purpuric
(d) Presence of blasts in peripheral smear rash. Investigations revealed the following results:
Hb-6.4 gm/dL; TLC-26,500/mm3 Platelet 35,000 mm3;
21. All of the following are good prognostic factors for prothrombin time-20 sec with a control of 13 sec; partial
acute lymphoblastic leukemia except thromboplastin time-50 sec; and Fibrinogen 10mg/dL.
(a) Age of onset between 2-8 years (AIIMS Nov 2008) Peripheral smear was suggestive of acute myeloblastic
(b) Initial WBC count less than 50000 leukemia. Which of the following is the most likely?
(c) Hyperdiploidy (AIIMS May 2006)
(d) t(9:22), t(8:14), t(4:11) (a) Myeloblastic leukemia without maturation
(b) Myeloblastic leukemia with maturation
22. AML with gum infiltration, hepatosplenomegaly is (c) Promyelocytic leukemia
most likely to be: (AIIMS May 2008) (d) Myelomonocytic leukemia
(a) ALL
30. In a patient with acute leukemia, immunophenotype
(b) M3
pattern is CD 19+ve, CD 10+ve, CD33+ve, CD 13+ve. He
(c) M2
may probably have (AIIMS May 2004)
(d) M4
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(a) Biphenotypic leukemia (c) MI

(b) ALL (d) HIV infection
(c) AML-M
2 38. Sideroblasts are seen in: (PGI Dec 2005)
(d) AML-M0
(a) Thalassemia
31. Which of the following is not compatible with a (b) Myelofibrosis
diagnosis of chronic myelomonocytic leukemia? (c) Alcoholism
(AIIMS Nov 2003) (d) Iron overload
9
(a) Peripheral blood monocytosis more than 110 /L
(b) Absence of Philadelphia chromosome 39. Absolute monocytosis is seen in: (PGI Dec 2006)
(c) More than 20% blasts in blood or bone marrow (a) Infectious mononucleosis
(d) Absent or minimal dysplasia in myeloid lineages (b) Kala-azar
(c) TB
32. A 60 year old man presented with fatigue, weight loss
(d) Brucellosis
and heaviness in left hypochondrium for 6 months.
The hemogram showed Hb, 10gm/dL, TLC 5 lakhs/ 40. Aplastic anemia can progress to: (PGI Dec 01)
3 3
mm , platelet count 4 lakhs/mm , DLC, neutrophil (a) AML
55%, lymphocytes 4%, monocytes 2%, basophils 6%, (b) Myelodysplastic syndrome
metamyelocytes 10%, myelocytes 18%, promyelocytes (c) CLL
2% and blasts 3%. The most likely cytogenetic (d) PNH
abnormality in this case is (AIIMS May 2003) (e) Iron deficiency anemia
(a) t (1:21)
(b) t (9:22) 41. True about aplastic anemia: (PGI June 2005)
(c) t (15, 17) (a) Splenomegaly
(d) Trisomy 21 (b) Nucleated RBC in peripheral blood.
(c) Reticulocytopenia

33. A 42-year old man was referred with a 2 week history (d) Thrombocytopenia
of fever weakness and bleeding gum. Peripheral smear (e) Neutropenia
showed pancytopenia. The bone marrow examination
revealed 26% blasts frequency exhibiting Auer rods and 42. Leucocytosis is seen in all except: (Delhi 2010)
mature myeloid cells. An occasional neutrophil with (a) Brucellosis
pseudo Pelger-Huet anomaly was also detected. Which (b) Acute MI
of the following cytochemical stains is most likely to be (c) Typhoid
positive? (d) Diphtheria
(a) Acid phosphatase (AIIMS Nov 2002) 43. The blast cells of acute lymphocytic leukemia in
(b) Non-specific esterase
childhood contain: (Delhi PG 2005)
(c) Myeloperoxidase
(d) Toluidine blue (a) Surface antigen
(b) CALLA Ag
34. AML with worst prognosis (AIIMS May 2007) (c) Antibodies to WBC
(a) 8/21 translocation
(d) Thrombocytosis
(b) Inversion 16
(c) Normal cytogenetics 44. Smudge cells in the peripheral smear are characteristic
(d) Monosomy 7 of: (Karnataka 09)
35. Pancytopenia with cellular marrow is seen in all except (a) Chronic myelogenous leukemia
(a) Megaloblastic anemia (AIIMS Nov 2006) (b) Chronic lymphocytic leukemia
(b) Myelodysplasia (c) Acute myelogenous leukemia
(c) Paroxysmal nocturnal hemoglobinuria (d) Acute lymphoblastic leukemia
(d) G6PD deficiency 45. Chromosomal translocation characteristic in acute
36. Highest LAP score is seen in (PGI Dec 2001) promyelocytic leukemia is (UP 2003)
(a) CML (a) t ( 15: 17)
(b) Polycythemia vera (b) t ( 22: 9)
(c) PNH (c) t ( 21: 17)
(d) Pregnancy (d) t ( 8: 21)
(e) Lymphoma 46. TRUE abut acute myelogenous leukemia
(a) Philadelphia chromosome is seen (UP 2003)
37. Causes of eosinophilia are: (PGI June 2004)
(b) Auer bodies are seen
(a) Hodgkins disease
(c) Common in childhood
(b) Filariasis
(d) Peroxidase negative granules
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47. In CML, serum vitamin B12 level is (UP 2003) 57. A 38 year old female Raman presented with the
(a) Slightly decreased complaints of fever with chills and rigors for last 10
(b) Normal days. Her blood reports show
(c) Markedly decreased Hemoglobin 14.1 g/dl
(d) Increased Hematocrit 42.3%
MCV 90 fL
48. BCR-ABL hybrid gene is present in (UP 2005) Platelet count 2.4 lac/mm3
(a) Burkitts lymphoma WBC count 14,000/mm3
(b) Retinoblastoma Differential count
(c) Breast carcinoma Segmented neutrophils 78%
(d) CML Bands 10%
49. The difference between leukemia and leukemoid Lymphocytes 8%
reaction is done by: (UP 2006) Monocytes 4%
(a) Total leukocyte count The bone marrow biopsy specimen show hyper-
(b) Leucocyte alkaline phosphatase cellularity with a marked increase in myeloid precursors
(c) Erythrocyte sedimentation rate at all stages of maturation and in band neutrophils. The
(d) Immature cells likely cause for the above mentioned findings would be
50. Neutropenia is caused by all except: (UP 2006) which of the following?
(a) Typhoid fever (a) Steroid (glucocorticoid) therapy
(b) Viral infection (b) Pulmonary abscess
(c) Brucellosis (c) Vigorous exercise
(d) Acute myelogenous leukemia
(d) Glucocorticoids
58. A 42 year woman Sunaya presents with complaints
51. Basophilic leucocytosis occurs in (UP 2007)
of bleeding gums for the past 20 days. The oral
(a) AML
examination shows thickened and friable gums. Also,
(b) ALL
she has hepatosplenomegaly with generalized non
(c) CML
tender lymphadenopathy. The blood count reveals:
(d) CLL
Hemoglobin 11.4g/dl
52. All are causes of splenomegaly except (RJ 2001) Platelet count 90,000/mm3
(a) Malaria WBC count 4600/mm3
(b) Kala azar The bone marrow biopsy shows 100% cellularity, with
(c) Hemolytic anemia many large blasts that are peroxidase negative and
(d) Aplastic anemia nonspecific esterase positive. What of the following is
53. In myelodysplastic syndrome, the following statement the most likely diagnosis for this patient?
is incorrect (AP 2000) (a) Acute lymphoblastic leukemia
(a) Platelet counts are normal or elevated (b) Acute megakaryocytic leukemia
(b) Leucocyte counts are normal or elevated (c) Acute promyelocytic leukemia
(d) Acute monocytic leukemia
(c) Hypocellular bone marrow
(d) Refractory anemia 59. Akshay, an 8 years old boy presents with severe
headache for 10 days. His examination revealed petechial
54. Leukoerythroblastic picture is seen in all except
hemorrhages, bone tenderness, hepatosplenomegaly
(a) Myelofibrosis (AP 2005) and generalized lymphadenopathy. His CBC shows:
(b) Secondary malignancy of bone marrow Hemoglobin 8.6 g/dl
(c) Thalassemia Platelet count 38,000/mm3
(d) Gaucher disease WBC count 15,200/mm3.
55. A round cell having, fine nuclear chromatin, prominent A bone marrow biopsy shows 100 % cellularity, with
nucleoli and fine azurophillic granule, cell is: predominance of large cells having scant cytoplasm,
(a) Myeloblast (Bihar 2006) lacking granules, delicate nuclear chromatin, and
(b) Lymphoblast rare nucleoli. The physician feels that the child can
(c) Monoblast have a complete remission following appropriate
(d) None chemotherapy. Which of the following markers is most
56. Autoimmune hemolytic anemia is seen in: likely to be seen in this patient?
(a) ALL (Jharkhand 2004) (a) Early pre-B (CD19+, TdT +) ; Hyperdiploidy
(b) AML (b) Early pre B (CD 19+, TdT+) ; t(9;22)
(c) CLL (c) Early pre B (CD 5+, TdT+) ; Normal karyotype
(d) CML (d) Early pre B (CD 5+, TdT+) ; t(9;22)
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60. An experimental study performed by Ayush Medical 62.8. CD-10 is seen in:
International reveals that children with an unknown (a) ALL (b) CLL
disease have blood cells with absence of surface (c) GCL (d) CML
molecules like CD1a, CD2, CD3, CD4, CD5 and CD8.
62.9. Auer rods are seen in
Which of the following may be the karyotype anomaly
(a) Lymphoblast (b) Myeloblast
seen in these children?
(c) Erythroblast (d) Megakaryoblast
(a) +21 (b) XXY
(c) 22q11.2 (d) t (15:17) 62.10. The peripheral blood eosinophil count in Eosinophilia
myalgia syndrome is usually
61. The presence of the Philadelphia chromosome is
(a) Between 500 to 2000 cells microilter
associated with a worse prognosis in patients with
(b) 2000 to 5000 cells/microliter
which of the following diseases?
(c) Less than 500 cells/microliter
(a) Acute lymphoblastic leukemia
(d) More than 5000 cells/microliter
(b) Acute myelogenous leukemia
(c) Chronic lymphocytic leukemia 62.11. Most common ALL subtype?
(d) Chronic myelogenous leukemia (a) Pre B cell (b) Pre T cell
(c) T cell (d) B cell
62. Examination of a peripheral blood smear demonstrates
leukemia composed of small mature lymphocytes
without blast forms. Which of the following is the most NON HOdGkiN LyMPHOMA
likely age of this patient?
(a) 1 year (b) 20 years 63. Progressive transformation of germinal centres (PTGC)
(c) 45 years (d) 65 years is a precursor lesion of: (DPG 2011)
(a) Hodgkins Lymphoma, nodular sclerosis
Most recent Questions (b) Hodgkins Lymphoma, mixed cellularity

(c) Anaplastic large cell Lymphoma
62.1. Reed Sternberg cells are found in: (d) Peripheral T cell Lymphoma
(a) Hodkins disease (b) Sickle cell anaemia
(c) Thalassemia (d) CML 64. Eosinophilic Abscess in lymph node is characteristically
seen in: (DPG 2011)
62.2. Specific stain for myeloblasts is:
(a) Kimuras disease
(a) Sudan black
(b) Hodgkins Lymphoma
(b) PAS
(c) Tuberculosis
(c) Myeloperoxidase (MPO)
(d) Sarcoidosis
(d) LAP
62.3. Dohle bodies are seen in which of the following? 65. A 50 years old male presents with massive splenomegaly.
(a) Multiple myeloma His differential diagnosis will include all, except:
(b) May-Heggline anomaly (a) Chronic myeloid leukemia (DPG 2011)
(c) Waldenstorm Macroglobulinemia (b) Polycythemia rubra vera
(d) Lymphoma (c) Hairy cell leukemia
(d) Aplastic anemia
62.4. Dohle bodies in neutrophils are comprising of:
(a) Mitochondria 66. Burkitts lymphoma is associated with: (AI 2010)
(b) Golgi apparatus (a) t (8:14)
(c) Lysosomes (b) t (9:22)
(d) Dilated endoplasmic reticulum (c) t (11; 14)
(d) t (8:21)
62.5. What is the chromosomal translocation in AML M3:
(a) t (18, 21) (b) t (15, 17) 67. All of the following immunohistochemical markers are
(c) t (8, 21) (d) t (9, 11) positive in the neoplastic cells of granulocytic sarcoma,
62.6. Which of the following is associated with good except: (AI 2006)
prognosis in ALL? (a) CD 45 RO
(a) T cell line (b) CD 43
(b) Philadelphia chromosome (c) Myeloperoxidase
(c) Hyperdiploidy (d) Lysozyme
(d) Hypodiploidy 68. Mantle cell lymphomas are positive for all of the
62.7. B cell ALL is due to which of the following? following, except: (AI 2006)
(a) T cells (b) Immature B cells (a) CD 23 (b) CD 20
(c) Immature T cells (d) Both T and B cells (c) CD 5 (d) CD 43
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69. The classification proposed by the International (b) CD 34 negative but surface Ig+
Lymphoma Study Group for non-Hodgkin lymphoma (c) CD 34 positive but surface Ig -
is (AI 2005) (d) CD 34 and surface Ig both () ve
(a) Kiel classification
74. Which of the following is false? (AIIMS Nov 09)
(b) REAL classification
(a) Bcl-6 is associated with Burkitts lymphoma
(c) WHO classification
(b) Bcl-2 is associated with follicular lymphoma
(d) Rappaport classification
(c) CD-10 is associated with mantle cell lymphoma
70. A 48 year old woman was admitted with a history of (d) CD 34 is associated with Diffuse large B Cell
weakness for two months. On examination, cervical Lymphoma
lymph nodes were found enlarged and spleen was
75. Post transplant lymphoma occurs due to proliferation
palpable 2 cm below the costal margin. Her hemoglobin
of which of the following cells
was 10.5 g/dl, platelet count 2.7109/L and total leukocyte
count 40109/L, which included 80% mature lymphoid (a) T-cell (AIIMS Nov 2006)
cells with coarse clumped chromatin. Bone marrow (b) B-cell
revealed a nodular lymphoid infiltrate. The peripheral (c) NK cell
blood lymphoid cells were positive for CD 19, CD 20 (d) Monocyte
and CD 23 and were negative for CD 79B and FMC-7. 76. Which of the following statements on lymphoma is not
The histopathological examination of the lymph node true? (AIIMS May 2006)
in this patient will most likely exhibit effacement of (a) A single classification system for Hodgkins disease
lymph node architecture by: (AI 2005) (HD) is almost universally accepted
(a) A pseudofollicular pattern with proliferation centers (b) HD more often tends to remain localized to a single
(b) A monomorphic lymphoid proliferation with a group of lymph nodes and spreads by contiguity
nodular pattern (c) Several types of non Hodgkins lymphoma (NHL)
(c) A predominantly follicular pattern may have a leukemic phase
(d) A diffuse proliferation of medium to large lymphoid (d) In general follicular (nodular) NHL has worse
cells with high mitotic rate prognosis compared to diffuse NHL
71. A four year old boy was admitted with a history of 77. Mantle cell lymphomas are positive for all of the
abdominal pain and fever for two months, maculopapular following except: (Delhi 2010)
rash for ten days, and dry cough, dyspnea and wheezing (a) CD23
for three days. On examination, liver and spleen were (b) CD20
enlarged 4 cm and 3 cm respectively below the costal (c) CD5
margins. His hemoglobin was 10.0 g/dl, platelet count (d) Cyclin D1
37109/L and total leukocyte count 70109/L, which
included 80% eosinophils. Bone marrow examination 78. Over-expression of BCL-2 proteins occurs in
revealed a cellular marrow comprising 45% blasts and (a) Burkitts lymphoma (UP 2005)
34% eosinophils and eosinophilic precursors. The blasts (b) Follicular lymphoma
stained negative for myeloperoxidase and nonspecific (c) Diffuse large B-cell lymphoma
esterase and were positive for CD 19, CD 10, CD 22 and (d) Small lymphocytic lymphoma
CD 20. Which one of the following statements is not 79. Starry sky appearance is seen in (UP 2007)
true about this disease? (AI 2005) (a) Burkitts lymphoma
(a) Eosinophils are not part of the neoplastic clone (b) Mantle cell lymphoma
(b) t (5:14) rearrangement may be detected in blasts (c) Extra nodal marginal zone B-cell lymphoma of
(c) Peripheral blood eosinophilia may normalize with MALT type
chemotherapy (d) Chronic myeloid leukemia
(d) Inv (16) is often detected in the blasts and the eosino-
phil 80. All are B cell lymphomas except (AP 2005)
(a) Burkitts lymphoma
72. All of the following statements about hairy cell
(b) Mycosis fungoides
leukemia are true except: (AI 2004) (c) Mantle cell lymphoma
(a) Splenomegaly is conspicuous (d) Follicular cell lymphoma
(b) Results from an expansion of neoplastic T lympho-
cytes 81. True statement regarding non Hodgkins lymphoma of
(c) Cells are positive for Tartarate Resistant Acid phos- follicular type is: (Kolkata 2002)
phatase (a) Increased incidence in adolescents
(d) The cells express CD25 consistently (b) Predominantly in males
(c) Prognosis is better than in diffuse type
73. True about Burkitts lymphoma: (AIIMS Nov 09) (d) Affects T cells only
(a) CD 34 and surface Ig both +ve
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82. MALToma is: (Jharkhand 2006) 85.4. The low grade non- Hodgkins lymphoma is:
(a) B-cell lymphoma (a) Follicular small cleaved lymphoma
(b) APUDoma (b) Follicular large cell lymphoma
(c) NK cell tumor (c) Diffuse large cell lymphoma
(d) T cell lymphoma (d) Lymphoblastic lymphoma
83. An old man, Amarnath presents with increasing 85.5. Which of the following is the most common non
abdominal discomfort, fatigue and easy bruising of Hodgkin lymphoma? (AIIMS Nov 2013)
his skin. He also has tender splenomegaly. Laboratory (a) Follicular lymphoma
investigations show: (b) Anaplastic large cell lymphoma
Hemoglobin 7.9 g/dl (c) Diffuse large B cell lymphoma
Platelet count 35,000/mm3 (d) Marginal zone lymphoma
WBC count 2500/mm3
Serum AST 77 U/L 85.6. Most common Non-Hodgkins lymphoma of orbit:
Serum ALT 86 U/L. (a) B cell (AIIMS May 2013)
(b) T cell
Which of the following is the most likely diagnosis? (c) NK cell
(a) Acute myelogenous leukemia (d) Plasma cell
(b) Cirrhosis
(c) Systemic lupus erythematosus 85.7. Which of the following is the most common site for
(d) Infectious mononucleosis extranodal lymphoma?
(a) Esophagus (b) Stomach
84. Molecular studies on an abdominal lymph node (c) Intestine (d) Skin
containing lymphoma demonstrate (2;8)(p12;q24)
translocation. This is most compatible with which of 85.8 Cell of origin of hairy cell leukemia is
the following diseases? (a) T cell (b) B cell

(a) Burkitts lymphoma (c) NK cell (d) Dendritic cell
(b) Mantle cell lymphoma
85.9. Which one of the following Non-Hodgkin Lymphomas
(c) Multiple myeloma
is aggressive?
(d) Small cell lymphoma
(a) Follicular Lymphoma
85. A 21-year-old male Imraan Hashmi with fatigue, (b) Burkitt Lymphoma
recurrent fever, and enlarged cervical lymph nodes (c) Small lymphocytic lymphoma
has numerous atypical lymphocytes in his peripheral (d) Lymphoplasmacytic lymphoma
blood smear. Lymph node biopsy shows expansion of
lymphoid follicles with preservation of the underlying 85.10. Histological presence of Hallmark Cells with horse
architecture. Numerous atypical lymphocytes are present shoe-like or embryoid like nuclei and voluminous
in the paracortical areas. This patient most likely has cytoplasm are seen in
(a) AIDS (a) Anaplastic large cell lymphoma (ALK positive)
(b) Burkitts lymphoma (b) Familial Medullary Carcinoma
(c) Hodgkins Disease (c) Familial Neuroblastoma
(d) Infectious mononucleosis (d) Lymphocyte predominance type Hodgkins
lymphoma
Most recent Questions 85.11. Prevalence of burkitt lymphoma is highest in?
(a) Australia (b) Africa
85.1. Marginal lymphoma is type of:
(c) Asia (d) America
(a) B cell lymphoma
(b) T cell lymphoma
(c) NK cell lymphoma HOdGkiN LyMPHOMA
(d) Hodgkin lymphoma
86. A 35-year-old man is diagnosed with non-Hodgkin
85.2. Which of the following is the marker of mantle cell
lymphoma. Even without knowing the specific
cancer?
diagnosis, it can safely be said that this patients
(a) CD5 +, CD25 (b) CD 5 +, CD 10 +
lymphoma is characterized by
(c) CD 5 +, CD 23 + (d) CD 5 +, CD 23
(a) B-lymphocytic origin
85.3. Mycosis fungoides is: (b) Histiocytic origin
(a) Fungal infections of skin (c) Lymph node localization
(b) Leukemia (d) Monoclonal origin
(c) Exfoliative erythroderma 87. A 26-year-old man Ronit has progressive, painless
(d) Cutaneous lymphoma enlargement of neck lymph nodes. Routine chest film
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and CT scan show marked enlargement of mediastinal 96. Lacunar cells are present in which Hodgkins
nodes. No nodules are seen in the liver or lungs. When lymphoma? (RJ 2000)
evaluating the biopsy of one of the involved nodes, Dr (a) Nodular sclerosis
Mohit, a pathologist would find which of the following? (b) Lymphocyte predominant
(a) Abnormal plasma cells
(c) Mixed cellularity
(b) Giant platelets
(c) Immature neutrophil precursors (d) All
(d) Reed-Sternberg cells 97. Popcorn cells are seen in which type of Hodgkins
88. Classical markers for Hodgkins disease are: disease? (AP2003)
(a) CD 15 and CD 30 (AI 2008) (a) Lymphocyte dominant
(b) CD 15 and CD 22 (b) Lymphocyte depleted
(c) CD 15 and CD 20 (c) Nodular sclerosis
(d) CD 20 and CD 30 (d) Mixed type
89. The subtype of Hodgkins disease, which is
98. An elderly patient presented with hypercellular bone
histogenetically distinct from all the other subtypes, is:
(a) Lymphocyte predominant (AI 2005) marrow, peripheral blood smear shows pancytopenia,
(b) Nodular sclerosis and 15% myeloblast cells. Most likely diagnosis is
(c) Mixed cellularity (a) Myelodysplastic syndrome (UP 2003)
(d) Lymphocyte depleted (b) Blast crisis in CML
(c) AML
90. All of the following are the good prognostic features for
Hodgkins disease except: (d) Polycythemia vera
(a) Hemoglobin > 10 gm/dl (AI 2004)
(b) WBC count < 15000/mm3 Most recent Questions
(c) Absolute lymphocyte count < 600/l

98.1. Which Hodgkins disease is associated with best
(d) Age < 45 years
prognosis:
91. The lymphocytic and histiocytic variant of Reed- (a) Lymphocyte depletion
Sternberg cell is seen in (AIIMS Nov 2005) (b) Mixed cellularity
(a) Follicular center lymphoma (c) Lymphocytic predominance
(b) Lymphocyte depleted Hodgkins disease (d) Nodular sclerosis
(c) Nodular sclerosis Hodgkins disease
(d) Lymphocyte predominant Hodgkins disease 98.2. Lacunar cells are seen in which type of Hodgkins
lymphoma:
92. Which cell is not seen in Hodgkins lymphoma (a) Lymphocyte predominance
(a) Reed Sternberg cell (PGI Dec 2000) (b) Lyphocyte depletion
(b) Lacunar cell (c) L and H cell (c) Nodular sclerosis
(d) Langerhans cell (e) Hodgkin cell (d) Mixed cellularity
93. Lacunar type of Reed Sternberg cells are seen in: 98.3. In a 45 year old female presenting with painless
(Delhi 2009 RP) supraclavicular lymphadenopathy, biopsy was taken.
(a) Mixed cellularity Hodgkins lymphoma It revealed the presence of binucleated acidophlic owl
(b) Nodular sclerosis Hodgkins lymphoma eye appearance with clear vacuolated space. The cell
(c) Lymphocyte depleted Hodgkins lymphoma was CD15 and CD30 positive. Which is the most likely
(d) Lymphocyte predominant Hodgkins lymphoma diagnosis?
94. The sub-type of Hodgkins lymphoma characteri zed by (a) Lymphocyte predominant Hodgkin lymphoma
L and H cells is: (Karnataka 09) (b) Nodular sclerosis Hodgkin lymphoma
(a) Nodular sclerosis (c) Mixed cellularity Hodgkin lymphoma
(b) Mixed cellularity (d) Lymphocyte depleted Hodgkin lymphoma
(c) Lymphocyte depletion
(d) Lymphocyte predominant MyELOPrOLifErATiVE diSOrdErS
95. Lacunar cells are seen in which type of Hodgkins
lymphoma (PGI-99) (UP 2004) (Kolkatta & Bihar 03) 99. Splenomegaly is associated with all except: (AI 2012)
(a) Nodular sclerosis (a) CML
(b) Mixed cellularity (b) Polycythemia vera
(c) Lymphocyte depletion (c) Essential thrombocythemia
(d) Lymphocyte predominant (d) Primary myelofibrosis
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100. Essential criteria for polycythemia vera according to (c) Chronic myeloid leukemia
WHO is: (AI 2010) (d) Polycythemia
(a) Low EPO
(b) JAK 2 mutation 103.5. Leukoerythroblastic reaction is seen in the following
(c) Bone marrow showing panmyelosis except:
(d) MPL point mutation (a) Secondaries in bone
101. Which of the following is not a chronic (b) Multiple myeloma
myeloproliferative disorder? (Delhi PG 2006) (c) Hemolytic anemia
(a) Polycythemia vera (d) Lymphoma
(b) Myeloid metaplasia
(c) CML 103.6. Increase in alkaline phosphatase is seen in:
(d) Essential thrombocytopenia (a) Chronic myeloid leukemia; CML
102. An old man Durga Prasad presents to you with (b) Leukemoid reaction
complaints of fatigue, weight loss, night sweats, and (c) Eosinophilia
abdominal heaviness for the past 10 months. Physical (d) Malaria
examination reveals marked splenomegaly but no
lymphadenopathy. His investigations are given below: 103.7. One of the following is not a myelo-proliferative
Hemoglobin 10g/dl disorder?
Platelet count 90,000/mm3 (a) Essential thrombocytosis
WBC count 15,250/mm3 (b) Myelofibrosis with myeloid metaplasia
Peripheral blood smear teardrop cells (c) Acute myeloblastic leukemia
Serum uric acid level 9 g/dl
(d) Chronic myeloid leukemia
Bone marrow biopsy Extensive marrow fibrosis and
groups of atypical megakaryo- 103.8 Isolated deletion of which chromosome is associated

cytes with myelodysplastic syndrome?
Which of the following is the likely cause for the old (a) 2q (b) 5q
mans splenomegaly? (c) 8q (d) 11q
(a) Hodgkin lymphoma
(b) Extramedullary hematopoiesis
(c) Portal hypertension PLASMA cELL dyScrASiAS
(d) Metastatic adenocarcinoma
104. Which of the following is the least common presentation
103. A child presents with seborrheic dermatitis, sinusitis
of multiple myeloma? (AI 2012)
and chronically draining ears. On examination child
(a) Anemia (b) Hyperviscosity
has failure to thrive with hepato-splenomegaly and
exophthalmos. Probable diagnosis is (c) Bone pains (d) Infection
(a) Histiocytosis-X 105. Which of the following metabolic abnormality is seen
(b) Wegeners granulomatosis in multiple myeloma? (DPG 2011)
(c) Chronic grnaulomatous disease (a) Hypernatremia (b) Hypokalemia
(d) Chediak higashi syndrome (c) Hypercalcemia (d) Hyperphosphatemia
Most recent Questions 106. Lymphoplasmacytoid lymphoma is associated with:

(a) IgG (AI 2010)
103.1. Polycythemia is absolute venous haematocrit of more (b) IgA
than: (c) IgD (d) IgM
(a) 45% (b) 55%
107. Which of the following statement is not true? (AI 2005)
(c) 65% (d) 70%
(a) Patients with IgD myeloma may present with no
103.2. CD marker of histiocytosis is: evident M-spike on serum electrophoresis.
(a) CD 1a (b) CD 1b (b) A diagnosis of plasma cell leukemia can be made if
(c) CD 1c (d) CD 1d circulating peripheral blood plasma blasts comprise
103.3. Shape of Birbeck granules is which of the following? 14% of peripheral blood white cells in a patient with
9
(a) Hockey stick (b) Bat white blood cell count of 1 10 /L and platelet count
9
(c) Ball (d) Tennis racket of 88 10 /L
(c) In smoldering myeloma plasma cells constitute 10-
103.4. Leucocyte alkaline phosphatase (LAP) is raised in all 30% of total bone marrow cellularity
conditions except: (d) In a patient with multiple myeloma, a monoclonal
(a) Myelofibrosis light chain may be detected in both serum and urine
(b) Essential thrombocythemia
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108. Which of the following is not a minor diagnostic (c) Monoclonal gammopathy of uncertain significance
criterion for multiple myeloma? (AIIMS Nov 08, 10) (d) Systemic lupus erythematosus
(a) Lytic bone lesions
117. Histiocytosis is NOT associated with (AP 2003)
(b) Plasmacytosis greater than 20%
(c) Plasmacytoma on biopsy (a) Spontaneous fractures
(d) Monoclonal globulin spike on serum electrophoresis (b) Cutaneous eruptions
of < 2.5 g/dl for IgG, < 1.5 g/dl for IgA) (c) Bone marrow suppression
(d) No lymphadenopathy
109. A 3 year old female child presented with skin papules.
Which of the following is a marker of Langerhans cell 118. M-spike in multiple myeloma is due to? (Bihar 2003)
histiocytosis? (AIIMS Nov 2007) (a) IgM (b) IgA
(a) CD 1a (b) CD 3 (c) IgG (d) None of these
(c) CD 68 (d) CD 57 119. Birbecks granule is found in: (Bihar 2006)
110. A 70-year-old male has a pathologic fracture of femur. (a) Langerhans cell (b) Langhans giant cell
The lesion appears a lytic on X-rays film with a (c) Lepra cell (d) Clue cell
circumscribed punched out appearance. The curetting
120. A 62 year old man Kuljeet developed weakness,
from fracture site is most likely to show which of the
following? (AIIMS May 2006) fatigue and weight loss over the past 4 months. He
(a) Diminished and thinned trabecular bone also complains of decreasing vision, headache and
(b) Sheets of atypical plasma cells dizziness. His hands have become sensitive to cold. On
(c) Metastatic prostatic adenocarcinoma the general physical examination of this individual,
(d) Malignant cells forming osteoid bone the physician observes generalized lymphadenopathy
and hepatosplenomegaly. The laboratory reports show
111. Hyperviscosity is seen in (PGI Dec 2003) hyperproteinemia with a serum protein level of 16g/dl
(a) Cryoglobulinemia
and the serum albumin concentration of 3.4 g/dl. The

treating physician performs a bone marrow biopsy
(c) MGUS
that demonstrated infiltration of small plasmacytoid
(d) Lymphoma
(e) Macroglobulinemia lymphoid cells with Russell bodies in the cytoplasm on
microscopic examination. Which of the following is the
112. Hyperviscosity syndrome is seen in: most likely finding in this patient?
(a) NHL (PGI Dec 2004) (a) Monoclonal IgM spike in serum
(b) Waldenstroms macroglobulinemia (b) WBC count of 2,40,000/mm3
(c) Multiple myeloma (c) Hypercalcemia
(d) Hodgkins lymphoma (d) Bence Jones proteinuria
(e) Acute promyelocytic leukemia
121. An old woman is seen in the emergency after fracturing
113. True about Langerhans cell histiocytosis is:
her hip. She is found to have a malignant tumor. She
(a) CD 68+ (PGI Dec 2005)
also has a history of recurrent pneumonia over the last 6
(b) CD 1+
(c) Birbecks granules are pathognomic months. Lab investigations reveal a normal white blood
(d) Proliferation of antigen presenting cells cell count, but decreased platelets and serum albumin
(e) Resembles dendritic cells with an elevated erythrocyte sedimentation rate (ESR).
Serum electrophoresis indicates an M-protein spike
114. Finding of multiple myeloma in kidney are all except: band of IgG kappa. The urine will most likely show the
(a) Tubular casts (Delhi 2010) presence of Bence-Jones proteins composed of
(b) Amyloidosis (a) IgG heavy chains
(c) Wire loop lesions
(b) kappa and lambda light chains of a 60:40 ratio
(d) Renal tubular necrosis
(c) kappa light chains
115. Proliferation and survival of myeloma cells are (d) lambda light chains
dependent on which of the following cytokines?
(a) IL-1 (Karnataka 2005) Most recent Questions
(b) IL-6
(c) IL-2 121.1. Russell bodies are found in which of the following
(d) IL-5 conditions?
(a) Multiple Myeloma
116. Plasma cell dyscrasias include all of the following (b) Gonadal tumor
except (Karnataka 2005) (c) Parkinsonism
(a) Waldenstorms macroglobulinemia (d) Intracranial neoplasms
(b) Heavy chain disease
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121.2. Which histiocytosis involves the bones: (b) Defect in intrinsic pathway
(a) Malignant (c) Platelet function defect
(b) Langherhans (d) Defect in common pathway
(c) Sinus histiocytosis
128. All are true about thrombotic thrombocytopenic
(d) Option not recalled
purpura except? (AIIMS Nov 2008)
121.3. Beta-2 microglobulin is a tumor marker for (a) Microangiopathic hemolytic anemia
(a) Multiple myeloma (b) Thrombocytopenia
(b) Lung cancer (c) Normal complement level
(c) Colonic neoplasm (d) Grossly abnormal coagulation tests
(d) Choriocarcinoma
129. D.I.C. is seen in: (AIIMS May 2007)
(a) Acute promyelocytic leukemia
PLATLETS ANd BLEEdiNG diSOrdErS (b) Acute myelomonocytic leukemia
(c) CMC
122. A newborn baby presented with profuse bleeding from (d) Autoimmune hemolytic anemia
the umbilical stump after birth. Rest of the examination
and PT, APTT are within normal limits. Most likely 130. All of the following can cause megakaryocytic
diagnosis is which of the following? thrombocytopenia, except (AIIMS Nov 2004)
(a) Factor X deficiency (a) Idiopathic thrombocytopenia purpura
(b) Glanzmanns thrombasthenia (b) Systemic lupus erythematosus
(c) von Willebrand disease (c) Aplastic anemia
(d) Bernard Soulier disease (d) Disseminated intravascular coagulation (DIC)
123. A 25 years old asymptomatic female underwent a pre- 131. A patient with cirrhosis of liver has the following
op coagulation test. Her bleeding time is 3minutes, PT coagulation parameters, Platelet count 2,00,000,

is 15/14sec, a PTT is 45/35 sec, platelet count is 2.5 lac/ Prothrombin time 25s/12s, Activated partial throm-
mm and factor VIII levels were 60IU/dL. What is her
3 boplastin time 60s/35s, thrombin time 15s/15s. In this
most likely diagnosis? (AIIMS Nov 2011) patient (AIIMS May 2004)
(a) Factor IX deficiency (a) D-dimer will be normal
(b) Lupus anticoagulant (b) Fibrinogen will be < 100 mg
(c) Factor VIII inhibitors (c) ATIII will be high
(d) VWD Type III (d) Protein C will be elevated
124. True about prothrombin time to (AIIMS Nov 2011) 132. The presence of small sized platelets on the peripheral
(a) Immediate refrigeration to preserve factor viability smear is characteristic of: (AIIMS Nov 2003)
(b) Platelet-rich plasma is essential (a) Idiopathic thrombocytopenia purpura (ITP)
(c) Done within 2 hours (b) Bernard Soulier syndrome
(d) Activated with kaolin (c) Disseminated intravascular coagulation
(d) Wiskott Aldrich syndrome
125. A 22 year old female having a family history of
autoimmune disease presents with the complaints of 133. Platelet aggregation in vivo is mediated by
recurrent joint pains. She has now developed petechial (a) Serotonin (PGI Dec 2003)
hemorrhages. She is most likely to have which of the (b) Ig mediators.
following disorders? (AIIMS Nov 2011) (c) Interaction among the leukocytes
(a) Megakaryocytic thrombocytopenia (d) Interaction among the platelets
(b) Amegakaryocytic thrombocytopenia (e) Macromolecules.
(c) Platelet function defects/Functional platelet defect 134. Conditions associated with incoagulable state:
(d) Acquired Factor VIII inhibitors (a) Abruption placentae (PGI Dec 2004)
126. Patient with bleeding due to platelet function defects (b) Acute promyelocytic leukemia
has which of the following features? (AI 2011) (c) Severe falciparum malaria
(a) Normal platelet count and normal bleeding time (d) Snake envenomation
(b) Normal platelet count and increased bleeding time (e) Heparin overdose
(c) Decreased platelet count and increased bleeding
time 135. In DIC, which is/are seen: (PGI June 2005)
(d) Normal platelet count and decreased bleeding time (a) Normal aPTT
(b) Increased PT
127. A 9-year-old boy presents with elevation in both PT and (c) Increased factor VIII
aPTT. What is the diagnosis? (AIIMS Nov. 2010) (d) Decreased fibrinogen
(a) Defect in extrinsic pathway (e) Decreased platelets
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136. Causes for DIC are: (PGI Dec 2005) 146. The chromosomal translocation involving bcl-2 in
(a) Anaerobic sepsis (b) Malignancy B-cell lymphoma is (UP 2008)
(c) Lymphoma (d) Leukemia (a) t (8: 14) (b) t (8: 12)
(e) Massive blood transfusion (c) t (14: 18) (d) t (14: 22)
137. Platelet function defect is seen in: (PGI June 03) 147. Agranulocytosis means: (Kolkata 2000)
(a) Glanzmann syndrome. (a) Decrease in neutrophil count
(b) Bernard Soulier syndrome (b) Decrease in platelet count
(c) Wiskott Aldrich syndrome
(c) Increase in RBC count
(d) Von-Willebrand disease
(d) Decrease in RBC count
(e) Weber Christian disease
138. VWF factor deficiency causes: (Delhi PG 2008) 148. Thrombocytopenia syndrome is caused by decrease in
(a) Platelet aggregation platelet counts below: (Bihar 2004)
(b) Factor VIII in plasma (a) 50,000/cmm (b) 1,00,000/cmm
(c) Defective platelet adhesion (c) 1.2 lac/cmm (d) 20, 000/cmm
(d) All of the above 149. A 28-year-old woman Salma presents complaining of
139. Thrombospondin is (Delhi PG 2008) nosebleeds. She also has easy bruising and excessively
(a) Coagulation protein heavy bleeding during her periods. There is no history
(b) Coagulation promoting protein of drug intake. Physical examination shows scattered
(c) Contractile protein petechiae with normal sized spleen. Laboratory
(d) Angiogenesis inhibitory protein examination shows platelet count of 37000/microliter
140. Which is must for prothrombins time (PT)? and a bleeding time of 16 minutes. The bone marrow
(a) Thromboplastin (Delhi PG 2007) shows an increased number of megakaryocytes.
(b) Prothrombin Antinuclear antibody is negative. Autoantibodies

(c) Fibrin directed against which of the following antigens would
(d) Fibrinogen likely be found in this patients serum?
(a) Acetylcholine receptor
141. Thrombocytosis is seen in: (Delhi PG 2005)
(b) Erythrocyte membrane protein
(a) Myelofibrosis
(b) SLE (c) Glycoprotein IIb/IIIa
(c) Azidothymidine therapy (d) Intrinsic factor
(d) Myelodysplastic syndrome 150. A young female Vibhuti presents with a several month
142. All of the following are true about Willebrand factor history of easy bruising and increased menstrual flow
except: (Delhi PG-2005) is evaluated for a bleeding disorder. She has idiopathic
(a) Synthesized by hepatocytes thrombocytopenic purpura (ITP). In this disorder, the
(b) Its deficiency can cause factor 8 defect also low platelet count is due to which of the following?
(c) Its deficiency may cause problem with platelet (a) Antiplatelet antibodies
adhesion (b) Defective platelet aggregation
(d) It serves as carrier for the factor eight (c) Hypersplenism
143. All of the following clotting factors are completely (d) Ineffective megakaryopoiesis
synthesized from liver except (UP 2002)
(a) II (b) V Most recent Questions
(c) VII (d) VIII
150.1. Glanzmann disease is characterised by which of the
144. Cryoprecipitate contain all except (UP 2002) following?
(a) Fibrinogen (a) Congenital defect of RBCs
(b) Factor VIII (b) Defect of neutrophils
(c) von Willebrand factor (c) Congenital defect of platelets
(d) Antithrombin
(d) Clotting factor deficiency
145. Bleeding time is abnormal in: (UP 2006)
150.2. All of the following are true about DIC except:
(a) Hemophilia
(a) Platelet aggregation
(b) Christmas disease
(c) von Willebrand disease (b) Fibrin deposition in microcirculation
(d) Vitamin K-deficiency (c) Decreased fibrin degradation products
(d) Release of tissue factor
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150.3. All are true regarding thrombotic thrombocytopenic (b) Relapse is rare
purpura except: (c) Splenectomy is the treatment of choice for relapse
(a) Normal complement levels (d) Minority have refractory forms of ITP and difficult to
(b) Microangiopathic hemolytic anemia treat
(c) Thrombocytopenia
150.6 Splenectomy is useful in which of the following?
(d) Thrombosis
(a) Chronic ITP
150.4. Glycoprotein IIb-IIa complex is deficient in (b) Sickle cell anemia
(a) Bernard Soulier syndrome (c) Tuberculosis
(b) Glanzmann disease (d) Good pasture syndrome
(c) Von willebrand disease
150.7. Pancreatic insufficiency and cyclic neutropenia is a part
(d) Gray platelet syndrome
of which syndrome
150.5. All the following statements are correct about treatment (a) Young syndrome
in chronic immune thrombocytopenic purpura except (b) Colts syndrome
(a) Most of the patients respond to immunosuppressive (c) Shwachman syndrome
doses of glucocorticoids (d) Roots syndrome
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explanations
1. Ans. (d) Lymphocytosis (Ref: Robbins 8th/324)
Flow cytometry can rapidly and quantitatively measure several
individual cell characteristics, such as membrane antigens and
the DNA content of tumor cells.
Flow cytometry has also proved useful in the identification and
classification of tumors arising from T and B lymphocytes and
from mononuclear-phagocytic cells.
2. Ans. (c) Acute megakaryocytic leukemia. (Ref: Robbins 8th/622, 9/e p612, Wintrobes 12th/1857-8)
Direct quote from Robbins In some AMLs, blasts show megakaryocytic differentiation, which is often accompanied by
marrow fibrosis caused by the release of fibrogenic cytokines
Acute megakaryocytic leukemia is the most common variant of AML associated with Down syndrome. The release of
PDGF (platelet derived growth factor) is responsible for marrow fibrosis.
3. Ans. (C) Common leukocyte antigen (Ref: Robbins 8th/600, 9/e p590)
CD45 is present on all the leukocytes; it is also known as leukocyte common antigen (LCA).
4. Ans. (b) Immunophenotyping (Ref: Robbins 8th /604, 9/e p593)
Adult patient presenting with generalized lymphadenopathy and blood film shows 70% immature looking lymphocytes
is highly suggestive of chronic lymphocytic leukemia.
Immnophenotyping can be one of the best ways to differentiate between CLL and other B cell neoplasms.
Important points about CLL
Most of the patients are often asymptomatic at diagnosis. When symptoms appear, they are nonspecific and include
easy fatigability, weight loss, and anorexia. Hepatosplenomegaly and generalized lymphadenopathy are present in
50% to 60% of symptomatic patients.
The immunophenotype of CLL is distinct. The tumor cells express the pan-B cell markers CD19 and CD20, as well as
CD23 and CD5, the latter a marker that is found on a small subset of normal B cells. Low-level expression of surface
Ig (usually IgM or IgM and IgD) is also typical.
5. Ans. (c) Acute lymphoid leukemic in less than 1 year has a poor prognosis (Ref: Robbins 8th/603, 9/e p592, Wintrobe 12th)
Prognostic factors in ALL have been discuss in text
Explaining other options,
Chronic myeloid leukemia occurs beyond 50 years of ageRobbins 8th/
Hairy cell leukemic is present in median age of 55 years and has M:F ratio of 5:1. HCL tends to follow an indolent
course. For unclear reasons, the tumor cells are exceptionally sensitive to particular chemotherapeutic regimens,
332
which produce long-lasting remissions. The overall prognosis is excellent. So, the condition is not having additional
increase in improvement with age less than 50 years.
The median age of diagnosis of Chronic lymphocytic leukemia is 60 years and there is a 2:1 male predominance.
Robbins 8th/603
6. Ans. (c) RBC (Ref: Robbins 8th/592-593, 9/e p580)
The following flowchart is self explanatory for this question:
B: Basophil, E: Eosinophil, N: Neutrophil

So, on the injection of a myeloid stem cell, it can give rise to a cell of its lineage which can be either of the RBCs, monocytes,
neutrophils, eosinophils, basophils and platelets. The answer is therefore, red blood cells.
7. Ans. (d) T cell Lymphoblastic ALL (Ref: Robbins 8th/601-3, 9/e p592)
8. Ans. (c) Paroxysmal cold haemoglobinuria (Ref: Robbins 8th/625, 653,664, 9/e p544, Wintrobes 12th/965)

Analyzing all the options one by one;
Option adirect quote.. about 5% to 10% of patients eventually develop acute myeloid leukemia or a myelodysplastic
syndrome, possibly because hematopoietic stem cell have suffered some type of genetic damage. (Robbins 8th/653)
Even PNH is associated with aplastic anemia as both the disorders have an autoimmune basis.
Option bdirect quote.., aplastic anemia results from a fundamental stem cell defect supported by the presence of karyo-
typic aberrations in many cases; the occasional transformation of aplasias into myeloid neoplasms, typically myelodyspla-
sia or acute myeloid leukemia; and the association with abnormally short telomeres. (Robbins 8th/664)
Option ddirect quote.. The term myelodysplastic syndrome (MDS) refers to a group of clonal stem cell disorders
characterized by maturation defects that are associated with ineffective hematopoiesis and a high risk of transformation to
AML. (Robbins 8th/625).
So the answer of exclusion is PCH (paroxysmal cold hemoglobinuria). It is an autoimmune haemolytic anemia due to IgG autoantibod-
ies which bind to P blood group antigen and cause intravascular hemolysis and hemoglobinuria. Most cases are seen in children and
have recovery within a month.....Wintrobes.
9. Ans. (c) Mixed phenotypic leukaemia (Ref: Wintrobes 12th/1814-8, Dacie and Lewis hematology 10th/344-6)
Mixed lineage acute leukemia is alternatively also known as bilineal acute leukemia. As is suggested by the name, there
are 2 populations of cells which are morphologically and immunophenotypically distinct from each other. Analyzing the
markers on the cells,
B lymphoid markers: CD10, CD19 and CD79
T lineage markers: CD2, CD3 and CD7
Myeloid markers; CD13, CD33, CD117 and myeloperoxidase (MPO).
Non lineage specific markers which are expressed in hematopoietic progenitor cells: CD34, HLA-DR and TdT
Comparing this with the information provided in the stem of our question, it is easy to decipher that the cells mentioned
are CD10+ve, MPO +ve, CD19+ve, CD33-ve, CD117 +ve and CD3-ve which is showing both lymphoid (CD10, CD19;B
lymphoid lineage) and myeloid (CD117 and MPO+-; myeloid lineage) markers. So, the answer is Mixed phenotypic
leukemia
A word about the last option d, please note that in un-differentiated acute leukemia, blasts usually lack any evidence of
lineage differentiation. (Ref Wintrobes 12th/1814-8)
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10. Ans. (b) t(9;22) t(4;11) (Ref: Robbins 8th/603, 9/e p592-593)
GOOD PROGNOSIS BAD PROGNOSIS
Female sex Male sex
Pre B cell phenotype Pre T cell phenotype
Hyperdiploidy (>50 chromosomes) or t(12;21) Pseudodiploidy or t (9;22) or presence of Philadelphia chromosome, t (8;14),
Trisomy of chromosomes 4,7,10 t (4;11)
11. Ans. (a) Inv 16 (Ref: Wintrobe 12th/1859, Robbins 8th/624, 9/th 614, T. Singh 2nd/168)
Prognostic markers for AML
Age <40 years Age <2 years or >55 years
M2, M3, M4 forms of AML M0, M6, M7 forms of AML
Blast cell with Auer rods Complex karyotypes
TLC < 25 X 109/L TLC > 100 X109/L
t(15;17), t (8;21), inv 16 Deletions 5q, 7q
Rapid response to therapy Delayed response to therapy
Leukemia without preceding MDS AML with preceding MDS or anticancer drug exposure
12. Ans. (d) CD 117 (Ref: Wintrobes 11th/4145)

As per Wintrobes the markers for myeloid series are CD13, CD33, CD 11b, CD15, CD117 and cMPO.
c MPO is the most lineage specific marker amongst these.
Regarding other options, CD 34 - Myeloid and lymphoid blasts, stem cells, CD 45 - Leukocyte common antigen (non-
erythroid hematopoietic cells), CD 99 - Ewings sarcoma/primitive neuroectodermal cells.
13. Ans. (b) B cell ALL (Ref: Robbins 8th/608, 9/th/597, Harrison 17th/696)
t (2;8) is causing translocation between immunoglobulin chain on chromosome 2 and the myc gene present on chromo-
some 8 and is seen in Burkitts lymphoma/leukemia. The translocation results in the increased expression of c-MyC
resulting in development of neoplasia.
14. Ans. (a) Mature B-cells (Ref: Robbins 7th/677, 9th/590)
Acute Lymphoblastic Leukemias (ALL) of the L3 (FAB) subtype are tumors of Mature B-cells (e.g. Burkitts lymphoma)
15. Ans. (d) M6 (Ref: Robbins 7th/759, Hematology Basic Principles and Practice, Hoffman, Benz et al.4th/1080)
Nonspecific esterase (NSE) is characteristic of M4 (Acute myelomonocytic) and M5 (Acute monocytic) leukemia only. NSE positivity is
not a characteristic feature of other subclasses of AML.
However, NSE positivity may also be seen in 15-20% of cases of M3 and in some cases of M7.
NSE positivity is not a feature of M0, M1, M2 and M6 classes of AML.
16. Ans. (d) Tartarate resistant acid phosphatase positivity is typically seen in hairy cell leukemia (Ref: Wintrobes
11th/2468, 2470, 2471, Robbin 9/e p603-604)
Tartarate resistant acid phosphatase (TRAP) is an important tool in differential diagnosis of hairy cell leukemia
(HCL). The test is positive in 95% of cases of HCL and usually negative or weakly positive in other disorders.
TRAP is also positive in some cases of splenic marginal zone lymphoma.
LAP (leukocyte alkaline phosphatase) score is decreased in CML and PNH (paroxysmal nocturnal hemoglobinuria).
However, LAP score often increases when CML transforms to a blast crisis or accelerated phase.
17. Ans. (c) 5q (Ref: Wintrobes 12th/1959-64, Ann Hematol. 2008 July; 87(7): 515526)
The article in the Annals of hematology Cytogenetic features in myelodysplastic syndromes by Detlef Haase gives the
different causes as percentage of myelopdysplastic syndromes. This is a typical example of question where the changed
data may lead to the question being repeated in the future exam friends.
Myelodysplastic syndromes are a group of clonal hematopoietic stem cell diseases characterized by dysplasia and
ineffective hematopoiesis in one or more of the major myeloid stem lines.
Direct quote from the Haases paper..Deletions within the long arm of chromosome 5 are the most frequent cytogenetic
changes in MDSQ accounting for roughly 30% of abnormal cases.
The cytogenetic abnormalities in adult myelodysplastic syndrome are:
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5q 30%
Monosomy 7 20%
Complex chromosome abnormalities are defined by the simultaneous occurrence of at least three independent abnormalities within one
cell clone. They are also seen in almost 30% cases.
Direct quote from Williams Hematology 8th/edn The most common abnormalities are 5q, -7/7q, +8, 18/18q, and
20q. Monosomy 7 is the second most frequent cytogenetic abnormality in the marrow cells of patients with myelodys-
plasia.
So, we would prefer to go with (c) deletion of 5q as the preferred answer.
18. Ans. (b) CD3 (Ref: Harrison 17th/2020, 2032, Robbins 9/e 190)
When a cluster of monoclonal antibodies were found to react with particular antigen it was defined as a separate marker
and given a CD (cluster of differentiation) number.
CD3 is used as a pan T-cell marker (present on all stages of T-cells [ProT, Pre-T, Immature and mature T-cells]
CD19 is a Pan B-cell marker.
CD-1 Thymocytes and Langerhans associated
CD - 1, 2, 3, 4, 5, 7, 8 T-cell markers
CD - 10, 19, 20, 21, 22, 23 B-cell markers
CD - 10 CALLA antigen
CD - 13, 14, 15, 33 Monocyte macrophage associated
CD - 16, 56 NK- associated
CD - 41 Platelet marker
CD - 21 EBV receptors

19. Ans. (d) CD135 (Ref: Robbins 9/e 590, 8th/600, 7th/670, www.wikipedia.com)
B cell associated markers are CD10 (CALLA), CD19, CD20, CD21 (EBV receptor), CD22 and CD23.
Concept of CD135
CD135 is a proto-oncogene. It is also the receptor for the cytokine Flt3 ligand (Flt3L) and has the presence of tyrosine kinase
activity. Its mutation can lead to acute myelogenous leukemia (AML) and is associated with a poor prognosis.
CD135 is an important cell surface marker used to identify hematopoietic progenitors in the bone marrow. Specifically, multipotent
progenitors (MPP) and common lymphoid progenitors (CLP) express high surface levels of CD135. This marker is therefore used
to differentiate hematopoietic stem cells (HSC), which are CD135 negative, from MPPs, which are CD135 positive.
20. Ans. (c) Presence of testicular involvement at presentation (Ref: Robbins 9/e 592, 8th/603)
GOOD PROGNOSIS BAD PROGNOSIS
Female sex Male sex
Pre B cell phenotype Pre T cell phenotype
Hyperdiploidy (>50 chromosomes) or t(12;21) Pseudodiploidy or t (9;22) or presence of Philadelphia chromosome, t (8;14),
Trisomy of chromosomes 4,7,10 t (4;11)
Friends, please remember age is less than 2 years is given as bad prognosis in Robbins whereas in NELSON it is mentioned
that the age for bad prognosis is less than 1 year. Nelson also mentions the testicular involvement to be a bad prognostic
factor. Since in the given question, both (less than 2 years as well as testicular involvement) are mentioned we would go
for testicular involvement as the better answer here.
21. Ans. (d) t(9:22), t(8:14), t(4:11) explained earlier. (Ref: Robbins 9/e 592, 8th/603)
22. Ans. (d) M4 (Ref: Robbin 7th/693, Harrison 17th/680, Wintrobes 12th/1857)
Signs and symptoms related to infiltration of tissues are usually less striking in AML than in ALL. Mild lymphadenopathy
and organomegaly can occur. In tumors with monocytic differentiation M4 and M5 (more commonly), infiltration of the
skin (leukemia cutis) and the gingiva leading to gum hypertrophy can be observed, likely reflecting the normal tendency
of non-neoplastic monocytes to extravasate into tissues.
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M5 AML is the commonest AML associated with extramedullary diseaseQ (skin lesions/gum infiltration/CNS disease/testicular
involvement).
After M3 AML, M5 AMLQ is the commonest AML associated with the development of DIC.
23. Ans. (c) CD117 (Ref: Devita 6th/503, Robbins 7th/826, 9/e 614)
Explained in an earlier question
24. Ans. (d) Congenital dyserythropoietic anemia (Ref: Harrison 17th/663)
Differential diagnosis of pancytopenia
Congenital Dyserythropoietic Anemia (CDA)

CDA presents with anemia only (not pancytopenia). Anemia is normocytic or macrocytic. Bone marrow shows marked
erythroid hyperplasia. Three types of CDA have been identified as:
CDA Type I: It presents with anemia with or without jaundice. Bone marrow shows marked erythroid hyperplasia with polychromatophilic
and orthochromatophilic erythroblasts. There is distinct dissociation of nuclear and cytoplasmic maturation with immature megaloblastoid
nuclei and mature cytoplasm.
CDA Type II It is an autosomal recessive disorder. Recurrent or persistent mild jaundice, hepatosplenomegaly and anemia are the
presenting features. Gall stones are common. Blood smear shows anisocytosis, poikilocytosis, tear drop cells and basophilic stippling
Bone marrow shows erythroid hyperplasia with binucleated or multinucleated mature blasts. RBCs get lysed in acidic serum from
normal persons but not from patients own serum.
CDA type III: Anemia is mild and macrocytic. Bone marrow findings are similar to CDA type II. However, acid serum lysis test is negative.
Note: In PNH, RBCs get lysed in patients own acidified serum.
25. Ans. (a) CD-15 (Ref: Robbins 7th/670, 9/e 590, Harrison 17th/1908, 689, Wintrobes 12th/2507)
Direct lines from Wintrobes hematology..CD-15 is expressed on neutrophils, eosinophils and monocytes but not on
platelets, lymphocytes and erythrocytes.
About option (d), CD 24 is expressed on B cells but it decreased with B cell activation and differentiation and is lost at the
plasma cell stage. It is also present ion granulocytes and thymocytes but not on mature T cells. Data shows its increased
levels are associated with colon/breast and pancreatic cancer.
26. Ans. (a) Monocytes (Ref: Wintrobes 12th/15)
Acid phosphatase is found in all hematopoietic cells, but the highest levels are found in macrophages and osteoclasts. A dot like
pattern is seen in many T lymphoblasts.
Tartarate resistant acid phosphatase (TRAP) is seen in osteoclasts and Hairy cell leukemia. Positive TRAP staining
may be seen in activated T lymphocytes, macrophages, Gaucher cells, mast cells and some marginal zone lympho-
mas. Conditions associated with increased TRAP staining are:
Hairy cell leukemia
Gauchers diease
HIV-induced encephalopathy
Osteoclastoma
Osteoporosis
Metabolic bone diseases
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27. Ans. (c) Chronic myelogenous leukemia (Ref: Harrison 17th/683-684; Robbins 7th/697, 698, 9/e 617-618)
The peripheral blood picture of this patient is quite characteristic of chronic myeloid leukemia.
Chronic myeloid leukemia is a stem cell disease that is characterized by leukocytosis with granulocytic immaturities, basophilia,
splenomegaly and distinct chromosomal abnormality Philadelphia chromosome.
28. Ans. (b) An immature T cell phenotype [Tdt/CD34/CD7 positive] (Ref: Robbins 7th/670-673, 9/e 590-593)
Increased leukocyte count in the range of 138 109/L and on peripheral blood examination 80% of them constituting blast cells
indicate acute leukemia.
The age group (adolescent) and the mediastinal mass suggests that this leukemia is likely to be a T-cell leukemia.
T-cell ALL tends to present in adolescent males as lymphomas often with thymic involvement
So, the diagnosis is T-cell ALL.
Immunophenotypic classification of acute lymphoblastic leukemia
Pre-T-cell ALL TdT, CD2, CD3, CD4, CD5, CD7, CD8, CD34
Early pre-B TdT, DR, CD10, CD19, CD24
Pre-B-cell TdT, DR, CD10, CD19, CD20, CD24, Surface Ig
B-cell DR, CD19, CD20, CD24, Surface Ig
29. Ans. (c) Promyelocytic leukemia (Ref: Robbins 7th/693, 656-658)

The child presented with acute onset of bleeding, along with the following laboratory findings:
Thrombocytopenia (35000/mm3 as compared to normal value of 1, 50,000/mm3)
Increased prothrombin time (20s as compared to control of 13s)
Increased partial thromboplastin time (50s vs. normal 26-32s)
Decreased fibrinogen (10 mg/dL vs. normal of 233-496 mg/dl)
These hematological abnormalities indicate disseminated intravascular coagulation.

Most common form of AML associated with DIC is M3-AML (Acute promyelocytic leukemia).
30. Ans. (a) Biphenotypic leukemia (Ref: Robbins illustrated 8th/600)
CD stands for cluster differentiation. These are actually group of protein markers present on the surface of white
blood cell. These markers are used to classify the lineage of the leukocytes and are detected by immunophenotyping.
CD 10 +ve and CD 19+ve is the marker for B-cell lineage, whereas CD 33 and CD 13 is associated with monocyte and
macrophages.
So, the patient is having acute leukemia with immunophenotype pattern of more than one cell linkage called as
acute leukemia of ambiguous lineage. Biphenotypic leukemia is a subtype of leukemia of ambiguous lineage.
31. Ans. (c) More than 20% of blasts in blood or bone marrow. (Ref: Wintrobes 12th/1999-2000)
WHO criteria for chronic myelomonocytic leukemia (CMML)
1. Absolute monocytosis > 1 109/L in the peripheral blood
2. Blasts + monocytes < 20% in blood and bone marrow
3. Absence of philadelphia chromosome or BCR/ABL fusion gene
4. Dysplasia in one or more of myeloid lineages
If bone marrow blasts + monocytes > 20%, it is diagnosed as acute myeloid leukemia
Unlike classic CML, chronic myelomonocytic leukemia has absence of basophilia and eosinophilia and more monocytes. Also
CML does not have granulocyte dysplasia (present in CMML).
32. Ans. (b) t ( 9;22) (Ref: Robbins 9/e 614, 8th/627-628, T. Singh 1st/186-190, Harrison 17th/683 84)
An old man having fatigue and weight loss (due to anemia and cancer) and heaviness in left hypochondrium (most
likely due to splenomegaly). He also has elevated TLC (most likely due to leukemia). But the no. of blast cells is 3%, so it
cannot be acute leukemia. Old man with leukemia and splenomegaly is suggestive of CML which is associated with
t (9; 22).
Other options
t (15, 17) is associated with acute myeloid leukemia. For the diagnosis of acute leukemia, the number of blasts in the
blood should be >20%.
33. Ans. (c) Myeloperoxidase (Ref: Robbins illustrated 7th/692-693, 9/e p613)
Patient here gives a short history (acute onset) of development of pancytopenia (fever; weakness and gum bleeding suggest
leucopenia; anemia and thrombocytopenia respectively).
The presence of 26% blasts in the bone narrow suggests the development of acute leukemia and the presence of Auer rods
means that the diagnosis is most likely AML.
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Pseudo Pelger Huet cells are neutrophils having greater than 2 nuclear lobes and are usually seen in myelodysplastic
syndrome. In 10% patients, MDS can give rise to AML. So, the AML in question may have developed from MDS.
The chief cell in AML is myeloblast for which the staining is positive for myeloperoxidase.
Note: Acid phosphatase is useful for lymphoblasts which are seen in ALL
34. Ans. (d) Monosomy 7 (Ref: T. singh 1st/175, Robbins 9/e p612)
There are certain factors which determine the prognosis in AML
In a number of studies in last 2 decades it has been observed that cytogenetic markers are major determinants in as-
sessment of prognosis.
Good prognosis t (8; 21), inv (16) or t (15; 17)
Moderately favorable outcome No cytogenetic abnormality
Poor prognosis inv (3), monosomy 7
For all Prognostic factors in acute myeloid leukemia, see text.
35. Ans. (d) G6PD deficiency (Ref: Harrison 17th/663)
36. Ans. (b) Polycythemia vera (Ref: Wintrobes Clinical Haematology 12th/15)
High levels of LAP score are found in:
Infection
Inflammatory disorder
Growth factor therapy
Pregnancy
OCP
Stress
Myeloproliferative disorders (except CML)
Drugs (e.g. Lithium, Corticosteroid, Estrogen)
*Abnormally high values of LAP is seen in myeloproliferative disorder e.g. polycythemia vera and myelofibrosis
*Decreased LAP score is seen in CML (chronic phase) and PNH (paroxysmal nocturnal hemoglobinuria).
37. Ans. (a) Hodgkins disease; (b) Filariasis; (d) HIV (Ref: Harrison 17th/383)
Conditions producing allergic reactions and resulting eosinophilia are:
Drugs: Iodides, Aspirin, Sulfonamides, Nitrofurantoin, Penicillins, Cephalosporins.
Disease conditions: Hay fever, Asthma, Eczema, Serum sickness, Allergic vasculitis, Pemphigus, All types of parasitic
infections.
Collagen vascular diseases: RA, Eosinophilic fasciitis, Allergic angiitis, Polyarteritis nodosa.
Malignancy: Hodgkins disease, Mycosis fungoides, CML, Carcinoma of stomach, ovary, lung, Pancreas and uterus.
Other diseases: Jobs syndrome, Sarcoidosis, Skin disease.
Viral infection like HIV and human T-cell Iymphotropic virus (HTLV-l).
In MI polymorphonuclear leukocytosis seen.
38. Ans. (b) Myelofibrosis; (c) Alcoholism; (d) Iron Overload; (Ref. de Gruchys 5th/56)
Sideroblasts are erythroblasts with Prussian blue positive iron granules in their cytoplasm. They can be found in circulation
in the following diseases:
*Drugs and chemicals: *Hematological disorders: *Inflammatory disorders:
Antitubercular drugs (INH, Myelofibrosis Rheumatoid arthritis
cycloserine) Polycythemia vera SLE
Lead Myeloma Carcinoma
Ethanol Acute leukemia Myxedema
Hodgkins disease Malabsorption
Hemolytic anemia Iron overload.
39. Ans. (b) Kala-azar; (c) TB; (d) Brucellosis (Ref: Harrison 17th/342, Harsh Mohan 6th/350)
CAUSES OF MONOCyTOSIS:
Bacterial infections: TB, sub acute bacterial endocarditis, syphilis, brucellosis.
Viral infections
Protozoa and Rickettsial infections: Malaria, typhus, trypanosomiasis, kala-azar, RMSF.
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Hematopoietic disorder: Monocytic leukemia, lymphoma, myeloproliferative disorder, multiple myeloma, lipid stor-
age disorder.
Malignancies: Ca ovary, stomach and breast.
Granulomatous diseases e.g. sarcoidosis, IBD.
Collagen vascular diseases.
40. Ans. (a) AML; (b) Myelodysplastic anemia; (d) Paroxysmal nocturnal hemoglobinuria (Ref: DeGruchys 5th/127,
Harrison 17th/663)
Aplastic anemia is a pancytopenia with bone marrow hypocellularity. It can progress to
Paroxysmal Nocturnal hemoglobinuria
Myelodysplastic anemia
Rarely acute leukemia
Pure red cell aplasia is a selective disease of absence of erythrocyte progenitor cells. In contrast to aplastic anemia and MDS, the
unaffected lineage (WBC and platelets) appear quantitatively and qualitatively normal.
Myelofibrosis is a clonal disorder of a multipotent hematopoietic progenitor cell of unknown origin and is characterized
by
Marrow fibrosis
Myeloid metaplasia with extramedullary erythropoiesis
Splenomegaly
41. Ans. (c) Reticulocytopenia; (d) Thrombocytopenia; (e) Neutropenia (Ref: Robbins 7th/647, 9/e p653)
Aplastic anemia is a disorder of marrow failure which stems from suppression or disappearance of multipotent myeloid
stem cells. It is characterized by: Anemia, Neutropenia , Thrombocytopenia, and Reticulocytopenia. Splenomegaly is
characteristically absent; if present, the diagnosis of aplastic anemia is almost ruled out. Bone marrow shows hypocellular
marrow largely devoid of hematopoietic cells, often only fat cells, fibrous stroma, and scattered or clustered foci of

lymphocytes and plasma cells.
Nucleated RBCs in peripheral smear (leukoerythroblastic picture) are found in cases of marrow fibrosis.
42. Ans. is c i.e. Typhoid (Ref: Harsh Mohan 6th/348)
43. Ans. (b) CALLA Ag (Ref: Robbins 7th/330)
CALLA (common acute lymphoblastic leukemia antigen) is CD 10
CALLA positive acute leukemias have best prognosis.
44. Ans. (B) Chronic lymphocytic leukemia (Ref: Robbins 7th/673, 9/e 593)
In CLL, the peripheral blood contains increased numbers of small, round lymphocytes with scant cytoplasm. These cells
are fragile and are frequently disrupted in the process of making smears, producing so-called smudge cells.
45. Ans. (a) t (15: 17) (Ref: Robbins 9/e 612, 8th/624; 7th/692)
46. Ans. (b) Auer bodies are seen (Ref: Robbins 9/e 613, 8th/62; 7th/692-693)
47. Ans. (d) Increased (Ref: Robbins 7th/697-698, Wintrobes 12th/205, Williams CMDT 2010/458)
Wintrobes hematology mentiones.. granulocytes contain and release B12 binding proteins. Markedly elevated transco-
balmin I level are seen in chronic myelocytic leukemia and myeloid metaplasia whereas low levels are seen in chronic
leucopenia and aplastic anemia.
Williams hematology 8th/adds that the increase is proportional to the total leukocyte count in untreated patients and falls
with treatment.
Conditions having elevated levels of cobalamin
Hematological conditions Non-hematological conditions
Chronic myelogenous leukemia Acute hepatitis
Promyelocytic leukemia Cirrhosis
Polycythemia vera Hepatocellular carcinoma
Hypereosinophilic syndrome Metastatic liver disease
48. Ans. (d) CML (Ref: Robbins 8th/627; 7th/697-698)

49. Ans. (b) Leucocyte alkaline phosphatase (Ref: Robbins 8th/595, 9/e 584)
50. Ans. (d) Glucocorticoids (Ref: Harsh Mohan 6th/348)
51. Ans. (c) CML (Ref: Robbins 8th/627; 7th/438, 9/e 584)
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52. Ans. (d) Aplastic anemia (Ref: Robbins 9/e p654, 8th/634-635, 7th/704)
53. Ans. (c) Hypocellular bone marrow (Ref: Robbins 9/e 615, 8th/625; 7th/695)
54. Ans. (c) Thalassemia (Ref: Robbins 9/e p582, 620, 653, 8th/650; 7th/701)
55. Ans. (c) Myeloblast (Ref: Robbins 8th/602, 9/e p613)
56. Ans. (c) CLL (Ref: Robbins 8th/605, 9/e p594)
57. Ans. (b) Pulmonary abscess Read explanation below (important concept friends)
Chronic infections/chronic inflammatory conditions, such as pulmonary abscess may lead to an expansion of the myeloid
precursor pool in the bone marrow which manifests as neutrophilic leukocytosis.
Steroid therapy may increase the release of marrow storage pool cells and diminish neutrophilic extravasation into tissues.
Even vigorous physical exercise can produce neutrophilia transiently from demargination of neutrophils.
In acute myelogenous leukemia, the marrow is filled with blasts, not maturing myeloid elements.
58. Ans. (d) Acute monocytic leukemia (Ref: Robbins 7th/693, 9th/612)
Sunaya has an aleukemic leukemia in which leukemic blasts fill the marrow but the peripheral blood count of leukocytes
is not high. The staining of the blasts suggests presence of monoblasts (peroxidase negative and nonspecific esterase
positive). So, the likely diagnosis for her is M5 leukemia, which is characterized by increased chances of tissue infiltration
and organomegaly.
Other options;
Acute lymphoblastic leukemia is typically seen in children and young adults.
Acute megakaryocytic leukemia is typically accompanied by myelofibrosis and is rare. The blasts react with platelet-
specific antibodies
Acute promyelocytic leukemia (M3-AML) has many promyelocytes filled with azurophilic granules, making them
strongly peroxidase positive.
59. Ans. (a) Early pre-B (CD19+TdT +); Hyperdiploidy (Ref: Robbins 8th/603, 9/e p592-593)
The physician thinks the child will have remission. So, it means that this child should have ALL with good prognosis. The
markers for a good prognosis for acute lymphoblastic leukemia (ALL) are:
Early precursor B cell type
Hyperdiploidy
Age of patient between 2 and 10 years
Chromosomal trisomy
t(12;21)
Marrow infiltration by the leukemic cells leads to pancytopenia.
Poor prognostic markers for acute lymphoblastic leukemia/lymphoma are
Count >100,000
Presence of t(9;22)
Presentation in adolescents, and adulthood
60. Ans. (c) 22q11.2 (Ref: Robbins 8th/635, 9/e p626)

The stem of the question describes the markers of cortical lymphocytes in the thymus of a child. The absence of these cells
can be seen in the DiGeorge syndrome with 22q11.2. These patients also have parathyroid hypoplasia and congenital heart
disease.
Down syndrome (trisomy 21) can have thymic abnormalities and the T-cell dysregulation that predisposes to acute leukemia,
but the thymus is typically present.
Males with Klinefelter syndrome (XXY) do not have immunological abnormalities.
The t(15;17) is associated with acute promyelocytic leukemia.
61. Ans. (a) Acute lymphoblastic leukmia (Ref: Robbins 8th/603, 9/e p593)
The presence of the Philadelphia chromosome, a translocation from the long arm of chromosome 22 to chromosome 9
[t(9;22)], is associated with a more favorable prognosis in patients with chronic myelogenous leukemia but it associated
with an unfavorable outcome in Acute lymphoblastic leukemia (ALL).
62. Ans. (d) 65 years (Ref: Robbins 8th/604, 9/e p593)
Different leukemias tend to affect populations of different ages. The disease described is chronic lymphocytic leukemia
(CLL), which is a disease of older adults.
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The 1 year-old (choice A) would be most likely to have acute lymphocytic leukemia (ALL).
The 20 year-old (choice B) would be most likely to have acute myelocytic leukemia (AML).
The 45 year-old (choice C) would be likely to have either AML or chronic myelogenous leukemia (CML).
62.1. Ans. (a) Hodkins disease (Ref: Robbins 8/e p618-9)

ReedSternberg cells have an owls eye appearanceQ with prominent eosinophilic inclusion-like nucleoli.
ReedSternberg cells are CD30 and CD15 positive, usually negative for CD20 and CD45.
The ReedSternberg cells can also be found in reactive lymphadenopathy associated with infectious mononucleosis,
carbamazepine associated lymphadenopathy and non-Hodgkin lymphomas.
62.2. Ans. (c) Myeloperoxidase (Ref: Robbins 8/e p602 Pathology and Genetics of Tumours of Haematopoietic and Lymphoid
Tissues p79)
This is what we have knowledge of:
Lymphoblast: PAS positive
Myeloblast: Sudan black, myeloperoxidase and non-specific esterase
Please know that:
WHO manual pg 69 writes that.. MPO is specific for myeloid differentiation. Sudan Black B reactivity is similar to
MPO in myeloblasts and monoblasts. The specificity of Sudan Black is less than MPO.
62.3. Ans. (b) May-Heggline anomaly A Color Atlas and Instruction Manual of Peripheral Blood Cell Morphology pg 221,
(Ref: Robbins 8/e p594)
Dhle bodies are basophilic leukocyte inclusions located in the peripheral cytoplasm of neutrophils. They are said to be
remnants of the rough endoplasmic reticulum.
Conditions associated with Dohle bodies
Burns

Infections
Physical trauma
Neoplastic diseases
Wisslers disease
May-Hegglin anomaly (seen in neutrophil, monocyte, lymphocyte)
Chdiak-Steinbrinck-Higashis syndrome
62.4. Ans. (d) Dilated endoplasmic reticulum explained earlier
62.5. Ans. (b) t (15,17) (Ref: Robbins 9/e p612, 8/e p624)
Commonly asked information in NEET EXAM!
t(9;22) (Philadelphia chromosome): CML (bcr-abl hybrid)
t( 8;14) Burkitts lymphoma (c-myc activation)
t( ll ; l4): Mantle cell lymphoma (cyclin D1 activation)
t( l4; 18 ): Follicular lymphomas (bcl-2 activation)
t( l5;17): M3 type of AML (responsive to all-trans retinoic acid)
62.6. Ans. (c) Hyperdiploidy (Ref: Robbins 8/e p602-3, 9/e p592-593)
Female sex Male sex
Pre B-cell phenotype Pre T-cell phenotype
Hyperdiploidy (>50 chromosomes) or t(12;21) Pseudodiploidy or t (9;22) (Philadelphia chromosome) or t (8;14) or t (4;11)
Trisomy 4,7 and 10
62.7. Ans. (b) Immature B cells (Ref: Robbins 8/e p600)

As per the table given in Robbins, B cell ALL is due to immature B cells.
62.8. Ans. (a) ALL (Ref: Robbins 8/e p602, 7/e p670)
CD 10 is called as common acute lymphoblastic leukemia antigen or CALLA. It is seen in acute lymphoid leukemia (ALL).
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62.9. Ans (b) Myeloblast (Ref: Robbins 9th/612-3)

62.10. Ans (d) More than 5000 cells/microliter (Ref: Washington Manual 2013, table 11-4)
62.11. Ans: (a) Pre B cell (Ref: Robbins 9th/590)
Most common subtype of A.L.L is L1 according to older classification and Pre B cell variety by the latest WHO classifica-
tion. The recent WHO International panel on ALL recommends that the FAB classification be abandoned, since the mor-
phological classification has no clinical or prognostic relevance. It instead advocates the use of the immunophenotypic
classification.
63.Ans. (a). Hodgkins Lymphoma, nodular sclerosis (Ref: Loachims lymph node pathology/186)
Direct quote. Progressive transformation of germinal centers (PTGC) is a benign reaction pattern in lymph nodes. It
is most often associated with reactive follicular hyperplasia. It is also associated with nodular sclerosis and lymphocyte
predominant Hodgkins lymphoma.
64. Ans. (a) Kimuras disease (Ref: Loachims lymph node pathology/190)
Kimura Disease is a chronic inflammatory disorder prevalent in Asians. It involves subcutaneous tissues and lymph nodes
predominantly in the head and neck region and is characterized by angiolymphoid proliferation and eosinophilia.
Histopathology
Lymphoid infiltrates with formation of follicles and germinal centers accompanied by plasma cells, mast cells and particularly large
amount of eosinophils are present in subcutis.
Lymph nodes are enlarged and show markedly hyperplastic follicles with reactive germinal centers and a well-defined peripheral
mantle.
Diffuse eosinophilia, eosinophilic abcesses and infiltration of germinal centres, sometimes resulting in folliculolysis, are part of the
process.
Polykaryocytes of the Warthin Finkeldey type, characterized by the overlapping, grape-like arrangement of nuclei, are common,
often within the germinal centers.
65. Ans. (d) Aplastic anemia (Ref: Harrison 17th/374, Robbins 9/e p653)
Massive splenomegaly is labeled when spleen extends greater than 8 cm below left costal margin and/or weighs more
than 1000 g.
Diseases Associated with Massive Splenomegaly
Chronic myelogenous leukemia Gauchers disease
Lymphomas Chronic lymphocytic leukemia
Hairy cell leukemia Sarcoidosis
Myelofibrosis with myeloid metaplasia Autoimmune hemolytic anemia
Polycythemia vera Diffuse splenic hemangiomatosis
66. Ans. (a) t (8:14) (Ref: Robbins 8th/608, 9/e p597)
67. Ans. (a) CD 45 RO (Ref: Flow Cytometry and Immunohistochemistry for Hematologic Neoplasms, Lippincott Williams
and Wilkins, Tsieh Sun 1st/133; Neoplastic Hematology Daniel Knowles 2nd/1342
Direct quote from Tsieh Sun .....myeloid sarcoma usually expresses CD45 but rare cases may demonstrate T cell markers,
such as CD45RO, CD3 and CD7. So, the answer of choice is CD45RO.
Salient features of Lab diagnosis of Granulocytic sarcoma
1. Screening panel for CD45, CD19 and CD20.
2. Standard flowcytometry panel includes CD13, 14, 15 , 33and myeloperoxidase
3. Immunohistochemistry panel may include chloroacetate esterase (Leder stain), lysozyme, CD15, CD43 and CD 68
4. LysozymeQ and CD43Q are the most sensitive markers
5. Two new markers CD99Q and CD117Q can be added in equivocal cases.
6. Common cytogenetic abnormalities include t(8;21), inv (16) and t(9;11) Q
Additionally, the percentage of these molecules can be derived from the data given in Neoplastic Hematology.
Immunohistochemistry Molecule %
CD 45 90%
CD 43 50%
Lysozyme 75%
Leder stain (chloroacetate esterase) >75%
No mention of staining with CD45RO is there, so, we prefer CD45 RO as the answer of choice.
68. Ans. (a) CD 23 (Ref: Robbins 7th/683; http://www.emedicine.com/med/topic1358.htm, Robbins 9/e p603)
Mantle cells lymphomas are usually CD23 negative. They are positive for CD5, CD20 and CD43.
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Characteristic immunophenotypes of major subtypes of lymphoma

Follicular CD20+, CD3, CD10+, CD5
Small lymphocytic CD20+, CD3, CD10, CD5+, CD23+
Mantle cell CD20+, CD3, CD10, CD5+, CD23, CD43+, PRADI+
Burkitt CD20+, CD3, CD10+, CD5; Tdt
69. Ans. (b) REAL Classification (Ref: Robbins 7th/688; AJC cancer staging handbook)
In 1994, a group of hematopathologists, oncologists and molecular biologists came together (International Lymphoma
Study Group) and introduced a new classification, called the Revised European- American Classification of Lymphoid
Neoplasms (REAL).
WHO has reviewed and updated the REAL classification in 1999 resulting in inclusion of additional rare entities.
Non-Hodgkins lymphoma (NHL) has been classification by many groups. Major classification systems are:
Rappaport classification (Developed in 1966)
Working formation classification
REAL classification (Developed in 1994)
WHO classification (modified REAL classification, 1999)
1. Rappaport classification: It is based on microscopic appearance of tumor cells.
Size: Lymphocytic or histiocytic
Growth pattern: Diffuse or nodular
2. Working classification: According to this system, NHL is divided according to prognostic criteria into:
Low grade Intermediate grade High grade

Small lymphocytic NHL Follicular large cell NHL Small non-cleaved NHL (Burkitts)
Follicular small cleaved NHL Diffuse small cleaved NHL Immunoblastic lymphoma
Follicular mixed small cleaved Diffuse small cleaved NHL Lymphoblastic lymphoma
and large-cell NHL Diffuse mixed small cleaved and large-cell NHL
Diffuse large-cell NHL
3. Revised European-American classification of lymphoma (REAL) It includes:
Precursor B-cell neoplasm
Peripheral B-cell neoplasm
Precursor T-cell neoplasm
Peripheral T-cell neoplasm
Hodgkins lymphoma
4. WHO classification: It takes into account morphologic, clinical, immunological and genetic information. For its details,
see text.
70. Ans. (d) A diffuse proliferation of medium to large lymphoid cells with high mitotic rate (Ref: Robbins: 7th/673-674,
9th/p 593-594, several journals through internet)
This is a case of chronic lymphocytic leukemia (CLL) as indicated by the characteristic clinical picture and
immunophenotypic characteristics. (Typically, CLL cells express CD5, CD19, CD23 and show absence of CD79B,
CD22 and FMC7)
Histopathological examination in a case of typical CLL shows diffuse effacement of lymphocyte architecture by small
to medium sized lymphocytes with clumped chromatin, indistinct or absent nucleoli and scanty cytoplasm.
The round lymphocytes may give way focally to paler areas consisting of larger round cells (prolymphocytes). These
paler areas are often referred to as proliferation centers and when present are pathognomic for CLL/SLL. They
contain relatively large number of mitotically active cells.
Follicular lymphoma is positive for CD10, CD79b and FMC7 but negative for CD25 and CD43.
CLL and prolymphocytic leukemia are CD23 positive.
Mantle cell lymphoma is also CD5 positive but here the cells are CD23 negative and CD 79b and FMC7 positive.
71. Ans. (d) Inv (16) is often detected in the blasts and the eosinophils (Ref: Annals of Hematology: 2000 May: 79(5): 272-4)
This is a case of ALL with hypereosinophllic syndrome. Inv (16) is associated with AML and not ALL, and therefore represents the
incorrect statement amongst the option. About other options, the relevant points:
Eosinophils are not a part of this neoplasm differentiating it from eosinophilic leukemia.
t(5;14) may be observed in about half of such patients. The symptoms may resolve after dug therapy.
For details, see the journal with the relevant article.
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72. Ans. (b) Results from an expansion of Neoplastic T-lymphocytes (Ref: Harrisons 17th/697; Robbins 7th/683, 9/e p588)
Hairy cell leukemia is a type of B-cell leukemia. For details, see text.
73. Ans. (b) CD 34 negative but surface Ig+ (Ref: Robbins 9/e p597-598, 8th/608, 7th/677-678, Harrison 17th/, 696)
Burkitts lymphoma is a cancer characterized by the presence of hallmark translocation t (8;14)Q.
The translocation results in the increased expression of c-MyCQ resulting in development of neoplasia.
Immunophenotyping reveals the tumor cells expressing bcl-6 protein, surface Ig, CD19, CD20 and CD10 (CALLAQ.
74. Ans. (d) CD 34 is associated with Diffuse large B Cell Lymphoma (Ref: Robbins 9/e p603 8th/605-608, 612-613, 7th/675-
678, Wintrobes 12th/2223)
Burkitts lymphoma Follicular lymphoma Mantle cell lymphoma
Hallmark translocation t (8;14) t (14;18) t (11; 14)
Over expression of gene bcl-6 bcl-2 bcl-1
Immunophenotyping sIgM+, CD5, CD10+, CD19+, sIg, CD5, CD10+, CD19+, bright sIgM+, sIgD+, CD5+, CD10,
CD20+, CD23, CD45+ CD20+, CD23/+, CD38+, CD45+ CD19+, CD20+, CD23, Cyclin
D1+, FMC-7+
Though Williams hematology mentiones (Table 92.1) and even we normally read that the Mantle cell lymphoma is
CD10- but WHO manual writes that mantle cell lymphoma may show expression of CD10 molecule rarely. This is
also supported by Wintrobes 12th/pg 2223 where the table clearly mentions that Mantle cell lymphoma may be CD10+/-.
So, option C may be assumed to be true (after all AIIMS questions can be nerve wrecking friends. This question has been
altered to suit the easy goals in other MCQ books).
The answer of exclusion is therefore D as CD 34 is the marker for hematopoetic stem cell. Diffuse large B cell lymphoma
has the phenotype of sIgM+, sIgD+/, CD5/+, CD10/+, CD19+, CD20+, CD45+, PAX5+. The tumor cells can be BCL-6
positive in 40% cases when associated with t (3;14) or bcl-2 positive in 20% with t(14;18).
75. Ans. (b) B-cell (Ref: Harrison 17th/845, 847, Robbins 9/e p1313)
Post-transplant Lymphoproliferative Disorders (PTLDs) are lymphomas developing after solid organ transplantation
e.g. kidney, liver, heart or lung transplants.
PTLDs are almost always related to infection by the Epstein-Barr virus (EBV) which causes a cancerous transformation
of B-cells. In normal individuals immune cells can tackle the EBV infection, but in organ transplants, the high doses of
drugs used suppress the immune system and the the chances of developing lymphomas increase.
Difference between Post transplant lymphomas and non Hodgkins lymphomas. PTLDS have the following:
Extranodal involvement (brain, lungs and the intestines)

Poorer prognosis
76. Ans. (d) In general follicular (nodular) NHL has worse prognosis compared to diffuse NHL (Ref: Robbins 7th/674- 6,
667-8)
Hodgkins lymphoma is clinically and histologically distinct from the non-Hodgkins lymphoma. While non-Hodg-
kin lymphomas frequently occur at extranodal sites and spreads in an unpredictable fashion, Hodgkins lym-
phoma arises in a single node or chain of nodes and spreads first to anatomically contiguous nodes. Several ways
of classifying Hodgkins lymphoma exist Rappaport, REAL classification and now WHO (modified REAL classifi-
cation).
The prognosis of non Hodgkins lymphoma varies markedly with various histological types of non Hodgkins lymphoma, In
general lymphomas with a follicular histological pattern are of lower grade (longer survival) than those of diffuse pattern.
77. Ans. is b i.e. CD 23 (Ref: Harrison 17th/695, Robbins 7th/683, 9/e p602-603)
Mantle cell lymphomas are positive for CD43, CD20, BCl-1 Protein (Cyclin D1) and CD5.
78. Ans. (b) Follicular lymphoma (Ref: Robbins 8th/605; 7th/675, 9/e p594)
79. Ans. (a) Burkitts lymphoma (Ref: Robbins 8th/608, 7th/677 9/e p597)
80. Ans. (b) Mycosis fungoides (Ref: Robbins 9/e p605, 8th/1184-1185; 7th/685)
81. Ans. (c) Prognosis is better than in diffuse type (Ref: Robbins 9/e p594-595, 8th/619)
82. Ans. (a) B-cell lymphoma (Ref: Robbins 9/e p603, 8th/613, 7th/826)
83. Ans. (b) Cirrhosis (Ref: Robbins 8th/634)
Pancytopenia with the splenomegaly is suggestive of hypersplenism as a cause for the patients anemia, leucopenia and
thrombocytopenia. A common cause of congestive splenomegaly is portal hypertension resulting from cirrhosis. The
elevated AST and ALT is also suggestive of liver disease. Regarding other options friends, please note:
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The WBC count should be high with acute leukemias.

SLE can lead to cytopenias from reduced bone marrow function, but there is no associated splenomegaly.
Infectious mononucleosis may lead to splenomegaly but it is more common in younger individuals.
84. Ans. (a) Burkitts lymphoma: (Ref: Robbins 9/e p597, 8th/608)
Burkitts lymphoma is actually associated with three translocations. The common variant t(8;14)(q24;q32), involving the
oncogene myc on chromosome 8, and the heavy immunoglobulin chain on chromosome 14. The other two variants are:
t(8;22)(q24;q11), involving myc and the lambda light chain immunoglobulin site, and t(2;8)(p12;q24), involving the kappa
light chain and myc.
85. Ans. (d) Infectious mononucleosis: (Ref: Robbins 9/e p361, 8th/355-357)
Infectious mononucleosis is a benign infection caused by the Epstein-Barr Virus (EBV). Although B lymphocytes are in-
fected by the virus, the characteristic atypical cells are activated suppresser T cells explaining the paracortical location
(normally a T cell zone) in the lymph node. Lymph nodes in viral infections show expansion of germinal centers without
loss of normal architecture. All lymphomas, including Burkitts, Hodgkins and non-Hodgkins lymphomas, destroy the
normal architecture of the lymph node.
85.1. Ans. (a) B cell lymphoma (Ref: Robbins 9/e p603, 8/e p613)
Marginal zone lymphoma is a B cellQ tumour has the presence of translocation t(11;18) Q. It is associated with H. pyloriQ
infection. They have the following exceptional characteristics:
Often arise within tissues involved by chronic inflammatory disorders of autoimmune or infectious etiology
Remain localized for prolonged periods, spreading systemically only late in their course
May regress if the inciting agent (e.g., Helicobacter pylori) is eradicated
85.2. Ans. (d) CD 5 +, CD 23 (Ref: Robbins 9/e p602-603, 8/e p612-3)

Follicular lymphoma CD20+, CD3, CD10+, CD5
Small lymphocytic lymphoma CD20+, CD3, CD10, CD5+, CD23+
Mantle cell lymphoma CD20+, CD3, CD10, CD5+, CD23, CD43+, PRADI+
Hodgkin lymphoma CD30+, CD15+
85.3. Ans. (d) Cutaneous lymphoma (Ref: Robbins 9/e p605, 8/e p1184-1185, 7/e p1685)
Mycosis fungoides is a T cell lymphoma affecting skin which can evolve into generalized lymphoma.
Histological hallmark: Sezary Lutzner cellsQ which are helper T cells forming band like aggregates in superficial dermis
and have cerebriform contourQ.
May invade epidermis as single cells and small clusters called as Pautrier microabscessesQ.
85.4. Ans. (a) Follicular (Ref: Robbins 8/e p605, 7/e p675)
This was based on the working classification of NHL:
Low grade Intermediate grade High grade

Small lymphocytic NHL Follicular large cell NHL Small non-cleaved NHL (Burkitts)
Follicular small cleaved NHL Diffuse small cleaved NHL Immunoblastic lymphoma
Follicular mixed small cleaved and Diffuse small cleaved NHL Lymphoblastic lymphoma
large-cell NHL Diffuse mixed small
cleaved and large-cell NHL
Diffuse large-cell NHL
85.5. Ans. (c) Diffuse large B cell lymphoma (Ref: Robbin 8/e p606)
Diffuse large B-cell lymphoma (DLBCL) is the most common form of NHL (Ref: Robbind 8/e p606)
85.6. Ans. (a) B cell (Ref: Robbin 8/e p1348, Eyelid, Conjunctival, and Orbital Tumors 2/e p746 )
Direct quote... Non Hodgkin Lymphoma of the B cell lineage is the most common type in the orbit....... Eyelid, Conjunc-
tival, and Orbital Tumors
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Also know: for a future question

The most frequently encountered primary neoplasms of the orbit are vascular in origin like the capillary hemangioma, the
lymphangioma and the encapsulated cavernous hemangioma.
MC intraocular tumour in children: Retinoblastoma
MC intraocular tumour in adults: choroidal malignant melanoma
85.7. Ans. (b) Stomach (Ref: Robbin 9th/ 773)

Although extranodal lymphomas can arise in virtually any tissue, they do so most commonly in the GI tract, particularly
the stomach.
85.8. Ans. (b) B cell (Ref: Robbin 9/e p603)
85.9. Ans. (b) Burkitt Lymphoma (Ref: Robbin 9/e p597)
Burkitt lymphoma is believed to be the fastest growing human tumordirect line
The tumor exhibits a high mitotic index and contains numerous apoptotic cells, the nuclear remnants of which are
phagocytosed by interspersed benign macrophages. These phagocytes have abundant clear cytoplasm, creating a charac-
teristic starry sky pattern.
85.10. (a) Anaplastic large cell lymphoma (ALK positive) (Ref: Robbin 8/e p605)
Anaplastic Large-Cell Lymphoma (ALK Positive) is an uncommon entity which is defined by the presence of rearrange-
ments in the ALK gene on chromosome 2p23.
This tumor is typically composed of large anaplastic cells, some containing horseshoe-shaped nuclei and voluminous cy-
toplasm (so-called hallmark cells).
85.11. Ans. (b) Africa.Indian exam asking global question
86. Ans. (d) Monoclonal origin (Ref: Robbins 9/e p583, 8th/599)
All lymphomas are monoclonal, derived from neoplastic expansion of a single transformed cell clone. Gene rearrangement
studies, therefore, can be used for diagnostic purposes to determine whether a lymphoid population is monoclonal (ie,
neoplastic) or polyclonal (i.e., reactive).
Most, but not all, non-Hodgkin lymphomas are of B lymphocytic origin (choice A).
Approximately 80% of non-Hodgkin lymphomas are derived from B lymphocytes; the remaining 20% are of histiocytic (choice B)
or T lymphocytic origin.
Lymph node localization (choice C) is variably present in non-Hodgkin lymphomas. Two thirds of these lymphomas come to clinical
attention with nontender nodal enlargement involving one or more lymph nodes. The remaining one third of cases present with
extranodal involvement of skin, brain, and gastrointestinal tract, for example. In contrast, virtually all cases of Hodgkin lymphoma
present with lymph node enlargement.
87. Ans. (d) Reed-Sternberg cells (Ref: Robbins 9/e p610, 8th/617)
This is a classic presentation of Hodgkins disease, which is a form of lymphoma characterized by neoplastic proliferation
of Reed-Sternberg cells admixed with variable numbers of reactive lymphocytes, neutrophils, and eosinophils.
Abnormal plasma cells (choice A) would be a feature of multiple myeloma or some B-cell leukemias and lymphomas.
Giant platelets (choice B) are a feature seen in several myeloproliferative disorders (notably essential thrombocytopenia),
which do not cause lymphadenopathy. Immature neutrophil precursors (choice C) would most likely be a feature of a
myeloid leukemia, which would not cause a lymphadenopathy.
88. Ans. (a) CD 15 and 30 (Ref: Robbins 9/e p608, 7th/422-423)
In classical HL, CD15 and CD30 are the surface markers. In non classical HL, CD20 and BCL/6 are the markers.
89. Ans. (a) Lymphocyte predominance (Ref: Robbins 9/e p609, 7th/668, 686, 689)
Nodular Lymphocyte Predominance Hodgkins disease is now recognized as an entity entirely distinct from classical
Hodgkins disease.
In lymphocyte predominant Hodgkins disease, the Reed Sternberg cells have a characteristic B cell immunophenotype distinct from
that of classical Hodgkins i.e. CD15 and CD30 negative but express J chain, CD45 and EMA (Epithelial Membrane Antigen).
Lymphoblast PAS positive

Myeloblast Sudan black, myeloperoxidase and non-specific esterase
90. Ans. (c) Absolute lymphocyte count < 600/l (Ref: Hodgkins lymphoma: A Comprehensive Update on Diagnostics and
Clinics By Andreas Engert/2010/104)
Seven adverse prognostic factors described for advanced Hodgkins disease are
346
1. Male gender
2. Age > 45 years
3. Stage IV disease
4. Hemoglobin < 10.5 g/dl
5. Leukocytosis with WBC > 15,000/l
6. A serum albumin level <4 g/dl
7. Lymphocytopenia with either Absolute lymphocyte count < 600/l or lymphocyte being < 8% of WBCs
91. Ans. (d) Lymphocyte predominant Hodgkins disease (Ref: Robbins 7th/686, 9/e p609)
Explained in text.
92. Ans. (d) Langerhans cell. (Ref: Robbins 9/e p 608-609, 7th/686, 688)
Langerhans cells are epidermal dendritic cells that take up and process antigenic signals and communicate the information to
lymphoid cells.
93. Ans. (B) Nodular sclerosis Hodgkins lymphoma (Ref: Robbins 9/e p608, 8th/618)
94. Ans. (D) Lymphocyte predominant (Ref: Robbins 7th/688, 9/e p609)
95. Ans. (a) Nodular sclerosis (Ref: Robbins 9/e p608, 8th/618; 7th/688)
96. Ans. (a) Nodular sclerosis (Ref: Robbins 9/e p608, 8th/618-619, 7th/686)
97. Ans. (a) Lymphocyte dominant (Ref: Robbins 9/e p609, 8th/619; 7th/689)
98. Ans. (a) Myelodysplastic syndrome (Ref: Robbins 9/e p614-615, 8th/625-626; 7th/695-696)
98.1. Ans. (c) Lymphocytic predominance (Ref: Robbins 9/e p608-609, 8/e p618-9)
WHO Classification of Hodgkin Lymphoma

Nodular sclerosis Mixed cellularity Lymphocyte rich Lymphocyte depleted Lymphocyte
predominant (no
classical HL)
MC type of HL MC type of HL in Associated with HIV H > F
india
Incidence equal in M and F M>F M>F M>F M>F
RS cell variant in Has eosinophils and Mononuclear 3 unique RS cell LH cells (popcorn
lacunar cell (clear space plasma cells and RS cell (pleomorphic, mummified, cells) in background
surrounding cell) Maximum number of Lowest number necrobiotic type) Other cells scanty or
RS cell of RS cells Maximum area of necrosis absence of B cells
Cells are CD 15 +CD30+ Cells are CD15 + Cells are CD15 Cells are CD15 + CD30+ RS cell are CD20
CD30+ + CD30 + and + CD15, CD30
CD20 BCL6 +, EMA +Q
No association with EBV Associated with EBV Associated with Associated with EBV Not associated with
EBV EBV
Excellent prognosis Prognosis very good Good to Poor prognosis Excellent prognosis
excellent
prognosis
Adolescent and young Biphasic incidenceQ Old age group Old age group Young males
adult (young adults as well
as > 55 years)
* EMA is Epithelial Membrane Antigen
98.2. Ans (c) Nodular sclerosis...See earlier explanation (Ref: Robbins 9/e p608)
98.3. Ans. (b) Nodular sclerosis Hodgkin lymphoma (Ref: Robbin 8/e p618-9)
Presence of binucleated acidophlic owl eye appearance with CD15 and CD 30 is suggestive of Reed Sternberg cell.
Lymphocyte depletion HL occurs predominantly in the elderly and in HIV+ individuals
In lymphocyte predominant HL, the Reed Sternberg cells are positive for CD20 and BCL6, and are usually negative for
CD15 and CD30.
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Mixed-cellularity HL is more common in males, in elderly with presence of constitutional symptoms. Involved lymph
nodes are diffusely effaced by a heterogeneous cellular infiltrate, which includes T cells, eosinophils, plasma cells, and
benign macrophages admixed with Reed-Sternberg cells
99. Ans. (c) Essential thrombocythemia (Ref: Robbins 8th/629, 9/e p620 Harrison 17th/374)
This. is a modified version of DPG2011 question. Please see the table for causes of Massive Splenomegaly given earlier.
In CML first symptom of CML is a dragging sensation in the abdomen caused by splenomegaly Robbins 8th/627-8
Polycythemia vera Robbins 8th/629, 9/e p619.. spent phase of polycythemia has extensive extramedullary hematopoeisis
principally in the spleen which enlarges greatly
Primary myelofibrosis page 631, 9/e p621 it comes to attention because of progressive anemia and splenomegaly
100. Ans. (b) JAK 2 mutation (Ref: Robbins 9/e p618, 8th/626-8, Wintrobes hematology 12th/1991-2; Journal Blood 110:1092,
2007)
Polycythemia vera is the most common of the chronic myeloproliferative disorders. As discussed is text: JAK 2 mutation
is a major criteria. However this mutation is not diagnostic of PV as it is also seen in essential thrombocytosis, chronic idi-
opathic myelofibrosis (CIMF) and atypical myeloproliferative disorders.
Other options, options a and c are minor criteria whereas Option d, remember friends that
MPL point mutation is seen in 5-10% patients with essential thrombocytosis and primary myelofibrosis.
Burkitts lymphoma is having the germinal B cell as the cell of origin. This condition is diagnosed with the demonstration of a very high
proliferative fraction and the presence of any of the following cytogenetic abnormalities on the surface of the cells
t (8;14) (most commonly)
t (2;8) or
t (8;22)
101. Ans. (d) Essential thrombocytopenia (Ref: Robbins 7th/696, 9/e p616)
Essential thrombocytosis (and not Essential thrombocytopenia) is a myeloproliferative disorder.

102. Ans. (b) Extramedullary hematopoiesis (Ref: Robbins 9/e p620, 8th/630, Harrison 18th/900-1)
The patient has the classic features of myelofibrosis with myeloid metaplasia. It is a stem cell disorder, in which neo-
plastic megakaryocytes secrete fibrogenic factors leading to marrow fibrosis. The neoplastic clone goes to spleen where
it shows trilineage hematopoietic proliferation (extramedullary hematopoiesis) with prominent megakaryocytes. The pe-
ripheral blood has immature RBC and WBC precursors (leukoerythroblastic picture).
Teardrop RBCs are altered shaped red cells found when marrow undergoes fibrosis.
Marrow injury also can be the result of other causes (e.g. metastatic tumors or irradiation). These causes also can give rise to a
leukoerythroblastic picture but splenic enlargement with trilineage proliferation usually is not seen. The other options Hodgkin lymphoma
and portal hypertension can cause splenic enlargement but not marrow fibrosis. Adenocarcinoma metastases to the spleen are
uncommon.
103. Ans. (a) Histiocytosis-X (Ref: Robbins 8th/631-2, 9/e p621)

Histiocytosis is an umbrella designation for a variety of proliferative disorders of dendritic cells or macrophages. It is
divided into three categories: Letterer-Siwe syndrome, Hand-Schuller-Christian disease, and eosinophilic granuloma.
Letterer-Siwe disease
Also known as Multifocal multisystem Langerhans cell histiocytosis

Occurs most frequently before 2 years of age but occasionally affects adults.
Chief clinical feature is the development of cutaneous lesions resembling a seborrheic eruption, which is caused by infiltrates
of Langerhans cells over the front and back of the trunk and on the scalp.
Affected patients also have concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and, eventually,
destructive osteolytic bone lesions.
Extensive infiltration of the marrow often leads to anemia, thrombocytopenia, and predisposition to recurrent infections such
as otitis media and mastoiditis.
The course of untreated disease is rapidly fatal.
103.1. Ans. (c) 65% (Ref: Textbook of Clinical Pediatrics 2/e p356)
Direct lines. Polycythemia is defined as venous hematocrit exceeding 65%.
Polycythemia is not to be confused with the polycythemia vera for which the following information is asked repeatedly.
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Revised WHO criteria for polycythymia vera
Major criteria Hemoglobin > 18.5 g/dL in men or > 16.5 g/dL in women or evidence of increased red cell volume
Presence of JAK2 mutationQ
Also know:
Lines from Harrison. Unless the hemoglobin level is 20 g/dl (hematocrit 60%), it is not possible to distinguish
true erythrocytosis from disorders causing plasma volume contraction.
Stress or spurious erythrocytosis is called as Gaisbcks syndrome.
103.2. Ans. (a) CD 1a (Ref: Robbins 9/e p622, 8/e p631)

In Langerhans cell histiocytosis, the presence of Birbeck granules in the cytoplasm is characteristic.
In this condition, Birbeck granulesQ are pentalaminar tubules, often with a dilated terminal end producing a tennis
racketlike appearanceQ, which contain the protein langerin.
In addition, the tumor cells also typically express HLA-DR, S-100, and CD1aQ.
103.3. Ans. (d) Tennis racket (Ref: Robbins 8/e p631, 9/e p622)
Questions like this have been asked in the national board exam. So, be familiar with this fact.
103.4. Ans. (c) Chronic myeloid leukemia (Ref: Robbins 8/e p628 , 9/e p618)
Leukocyte alkaline phosphatase (LAP) is found within the white blood cells. Revise the following condition s asked in the exam:
High LAP score Low LAP score
Leukemoid reaction Chronic myelogenous leukemia (CML)
Polycythemia vera (PV) Paroxysmal nocturnal hemoglobinuria (PNH)

Essential thrombocytosis (ET) Acute myelogenous leukaemia (AML).
Primary myelofibrosis (PM) Sideroblastic anemia
103.5. Ans. (c) Hemolytic anemia (Ref: Robbins 8/e p595, Blood 2/e p255, T. Singh 1/e p198)
Leukoerythroblastosis is a term used for an anemia characterized by the presence in the peripheral blood of immature
red cells and a few immature white cells of the myeloid series that is erythroblasts and leukoblasts. The following are the
causes of leukoerythroblastosis:
Causes of leukoerythroblastosis
Marrow invasion Tumors (lymphoma, Hodgkin disease, leukemia, multiple myeloma, bony metastasis)
Infections (sepsis, TB, osteomyelitis)
Miscellaneous (osteopetrosis, histiocytosis, storage disease, vasculitis including rheumatoid arthritis )
Myeloproliferative disorders Polycythemia vera
Myelofibrosis
CML
Erythroleukemia
Thrombocythemia
Down syndrome
Hematological disease Erythroblastosis fetalis
Pernicious anemia
Thalassemia major
Severe hemolytic anemia
Hypoxia Congestive heart failure
Cyanotic congenital heart disease
Respiratory disease
Please remember friends that severe hemolytic anemias may be associated with a similar picture but routinely, leukoeryth-
roblastosis is not observed with hemolytic anemia.
103.6. Ans. (b) Leukemoid reaction.. (Ref: Robbins 8/e p595, 9/e p584, Hematology 3/e p402)
LAP is found in the membranes of secondary granules of neutrophils. Its activity is measured in mature neutrophils and
band cells onlyQ.
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Eosinophils do notQ show alkaline phosphatase activity and must not be mistaken with mature neutrophils with a score
of zero. Malaria is characterized by monocytosis.
Increased LAP Score Decreased LAP Score

Leukemoid reaction PNH
Pregnancy IIIrd trimester Sideroblastic anemia
Polycythemia vera CML
Infection, inflammation Myelodysplastic disorders
LAP score is normal in juvenile CML.
103.7. Ans. (c) Acute myeloblastic leukemia (Ref: Robbins 9th/ 616)
Myeloproliferative disorders are charcterised by an increased production of one or more types of blood cells. The common
pathogenic feature is the presence of mutated, constitutively activated tyrosine kinases or other acquired mutations result-
ing in growth factor independence. The examples include:
Chronic myelogenous leukemia
Chronic neutrophilic leukemia
Polycythemia vera
Primary myelofibrosis
Essential thrombocythemia
Chronic eosinophilic leukemia
Mastocytosis
103.8. Ans. (b) 5q (Ref: Robbins 9/e p615)
104. Ans. (b) Hyperviscosity (Ref: Robbins 8th/610-1, 9/e p600, Harrison 18th/938-940, Wintrobes hematology 12th/2374-8)
According to Harrison,
Bone pain is seen in 70% patients

Infections is the next common (>75% have serious infection at some time in their course)
Normocytic normochromic anemia is seen in 80% patients
105. Ans. (c) Hypercalcemia (Ref: Harrison 17th/702, 9/e p600)
106. Ans. (d) IgM (Ref: Robbins 8th/65, 9/e p601)
Lymphoplasmacytoid lymphoma (or Waldenstroms macroglobulinemia) is a B cell neoplasm presenting in 6th or 7th
decade of life having features similar to CLL/SLL and multiple myeloma (MM). Like MM, there is presence of a M or
monoclonal spike (caused due to IgM whereas in MM, it is caused by IgG).
# Also remember
Deletion involving chromosome 6q is the commonest abnormality in Waldenstroms macroglobulinemia.
107. Ans. (b) A diagnosis of plasma cell leukemia (Ref: Wintrobes haematology 11th/2620, 2593)
Plasma cell leukemia by definition is characterized by more than 20% plasma cells in the peripheral blood.
The patient in question has 14% plasma blasts in the peripheral blood and thus does not fit into category of plasma cell
leukemia.
Distinguishing Features In Various Types of Plasma Cell Disorders:
1. Plasma cell leukemia
More than 20% plasma cells in the peripheral blood
Absolute plasma cell count of more than 2 X 109/L
2. IgD Myeloma
Presence of Monoclonal IgD in the serum usually indicates IgD myeloma
No evident M spike on serum protein electrophoresis
Higher incidence of renal insufficiency, amyloidosis and proteinuria than IgG/IgA myeloma.
Higher incidence of extramedullary involvement and inferior survival rates.
3. Monoclonal gammopathy of undetermined significance (MGUS)
Serum monoclonal protein <3g/dl
Clonal bone marrow plasma cells < 10%
Absence of end organ damage such as hypercalcemia, renal failure, anemia and bone lesions (CRAB)
No lytic bone lesions
No evidence of other B-cell proliferative lesion
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4. Smoldering multiple myeloma (Asymptomatic multiple myeloma)

Both criteria must be met
Serum monoclonal protein ( > 3 g/dl) and/or > 10% clonal bone marrow plasma cells or both
Absence of end organ damage (CRAB)
5. Multiple myeloma
All three criteria must be present
* Monoclonal protein present in serum or urine
* > 10% clonal bone marrow plasma cells on biopsy or histological evidence of plasmacytoma
* Evidence of end organ damage (CRAB):
HyperCalcemia (> 11.5 g/dl)
Renal insufficiency (Serum creatinine > 1.73 mmol/L)
Anemia (Hb< 10g/dl or > 2g/dl lower than normal)
Bone marrow plasma cell labeling index > 1%
Lytic lesions or osteoporosis and > 30% plasma cells in marrow
108. Ans. (c) Plasmacytoma on biopsy (Ref: T. Singh 1st/210-211, Robbins 9/e p600-601)
The commonly used diagnostic criteria of multiple myeloma are:
MULTIPLE MyELOMA
Major criteria
1. Plasmacytoma on tissue biopsy
2. Bone marrow plasmacytosis with > 30% plasma cells
3. Monoclonal globulin spike on serum electrophoresis (> 3.5g/dL for IgG, > 2 g/dL for IgA) or on urine (> 1g/24 h of Bence-Jones
protein)

Minor criteria
1. Bone marrow plasmacytosis 10 to 30% plasma cells
2. Monoclonal globulin spike less than the level defined above
3. Lytic bone lesions
4. Reduced normal immunoglobulin (<50% of normal); IgM <0.05 g/dL, IgA < 0.1g/dL, IgG < 0.6 g/dL
The diagnosis of multiple myeloma requires a minimum of two major criteria or one major criteria + one minor criteria, or
three minor criteria.
109. Ans. (a) CD 1a (Ref: Robbins 9/e p622, 7th/701, 702)
Histiocytosis is a broad term for a number of dendritic cells or macrophages proliferative disorders. Langerhans cell is
a special type of dendritic cell in the skin functioning as antigen presenting cell. In the past, these disorders were called
histiocytosis X and were subdivided into three categories:
Letterer-Siwe syndrome
Hand-Schller-Christian disease,
Eosinophilic granuloma.
The tumor cells in each are derived from dendritic cells and express HLA-DR, S-100, and CD1a.
They have abundant, often vacuolated cytoplasm and vesicular nuclei containing linear grooves or folds.
The presence of Birbecks granules in the cytoplasm is characteristic. Under the electron microscope, Birbecks granules have
a tennis-racket appearance.
110. Ans. (b) Sheets of atypical plasma cells (Ref: Robbins 9/e p599, 7th/679)
Old patient along with lytic circumscribed punched out X-ray appearance suggests multiple myeloma
Multiple myeloma most often presents as multifocal destructive bone tumors composed of plasma cells throughout
the skeletal system.
111. Ans. (a) Cryoglobulinemia; (b) Multiple myeloma; (d) Lymphoma; (e) Macroglobulinemia
(Ref: Williams Haemotology 6/1268)
Hyperviscosity is seen in
Multiple myeloma
Waldenstroms macroglobulinemia
Cryoglobulinemia
MGUS (Monoclonal Gammopathy of uncertain significance): Here M Protein can be identified in the Serum of 1% of healthy individual
>50 years. age and 3% in older than 70 years of it is the most common form of monoclonal gammopathy. In MGUS less than 3g/dL of
monoclonal protein is present in serum and there is no Bence Jones proteinuria.
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Hyperviscosity is defined on the basis of the relative viscosity of serum as compared with water. Normal relative viscosity of serum is 1.8
112. Ans. (b) Waldenstroms macroglobulinemia; (c) Multiple myeloma. (Ref: Williams Hematology 6th-1268)
113. Ans. (b) CD l+ ; (c) Birbecks granules are pathognomonic; (d) Proliferation of antigen presenting cells; (e) Resembles
Dendritic cells; (Ref: Robbins 9/e p622, 7th/701)
114. Ans. is c i.e. Wire loop lesions (Ref: Harrison 17th/573, Robbins 7th/232 9/e p223)
Wire loop lesions are characteristic of SLE and are not seen in multiple myeloma.
115. Ans. (b) IL-6 (Ref: Robbins 7th/679, 9/e p599)
116. Ans. (d) Systemic lupus erythematosus (Ref: Robbins 7th/678-679)
Plasma cell dyscrasias are characterized by proliferation of B-cell clone which synthesizes and secretes a single homog-
enous immunoglobulin or its fragments. This entity includes Multiple myeloma, Waldenstroms macroglobulinemia,
Heavy chain diseases, Primary or immunocyte associated amyloidosis and Monoclonal Gammopathy of Undetermined
Significance (MGUS).
117. Ans. (d) No lymphadenopathy (Ref: Robbins 9/e p622, 8th/631-632, 7th/701-702)
118. Ans. (c) lgG (Ref: Robbins 9/e p600, 8th/609-611; 7th/680)
119. Ans. (a) Langerhans cell (Ref: Robbins 9/e p622, 8th/631; 7th/701)
120. Ans. (a) Monoclonal IgM spike in serum (Ref: Robbins 8th/610-2, Harrison 18th/942-3)
Kuljeet has symptoms of hyperviscosity syndrome like visual disturbances, dizziness, and headache. He is also having
Raynauds phenomenon. His bone marrow is infiltrated with plasmacytoid lymphocytes having immunoglobulins in the
cytoplasm (Russell bodies). These findings are suggestive of the patient suffering from lymphoplasmacytic lymphoma/
Waldenstroms macroglobulinemia. This disorder is characterized by neoplastic B cells producing IgM leading to a mono-
clonal IgM spike in the serum. The IgM molecules aggregate resulting in hyperviscosity.
Concept
There is no leukemia phase in Waldenstroms macroglobulinemia.
Multiple myeloma (also associated with monoclonal gammopathy) does not cause enlargement of liver and spleen.
Hypercalcemia occurs with myeloma because of bone destruction, and punched out lytic lesions are typical of multiple myeloma.
Light chain in urine (Bence Jones proteins) is also a feature of multiple myeloma.
121. Ans. (c) Kappa light chains: (Ref: Robbins 9/e p600, 8th/610)
The patient suffers from multiple myeloma in which malignant cells are responsible for the production of excessive
amounts of immunoglobulin (usually IgG or IgA). Plasma cells synthesize a greater amount of light chains than heavy
chains. In multiple myeloma, the light chains will be monoclonal. This patient is making a monoclonal population of kappa
light chains and excreting them in the urine as Bence-Jones proteins. These patients make decreased levels of normal im-
munoglobulins of all isotypes, thus making them susceptible to infections (also the commonest cause of death). Infiltration
of bone by the myeloma cells may lead to pathological fractures.
121.1. Ans. (a) Multiple Myeloma (Ref: Robbins 9/e p599, 8/e p610)
In multiple myeloma, cytologic variants stem from the dysregulated synthesis and secretion of immunoglobulins, which
often leads to intracellular accumulation of intact or partially degraded protein. Such variants include:
Flame cells: with fiery red cytoplasm,
Mott cells: with multiple grapelike cytoplasmic droplets
The globular inclusions are referred to as Russell bodies (if cytoplasmic) or Dutcher bodies (if nuclear).
121.2. Ans. (b) Langherhans (Ref: Robbins 9/e p622, 8/e p631-2)
LCH has the following presentations:
Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease)
Occursmost frequently before 2 years of age
Dominant clinical feature is the development of cutaneous lesions resembling a seborrheic eruption over the
front and back of the trunk and on the scalp.
Presence of concurrent hepatosplenomegaly, lymphadenopathy, pulmonary lesions, and (eventually) destructive
osteolytic bone lesions.
Unifocal and multifocal unisystem Langerhans cell histiocytosis (eosinophilic granuloma)
Characterized by proliferations of Langerhans cells admixed with variable numbers of eosinophils, lymphocytes,
plasma cells, and neutrophils.
352

Typically arises within the medullary cavities of bones, most commonly the calvarium, ribs, and femur. Less
commonly, unisystem lesions of identical histology arise in the skin, lungs, or stomach.
Unifocal lesions most commonly affect the skeletal system in older children or adults. Unifocal disease is indolent
and may heal spontaneously or be cured by local excision or irradiation.
Multifocal unisystem disease usually affects young children, who present with multiple erosive bony masses
that sometimes expand into adjacent soft tissue.
Hand-Schuller-Christian triad: calvarial bone defects + diabetes insipidus + exophthalmos
Pulmonary Langerhans cell histiocytosis
Seen in adult smokers
Regress spontaneously upon cessation of smoking.
121.3. Ans. (a) Multiple myeloma (Ref: Harsh Mohan 6th/383, Robbins 9th/)
Increased levels of microglobulin are seen in the urine and serum of patients with multiple myeloma.
Harrison 18th/941. Serum 2 -microglobulin is the single most powerful predictor of survival and can substitute for staging.
122. Ans. (b) Glanzmanns thrombasthenia > (d) Bernard Soulier disease (Ref: Robbins 8th/, Wintrobes 12th/1365-1370)
Presence of normal PT and aPTT rules out the presence of any clotting factor deficiency. So, options like factor X deficiency
and von Willebrand disease are ruled out. Clinically, both Glanzmann thrombasthenia and Bernard Soulier syndrome are
indistinguishable. However, most of the haematologists agreed on placing Glanzmann thrombasthenia in preference to
Bernard Soulier syndrome as the answer. We got an article supporting the increased prevalence of Glanzmann in compari-
son to Bernard Soulier in Western India as well.
Name of disease Bernad Soulier disease Glanzmanns thrombasthenia
Cause of disease Defect in the platelet GpIb-IX complex Defect in platelet Gp IIb/IIIa

Lab findings BT, mild thrombocytopenia, deficient or low levels BT, deficient clot retraction time, deficient platelet
of platelet GpIb-IX complex by flowcytometry aggregation with ADP, collagen, thrombin, adrenaline
Ristocetin aggregation test is defective Ristocetin aggregation test and coagulation tests are
normal
Platelet morphology Giant platelets under normal smear Platelets are normal under microscope
123. Ans. (c) Factor VIII inhibitors (Ref: Robbins 8th/672-3, Wintrobe 12th/1447-1453, Harrison 18th/982)
This is a case of 25 year old asymptomatic female whose parametric inference is as follows:
BT is 3min (normal)
PT is 15 sec/14 sec (normal)
aPTT is 45sec/35sec(raised)
Platelet count is 2.5lac/mm3 (normal)
Factor VIII levels were 60IU/dL (normal i.e. between 50-150IU/dL).
Analyzing all the options one by one

Option a Factor IX deficiency would have resulted in increased aPTT. However females are less likely to suffer from
hemophilia B because it is an X-linked disease.
Option b.. Lupus anticoagulant (Wintrobe 12th/1452, Harrison 18th/982) clearly says that these patients have
thrombocytopenia (here platelet count is normal), prolonged PTT and hypoprothrombinemia due to antibodies against
prothrombin (normal in this case)
Option c.Factor VIII inhibitors (Wintrobe 12th/1441-1444, Harrison 18th/982); Tejender Singh hematology page no 308)
Acquired coagulant inhibitor is immune-mediated condition characterized by autoantibody against a specific clotting
factor and factor VIII is most common target.
In 50% of patients no underlying disease is indentified at the time of diagnosis. In remaining the causes are autoimmune
disease, malignancies, dermatologic diseases, pregnancy and post partum.
Diagnosed by isolated prolongation of PTT with normal PT (coagulation profile is similar to haemophilia A). Platelet
count and bleeding time is normal (matches with the data given in our question).
Option d. VWD type III (Robbins 8th/672-3):Bleeding time will be prolonged (in this patient BT is normal) with
abnormal platelet count. So, optiond is excluded.
So the likely diagnosis for the patient in the stem of the question is presence of acquired coagulation inhibitors against
Factor VIII.
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124. Ans. (c) Done within 2 hours (Ref: Dacie and Lewis practical hematology 10th/392, 398)
For Prothrombin Time estimation
Platelet poor plasma is used
Sample should be kept at room temperatureQ (if stored at room temperature, PT is shortened due to VII activation in cold)
Activation is done with thromboplastin (derived from rabbit brain or lung)
Activation with kaolin is done for PTT not for PT
PT, APTT are carried out on fresh samples
The test done within 2 hoursQ
Normal value is 11-16 secQ
Interpretation of increased prothrombin time
Administration of oral anticoagulants (vitamin K antagonists)
Liver disease particularly obstructive type
Vitamin K deficiency
Disseminated intravascular coagulation
Rarely, previously undiagnosed factor VII, X, V or prothrombin deficiency or defect
For Activated Partial Thromboplastin Time estimation
Platelet poor plasma is used
Sample should be kept at room temperatureQ
Activation is done with kaolin/silica/ellagic acid
Normal value is 26-40 secQ
Conditions with elevated aPTT
Seen in DIC, liver disease, massive transfusion with plasma depleted RBCs, circulating anticoagulant (inhibitor), deficiency of
clotting factor other than VII, administration of or contamination of heparin or other anticoagulants.
Sample should be kept at room temperature for estimation for prothrombin time, lupus anticoagulant and factor VII assays.
125. Ans. (d) Acquired Factor VIII inhibitors (Ref: Wintrobes 12th/1442-4, 1274)
The clinical presentation in a young female of recurrent joint pains with petechial hemorrhage is suggestive of an autoim-
mune disease. Options a, b and c are rare because these would present with some additional symptoms apart from the
ones mentioned in the question. They would also be present since birth.
Talking about option d,
A female patient is unlike to have hemophilia as it is an X linked disorder. However, she can have autoantibodies against
factor VIII. This could be due to other conditions mentioned below in the accompanying box.
Concept of Inhibitors (updated from Wintrobes 12th, Harrison 18th/982)
*A relatively rare cause of prolonged aPTT is presence of antibodies against coagulation plasma proteins called inhibitors. It can be
seen due to the following reasons:
Hemophilia A and B patients receiving clotting factors to control their bleeding episodes
Pregnancy
Autoimmune diseases
Malignancies (lymphoma, prostate cancer)
Dermatologic conditions
*Clinical manifestations include bleeding episodes in soft tissues, skin, GIT and genitourinary tract.
*The diagnosis is made with a prolonged aPTT with normal PT and TT which is not corrected with mixing the
test plasma with normal pooled plasma for 2hrs at 370C.
*Treatment is done with high dose i.v. immunoglobulins and anti CD20 monoclonal antibody.
126. Ans. (b) Normal platelet count and increased BT (Ref: Harrison 17th/723, Robbins 8th/670, Robbins 9/e 656)
The stem of the question clearly mention the fact that there is platelet function defect. It means that the platelet count is
normal with a problem in the functioning of platelets. see text for details.
Bleeding time represents the time taken for a standardized skin puncture to stop bleeding and it gives an in vivo assessment of
platelet response to limited vascular injury. The value varies from 2 to 9 minutes. It is abnormal when there is a defect in platelet
numbers or function.
Nowadays, quantitative measures of platelet function are being introduced by using an electronic particle counter.
127. Ans. (d) Defect in common pathway (Ref: Robbins 9th/119)

Defect in the extrinsic pathway causes elevation of PT
Defect in the intrinsic pathway causes elevation of aPTT.
Defect in common pathway cause elevation of both PT and aPTT.
354 Platelet function defect causes elevation of BT.
128. Ans. (d) Grossly abnormal coagulation tests (Ref: Harrison 17th/722, Robbins 9/e p659-660)
Thrombotic thrombocytopenic purpura arises from deficiency or inhibition of the enzyme ADAMTS13, which is responsi-
ble for cleaving large multimers of von Willebrand factor (vWF).
The combination of hemolytic anemia with fragmented RBCs, thrombocytopenia, normal coagulation tests, fever, neuro-
logical disorders and renal dysfunction is virtually pathognomic of TTP.
If coagulation tests indicate a major consumption of procoagulants, the diagnosis of TTP is doubtful.
129. Ans. (a) Acute promyelocytic leukemia (Ref: Harrison 17th/679, Robbins 9/e p612)
AML is classified by French-American-British (FAB) classification into various categories from M0 to M7. This classifica-
tion has already been discussed in text. In which DIC is associated with AML-M3 or Acute promyelocytic leukemia.
Recently WHO has also classified AML. WHO classification includes different biologically distinct groups based on immu-
nophenotype, clinical features, and cytogenetic and molecular abnormalities in addition to morphology. In contrast to the previously
used French-American-British (FAB) scheme, the WHO classification places limited reliance on cytochemistry.
WHO CLASSIFICATION OF AML
AML with recurrent AML with multilineage AML and myelodysplastic AML not otherwise categorized
genetic abnormalities dysplasia syndromes, therapy-related
*t(8;21 *Following a *Alkylating agent related *AML minimally differentiated
*inv(16) myelodysplastic *Topoisomerase type II *AML without maturation *AML with maturation
*Acute promyelocytic syndrome inhibitor-related *Acute myelomonocytic leukemia
leukemia, t(15;17) *Without antecedent *Other types *Acute monoblastic and monocytic leukemia
myelodysplastic *Acute erythroid leukemia
syndrome *Acute megakaryoblastic leukemia
*Acute basophilic leukemia
*Acute panmyelosis with myelofibrosis

*Myeloid sarcoma
Another important difference between the WHO and FAB systems is the blast cutoff for a diagnosis of AML as op-
posed to myelodysplastic syndrome (MDS);
According to FAB classification AML is diagnosed when bone marrow shows 30% blasts whereas WHO keeps this value at 20%.
130. Ans. (c) Aplastic anemia (Ref: Harrison 17th/719,720, 667-668 & 16th/674, 622)
Megakaryocyte is a precursor of platelet. Any peripheral destruction of platelets causes increased activity of bone
marrow resulting in megakaryocytic thrombocytopenia because of compensatory increase in megakaryocytes.
However, if thrombocytopenia occurs due to any defect in the bone marrow itself, the compensatory increase in
megakaryocytes will not occur. This is known as amegakaryocytic or hypoplastic thrombocytopenia.
Aplastic anemia is also an example of amegakaryocytic thrombocytopenia.
131. Ans. (a) D-dimer will be normal (Ref: Wintrobes Hematology 11th/1672)
Coagulation defects in severe liver disease include elevated thrombin time, prothrombin time and activated partial
thromboplastin time.
All factors procoagulant as well as anti clotting factors (antithrombin III, protein C and protein S) being synthesized
in the liver are reduced in liver dysfunction.
Fibrin degradation products are increased in patients with severe liver disease and DIC because endogenous plas-
minogen activators are removed by the normal liver. In severe liver disease, they circulate for long time and cause
activation of the fibrinolytic system.
D-dimer is usually normal in liver disease patients. It is increased with DIC.
Wintrobes mentions page 1396-7 that ..Normal fibrinogen level is 150-350 mg/dl and the levels between 50-100mg/dl are
required for normal hemostasis. However, I could not find any level specifically in cirrhosis patients friends.
132. Ans. (d) Wiskott Aldrich syndrome (Ref: Robbins 7th/244, 8th/235, 9/e p242)
Wiskott Aldrich syndrome is characterized by the triad of:
Severe eczema
Thrombocytopenia
Recurrent infections
The platelets are small and are reduced in number in Wiskott Aldrich syndrome.
About other options, in ITP, Bernard Soulier syndrome and Myelofibrosis, there is increase in size of platelets.
133. Ans. (a) Serotonin; (b) Ig mediators; (d) Interaction among the platelets; (e) Macromolecules; (Ref: Williams Haematology
61th/1366, Harrison 17th/363-364, Robbins 9/e p117-118)
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Agonists of platelet aggregation:

Adhesins vWF Plasmin Serotonin
Thrombospondin Fibrinogen Immunocomplex Vasopressin
TxA2 ADP Epinephrine
P-selectin mediates the interaction between WBC and platelets.
134. Ans. (a) Abruptio placentae; (b) Acute pro-myelocytic leukemia; (c) Severe falciparum malaria; (d) Snake envenoma-
tion; (e) Heparin overdose. (Ref: Robbins 7th/657, 9/e 663-664, KDT 5th- 562)
135. Ans. (b) Increased PT; (d) Decreased Fibrinogen; (e) Decreased platelets (Ref: Robbins 7th/657, 9/e 664-665)
Laboratory findings in DIC:
*Low platelet count.
*Microangiopathic hemolytic anemia
*Elevated prothrombin time, thrombin time, and activated partial thromboplastin time
*Plasma fibrinogen level decreased
*Fibrin degradation products (FDP) are raised.
*Factor V and factor VIII decreased.
136. Ans. (a) Anaerobic Sepsis; (b) Malignancy; (c) Leukemia. (Ref: Robbins 7th/657, 9/e 663-664)
137. Ans. (a) Glanzmanns syndrome; (b) Bernard-Soulier syndrome; (c) Wiskott Aldrich syndrome; (d) von Willebrand
disease (Ref: Harrison 17th/723, Robbins 9th/660)
For details, See text
Leucocytosis is seen in all of the given options i.e. brucellosis, acute MI, and diphtheria but in typhoid, there is leucopenia.
138. Ans. (d) All of the above (Ref: Harrison 17th/723-724; Robbins 8th/118, 9/e p662)
139. Ans. (d) Angiogenesis inhibitory protein (Ref: Robbins 9/e p306, 8th/96, 7th/105)
Thrombospondin, is a family of large multi-functional proteins, some of which, similar to SPARC (secreted protein
acidic and rich in cysteine), inhibit angiogenesis.
The production of thrombospondin-I has been shown to be inversely related to the ability of a cell line to produce
a tumor and vessels in vivo; loss of thrombospondin-I production allowed non-tumorigenic cells to become tumori-
genic.
Thrombospondin-I is regulated by wild-type p53.
140. Ans. (a) Thromboplastin (Ref: Robbins, 7th/649, 9/e 656)
141. Ans. (a) Myelofibrosis (Ref: Harrison 17th/723)
Causes of Thrombocytosis
Iron deficiency anemia Myelodysplasia
Hyposplenism Post surgery
Postsplenectomy Infection
Malignancy Polycythemia vera
Collagen vascular disorder Hemolysis
Idiopathic myelofibrosis Hemorrhage
Essential thrombocytosis Idiopathic sideroblastic anemia
CML Rebound (cessation of ethanol intake, correction of B12 and folate deficiency).
142. Ans. (a) Synthesized by hepatocytes (Ref: Robbins 8th/670-671, 9/e 661)
von-Willebrand factor (vWF) facilitates platelet adhesion to vascular endothelium and serves as the plasma carrier
for the factor VIII.
It is synthesized in endothelial cells and megakaryocytes.
The Weibel Palade bodies are storage organelle for vWF.
Principal site of synthesis of factor VIII is liver.
143. Ans. (d) VIII (Ref: Robbins 8th/835, 9/e 661)
144. Ans. (d) Antithrombin (Ref: Harsh Mohan 6th/340)
145. Ans. (c) von Willebrand disease (Ref: Robbins 8th/672-673; 7th/649, 9/e 662)
146. Ans. (c) t (14: 18) (Ref: Robbins 9/e 591, 8th/605-606, 7th/677)
147. Ans. (a) Decrease in neutrophil count (Ref: Robbins 8th/592-593, 9/e p582)
148. Ans. (b) 1,00,000/cmm (Ref: Robbins 9/e p657, 8th/667; 7th/650)
356
149. Ans. (c) Glycoprotein IIb/IIIa (Ref: Robbins 9/e 657-658, 8th/667-668)
The history of nosebleeds and menorrhagia, the petechiae, thrombocytopenia and increased bleeding time all suggest
a platelet disorder. The decreased platelet count suggests a thrombocytopenic disorder rather than a platelet function
disorder. The absence of antinuclear antibody rules out SLE (a significant cause of thrombocytopenia). The negative drug
history rules out drug-associated thrombocytopenia. So, a probable diagnosis of idiopathic thrombocytopenic purpura can
be made. ITP is an acquired thrombocytopenia caused by formation of autoantibodies directed against the platelet mem-
brane proteins glycoprotein IIb/IIIa, followed by splenic destruction of opsonized platelets. The disease typically occurs
in women from 20-40 years of age.
Antibodies to erythrocyte membrane proteins (choice B) are seen in autoimmune hemolytic anemia whereas antibodies to
intrinsic factor (choice D) are seen in pernicious anemia.
150. Ans. (a) Antiplatelet antibodies (Ref: Robbins 8th/667, 9/e p657)
ITP is a chronic autoimmune disorder in which antibodies against platelet glycoproteins cause platelet destruction
and removal by the reticuloendothelial system. Secondary thrombocytopenia can also be produced by lupus, viral
infections, and drugs. The diagnosis of ITP is made only when secondary thrombocytopenia has been ruled out.
Defective platelet aggregation (choice B) is responsible for thrombasthenia that causes prolonged bleeding time but
normal platelet count.
Hypersplenism (choice C) causes thrombocytopenia when an enlarged spleen traps normal platelets in the absence of
other specific platelet disorders. This type of thrombocytopenia can be cured with splenectomy. The thrombocytope-
nia in ITP often improves with splenectomy, ITP does not cause splenomegaly.
Megakaryopoiesis (choice D) is disturbed in any disorder that causes bone marrow failure, including drug toxicity,
leukemia, and infections. So, thrombocytopenia is often part of a pancytopenia.
150.1. Ans. (c) Congenital defect of platelets (Ref: Robbins 8/e p670, 9/e p660)
Glanzmann thrombastheniais a defect in platelet aggregation (both have g in them).

Bernard Soulier syndrome is a defect in platelet adhesion (both haved in them).
Glanzmann thrombasthenia, which is also transmitted as an autosomal recessive trait. Thrombasthenic platelets fail to
aggregate in response to adenosine diphosphate (ADP), collagen, epinephrine, or thrombin because of dysfunction of
glycoprotein IIb-IIIa, an integrin that participates in bridge formation between platelets by binding fibrinogen
150.2. Ans. (c) Decreased fibrin degradation productsdiscussed earlier (Ref: Robbins 9/e 662-663, 8/e p673-674, 7/e p658)
DIC is associated with increased fibrin degradation products.
150.3. Ans. (a) Normal complement levels (Ref: Robbins 9/e 659-660, 8/e p669-670, 7/e p652-653)
Classically, the following five features (pentad) are indicative of TTP:
Fluctuating neurological symptoms, such as bizarre behavior, altered mental status, stroke or headaches
Kidney failure
Fever
Thrombocytopenia (low platelet count), leading to bruising or purpura
Microangiopathic hemolytic anemia (anemia, jaundice and a characteristic blood film)
HUS and TTP are both caused by insults that lead to the excessive activation of platelets, which deposit as thrombi
in microcirculatory beds. These intravascular thrombi cause a microangiopathic hemolytic anemia and widespread organ
dysfunction, and the attendant consumption of platelets leads to thrombocytopenia.
Wintrobes mentions that.. immune complex formation and activation of the complement activation has been seen in
TTP.
150.4.Ans (b) Glanzmann disease (Ref: Robbins 9th/118)
Inherited deficiency of GpIIb-IIIa results in a bleeding disorder called Glanzmann thrombasthenia.
150.5. Ans (b) Relapse is rare (Robbins 9th/658)
Direct quote. Almost all patients respond to glucocorticoids (which inhibit phagocyte function), but many eventually
relapse.
In individuals with severe thrombocytopenia, splenectomy normalizes the platelet counts.
Immunomodulatory agents such as intravenous immunoglobulin or anti-CD20 antibody (rituximab) are often
effective in patients who relapse after splenectomy or for whom splenectomy is contraindicated.
Peptides that mimic the effects of thrombopoietin (so-called TPO-mimetics) are also useful for improving the platelet
counts of the patients.
150.6 Ans: (a) Chronic ITPsee earlier explanation
150.7. Ans (c) Shwachman syndrome.(Ref: Harrison 18th/Ch 107)
Shwachman-Diamond syndrome is associated with pancreatic insufficiency, marrow failure and malabsorption.
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GOLdEN POiNTS fOr QUick rEViSiON / UPdATEd iNfOrMATiON frOM 9TH EdiTiON Of rOBBiNS
(WHiTE BLOOd cELLS & PLATELETS)
Macrophage activation syndrome/ Hemophagocytic Lymphohistiocytosis....585-6

Hemophagocytic lymphohistiocytosis (HLH) is a reactive condition having the signs and symptoms of systemic inflammation
related to macrophage activation as well as having marked by cytopenias.
The most common trigger for HLH is infection, particularly with Epstein-Barr virus (EBV).
Pathogenesis
The condition is characterized by the systemic activation of macrophages and CD8+ cytotoxic T cells which phagocytose blood
cell progenitors in the bone marrow. The mediators released by these cells suppress hematopoeisis and produce symptoms of systemic
inflammation (cytokine storm). Even familial forms of the disease have activating mutations in cytotoxic T cells and natural killer cells.
Clinical Features
Most patients present with an acute febrile illness associated with splenomegaly and hepatomegaly. Bone marrow examination demonstrates
hemophagocytosis. Blood picture is characterized by anemia, thrombocytopenia, and very high levels of plasma ferritin and soluble IL-2
receptor (the latter two indicative of severe inflammation), as well as elevated liver function tests. The disease may progress to disseminated
intravascular coagulation and may be fatal.
Treatment involves the use of immunosuppressive drugs and mild chemotherapy. Some individuals may require
hematopoietic stem cell transplantation.
chronic lymphocytic leukemia.593

Deep sequencing of CLL genomes has also revealed gain-of-function mutations involving the NOTCH1 receptor in 10% to 18% of tumors,
as well as frequent mutations in genes that regulate RNA splicing.
common forms of Lymphoid Leukemia and Lymphoma.598
Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
Most common type of cancer in children, may be derived from either precursor B of T cells
Highly aggressive tumors manifest with signs and symptoms of bone marrow failure, or as rapidly growing
masses.
Tumor cells contain genetic lesions that block differentiation, leading to the accumulation of immature, nonfunctional
blasts.
Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia
Most common leukemia of adults

Tumor of mature B cells that usually manifests with bone marrow and lymph node involvement
Indolent course, commonly associated with immune abnormalities, including an increased susceptibility to
infection and autoimmune disorders
Follicular Lymphoma
Most common indolent lymphoma of adults

Tumor cells recapitulate the growth pattern of normal germinal center B cells; most cases are associated with a
(14;18) translocation that results in the over expression of BCL2.
Diffuse Large B-Cell Lymphoma
Most common lymphoma of adults

Heterogeneous group of mature B-cell tumors that shares a large cell morphology and aggressive clinical behavior
Rearrangements or mutations of BCL6 gene are recognized associations; one third carry a (14;18) translocation
involving BCL2 and may arise from follicular lymphomas.
358
Burkitt Lymphoma
Very aggressive tumor of mature B cells that usually arises at extranodal sites.
Strongly associated with translocations involving the MYC proto-oncogene
Tumor cells often are latently infected by EBV.
Myeloid Neoplasms
Myeloid tumors occur mainly in adults and fall into three major groups:
Acute myeloid leukemias (AMLs)
Aggressive tumors comprised of immature myeloid lineage blasts, which replace the marrow and suppress normal
hematopoiesis
Associated with diverse acquired mutations that lead to expression of abnormal transcription factors, which inter-
fere with myeloid differentiation
Often also associated with mutations in genes encoding growth factor receptor signaling pathway components or
regulators of the epigenome
Myeloid tumors in which production of formed myeloid elements is initially increased, leading to high blood
counts and extramedullary hematopoiesis
Commonly associated with acquired mutations that lead to constitutive activation of tyrosine kinases, which mimic
signals from normal growth factors. The most common pathogenic kinases are BCR-ABL (associated with CML)
and mutated JAK2 (associated with polycythemia vera and primary myelofibrosis).

All can transform to acute leukemia and to a spent phase of marrow fibrosis associated with anemia, thrombocy-
topenia, and splenomegaly.
Myelodysplastic Syndromes
Poorly understood myeloid tumors characterized by disordered and ineffective hematopoiesis and dysmaturation
Recently shown to frequently harbor mutations in splicing factors and epigenetic regulators
Manifest with one or more cytopenias and progress in 10% to 40% of cases to AML
Langerhans cell histiocytosis.621
The most common mutation is an activating valine to- glutamate substitution at residue 600 in a serine/threonine protein
kinase called BRAF. The latter is also commonly involved in patients with hairy cell leukemia.
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CHAPTER
HEART
9 Cardiovascular System
The human heart is a muscular pump responsible for maintaining the circulation of the blood
and perfusion of different organs of the body. The thickness of the left ventricle is almost three
times that of the right ventricle. The cardiac output is about 5 liters per minute. The heart is
supplied by the coronary arteries:

1. Left coronary artery: It divides into left anterior descending artery (LAD) and the left The volume of the blood pumped
circumflex artery (LCX). The LAD is responsible for supplying the following regions by the heart in a single beat is
of the heart: called as stroke volume (about

Apex of the heart 70 ml).

Anterior 2/3rd of the interventricular septum

Anterior wall of the left ventricle
The LCX mainly supplies the lateral wall of the left ventricle.

2. Right coronary artery: It supplies

The entire right ventricular free wall Normal ejection fraction is

Posterobasal wall of the left ventricle 65%

Posterior 1/3rd of the interventricular septum.
Out of the three layers of the heart (pericardium, myocardium and endocardium), the
least collateral perfusion is present in the endocardium. So in any conditions associated with The most important source of
reduced perfusion (hypotension/shock), there are increased chances of sub endocardial energy for the cardiac myocytes
ischemia. The coronary artery supplying the posterior 1/3rd of the ventricular septum is the fatty acids.
(by giving rise to the posterior descending branch) is called dominant. In majority of the
individuals (~80%), this vessel arises from the RCA, so they have right dominant circulation.
The myocardium or the cardiac muscle is composed of the cardiac myocytes which cannot
undergo division or hyperplasia in response to stress. The only adaptation that can be seen in
a cardiac muscle can be hypertrophy which can be of the following types:
Concentric hypertrophy/pressure overload hypertrophy: It is due to deposition of the SA node is the pacemaker of
sarcomeres (functional intracellular contractile unit of the cardiac muscle) in parallel to the long the heart
axis of the cells. It is associated with hypertension and aortic stenosis. AV node is the gatekeeper of
Volume overload hypertrophy: In this, dilatation with increased ventricular diameter is present. the heart
It is seen with valvular regurgitation (mitral or aortic regurgitation), thyrotoxicosis and severe
anemia.
HEART FAILURE
It is a clinical condition characterized by the inability of the heart to pump blood in

proportion with the requirements of the metabolic tissues of the body or being able to do so at
increased filling pressures. It may be divided into systolic or diastolic failure depending on
whether there is abnormality in the cardiac contractility (systolic failure; as seen in ischemic
heart disease, pressure or volume overload, dilated cardiomyopathy) or in the ventricular
relaxation (diastolic failure; as in constrictive pericarditis, myocardial fibrosis or amyloid
deposition). We can also classify heart failure as:
L eft ventricular failure/left sided heart failure (LVF)

It is most commonly caused by ischemic heart disease, hypertension, aortic or mitral valvular disease
and myocardial disease (non-ischemic). The features include hypertrophy and fibrosis in the Lungs are the most commonly
myocardium associated with secondary involvement of the atria which shows enlargement. affected organ in LVF.
Atrial involvement results in the development of the atrial fibrillation which is responsible
for thrombus formation or embolic stroke. The other organs affected include:
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Lungs
It is the most commonly affected organ. The increased pressure in the pulmonary vein causes
pulmonary edema (heavy wet lungs). The edema fluid accumulates in the alveolar space.
There is leakage of hemosiderin and other iron containing particles which are phagocytosed by
macrophages. The iron gets converted to hemosiderin leading to the formation of siderophages
or heart failure cells (hemosiderin containing macrophages).
The alveolar fluid impairs gaseous exchange giving rise to breathlessness or dyspnea (earliest
Siderophages or heart failure
feature of LVF), orthopnea (dyspnea on lying down) and paroxysmal nocturnal dyspnea (dyspnea
cells are hemosiderin containing
at night).
macrophages.
There is presence of Kerley B lines on chest X-ray due to transudate in the interlobular septa.
Kidneys
In the early stages, decreased renal perfusion causes activation of the renin-angiotensin-aldosterone
system whereas in the later stages, continued reduced renal perfusion may precipitate prerenal
azotemia.
Brain
It may suffer from hypoxic ischemic encephalopathy.
Left ventricular failure is the i ht sided heart failure

Rg
most common cause of the right Left ventricular failure is the most common cause of the right sided heart failure whereas pure right
sided heart failure.
sided failure is seen in chronic severe pulmonary hypertension and is called as cor pulmonale.
Cardiovascular System
Cardiac cirrhosis is character-

ised by nutmeg liver.
The features seen as a result of the inability of the right heart to pump blood in different
organs include:
Liver
There is presence of congestive hepatomegaly. In addition, if associated LVF is present, the centrilobular
necrosis is also seen which is replaced by fibrotic tissue in longstanding cases and is known as cardiac
sclerosis or cardiac cirrhosis.
Spleen
Congestive splenomegaly is seen.
Kidney
These show the congestion resulting in severe azotemia. The congestion is more prominent in RVF
than in LVF.
Pleural effusion, pericardial effusion and ascites are also seen.
The hallmark of the right sided heart failure is peripheral edema of the dependent
parts of the body particularly pedal and pretibial edema.
Anasarca is the generalized massive edema seen in heart failure.
C V
RHEUMATI FE ER A ND RHEUMATIC HEART DISEASE (RHD)
Most commonly affected age Rheumatic fever is an acute immunologically mediated multisystem inflammatory disease that
group in rheumatic fever is 5-15 occurs few weeks after an attack of group A b- hemolytic streptococcal pharyngitis. It is not an
years. infective disease. The most commonly affected age group is children between the ages of
5-15 yearsQ. Only 3%Q of patients with group A streptococcal pharyngitis develop acute
rheumatic fever.
362
The disease is a type II hypersensitivity reaction in which antibodies against M protein

of some streptococcal strains (1, 3, 5, 6, and 18) cross-react with the glycoprotein antigens in
the heart, joints and other tissues (molecular mimicry).
WHO criteria for diagnosis of RF and RHD [Based on revised (1992) Jones criteria]
1. Major manifestations:
J
Joint involvement (Polyarthritis)
O
N - Nodules (Subcutaneous)
E - Erythema marginatum
S - Sydenhams chorea
Criteria - Carditis
2. Minor manifestations:
Clinical: Fever polyarthralgia
Migratory polyarthritis is the
Laboratory: Increased ESR or C-RP commonest major manifesta-
ECG: Prolonged PR interval tion of Jones criteria seen clini-
cally.
3. Supporting evidence of a preceding streptococcal infection within last 45 days:
Elevated or rising ASO or other Ab titers
Positive throat culture
Rapid antigen test for group A streptococcus.
Note:

1. Two major or one major and two minor manifestations plus any of the evidence of preceding
group A streptococcal infection is required for diagnosis of primary episode of rheumatic fever.

2. 1992 revised Jones criteria do not include elevated TLC (total leukcocyte count) as a laboratory
minor manifestation [instead, it includes elevated C-reactive protein] and do not include recent
scarlet fever as supporting evidence of recent streptococcal infection.
Salient features of the major criteria

Carditis
All the layers of the heart namely pericardium, myocardium and endocardium are involved, so this is
called pancarditis. The pericarditis is associated with fibrinous/serofibrinous exudate and is called
as bread and butter pericarditis. Valvular involvement is common in rheumatic heart disease. The
most common valve to be affected is the mitral valve and least commonly affected is pulmonary valve. Pancarditis is a characteristic
In acute rheumatic heart disease, the most common valvular lesion is mitral regurgitation and manifestation of the cardiac
in chronic rheumatic heart disease, it is mitral stenosis. involvement in rheumatic fever.
Migratory polyarthritis
There is involvement of the large joints of the body. It is more commonly seen in the adults as compared
to children. The arthritis involves one joint after the other (migratory) and subsides spontaneously
without any residual deformability in the joints (non-erosive arthritis). Clinically, this is the most
commonly seen manifestation and the joint pain shows dramatic response to salicylates like aspirin.
Subcutaneous nodules
These are painless subcutaneous lesions found on the extensor surface of the elbows, shin and the
occiput.
Erythema marginatum The plump macrophages
There is presence of red macular rash more easily appreciated in fair skinned individuals sparing the called Anitschkow cells are
face and without residual scarring. pathognomonic for rheumatic
fever.
Sydenhams chorea
It is a late manifestation of the disease characterized by presence of involuntary, purposeless
movements associated with emotional lability of the patient.
Microscopically, the characteristic feature of rheumatic heart disease is Aschoffs body.
The latter consist of foci of swollen eosinophilic collagen surrounded by T-lymphocytes, few
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plasma cells and plump macrophages called Anitschkow cells (pathognomonic for RF).
These distinctive cells have abundant cytoplasm and central round-to-ovoid nuclei in which
the chromatin is disposed in a central, slender, wavy ribbon (hence, they are also called as
caterpillar cells).
The myocardium has Aschoffs bodies in the perivascular location. The involvement
Most commonly affected of the endocardium results in fibrinoid necrosis within the cusps or along the tendinous
valve is mitral valve and the cords which also have small vegetations called verrucae present along the lines of closure. The
least commonly affected is presence of mitral regurgitation also induces irregular thickening in the left atrial wall called
pulmonary valve. as MacCallum plaques.
Chronic RHD is characterized by organization of the acute inflammation and subsequent
fibrosis. The valves show leaflet thickening, commissural fusion and shortening, and
thickening and fusion of the tendinous cords. There is mitral stenosis called as fish-mouth or
button-hole stenosis. Mitral stenosis may also lead to atrial fibrillation and thromboembolic
phenomenon in these patients.
N C V NDOCARDITIS (IE)
I FE TI E E
It is colonization or invasion of heart valves and mural endocardium by microbiologic

agent leading to formation of bulky, friable vegetations composed of thrombotic debris and
organisms with destruction of underlying cardiac tissues. It can be

Acute

Subacute
Acute endocarditis Subacute endocarditis
Necrotizing, ulcerative, invasive valvular Insidious infection following a protracted course
infection on a previously normal valve. on a previously damaged valve
Highly virulent organisms Low virulence organisms

Death of the patient within days to weeks Recover after antibiotic therapy
MC caused by Staph. aureus MC caused by a-hemolytic (viridans)
Streptococcus
Important Microbiology Link!
Organism in the infective endocarditis Predisposing condition

Staphylococcus aureus a. Intravenous drug abusers
b. Native cardiac valve
Staphylococcus epididermis Patients having prosthetic or artificial valve
Staphylococcus viridians Previously damaged valve
Staphylococcus mutans Patients who have had recent tooth extraction
Apart from all these enterococci and the HACEK group of bacteria (Hemophillus, Actinobacillus,
Cardiobacterium, Eikenella and Kingella) can cause infective endocarditis.
The aortic valve is the most rhl

Mo p o ogy
commonly affected valve in The friable, bulky destructive vegetations containing fibrin, bacteria and inflammatory cells
prosthetic valve endocarditis. are found on the valve cusps. These can also extend on to chordae. The aortic valve and the
mitral valve are most commonly infected whereas the right side of heart is affected in intravenous
drug abusers. When the vegetations erode into myocardium, they can form an abscess called
Ring abscess. The systemic embolisation can result in septic infarcts.
Blood culture is the

Clinical features
investigation of choice in Fever is the most consistent sign of IE. The other features include weight loss, flu-like syndrome,
infective endocarditis. cardiac murmur, systemic emboli, Roth spots (due to retinal emboli), Osler nodes (painful,
subcutaneous nodules on the fingers and toes) and Janeway lesions (red painless lesions on
the palms and soles).
The disease is diagnosed by Dukes criteria.
364
Complications
Cardiac complications
Valvular insufficiency or stenosis
Myocardial ring abscess
Suppurative pericarditis
Valvular dehiscence
Embolic complications
With left sided lesion Brain, spleen, kidney
With right sided lesion Lung infarct, lung abscess
Renal complications
Embolic infarct
Focal (more common) or diffuse glomerulonephritis (less common)
MARA TI EN C NDOCARDITIS/NON BACTERIAL THROMBOTIC ENDOCARDITIS (NBTE)

It is seen in patients suffering from debilitating diseases like malignancy (carcinoma
pancreas and acute promyelocytic leukemia) and hypercoagulable states (DIC)
Vegetations on heart valves are sterile and do not contain microorganisms. These
are usually present along the line of closure, single or multiple.
N S C S NDOCARDITIS (SLE)
LIBMA - A K E
Seen in patients of SLE

Vegetations are small or medium sized, sterile, granular and pink on either or both
sides of valve leaflets.
Mitral and tricuspid valves are involved and show fibrinoid necrosis.
Summary of salient features of vegetations in different endocarditis
Rheumatic Fever Non Bacterial Libman Sacks Endocarditis Infective
Thrombotic (Marantic Endocarditis
Endocarditis)
Small, warty Small, warty Medium sized (small) Large
Firm Friable Flat, Verrucous Bulky
Friable Irregular Irregular
Along lines of Along lines of closure On surface of cusps Vegetations on
closure (both surfaces may be in- the valve cusps
volved but the undersurface is Less often on
more likely affected, less com- mural endocar-
monly mural endocardium is dium
involved
In pockets of valves
Sterile (no or- Sterile Sterile Non-sterile
ganism) (bacteria)
Embolisation is Embolisation is Embolisation is uncommon Embolisation is
uncommon common very common
(max chances)
In rheumatic In cancers (like In SLE In infective en-
heart disease M3-AML, pancreatic docarditis
cancer), deep
vein thrombosis,
Trosseau syndrome
The most frequent causes of the functional valvular lesions

Aortic stenosis: Calcification of anatomically normal and congenitally bicuspid
aortic valves

Aortic regurgitation: Dilation of the ascending aorta due to hypertension and aging

Mitral stenosis: Rheumatic heart disease

Mitral regurgitation: Myxomatous degeneration (mitral valve prolapse).
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barlow syndrome
It is more common in females Q
In this valvular abnormality, one or both mitral leaflets are floppy and prolapse, or
balloon back into the left atrium during systole. This gives rise to the mid systolic click.
Most of the patients are usually asymptomatic Q
The condition is discovered only on routine examination by the presence of a

Q
midsystolic click as an incidental finding on physical examination.

Q
In those cases where mitral regurgitation occurs, there is a late systolic or some-
times holosystolic murmur
Some patients may present with chest pain mimicking angina, dyspnea, and fa-
tigue or, psychiatric manifestations, such as depression, anxiety reactions, and
personality disorders
Microscopically, The characteristic anatomic change in myxomatous degeneration
is intercordal ballooning (hooding) of complete or portions of the mitral leaflets.
The affected leaflets are often enlarged, redundant, thick, and rubbery. The tendi-
nous cords are elongated, thinned, and occasionally ruptured.
Annular dilation is a characteristic association(this finding is rare in other causes
of mitral insufficiency)
Mitral valve prolapse is defined and revealed by echocardiography Q
The risk of complications like Infective endocarditis, Mitral insufficiency, Stroke or
other systemic infarct and Arrhythmias is higher in men, older patients, and those
with either arrhythmias or some mitral regurgitation, as evidenced by holosystolic
murmurs and left-sided chamber enlargement.
I SCHEMIC HEART DISEASE

Ischemia of the heart is a result of imbalance between the perfusion and demand of the heart
for oxygenated blood. Atherosclerotic narrowing resulting in coronary arterial obstruction is
the cause of ischemic heart disease in almost 90% of the patients.
Sudden Cardiac Death

Suden cardiac death is most It is defined as the death of an individual within 1 hour of onset of symptoms. It is most
commonly due to ventricular commonly due to ventricular fibrillation.
fibrillation. In case of coronary vessel occlusion leading to ischemia, there is physiological
compensatory vasodilation resulting in augmentation of coronary blood flow. When
atherosclerotic obstruction is 75% or greater, exercise induces symptoms of ischemia and
if stenosis is more than 90%, symptoms occur even at rest. The initiating event in most of
these patients is disruption of partially stenosing plaque with ulceration, rupture of plaque
or hemorrhage into the atheroma.
Stable Angina
In the ECG, subendocardial
Stable angina occurs when the myocardial oxygen demand is more than the supply. It takes
ischemia manifests as ST place when the coronary artery is occluded >75%. Stable angina is characterized by pain on
segment depression. exertion which is relieved on taking rest or taking vasodilators like nitrates. There is neither
any plaque disruption nor any plaque associated thrombus. ECG changes include ST segment
depression and T wave inversion (subendocardial ischemia of the left ventricle).
366
Prinzmetal or Variant Angina

It is an episodic angina due to coronary artery spasm resulting in pain at rest. It is characterized
by ST segment elevation on the ECG (due to transmural ischemia).
In the ECG, transmural
C
Unstable or rescendo Angina ischemia manifests as ST
segment elevation.
It is induced by atherosclerotic plaque disruption with superimposed partial thrombosis
or vasospasm or both of them. The pain occurs with increasing frequency and for a longer
duration and is characteristically precipitated by progressively less exertion.
Myocardial Infarction (MI)

Myocardial infarction Concept
The main difference between
angina and the MI is elevation
Subendocardial MI Transmural MI of cardiac enzymes in the
latter which is not seen usually
Ischemic necrosis limited to 1/3rd of Ischemic necrosis involves full thickness of ventricular with angina. In one third of
ventricular wall wall the patients, angina may be
Caused by incomplete coronary Caused by severe coronary atherosclerosis, with acute associated with elevation of
artery occlusion. plaque rupture and superimoposed occlusive thrombus. cardiac enzymes.
Pathogenesis of MI
Changes in atheromatous plaque (hemorrhage/ulceration/ruputre)

Exposure of underlying collagen and platelet aggregation

Platelets release mediators which cause vasospasm

Activation of extrinsic clotting pathway and increased thrombus formation

Complete occulsion of coronary vessel by thrombus
Myocardial Response
Feature Time
Cessation of aerobic respiration or onset of ATP depletion Seconds
Loss of contractility <2 min

ATP reduced to 50% of normal 10 min
ATP reducedto 10% of normal 40 min
Irreversible cell injury 20-40 min
Microvascular injury >1 hr
C
Evolution of Morphological hanges in MI
Time Gross Light Microscopy

Reversible injury
0-30 min. None None
Irreversible injury
The neutrophils are present
30 min to 4 hr. None Waviness of fibers at border (earliest change) between 48-72 hours but after
4-12 hr. Occasional dark mottling Beginning of coagulative necrosis, edema and 72 hours, the macrophages
hemorrhage predominate and cause early
phagocytosis.
12-24 hr. Dark mottling Ongoing coagulative necrosis, marginal
contraction band necrosis, beginning of
neutrophilic infiltration
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1-3 days Mottling with yellow tan infarct Coagulation necrosis, interstitial neutrophilic
center. infiltrate
3-7 days Hyperemic borders, central Beginning of disintegration with dying neutrophils,
yellow tan softening early phagocytosis by macrophages
7-10 days Maximum yellow tan and soft Early formation of fibrovascular granulation tissue
depressed red-tan margin at margins
10-14 days Red gray depressed infarct Well established granulation tissue and collagen
borders deposition
2-8 weeks Gray-white scar progressive Collagen deposition, Cellularity
from border towards infarct core
> 2 months Scarring complete Dense collagenous scar
Note:
When the infarcts are less than 12 hours old, they can be diagnosed only with the help of the
dye triphenyl tetrazolium chloride (TTC). The dye reacts with the LDH enzyme present only in
the living cardiac fibers so it gives brick-red color to the living tissue whereas the tissue already
undergone infarction shows the unstained pale zone.
In the case of the infarction being modified by reperfusion, the characteristic, microscopic fea-
ture is the presence of necrosis with contraction band (in irreversible injured myocytes, the
increased calcium ions cause hypercontraction of the sarcomeres).
Diagnosis of MI
MI should be suspected in any patient developing severe chest pain, rapid weak pulse,
MI is the leading cause of death sweating, dyspnea and edema. Infact, rapid pulse is the first sign and dyspnea is the first
in diabetes mellitus. Diabetics symptom of acute MI. The ECG shows the ST segment elevation in acute MI whereas Q
have silent MI. wave indicates old MI.
Laboratory investigations show nonspecific markers like increased ESR, leukcocytosis
and elevated C-reactive protein. The specific markers include:
Enzyme Initiation of rise Peak Return to baseline
CK-MB 2-4 hours 24 hours 48-72 hours
Troponin T and I (TnT, TnI) 2-4 hours 48 hours 7-10 days
AST/SGOT In 12 hours 48 hours 4-5 days
Sequence of elevated enzymes LDH 24 hours 3-6 days 2 weeks

after MI (Time to CALL
emergency)

Time to Troponin
IM PORTANT POINTS ABOUT THE CARDIAC ENZYMES
C CK-MB
A AST Troponin T and Troponin I
L LDH1 These are the proteins that mediate calcium mediated contraction of the cardiac and the skeletal
muscles. They are very specific for MI. Troponin I is more important than troponin T (remember, I for
Important). If the patient has another MI (due to reinfarction within 1 week), these enzymes cannot be
used for diagnosis of reinfarction because their levels remain elevated for a long time from the first
attack. In that condition, we prefer an enzyme elevated for a short duration.
Concept Creatine kinase (CK)
Myoglobin: earliest enzyme to
It is an alternative to troponin measurement. It has got 3 isoforms:
increase after MI.
CK-MM- Present in the skeletal muscle and heart
Troponin: Most sensitive as CK-MB- Present in the myocardium and a small amount in skeletal muscle
well as specific for MI. CK-BB Present in the brain, lung and other tissues.
Elevation of the CK-MB isoforms is seen in MI. Any absence of elevation of CK-MB in the first-two days
CK-MB: enzyme of choice for excludes the diagnosis of MI. This is the enzyme of choice for diagnosing reinfarction.
diagnosing reinfarction.
Myoglobin
It is a small monomer with a rapid rise and fall in serum (has a narrow window). It is the earliest enzyme
to increase after MI.
368
LDH
Normally, serum LDH2 is greater than LDH1 but in MI, LDH1 is more than LDH2. This is called flipping
of LDH ratio.
Complications of MI
Contractile dysfunction resulting in cardiogenic shock.
Dressler syndrome is treated
Arrhythmia- Ventricular fibrillation is the most common arrhythmia within one hour whereas with the help of NSAIDs with/
supraventricular tachycardia is the most common arrhythmia after one hour of MI. without the use of steroids.
Cardiac rupture syndrome: Rupture of ventricular free wall is the most common cardiac rupture
syndrome. It results in cardiac tamponade. The anterolateral wall at the midventricular level is the
most common site for postinfarction free wall rupture. It is most frequent 3 to 7 days after MI.
The rupture of ventricular septum leads to formation of left to right shunt. The rupture of papillary
muscles can cause mitral regurgitation.
Concept
Pericarditis- It is the epicardial manifestation of the underlying myocardial injury and is also
known as Dressler syndrome or post MI syndrome. It is an autoimmune reaction, which takes Rupture of the left ventricle, a
place around 2-3 weeks after a transmural MI. though it has been reported to occur even after 48 complication of acute myocardial
hrs. It is associated with pleural effusion, pleuritic chest pain and pericardial effusion. infarction, usually occurs when
the necrotic area has the least
Right ventricular infarction.
tensile strength, about 4 to 7
Ventricular aneurysm: This may contribute to thromboembolism also days after an infarction, when
repair is just beginning.
Papillary muscle dysfunction: This leads to post infarct mitral regurgitation.
CARDIAC TUMORS
Myxoma
Myxomas are the most common primary tumor of the heart in adults. Though they may arise
in any cavity of the heart but nearly 90% are located in the atria, with a left-to-right ratio of
approximately 4:1 (atrial myxomas). The major clinical manifestations are due to valvular
ball-valve obstruction, embolization, or a syndrome of constitutional symptoms, such as
fever and malaise the latter most commonly due to the effect of interleukin-6.
Approximately 10% of patients with myxoma have a familial cardiac myxoma syndrome
(known as Carney syndrome) characterized by autosomal dominant transmission, multiple The most common cardiac
cardiac and often extracardiac (e.g. skin) myxomas, spotty pigmentation, and endocrine tumor is the secondaries or
overactivity. The familial form is associated with mutation of the gene PRKAR1 on chromosome metastasis.
17 (a tumor suppressor gene).
The tumors are almost always single. The region of the fossa ovalis in the atrial septum
is the favored site of origin. Histologically, myxomas are composed of stellate or globular
myxoma (lepidic) cells, endothelial cells, smooth muscle cells, and undifferentiated cells The most common primary
embedded within an abundant acid mucopolysaccharide ground substance and covered on cardiac tumor in the adults is
the surface by endothelium. the myxoma.
Rhabdomyoma
Rhabdomyomas are the most frequent primary benign tumor of the heart in infants and
children. They are actually hamartomas or malformations rather than true neoplasms.
Cardiac rhabdomyoma is associated with tuberous sclerosis due to defect in the TSCI or
TSC2 tumor suppressor gene. The TSC proteins stimulate the cell growth and are involved The most common cardiac
in myocyte overgrowth. tumor in the children is the
Rhabdomyomas are generally small, gray-white myocardial masses protruding into the rhabdomyoma.
ventricular chambers. Histologically they are composed of large, rounded, or polygonal cells
containing numerous glycogen-laden vacuoles separated by strands of cytoplasm running
from the plasma membrane to the more or less centrally located nucleus, the so-called spider
cells.
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BL OOD VESSELS
The blood vessels are responsible for the transport of blood in the circulation from the heart
to the various organs and back to the heart.
The histological layers which are seen in a blood vessel (particularly arteries) are:

1. Tunica intima (Innermost layer)

2. Internal elastic lamina

3. Tunica media (Middle layer)

4. External elastic lamina

5. Tunica adventitia (Outermost layer)
The outer half of the tunica media and the whole of tunica adventitia are supplied by vasa
vasorum whereas the other inner layers of the blood vessel get their nourishment by diffusion.
Types of blood vessels in the circulatory system and their important properties
Artery Elastic arteries - Tunica media is rich in elastin fibers e.g. Aorta and its large branches
Muscular arteries - Tunica media is rich in smooth muscle cells e.g. coronary and renal
arteriesQ
Arteriole Principle site of resistance to blood flow, so called Resistance vessels
Capillaries Have maximum cross-sectional surface areaQ
Venules Most important vessel involved in inflammationQ
Vein Maximum blood volume present in the veinsQ
Any injury/denudation of endothelial cells stimulate thrombosis and smooth muscle
cell proliferation. The normal blood vessels particularly the arteries have an elastic recoil
property referred to as the Windkessel effect. This effect is responsible for maintaining the
blood flow inside the vessels during the diastolic phase of cardiac contraction. Sclerosis
means loss of elasticity of vessels commonly associated with thickening. It may be of the
following types:
1. Arteriolosclerosis - It affects small arteries and arterioles, it can be of the following
types:
Hyaline arteriolosclerosis
Concept
Pink, hyaline thickening of arteriolar walls.
Endothelial cells contain
Seen in elderly, more commonly in benign hypertension, diabetes mellitus (DM) and benign
Weibel Palade Bodies having
von Willebrand factor and are nephrosclerosis.
identified by antibodies to CD31, Hyperplastic arteriolosclerosis
CD34 and vWF.
Onion skinning or concentric thickening of the arteriolar wall seen in malignant hypertension.
Fibrinoid necrosis/necrotizing arteriolitis (inflammatory cells in vessel wall particularly in kidney)
2. Monckebergs medial calcific stenosis

Seen is muscular arteries of people > 50 years of age.

Associated with dystrophic calcificationQ and is asymptomatic.
3.
Atherosclerosis
It is characterized by deposition of atheroma/fibrofatty plaque consisting of raised
focal lesion. Plaque is present within the intima, has a core of lipid (cholesterol and
cholesterol esters) and a covering of fibrous cap.
The histopathology shows:

1. Fibrous cap - Consists of smooth muscle cells, macrophages and foam cells.

2. Shoulder - Cellular area around cap having macrophages, smooth muscle cells and
Windkessel effect is the elastic T lymphocytes.
recoil property of the blood
vessels.

3. Necrotic core - Debris of dead cells, foam cells and cholesterol clefts.
Risk factors for atherosclerosis (Mnemonic: Atherosclerosis)
Coronary circulation is an A- Age ( with age)
example of autoregulatory
circulation. T- Type A personality
H- Hyperhomocysteinemia (corrected by adequate folic acid and vitamin B12 in diet)
370 E- Extra lipids (Hyperlipidemia); Extra BP (hypertension); Extra sugar (DM)
R- Reduced physical activity Concept

O- Obesity Lipoprotein a, or Lp(a), is an
S- Sex (More common in males, females in pre-menopausal age group are protected) altered form of LDL that contains
the apolipoprotein B-100 portion
C- CMV; Chlamydia infection; Cigarette smoking of LDL linked to apolipoprotein
L- Lipoprotein A A. It has structural similarity to
plasminogen. So, it competes
with plasminogen in clots
Pathogenesis decreasing the latters ability to
form plasmin and clear clots.
It is best explained by the Response to Injury HypothesisQ Increased Lp(a) levels are
associated with a higher risk of
According to this hypothesis, chronic endothelial injury results in increased permeability, coronary and cerebrovascular
leukocyte adhesion and thrombotic potential. This is associated with accumulation of disease, independent of total
lipoproteins (mainly LDL)Q followed by oxidation of lipoproteins in the vessel wall. The cholesterol or LDL levels.
blood monocytes initially adhere to the endothelium followed by their transformation into
macrophages and foam cells inside the intima along with adhesion of platelets. The activated
platelets release factors causing migration of smooth muscle cells from the media to intima
and their proliferation along with release of proteoglycans and collagen. This results in
Foam cells are lipid laden
enhanced accumulation of lipids. In advanced atheroma, the smooth muscle cells may
Smooth muscles cells/Tissue
undergo apoptosis and so, smooth muscle cell paucity may be observed. macrophages or Blood mono-
Foam cells are formed because oxidized LDL is ingested by the scavenger receptors present cytes.
on the macrophages and smooth muscle cells both intracellularly as well as extracellularly.
Natural History of Atherosclerosis
American Heart Association classification of human atherosclerosis:
Type Gross Microscopy
Clinically silent Leriche syndrome is aortoiliac
Type I Fatty dot (initial lesion) Isolated macrophage; foam cell occlusive disease due to ather-
osclerotic occlusion affecting the
Type II Fatty streak Intracellular lipid accumulation
bifurcation of the abdominal aor-
Type III Intermediate lesion Type II change + small extracellular lipid pool ta as it transitions into the com-
mon iliac arteries. It is character-
Clinically silent or overt ised by: buttock claudication
Type IV Atheroma lesion Type II + core of extracellular lipids plus sexual impotence along
Type V Fibroatheroma Lipid core and fibrotic layer with reduced femoral pulses.
Type VI Complicated lesion Surface defect, Hemorrhage and thrombus
Fatty streak
It is the earliest lesion of atherosclerosis and is composed of lipid filled foam cells. It begins as
yellow flat spots less than 1 mm which gradually progress to atheroma formation.
Fatty streak is the earliest
Significance of involved blood vessels in atherosclerosis lesion of atherosclerosis.
Abdominal Aorta - Most common site of atherosclerotic aneurysm in body
Coronary Arteries - Left Anterior Descending is MC coronary artery involvedQ
Poplitial Artery - MC peripheral vessel showing aneurysm formationQ
Descending Thoracic Aorta Involvement of blood vessels
Internal carotid artery affected in atherosclerosis in
Circle of Willis descending order: ACP of Delhi
Traffic is Cute:
Significance of complications of Atherosclerosis
Abdominal Aorta
Aneurysm: Due to weakness of the tunica media Coronary Arteries
Calcification: Dystrophic calcification is seen Poplitial Artery
Ulceration: Increases thrombus formation Descending Thoracic Aorta
Thrombosis: Most feared complication Internal carotid artery
Embolism: Erosion of athermanous plaque Circle of Willis
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N YSM
A EUR
Complications of Atherosclerosis A localized abnormal dilation of a blood vessel or the wall of the heart is called aneurysm. It
are ACUTE
is of two types:
Aneurysm
Calcification,
1. True aneurysm: Involves intact attenuated arterial wall or thinned ventricular
Ulceration, wall of the heart. The common causes include Atherosclerosis, syphilis and post MI
Thrombosis, ventricular aneurysms.
Embolism,
2. False/Pseudo- aneurysm: It is characterised by a breach in the vascular wall leading
to extravascular hematoma communicating with intravascular space. The two most
common causes of pseudoaneurysm are post MI rupture and leakage at the site of
vascular anastomosis.
Causes of True Aneurysm in Aorta
1. Atherosclerosis *It is the most common cause of true aneurysm in aorta
Atherosclerosis causes *The most commonly affected vessel is the abdominal aorta (below the origin of
abdominal aortic aneurysm. renal artery and above bifurcation into common iliac artery).
2. Syphilis *The thoracic aorta is involved in tertiary stage of syphilis
*Endarteritis of vasa vasorum results in patchy ischemia of tunica media. This is
responsible for the often seen tree barking appearance of the thoracic aorta.
*Aortic valve insufficiency can also occur which may result in cardiac hypertrophy.
The increase in the size of heart is called as cor bovinum/cow heart.
3. Other causes Trauma; infection (mycotic aneurysm; mostly due to Salmonella gastroenteritis)
and systemic disease (vasculitis)
Other important points about different causes of aneurysms
Cystic medial necrosis is characterized by weakness due to media due to degeneration of the
tunica media and it affects the proximal aorta.
Syphilitic aneurysms affect ascending aorta or aortic arch

Tuberculous aneurysms affect the thoracic aorta.
Traumatic aneurysms affect descending thoracic aorta just below the site of insertion of ligamentum
arteriosum.
The inherited causes of aneurysm and their causes are as follows (Robbins 8th/506-7):

Marfans syndrome: defective synthesis of the protein fibrillin

Ehlers-Danlos syndrome: defect in collagen type III

Loeys Dietz syndrome: defect in elastin and collagen types I and III due to mutation
in TGF-b receptor.
Hypertension is the commonest

O C DISSECTION
A RTI
cause of ascending aortic It occurs when blood splays apart the laminar planes of the media with the formation of
aneurysm. blood-filled channel within the aortic wall. It is mostly seen in men in the age group of 40-
60 years (with antecedent hypertension) and uncommonly in younger individuals with
connective tissue disease (Marfans syndrome). Medial degeneration is a characteristic pre-
existing lesion in most of the patients.
Dissection is classified into two types:

1. Type A - Involves ascending aorta with/without descending aorta. It is more
common and is more dangerous.

2. Type B - Does not involve ascending aorta but lesion begins distal to subclavian artery.
VASCULITIS
The inflammation of the vessel wall is called vasculitis. It may be classified on the basis of
pathogenesis or on the basis of size of the involved vessel.
372
Classification based on vessel size
Large vessel vasculitis Medium vessel vasculitis Small vessel vasculitis Concept
Giant cell (temporal) Classic PAN Antiendothelial antibodies are
arteritis Kawasakis disease found in SLE and Kawasakis
Takayasu arteritis Buergers disease disease.
Immune complex mediated Paucity of Immune complex
SLE Wegeners granulomatosis
Henoch-schonlein pupura Microscopic lyangitis
Cryoglobulin vasculitis Churg-strauss syndrome
Goodpature syndrome
Anti-neutrophil cytoplasmic antibodies (ANCAs) are autoantibodies against enzymes

inside the neutrophils c-ANCA is formed against proteinase 3 whereas p-ANCA is formed
against myeloperoxidase. These can be of the following types:
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G V SSEL VASCULITIS
LAR E E
Temporal arteritis is the most
common type of vasculitis in
1. Giant cell (Temporal) arteritis/Cranial arteritis
adults. It is the most common type of vasculitis in adultsQ (usually >50Q years)
This vasculitis is characterized by granulomatous arteritis of the aorta and its major
branches particularly the extracranial branches of the carotid artery. Since the superficial
temporal arteryQ is the most commonly involved vessel, the giant cell arteritis is called
as temporal arteritis.
Lastest Information (9th Edn.) Clinical features include constitutional symptoms like fever, fatigue, weight loss, jaw

c-ANCAPR3 ANCA painQ (most specific symptom), facial pain, localized headacheQ (commonest

p-ANCAMPO ANCA symptom; most intense along the anatomical course of the superficial temporal artery)
and sudden onset of blindness (due to involvement of ophthalmic artery).
Biopsy of temporal arteryQ is the investigation of choice.
Microscopically, there is presence of granulomatous inflammation with multinucleated
Corticosteroids are the drug of giant cells and fragmentation of internal elastic lamina.
choice for treatment of temporal
arteritis.
2. Takayasu arteritis/Aortoarteritis/Aortic Arch syndrome

It is seen in adult females < 50 years of age.

This condition is characterized by granulomatous vasculitis followed by
thickening of the aortic arch and decreased lumen of the vessels arising from the
aortic arch. The pulmonary, renal and coronary arteries may also be involved.
The subclavian artery is most
Clinical features include weak pulses in the upper limbs (so, the disease is
commonly involved vessel in also called as pulseless diseaseQ), ocular disturbances, hypertension and
Takayasu arteritis. neurological defects.
D
ME IUM E V SSEL VASCULITIS
1. Classic Polyarteritis Nodosa (PAN)
It is a systemic vasculitis of medium sized muscular arteries (no involvement of

arterioles/capillaries/venulesQ).
The most frequently involved vessels are those of the kidney and other viscera vessels.
The vessels of the pulmonary circulationQ are typically not
involved.
Characteristic feature of this disease is sharp segmental lesions showing transmural

Glomerulonephritis and vessels inflammation of vessel wall accompanied by fibrinoid necrosis and existence of all
of pulmonary circulation are stages of inflammation in the same vessel.
typically not involved in PAN. 30% patients have association with Hepatitis B antigenQ in their serum.
No glomerulonephritisQ is seen.
It is the commonest cause of mononeuritis multiplexQ.
2. Kawasakis disease (Mucocutaneous Lymph Node Syndrome)
It is the vasculitis affecting children < 5 years of age. So, it was designated as
Q
infantile polyarteritis earlier. It is characterized by fever, conjunctivitis and

Q
oral erythema, skin rash often with desquamation, erythema of palms and soles
and cervical lymphadenopathy.
For the diagnosis of Kawasaki disease, there must be presence of feverQ (most
important constitutional symtpom) for greater than 5 days plus any 4 of the
Treatment: High dose intrave- following:
nous g globulin with aspirinQ C - Conjunctivitis (non-exudativeQ; non purulent conjunctivitis)
is effective in reducing the mor- R - Rash (polymorphous non-vesicular)
bidity and mortality in Kawasakis E - Edema (or erythema of hands or feet)
disease.
A - Adenopathy (cervicalQ, often unilateralQ and non suppurativeQ)
M - Mucosal involvement (erythema or fissures or crusting at times referred as
strawberry tongueQ)
It is the most important cause of acquired heart disease in children in USA. It
may present with myocardial infarctionQ in children. It is having the presence
of anti-endothelial cell antibodiesQ. There is typically intimal proliferation and
mononuclear infiltration of vessel wall. The patients also have elevated platelet
count in this condition.
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SMALL VESSEL VASCULITIS p-ANCA is present in Micro-

1. Microscopic Polyarteritis/Microscopic Polyangiitis/Leukocytoclastic Vasculitis scopic Polyangiitis but is not
Necrotizing vasculitis affecting arterioles/capillaries/venules in which all seen with PAN.
lesions are of the same age.
Granulomatous inflammation is absent Q
Necrotizing glomerulonephritis and capillaritis are common.

Fibrinoid necrosis associated with infiltration of neutrophils which become
Palpable purpura in HSP
fragmented (leukocytoclasia). is due to vasculitis and not
2. Henoch-Schnlein purpura (HSP)/Anaphylactoid purpura Q
thrombocytopenia.
It is the commonest vasculitis in childen . Q
This is a vasculitis with IgA deposits affecting small vessels like arterioles,
Q
capillaries and venules of the skin, gut and glomeruli and commonly associated
with arthralgia.

Clinical features include palpable purpura (due to vasculitis and not reduced
platelet count)Q, colicky abdominal painQ, arthralgia in multiple joints and
glomerulonephritis.

It is caused due to immune complex deposition but complement levels are
usually normalQ.
3. Hypersensitivity vasculitis/Cutaneous vasculitis
Defined as inflammation of the blood vessels of the dermis.
Also called as hypersensitivity vasculitis/cutaneous leukocytoclastic angiitis.
Microscopic features include presence of vasculitis of small vessels characterized by a
leukocytoclasisQ (refers to the nuclear debris remaining from the neutrophils that have
infiltrated in and around the vessels during the acute stages).
Hallmark clinical feature is skin involvement typically appearing as palpable
purpuraQ appearing on most commonly lower limbs
Diagnosis is best made with biopsy showing vasculitis.
Removal of offending agent (if any) and steroids help most of the patients.
4. Churg-Strauss syndrome (Allergic granulomatosis and angiitis)
Lastest Information (9th Edn.)

Characteristically have necrotizing vasculitis accompanied by granulomas with
Wegeners granulomatosis is
eosinophilic necrosis. now called as granulomatosis

p-ANCA present in 50% of patients. with polyangitis

Strong association with allergic rhinitis, bronchial asthma and eosinophilia.

Principal cause of death includes coronary arteritis and myocarditis.
5. Wegeners granulomatosis (Granulomatosis with polyangitis)
Necrotizing vasculitis which is characterized by triad of

1. Acute necrotizing granulomas of either upper (more commonly) or lower respiratory
tract or both.

2. Focal necrotizing or granulomatous vasculitis most commonly affecting lungs and upper
airways.

3. Renal involvement in the form of focal necrotizing, often crescentic glomerulonephritis.
Concept
Clinical features include fever, weight loss, otitis media, nasal septal perforationQ,
strawberry gumsQ, cough, hemoptyis, palpable purpuraQ, joint pain and ocular features Limited Wegeners granulo-
(uveitis, conjunctivitis) matosis is characterized by only
Investigations show serum c-ANCAQ positivity, cavitatory lesionsQ in the chest X ray respiratory tract involvement
and red cell casts (indicative of glomerulonephritis) in the urine. without any renal involvement.
RA YNAUDS PHENOMENON
Raynauds disease or Primary Raynauds phenomenon is seen in young females. It is
characterized by intense vasospasm of small vessels in the digits of hands and feet induced by
cold and emotional stimuli (so, pulses are NOT affected).

Characteristic sequence of color change is
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Systemic sclerosis is the com-

monest cause of secondary
Raynauds phenomenon.

Structural changes are absent except in later course when thickening of intima is seen.
Secondary Raynauds phenomenon is associated with conditions like systemic
sclerosisQ (commonest cause), SLE, atherosclerosis and Buergers disease. It usually affects
people of age >30 years.
Also Know
Secondary Raynauds phenomenon patients are older in age and have more severe symptoms
and complications
More commonly have dilatation of the capillary bed at the base of the fingernails.
Index and middle fingers are more sensitive to attacks. Thumb is least sensitive.
Buergers disease (Thromboangiitis obliterans)

Segmental thrombosing vasculitis It is usually seen among heavy cigarette smokers.
often extends into contiguous Onset is before age 35
veins and nerves is a charac- It is associated with hypersensitivity to intradermal injections of tobacco extracts.
teristic features of Buergers Microscopic examination demonstrates segmental thrombosing vasculitis often extends into
disease. contiguous veins and nerves (a feature rarely seen in other types of vasculitis), encasing them
in fibrous tissue.
Thrombus contains microabscess with granulomatous inflammation.Q
This patient has distal lower extremity vascular insufficiency which may present as Calf, foot
or hand intermittent claudication, superficial nodular phlebitis and cold sensitivity (Raynauds
phenomenon). Severe distal pain even at rest can result and may be due to neural involvement.
Later complications include ulcerations and gangrene of the toes feet or fingers.
Treatment includes smoking cessation, drugs (peripheral vasodilators) and may even require
surgery.
VASCULAR TUMORS
Strawberry gums are seen in

Wegeners granulomatosis.
Benign Tumors
Strawberry tongue is seen in
Kawasaki disease.
Hemangioma
1. Capillary hemangioma
It is the most common type of vascular tumor which occurs in skin, mucus membrane
Strawberry hemangioma is a and viscera.
type of capillary hemagioma. Strawberry type of capillary hemangioma (also called as juvenile hemangioma) is very
common, growing rapidly in the first few monthsQ and regresses by age 7Q in newborns.
The child is normalQ at birth in almost 90% of cases.
Histologically, they are lobulated unencapsulated aggregates of closely packed, thin
walled capillaries which are blood filled and lined by a flattened endothelium.
376
2. Cavernous hemangioma

It is less common than capillary hemangioma with same age and anatomic Cavernous lymphangioma occurs
distribution. It more frequently involves deep structures as it shows no tendency in Turners syndrome at the
to regress. So, it usually requires surgery. neck region.

Morphologically, Cavernous hemangiomas are made up of large, cavernous
vascular spaces in which intravascular thrombosis and dystrophic calcification
is common.

They may be life-threatening as in von Hippel Lindau disease where they occur
in cerebellum, brainstem and the eye.
3. Pyogenic granuloma
It is a polypoid form of capillary hemangioma seen attached by a stalk to skin or oral
mucosa. It is associated with edema and inflammatory cells.
Granuloma gravidarum is present in the gingiva of pregnant women and it regresses
after delivery.
Y P NGIOMA
L M HA
1. Cavernous lymphangioma (also called as cystic hygroma)

Concept
Capillary lymphangioma is dis-
This is present in the neck region of the children.
tinguished from the capillary
Made up of dilated, cystic lymphatic spaces lined by endothelial cells.
channels only by the absence of
Lesions are non-encapsulated, so, removal is difficult.
blood cells.
2. Capillary Lymphangioma
It is a lesion composed of small lymphatic channels occurring subcutaneously in the
head and neck region and in the axilla.
GLOMUS TUMOR (Glomangioma)
Benign tumor arising from the smooth muscle cells of the glomus body which is an
arteriovenous anastomosis involved in thermoregulation.
Most commonly present in the distal portion of the digits (under fingernails).
Histologically, there is presence of branching vascular channels and stroma
containing nests/aggregates of glomus cells arranged around vessels.
N D
I TERME IATE/B R ERLI E TUM ROD N OS
S
Kaposis arcoma (K ) S
It is caused by KS Herpes virus or Human herpes virus 8 (HHV8) and has the following 4
forms:
Type of Kaposi sarcoma Association with HIV Chief affected organs
Classic/Chronic/European KS Absent Skin plaques and nodules
African/Endemic KS Absent No skin lesions; lymphadenopathy
present
Transplant associated/ Absent Lymph nodes, mucosa and visceral
Immunosuppression-associated KS organs
Epidemic/AIDS associated KS PresentQ Lymph nodes and viscera involved
The morphology is characterized by three stages:

1. Patch stage

2. Plaque stage

3. Nodular stage Often accompanied by involvement of lymph nodes and of viscera
particularly in African and AIDS-associated disease.
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MALI GNANT TUMORS

Hepatic angiosarcoma is
associated with carcinogens
including arsenic, thorotrast Angiosarcoma
(a radioactive contrast) and
polyvinyl chloride (PVC; a Malignant endothelial cell neoplasm most commonly seen in skin, soft tissue, breast and liver.
plastic). May also arise from dilated lymphatic vessels (lymphangiosarcoma).
Endothelial cell origin is demonstrated by staining for CD31, CD34 or vWF.
Hemangiopericytoma
Tumor derived from pericytes which are the cells present along the capillaries and
venules.
These tumors most commonly arise from pelvic retroperitoneum or the lower limbs
(particularly thighs).
Capillaries are arranged in fish-hook pattern and silver stain is used for diagnosing
this condition.
Quick review of superior vena cava and inferior vena cava syndromes
Syndromes Associated Cancers Clinical features
Superior Vena Bronchogenic cancer Q
Dilation of the veins of the head, neck and
Cava (SVC) Mediastinal lymphomaQ arms
syndrome Cyanosis
Respiratory distress
Inferior Vena Renal cell carcinomaQ Lower limb edema
Cava (IVC) Hepatocellular carcinomaQ Dilation of the superficial collateral veins of
syndrome the lower abdomen
Massive proteinuria (if renal vein is involved)
378

H eart failure, rheumatic heart disease, (c) Involvement of the major blood vessels is commonly
endoc arditis seen
(d) Equal involvement of both the sides of the heart
1. A young female patient came for routine examination. 7. Most friable vegetation is seen in: (AI 2010)
On examination a mid systolic click was found. (a) Infective endocarditis
There is no history of rheumatic heart disease. The (b) Libman Sacks endocarditis
histopathological examination is most likely to show (c) Rheumatic heart disease
which of the following? (AIIMS May 2012) (d) Rheumatoid heart disease
(a) Myxomatous degeneration and prolapsed of the
mitral valve 8. Aschoffs nodules are seen in: (AI 2005)
(b) Fibrinous deposition on the tip of papillary muscle (a) Subacute bacterial endocarditis
(c) Rupture of chordae tendinae (b) Libman-Sacks endocarditis
(d) Aschoff nodule on the mitral valve (c) Rheumatic carditis
(d) Non-bacterial thrombotic endocarditis
2. Least chances of infective endocarditis is associated
with (AI India 2012) 9. A 10-year-old boy, Pappu, died of acute rheumatic fever.
(a) Mild MS All the following can be expected at autopsy except:
(b) Mild MR (a) Aschoffs nodules (AI 2002)
(c) Small ASD (b) Rupture of Chordae tendinae
(d) Small VSD (c) McCallum patch
(d) Fibrinous pericarditis
3. A 45 yrs old male had severe chest pain and was admitted
to the hospital with a diagnosis of acute myocardial 10. NOT true about ASO titer: (AIIMS Nov 2009)
infarction. Four days later he died and autopsy (a) May be positive in normal people
showed transmural coagulative necrosis. Which of the (b) Major Jones criteria
following microscopic features will be seen on further (c) May be negative in post streptococcal glomerulone-
examination? (AIIMS May 2011) phritis
(a) Fibroblasts and collagen (d) May not be elevated even in presence of Carditis
(b) Granulation tissue 11. In mitral valve prolapse syndrome, histopathology of
(c) Neutrophilic infiltration surrounding coagulative mitral valve shows: (AIIMS Nov 2007)
necrosis (a) Hyaline degeneration
(d) Granulomatous inflammation (b) Elastic degeneration
4. Which one of the following is not included as major (c) Myxomatous degeneration
criteria in Jones criteria? (AIIMS Nov. 2010) (d) Fibrinoid necrosis
(a) Pancarditis
(b) Arthritis
12. Which of the following is not a complication of infective
endocarditis? (AIIMS Nov 2003)
(c) Subcutaneous nodules
(a) Myocardial ring abscess
(d) Elevated ESR
(b) Suppurative pericarditis
5. The mechanism of the development of Acute Rheumatic (c) Myocardial infarction
Fever is which of the following? (AIIMS May 2010) (d) Focal and diffuse glomerulonephritis
(a) Cross reactivity with exogenous antigen
(b) Innocent bystander effect
13. Aschoff bodies in Rheumatic heart disease show all of
the following features, except: (AIIMS Nov 2002)
(c) Due to toxin secretion by streptococci
(d) Release of pyrogenic cytokines (a) Anitschkow cells (b) Epithelioid cells
(c) Giant cells (d) Fibrinoid necrosis
6. Cardiac involvement in carcinoid syndrome is 14. Rheumatic heart disease can be diagnosed on the basis
characterized by: (AI 2010)
(a) Calcification tricuspid valve of: (PGI Dec 2001)
(b) Intimal fibrosis of right ventricle, tricuspid and (a) Aschoff bodies
pulmonary valve. (b) Vegetations along the lines of closure of valves
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(c) Endocardial involvement only 25. Chronic constrictive pericarditis is most commonly

(d) Follows skin and throat infection caused by: (RJ 2000)
15. Pathognomic feature of acute rheumatic fever is: (a) Staphylococcus (b) TB
(a) Pericarditis (Delhi 2009 RP) (c) Viral (d) Autoimmune
(b) Myocarditis 26. Aschoffs bodies are seen in: (RJ 2006) (Jharkhand 2003)
(c) Mitral stenosis
(a) Acute rheumatic fever
(d) Aschoffs nodules
(b) SLE
16. Vegetations on under surface of cusps are found in: (c) SABE
(a) Infective endocarditis (Delhi PG-2008, P 2006) (d) TB
(b) Libman-Sacks endocarditis
(c) SABE 27. Diagnostic feature of rheumatic fever is:
(d) Rheumatic fever (a) Antischkow cells (Kolkata 2001)
(b) Aschoffs nodule
17. Aschoffs nodules are seen in: (Delhi PG-2007)
(c) MacCallums patch
(a) Acute rheumatic fever
(b) Bacterial endocarditis (d) Epithelioid cells
(c) Pneumoconiosis 28. Rheumatoid factor is: (Bihar 2003)
(d) Asbestosis (a) lgM directed against lgG
18. Anitschkow cells are pathognomonic for: (b) lgE directed against lgM
(a) Acute rheumatic fever (Delhi PG-2006) (c) lgG directed against lgM
(b) Yellow fever (d) None
(c) Malarial spleen
(d) ITP 29. Major criteria for rheumatic fever, consists of all
except: (Bihar 2004)
19. All are the causes of myocarditis except: (a) Pancarditis
(a) Trichinosis
(Karnataka 2005)
(b) Arthritis
(b) Mycobacterium tuberculosis
(c) Corynebacterium diphtheriae (c) Subcutaneous nodule
(d) Systemic lupus erythematosus (d) Erythema nodosum
20. Disarrangement of myofibrils is found in: 30. An 8 year old girl, Guniya had sore throat following
(a) Dilated cardiomyopathy (UP 2001) which she developed severe joint pains. She has been
(b) Constrictive cardiomyopathy diagnosed with acute rheumatic fever. Instead of
(c) Fibroelastic cardiomyopathy recovering as expected, her condition worsened, and
(d) Hypertrophic cardiomyopathy she died. Which of the following is the most likely
21. Most common cause of mitral stenosis is: cause of death?
(a) Rheumatic heart disease (UP 2002) (a) Central nervous system involvement
(b) Infective-endocarditis (b) Endocarditis
(c) Diabetes mellitus (c) Myocarditis
(d) Congenital (d) Streptococcal sepsis
22. Calcification of aortic valve is seen in: (UP 2003) 31. Infective endocarditis is known to be caused by
(a) Hurlers syndrome different bacterial species. Which of the following
(b) Marfans syndrome
scenarios is most consistent with infective endocarditis
(c) Syphilis
caused by Staphylococcus aureus?
(d) None
(a) A 34-year-old female with known mitral stenosis
23. Most common cause of left sided cardiac failure is: develops low-grade fever and negative blood culture
(a) Myocardial infarction (UP 2006) (b) A 28-year-old male with persistently high fever with
(b) Systemic hypertension
tricuspid vegetations and tricuspid regurgitation on
(c) Rheumatic heart disease
trans-thoracic echocardiogram
(d) Infective endocarditis
(c) A 62-year-old female has persistent fever after being
24. Libman-Sacks endocarditis is found in: diagnosed with colon cancer
(a) Rheumatoid arthritis (UP 2001, 2007) (d) A 64-year-old male with fever and malaise has
(b) SLE
repeatedly negative blood culture and small mitral
(c) Syphilis
vegetation on trans-esophageal echocardiogram
(d) Lymphoma
380
Most Recent Questions mitral leaflet edges. The pathogenesis of this patients
vegetations is most similar to that of:
31.1. Which of the following is the feature of vegetations in
(a) Hypercalcemia of malignancy
Libmann Sacks endocarditis?
(b) Distant metastases
(a) Large and fragile
(c) Trousseau syndrome
(b) Small warty along the line of closure of valve
(d) Raynauds phenomenon
(c) Small or medium sized on either or both sides of 33. A 56-years-old male presented with sudden substernal
valve pain, impending doom and died 4 days after. On
(d) Small bland vegetations autopsy, there was a large transmural anterior wall
3 1.2. Which type of endocarditis has vegetation on both sides infarction. It would be associated with:
of the valves ?
(a) Presence of collagen and fibroblasts (AI 2009)
(a) Infective endocarditis

(b) Presence of neutrophils
(b) Libman Sacks endocarditis

(c) Granulomatous inflammation
(c) Rheumatic fever

(d) Granulation tissue
(d) Non bacterial thrombotic enodcarditis 34. All of the following statements regarding subendocar-
dial infarction are true, except:
3 1.3. Mc Callums patch is diagnostic of: (a) These are multifocal in nature (AI 2006)
(a) Infective endocarditis (b) These often result from hypotension or shock
(b) Rheumatic endocarditis (c) Epicarditis is not seen
(c) Myocardial infarction (d) These may result in aneurysm
(d) Tetralogy of Fallot (ToF)
35. A 60-year-old male presented with acute chest pain of
3 1.4. Heart failure cells are seen in which of the following 4 hours duration. Electrocardiographic examination
organs? revealed new Q wave with ST segment depression.
(a) Kidney (b) Heart He succumbed to his illness within 24 hours of
(c) Lungs (d) Brain admission. The heart revealed presence of a transmural
hemorrhagic area over the septum and anterior wall
3 1.5. Tigered effect in myocardium is due to: of the left ventricle. Light microscopic examination is
(a) Malignant change most likely to reveal: (AI 2004)
(b) Fat deposition
(a) Edema in between normal myofibers
(c) Seen in rheumatic fever
(b) Necrotic myofibers with presence of neutrophils
(d) Associated with myocarditis
(c) Coagulative necrosis of the myocytes with presence
of granulation tissue
3 1.6. ASLO titers are used in the diagnosis of:
(a) Acute rheumatoid arthritis

(d) Infiltration by histiocytes with hemosiderin laden
macrophages
(b) Acute rheumatic fever
(c) Ankylosing spondylitis 36. Which of the following increases the susceptibility to
(d) Osteoarthritis coronary artery disease? (AI 2003)
(a) Type V hyperlipoproteinemia
3 1.7. Mitral valve vegetations do not embolise usually to: (b) von Willebrands disease
(a) Brain (b) Liver (c) Nephrotic syndrome
(c) Spleen (d) Lung (d) Systemic lupus erythematosus
3 1.8. Which of the following cardiac valves is not commonly 37. A myocardial infarct showing early granulation tissue
involved in rheumatic fever? has most likely occurred: (AI 2002)
(a) Mitral (b) Aortic (a) Less than 1 hour
(c) Pulmonary (d) Tricuspid (b) Within 24 hours
(c) Within 1 week
3 1.9. Most common heart valve involved in IV drug user is (d) Within 1 month
(a) Mitral valve
(b) Aortic valve 38. Troponin-T is a marker of: (AIIMS May 2004)
(c) Pulmonary valve (a) Renal disease
(b) Muscular dystrophy
(d) Tricuspid valve
(c) Cirrhosis of liver
(d) Myocardial infarction
ischemic heart disease 39. Autopsy finding after 12 hrs in a case of death due to
M.I. is (Delhi 2010)
32. A 70-year-old male Rohan with advanced visceral cancer (a) Caseous pecrosis
dies of extensive myocardial infarction. Autopsy also (b) Coagulative necrosis
reveals sterile non-destructive vegetations along the (c) Fat necrosis
(d) Liquefactive necrosis
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40. In MI with hypothyroidism, what is the marker of

(c) Pulmonary embolism
choice? (Delhi PG-2008)
(d) Stable angina
(a) LDH
(b) CPK-MB
49. A 60 year old man Bhadru Kalraj is discharged after
being observed in the hospital for 4 days following
(c) Aldolase a myocardial infarction. He returns to his normal
(d) Troponin-I activities, which include sedentary work only. This
41. What is the investigation for second MI after 1 week of point in time following a myocardial infarct is note-
previous MI? (Delhi PG-2008) worthy for the special danger of which of the following?
(a) Troponin I
(a) Arrhythmia
(b) Troponin T
(b) Ventricular aneurysm
(c) CPK-MB
(c) Myocardial (pump) failure
(d) LDH
(d) Myocardial rupture
42. Earliest light microscopic change in myocardial 50. A 62 year-old male Sathish is admitted following an
infarction is: (UP 04, Bihar 03) acute ST-segment elevation myocardial infarction
(a) Waviness of the fibers experiences chest pain on day four of his hospitalization.
(b) Neutrophilic infiltration He describes the pain as sharp in quality, and adds that
(c) Phagocytic infiltration it increases with coughing and swallowing and radiates
(d) Coagulative necrosis to his neck. The blood pressure is 130/80 mmHg, pulse
is 90 beats per minute temperature is 38.3C (101F) and
43. Most common artery involved in myocardial infarction respirations are 20 per minute. Which of the following
is: (UP 2006) is the most likely cause of this patients chest pain?
(a) Right coronary artery
(a) Recurrent thrombosis of the affected coronary vessel
(b) Left coronary artery
(b) Thrombosis of a new coronary vessel
(c) Left anterior descending coronary artery
(c) Pericardial inflammation overlying the necrotic
(d) Left circumflex coronary artery segment of myocardium
44. In myocardial infarction scarring completes by:
(d) Pericardial inflammation due to autoimmune
reaction to necrotic tissue
(a) 1 day (RJ 2000)
(b) 1 week 51. An old man is found dead in his home. Autopsy
(c) 1 month reveals hemopericardium secondary to ventricular wall
(d) 3 months rupture. Roughly how long before his death did the
man probably have a myocardial infarction?
45. Dresslers syndrome is: (RJ 2000)
(a) 2 days
(a) Viral
(b) 7 days
(b) Bacterial
(c) 12 days
(c) Fungal
(d) 20 days
(d) Autoimmune
46. Heart muscle contains the isoenzymes: 52. 60 year-old male smoker develops severe chest pain. He
is diagnosed with MI based on his electrocardiogram
(a) MM (Kolkata 2001) and serial CK-MB levels. One week later he again
(b) MB complains of precordial pain and develops a fever of
(c) MM and MB 101.5F. Physical examination is remarkable for a loud
(d) BB friction rub. Which of the following is the most likely
47. Enzyme elevated in first 2 hours of MI is: diagnosis?

(a) CPK MB (Bihar 2004) (a) Caseous pericarditis
(b) LDH
(b) Fibrinous pericarditis
(c) SGPT
(c) Hemorrhagic pericarditis
(d) Acid phosphatase
(d) Purulent pericarditis
48. A 70 year old male Kulsheen presents to your OPD Most Recent Questions
with epigastric pain that typically starts about 30

minutes after meals and does not respond to antacids. 52.1. 7 day old MI the most sensitive biochemical marker:
He lost almost 3-4 kilograms over the last few weeks
(a) Troponin T
because he eats less for fear of pain. His past medical
history is significant for hypertension, hyperlipidemia,

(b) CPK MB
coronary artery bypass grafting, and right-sided carotid

(c) LDH
endarterectomy. Upper gastrointestinal endoscopy does

(d) Myoglobin

not reveal any abnormalities. The pathophysiology of 52.2. Post MI day 10 which enzyme is raised:
this patients symptoms is most close to
(a) CPK

(a) Peptic ulcer disease
(b) Troponin

(b) Esophageal spasm
(c) LDH

(d) Myoglobin
382
52.3. The cells seen after 72 hours in the infarcted area in MI the diabetic patient has 100 times risk of which of the
are: following? (AIIMS May 2012)
(a) MI
(a) Neutrophils
(b) Stroke
(b) Lymphocytes
(c) Lower limb ischemia
(c) Macrophages
(d) Vertebrobasilar insufficiency
(d) Monocytes
5 2.4. In myocardial reperfusion injury, the maximum effect
55. ALL of the following statements regarding athero-
sclerosis are true except: (AIIMS Nov 2012)
is caused due to which of the following?
(a) Omega-3 fatty acid (abundant in fish oil) decrease
(a) Neutrophil
LDL
(b) Monocytes
(b) Atherosclerosis in less important in age more than 45
(c) Eosinophils years age
(d) Free radicals (c) Cigarette smoking is independent risk factor for M.I
5 2.5. In myocardial infarctions, microscopes picture of (d) C reactive protein is independent risk factor for M.I
coagulation necrosis with neutrophilic infiltration is 56. Which of the following is the commonest histological
seen after: finding in benign hypertension? (AIIMS May 2011)
(a) 4-12 hr (a) Proliferative end arteritits
(b) 12-24 hr (b) Necrotizing arteriolitis
(c) 1-3 days (c) Hyaline arteriosclerosis
(d) 3-7 days (d) Cystic medial necrosis
5 2.6. Myocarditis is most commonly caused by 57. The presence of stroke, peripheral vascular disease and
(a) Influenza atherosclerosis is associated with which hormone?
(b) Measles virus (a) Insulin deficiency (AI 2010)
(c) Coxsackie virus (b) Hyperestrogenemia
(d) Epstein barr virus (c) Hypothyroidism
(d) Progesterone
Cardiac tumour 58. Most common cause of abdominal aortic aneurysm is:
(a) Atherosclerosis (AI 2010)
53. Which malignancy metastasizes to heart? (AP 2007) (b) Syphilis
(a) Bronchial carcinoma (c) Trauma
(b) Prostate carcinoma (d) Congenital
(c) Breast carcinoma
(d) Wilms tumor 59. Hallmark feature of benign HTN is: (AI 2009)
(a) Hyaline arteriosclerosis
Most Recent Questions (b) Cystic medial necrosis
(c) Fibrinoid necrosis
5 3.1. Most common benign heart tumor is: (d) Hyperplastic arteriosclerosis
(a) Rhabdomyoma 60. All are seen in malignant hypertension, except:
(b) Hemangioma (a) Fibrinoid necrosis (AI 2008)
(c) Lipoma (b) Hyaline arteriosclerosis
(d) Myxoma (c) Necrotizing glomerulonephritis
5 3.2. Most common tumour of heart is: (d) Hyperplastic arteriosclerosis
(a) Myxoma
(b) Rhabdomyosarcoma
61. Recurrent ischemic events following thrombolysis
has been pathophysiologically linked to which of the
(c) Fibroma
following factors: (AI 2003)
(d) Leiomyosarcoma
(a) Antibodies to thrombolytic agents
5 3.3. Atrial myxoma commonly arises from: (b) Fibrinopeptide A
(a) Left ventricle (c) Lipoprotein (A)
(b) Left atrium (d) Triglycerides
(c) Right ventricle
(d) Right atrium
62. 70-year-old man has abdominal pain with mass in
abdomen. Angiography reveals aneurysm of aorta.
Most likely cause is: (AIIMS Nov 2001)
htn, atherosclerosis, aneurysm (a) Trauma
(b) Atherosclerosis
54. In 2 patients with atherosclerosis, one is diabetic and (c) Syphilis
the other is non diabetic. In relation to the non diabetic, (d) Congenital
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63. In malignant hypertension hyperplastic arteriosclerosis involvement of the left anterior descending and
is seen in all except: (AIIMS May 2001) circumflex arteries. Which of the following cells
(a) Heart provides major proliferative stimuli for the cellular
(b) Kidney components of atherosclerotic plaques?
(c) Pericardial fat
(a) Neutrophils
(d) Peripancreatic fat
(b) Eosinophils
64. CAD predisposing factors: (PGI Dec 2002)

(c) Platelets
(a) Homocysteinemia

(d) Erythrocytes
(b) Increased lipoprotein B 73. Autopsy of a 14 year-old male who died in a motor
(c) Increased fibrinogen vehicle accident shows many yellow spots on the
(d) Increased HDL inner surface of the aorta. Which of the following best
(e) Increased plasminogen activator inhibitors describes the lesions?
(a) They are a very uncommon finding for a patient of
65. Features of essential hypertension: (PGI Dec 2002) this age.
(a) Concentric hypertrophy of LV
(b) Increased heart size

(b) Their distribution closely mimics that of future ath-
erosclerosis.
(c) Increased size of the heart muscles
(d) Myohypertrophy

(c) Once formed, they inevitably progress to atheromas
(e) Myohyperplasia

(d) They show predominantly intracellular lipid accu-
mulation.
66. In atherosclerosis, increased LDL in monocyte 74. Renal biopsy in an old man Hitesh demonstrates
macrophage is due to: (Delhi 2010)
concentric, laminated thickening of arteriolar walls due
(a) LDL receptors on macrophage
to proliferation of smooth muscle cells. This process is
(b) LDL receptors on endothelium
best described by which of the following terms?
(c) Lipids in LDL get auto-oxidized

(a) Atherosclerosis

(b) Hyaline arteriolosclerosis
67. Which of the following is the least common site of
(c) Hyperplastic arteriolosclerosis
atherosclerotic lesions? (Delhi 2009 RP)
(d) Mnckebergs arteriosclerosis
(a) Aortic bifurcation

(b) Pulmonary arterial trunk Most Recent Questions
(c) Common carotid artery
(d) Middle cerebral artery 74.1. Most common site of artery of atherosclerosis:
68. Vascular pathology of benign hypertension includes: (a) Right coronary artery
(a) Segmental fibrinoid necrosis (Delhi 2009 RP) (b) Left anterior descending coronary artery
(b) Hyaline arteriosclerosis (c) Left circumflex artery
(c) Periarteritis (d) Diagonal branch of LAD
(d) Loss of internal elastic lamina
7 4.2. Malignant hypertension causes which of the following
69. Accelerated phase of hypertension is characterized changes in the kidney?
microscopically by: (Delhi PG-2005) (a) No change in kidney
(a) Fibrinoid necrosis of arteriolar wall (b) Flea bitten kidney
(b) Hyaline arteriosclerosis (c) Irregular granular contracted kidney
(c) Elastosis of the intima (d) Large white kidney
(d) Marked calcification of the media
7 4.3. Cystic medical necrosis is seen in:
70. Most common site of atherosclerotic aneurysm is: (a) Marfan syndrome
(a) Coronary artery (RJ 2006)
(b) Renal artery (b) Friedrichs ataxia
(c) Arch of aorta (c) Down syndrome
(d) Abdominal aorta (d) Kawasaki disease
71. Monckebergs calcific sclerosis affects the medium 7 4.4. Most common cause of dissecting hematoma is because
sized muscular arteries by involving the structure of: of:
(a) Intima (AFMC 2000, AP 1999, 2001) (a) Hypertension
(b) Media (b) Marfan syndrome
(c) Adventitia (c) Iatrogenic
(d) All of the above (d) Kawasaki
72. A 52 year old male, Puneet, presents to the emergency 74.5. Atheromatous changes of blood vessels affects early in ?
of a tertiary care hospital with chest pain and syncope. (a) Kidney (b) Heart
The physician suspects a coronary pathology. Coronary
(c) Liver (d) Spleen
arteriography demonstrates significant atherosclerotic
384
74.6. Most common cause of aortic aneurysm is: 77. A 5 year old child presents with perivascular IgA
(a) Syphilis deposition and neutrophilic collection. There is
(b) Marfans syndrome erythematous rash on the lower limbs and non-
(c) Atherosclerosis blanching purpura. The likely diagnosis in the child is:
(d) Congenital

(a) Henoch-Schonlein Purpura (AIIMS Nov 2011)

(b) Wegners granulomatosis
7 4.7. Visceral aneurysm is most commonly seen in:
(c) Giant cell Vasculitis
(a) Splenic
(d) Kawasakis disease
(b) Renal 78. Pathogenesis of all of the following is granulomatous,
(c) Hepatic except: (AI 2010)
(d) Coronary (a) Wegeners granulomatosis
(b) Buergers disease
7 4.8. Medial calcification is seen in: (c) Takayasus arteritis
(a) Atherosclerosis (d) Microscopic polyangiitis
(b) Arteriolosclerosis
(c) Monckebergs sclerosis
79. ANCA is associated with: (AIIMS Nov 2009)
(a) Henoch-Schonlein Purpura
(d) Dissecting aneurysm (b) Goodpasture syndrome
7 4.9. Ascending aorta involvement is the commonest site of (c) Rheumatoid arthritis
(d) Wegeners granulomatosis
which aneurysm:
(a) Syphilitic 80. Which of the following is not a common cause of
(b) Atherosclerotic Vasculitis in adults? (AIIMS Nov 2009)
(c) Berry aneurysm (a) Giant Cell Arteritis
(b) Polyarteritis nodosa
(d) Traumatic
(c) Kawasaki disease
74.10. Onion skin thickening of arteriolar wall is seen in: (d) Henoch-Schonlein Purpura
(a) Atherosclerosis 81. Hypersensitivity vasculitis most commonly involves:
(b) Median calcific sclerosis (a) Arterioles (AIIMS May 09, Nov 08, DNB 2008)
(c) Hyaline arteriosclerosis (b) Post-capillary venules
(d) Hyperplastic arteriosclerosis (c) Capillaries
(d) Medium sized arteries
74.11. Atherosclerosis is seen with which bacteria
(a) Staph aureus 82. A patient presents with respiratory symptoms, i.e.
(b) Streptococcus pneumonia cough, hemoptysis and glomerulonephritis. His
(c) Chlamydia pneumoniae c-ANCA levels in serum were found to be raised. The
(d) Chlamydia trachomatis
most likely diagnosis is: (AIIMS Nov 2002)

(a) Goodpastures syndrome
74.12. Commonest histological finding in benign hypertension
(b) Classic polyarteritis nodosa
is:
(a) Proliferating endarteritis
(d) Kawasakis syndrome
(b) Necrotising arteriolitis 83. Vasculitis is seen in: (PGI Dec 2002)
(c) Hyaline arteriosclerosis (a) Buergers disease
(d) Cystic medial necrosis (b) HSP
(c) Gout
(d) Reiters disease
vasculitis, raynaud disease (e) Behcets syndrome
75. Which of the following is a feature of temporal arteritis? 84. Wegeners granulomatosis involve:
(a) Lung (PGI Dec 2003)
(a) Giant cell arteritis (AIIMS Nov 2012)
(b) Liver
(b) Granulomatous vasculitis
(c) Kidney
(c) Necrotizing vasculitis
(d) Upper respiratory tract
(d) Leucocytoclastic vasculitis
(e) Heart
76. Small vessels vasculitis seen in (AI India 2012)
85. Wegeners granulomatosis: (PGI Dec 2006)
(a) Giant cell arteritis
(a) Involve lung
(b) Takayasu arteritis
(b) Involves nose
(c) PAN
(c) Involve kidney
(d) Microscopic Polyangitis
(d) Treated with cytotoxic agent and/or steroids
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86. All are true about ANCA associated crescentic glomeru- 95. A 57 year-old woman Beenu Dash presents with
lonephritis, except: (Delhi 2009 RP) frequent headaches, which occur on one side and are
(a) Seen in Wegeners granulomatosis throbbing. She has fever and tenderness over both
(b) Seen in microscopic polyangitis temples. Investigations reveal a slightly decreased
(c) Seen in Henoch-Schnlein purpura hematocrit and an elevated erythrocyte sedimentation
(d) Is pauci immune in nature rate. This patient should be treated immediately to
prevent the development of
87. All of the following are small vessel vasculitis except:
(a) Blindness
(a) Kawasakis disease (Delhi PG-2006)
(b) Deafness
(b) Churg-Strauss syndrome
(c) Loss of tactile sensation
(c) Wegener granulomatosis
(d) Loss of the ability to speak
(d) None of the above 96. A 50 year-old man presents to his physician with
88. Polyarteritis nodosa can occur in association with which hematuria. Renal biopsy demonstrates a focal
necrotizing glomerulitis with crescent formation. The
of the following: (Delhi PG-2005)
patient has a history of intermittent hemoptysis and
(a) Hypertension (b) Trauma
intermittent chest pain of moderate intensity. A previous
(c) Drugs (d) Bronchial asthma chest x-ray had demonstrated multiple opacities, some
89. The term infantile polyarteritis nodosa was formerly of which were cavitated. The patient also has chronic
used for: (Karnataka 2009) cold-like nasal symptoms. Which of the following is the
(a) Goodpastures disease most likely diagnosis?
(b) Henoch-Schnlein Purpura
(a) Aspergillosis

(b) Wegeners granulomatosis
(d) Takayasus arteritis

(c) Renal carcinoma metastatic to the lung

(d) Tuberculosis
90. Most common organs involved in Wegeners
granulomatosis are: (UP 2004) Most Recent Questions
(a) Skin and nose
(b) Lung and kidney 96.1. Which of the following is not a characteristic of
(c) Heart and kidney Wegeners granulomatosis?
(d) Kidney and nervous system (a) Granuloma is vessel wall
(b) Focal necrotising glomerulonephritis
91. Polyarteritis nodosa does not involve: (AP 2003) (c) Positive for cANCA
(a) Pulmonary artery (d) Involves large vessels
(b) Bronchial artery
(c) Renal artery 9 6.2. Which is associated with vasculitis of medium size
vessels:
(d) Cerebral artery
(a) Temporal arteritis
92. C-ANCA antibodies are characteristic of: (AP 2003) (b) Wegners granulomatosis
(a) Sjgrens syndrome (c) Polyarteritis nodosa
(b) Giant cell arteritis (d) Henoch Schonlein purpura
9 6.3. All is true about Giant cell arteritis except:
(d) Kawasakis disease
(a) Involves large to small sized arteries
93. ANCA is seen in all except: (AP 2008) (b) Granulomatous inflammation
(a) Wegeners granulomatosis (c) Most commonly involved artery is abdominal aorta
(b) Henoch-Schnlein purpura (d) Segmental nature of the involvement
(c) Microscopic polyangiitis 9 6.4. In PAN, the lesions are seen in all except:
(d) Churg-Strauss disease (a) Lung
94. A 30 year old male Munish with exertional calf pain (b) Pancreas
and painful foot ulcers demonstrates hypersensitivity (c) Liver
to intradermally injected tobacco extract. Which of (d) Heart
the following pathologic processes is most likely 9 6.5. Which of the following is abdominal angiitis?
responsible for this patients condition? (a) Giant cell arteritis

(a) Lipid-filled intimal plaque (b) Takayasu arteritis

(b) Onion-like concentric thickening of arteriolar walls (c) Kawasaki disease

(c) Transmural inflammation of the arterial wall with (d) Polyarteritis nodosa
fibrinoid necrosis

(d) Segmental vasculitis extending into contiguous veins 9 6.6. Raynauds phenomenon what change is seen in vessels
and nerves initial stage:
386
No change
(a) 96.9. Glomus tumor is seen in:
Thrombosis
(b) (a) Retroperitoneum
Fibrinoid necrosis
(c) (b) Soft tissue
(d) Hyaline sclerosis (c) Distal portion of digits
(d) Proximal portion of digits
96.7. Frequency of renal involvement in Henoch Schonlein
Purpura (HSP) is ? 9 6.10. Sturge weber syndrome is associated with:
(a) 20-40% (a) Port wine stain
(b) >80% (b) Cavernous hemangioma
(c) 40-60% (c) Lymphangioma
(d) 10% (d) Hemangiosarcoma
9 6.8. Glomus cells are found in which of the following 9 6.11. All of the following are true about pyogenic granuloma
conditions? except
(a) Carotid body tumour (a) Bacterial infection
(b) Thyroid carcinoma (b) Bleeding
(c) Liver carcinoma (c) Benign tumour
(d) Glomus tumor (d) Capillary hemangioma
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E xplanations
1. Ans. (a) Myxomatous degeneration and prolapsed of the mitral valve (Ref: Robbins 9/e p556, 8th/563-565)
The important clues given in the question;
Female patient
Presenting for Routine examination (means she was asymptomatic)
Presence of mid systolic click on physical examination
Absence of history of rheumatic heart disease
All these are significant pointers towards a diagnosis of mitral valve prolapse or Barlow syndrome. The other name of the
same condition is Myxomatous degeneration of the mitral valve. So, the answer is option a
Direct lines from Robbins Most patients with mitral valve prolapse are asymptomatic, and the condition is discovered
only on routine examination by the presence of a midsystolic click as an incidental finding on physical examination
Concept
Commissural fusion that typifies rheumatic heart disease is absent in mitral valve prolapse.
2. Ans. (c) Small ASD (Ref: Ghai 7th/390,403, Adult congenital heart disease: a practical guide page/36-37)
Direct quote Ghai Infective endocarditis is very rare in patients of ostium secundum atrial septal defect, unless floppy mitral
valve is present.
Risk of infective endocarditis in various lesions
High Risk Moderate Risk Low Risk
Prosthetic heart value MVP + M.R. ASD

Tetralogy of Fallot Tricuspid stenosis MVP without MR
PDA Tricuspid regurgitation
Aortic regurgitation Pulmonary stenosis
Aortic stenosis Mitral stenosis
Coarctation of Aorta
VSD
Mitral regurgitation
3. Ans. (c) Neutrophilic infiltration surrounding coagulative necrosis (Ref: Robbins 8th/550; 7th/579)
4. Ans. (d) Elevated ESR (Ref: Robbins 9/e 559, 8th/566)
5. Ans. (a) Cross reactivity with exogenous antigen (Ref: Robbins 8th/566, 9/e 558)
Acute rheumatic fever results from immune response to group A streptococci (Strep. pyogenes) which cross-reacts with
host tissues. The antibodies directed against the M proteins of streptococci cross react with the self antigens in the heart. In
addition, CD4+ T cells specific for streptococcal peptides also react with self proteins in the heart and produce macrophage
activating cytokines. So, the damage to the heart tissue is a combination of antibody and T-cell mediated reactions.
6. Ans. (b) Intimal fibrosis of right ventricle, tricuspid and pulmonary valve. (Ref: Robbins 8th/569, 9/e 562)
Cardiac lesions are present in 50% of the patients with the carcinoid syndrome.
These are largely right-sided due to inactivation of both serotonin and bradykinin in the blood during passage
through the lungs by the monoamine oxidase present in the pulmonary vascular endothelium.
7. Ans. (a) Infective endocarditis (Ref: Robbins 9/e 560, 8th/567)
The hallmark of infective endocarditis is the presence of friable, bulky and potentially destructive vegetations containing fibrin,
inflammatory cells and bacteria or other organisms on the heart valves. Do refer to the table comparing different vegetations
in differrent condtions in the text.
8. Ans. (c) Rheumatic carditis (Ref: Robbins 7th/593, 9/e 558, Harrison 17th/2095)
Aschoffs bodies are characteristic focal inflammatory lesion of acute rheumatic fever found in any of the three layers of the
heart.
9. Ans. (b) Rupture of Chordae tendinae (Ref: Robbins 9/e 558-559, 7th/593-94, Harrisons 17th/2092)
388
Acute rheumatic fever is characterized by Pancarditis (i.e. endocarditis, myocarditis as well as pericarditis). Aschoff bodies can
be seen in all the three layers of heart.
McCallums patches are irregular thickening on subendocardial region, mostly in posterior wall of left atrium. It is exacerbated by
regurgitant jet and can be seen in acute rheumatic fever.
Pericardial inflammation in rheumatoid fever is accompanied by fibrous or serofibrous exudates, described as Bread and Butter
pericarditis.
Valvular damage is the hallmark of rheumatic carditis with the Mitral valve being the me affected value.
Myocardial involvement is almost never responsible in itself for cardiac failure.
10. Ans. (b) Major Jones criteria (Ref: Robbins 9/e 559, 8th/566, Harrison 17th/2095)
ASO titre may be positive due to streptococcal infection even in normal people. In some individuals with rheumatic cardi-
tis, ASO titre may not be elevated. In PSGN, the titre of anti DNA se B antibody is elevated more commonly than ASLO.
11. Ans. (c) Myxomatous degeneration (Ref: Robbins 7th/591-2,8th/563, 9/e 556, Harrison 17th/1472)
MVP/Myxomatous degeneration/Barlows syndrome/Floppy-valve syndrome

Characteristic anatomic change in myxomatous degenerationQ is interchordial ballooning of the mitral leaflets. The affected
leaflets are often enlarged, redundant, thick, and rubbery.
Annular dilationQ is a characteristic finding. (it is rare in other causes of mitral insufficiency).
There is reduction in the production of type III collagen and electron microscopy has revealed fragmentation of collagen fibrils.
Autosomal dominant disorder seen in femalesQ also associated with Marfans syndrome, Osteogenesis imperfecta, and Ehler-
Danlos syndrome.
Clinically most patients are aymptomaticQ, uncommonly they may develop chest pain, dyspnea and fatigue.
EchocardiographyQ is the investigation of choice.
12. Ans. (c) Myocardial infarction (Ref: Harrison 17th/791, Harsh Mohan 6th/448, Robbins7th 596-7, 8th/567, 9/e 561)
Cardiac complications Extra cardiac complications
Valvular stenosis or insufficiency Systemic emboli from left side of heart affect spleen, brain
Abscess on the myocardium (ring abscess) and kidneys whereas those from right heart affect pulmonary
Myocardial abscess abscess formation.
Suppurative pericarditis Antigen -antibody complexes cause focal (more commonly) and
Perforation, rupture and aneurysm of valve leaflets diffuse (less commonly) glomerulonephritis.
Cardiac failure
Harrison writes that Emboli to a coronary artery may result in myocardial infarction; nevertheless embolic transmural infarcts are
rare.
13. Ans. (b) Epithelioid cell (Ref: Robbins 7th/593-4, 8th/565-6, 9/e 558)
Aschoff bodies consist of foci of swollen eosinophilic collagen surrounded by lymphocytes (primarily T cells), occasional
plasma cells, and plump macrophages called Anitschkow cells (pathognomonic for rheumatic fever). These cells are also
called caterpillar cells. Some of the larger macrophages become multinucleated to form Aschoff giant cells.
14. Ans. (a) Aschoff bodies; (b) Vegetation along the line of closure (Ref: Robbins 7th/593-94, 9/e 558)
15. Ans. (d) Aschoffs nodule (Ref: Robbins 8th/565-566, 9/e 558)
16. Ans. (b) Libman Sacks endocarditis (Ref: Robbins 7th/597, 89, 9/e 562)
Vegetations in Libman Sacks endocarditis occur on surfaces of cusps. Both surfaces may be involved but, more commonly,
the undersurface is affected.
17. Ans. (a) Acute rheumatic fever (Ref: Robbin 7th/593, 9/e 558)
18. Ans. (a) Acute rheumatic fever (Ref: Robbin 8th/565, 7th/593, 9/e 558)
19. Ans. (b) Mycobacterium tuberculosis (Ref: Robbins 7th/607-609, 9/e 571)
Mycobacterium tuberculosis causes involvement of pericardium (Caseous pericarditis). It is the commonest cause of chronic
constrictive pericarditisQ.
Primary pericarditis is unusual and is almost always viralQ in origin.
20. Ans. (d) Hypertrophic cardiomyopathy (Ref: Robbins 9/e 569, 8th/576; 7th/604, 607)
21. Ans. (a) Rheumatic heart disease (Ref: Robbins 9/e 554, 8th/565,561; 7th/589)
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22. Ans. (c) Syphilis (Ref: Robbins 9/e p554-555, 8th/375-376, 7th/532)
23. Ans. (a) Myocardial infarction (Ref: Robbins 9/e p529, 8th/535; 7th/562)
24. Ans. (b) SLE (Ref: Robbins 9/e p562, 8th/220; 7th/598)
25. Ans. (b) TB (Ref: Harrison 17th/1493, Robbins 9/e p575)
26. Ans. (a) Acute rheumatic fever (Ref: Robbins 9/e p558, 8th/565, 7th/593)
27. Ans. (b) Aschoffs nodule (Ref: Robbins 9/e p558, 8th/565-566)
28. Ans. (a) lgM directed against lgG (Ref: Robbins 9/e p1210, 8th/1238)
29. Ans. (d) Erythema nodosum (Ref: Robbins 9/e p559, 8th/566, 7th/594)
30. Ans. (c) Myocarditis (Ref: Robbins 8th/566, 9/e p559, Harrison 18th/2754)
The most common cause of death that occur during rheumatic fever is cardiac failure secondary to valvular dysfunction.
Microscopically, the characteristic feature of rheumatic heart disease is Aschoffs bodyQ. The plump macrophages called
Anitschkow cellsQ are pathognomonic for RF.
Most commonly affected valve is mitral valveQ and the least commonly affected is pulmonary valveQ.
31. Ans. (b) A 28-year-old male with persistently high fevers with tricuspid vegetations and tricuspid regurgitation on
trans-thoracic echocardiogram (Ref: Robbins 9/e p560-561, 8th/567)
Endocarditis is an inflammation of the endocardium that can be caused by
Infectious agents such as S. aureus or S. viridans,
Inflammatory processes such as rheumatic fever or systemic lupus erythematosus (Libman-Sacks
endocarditis)
Other processes such as metastatic cancer, carcinoid etc.
S. aureus causes acute bacterial endocarditis with rapid onset of symptoms including shaking chills
(rigors), high grade fever, dyspnea on exertion and malaise. In IV drug abusers it causes right-sided en-
docarditis with septic embolization into the lungs leading to pulmonary abscesses. In non- intravenous
drug abuser, it causes rapid decompensation, heart failure, sepsis, septic embolization to the brain and
other end organs.
(Choice A) This clinical picture is most consistent with a patient who has suffered from acute rheumatic fever in the past
that has left her with mitral stenosis. It is likely that she has recently experienced yet another episode of rheumatic fever.
(Choice C) Streptococcus bovis is a part of the normal flora of the colon, and bacteremia or endocarditis caused by S. bovis
is associated with colonic cancer in approximately 25% of cases.
(Choice D) This case is most consistent with culture-negative endocarditis. He has vague symptoms that can be associated
with endocarditis, namely fever, fatigue, and malaise, and he has echocardiographic evidence of a valvular vegetation.
Special serologies and cultures need to be sent for organisms that do not grow in standard blood culture. These organisms
include Bartonella, Coxiella, Mycoplasma, Histoplasma, Chlamydia and the HACEK organisms (Haemophilus,
Actinobacillus, Cardiobacterium, Eikenella and Kingella).
31.1. Ans. (c) Small or medium sized on either or both sides of valve (Ref: Robbins 8/e p567, 9/e p560)
Summary of salient features of vegetations in different endocarditis
Rheumatic Fever Non Bacterial Thrombotic Libman Sacks Endocarditis Infective Endocarditis
(Marantic Endocarditis)
Small, warty Small, warty Medium sized (small) Large
Firm Friable Flat, Verrucous Bulky
Friable Irregular Irregular
Along lines of closure Along lines of closure On surface of cusps Vegetations on the valve
(both surfaces may be involved but the cusps
under-surface is more likely affected, less Less often on mural
commonly mural endocardium is involved) endocardium
In pockets of valves
Sterile (no organism) Sterile Sterile Non-sterile (bacteria)
Embolisation is Embolisation is common Embolisation is uncommon Embolisation is very
uncommon common (max chances)
In rheumatic heart In cancers (like M3-AML, In SLE In infective endocarditis
disease pancreatic cancer), deep
vein thrombosis, Trosseau
syndrome
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3 1.2. Ans. (b) Libman Sacks endocarditis (Ref: Robbins 8/e p567, 9/e p562)
Refer to the earlier question
3 1.3. Ans. (b) Rheumatic endocarditis (Ref: Robbins 8/e p566, 9/e p558)
In patients of rheumatic heart disease, subendocardial lesions, perhaps exacerbated by regurgitant jets, may induce irregu-
lar thickenings called MacCallum plaques, usually in the left atrium . Q
3 1.4. Ans. (c) Lungs (Ref: Robbins 8/e p 535, 9/e p529)
Robbins In patients with heart failure, some red cells extravasate into the edema fluid within the alveolar spaces,
where they are phagocytosed and digested by macrophages, which store the iron recovered from hemoglobin in the form
of hemosiderin. These hemosiderin-laden macrophages are often referred to as heart failure cells.
31.5. Ans. (b) Fat deposition (Ref: Robbins 8/e p34)
In a pattern of lipid deposition seen with prolonged moderate hypoxia, such as that produced by profound anemia, there
is intracellular deposits of fat, which create grossly apparent bands of yellowed myocardium alternating with bands of
darker, red-brown, uninvolved myocardium (tigered effect).
31.6. Ans. (b) Acute rheumatic fever discussed in detail earlier (Ref: Robbins 8/e p565-566, 9/e 559)
3 1.7. Ans. (d) Lung (Ref: Robbins 9/e p561, 8/e p566, 7/e p597)
Mitral valve vegetations are associated with systemic embolisation which can affect brain, liver, spleen and kidney.
Embolisation of the lung is associated with involvement of right heart (tricuspid valve vegetation) involvement.
3 1.8. Ans. (c) Pulmonary (Ref: Robbins 9/e p559, 8 /e p565-567, 7/e p597)
In chronic rheumatic heart disease, the mitral valve is affected alone in 65% to 70% of cases, and along with the aortic
valve in another 25% of cases. Tricuspid valve involvement is infrequent, and the pulmonary valve is only rarely affected.
3 1.9. Ans. (d) Tricuspid valve (Ref: Robbins 9/e p560, 8 /e p565-567, 7/e p597)
32. Ans. (c) Trousseau syndrome (Ref: Robbins 9/e p562, 8th/567)
The pathogenesis of nonbacterial thrombotic endocarditis (NBTE) often involves a hypercoagulable state. When the hypercoagulability
is the result of the procoagulant effects of circulating products of cancers the resulting cardiac valve vegetations may also be called
marantic endocarditis. The pathophysiology of NBTE is similar to that of Trousseaus syndrome (migratory thrombophlebitis) which may
also be induced by disseminated cancers like mucinous adenocarcinoma of the pancreas and adenocarcinoma of the lung which may
relate to procoagulant effects of circulating mucin.
(Choice A) Humoral hypercalcemia of malignancy, the most common cause of hypercalcemia is due to the production of
a parathyroid hormone (PTH)-like substance by tumors. It would not cause a hypercoagulable state or vegetations.
(Choice B) Cancer metastases to the heart usually involve the pericardium or myocardium. Valve metastases are less
frequent and would probably have shown invasive characteristics on histological examination.
(Choice D) Raynauds phenomenon involves episodic, ischemic attacks of the digits that produce pallor and numbness.
These episodes maybe induced by cold or emotional stimuli. The pathophysiology is thought to involve abnormal
sensitivity of digital arteries/arterioles to vasoconstrictive influences. Raynauds phenomenon occurs in the absence of
any hypercoagulable state.
33. Ans. (b) Presence of neutrophils (Ref: Robbins 9/e p544, 8th/550)
As discussed in the text, granulation tissue appears between 7-10 days and collagen appears after 2 months. Between 3-7
dyas, neutrophils start disintegrating with early phagocytosis caused by macrophages. Presence of macrophages would
have been a better answer but in the given question, presence of neutrophils is the best option.
34. Ans. (d) These may result in aneurysm (Ref: Robbins 9/e p543, 7th/575)
Ventricular aneurysms result from transmural infarcts, which involve the whole thickness of myocardium from epicardium
to endocardium. Subendocardial infarcts being limited to only the inner one-third or at most one half of the ventricular wall
do not cause ventricular aneurysms.
Aneurysm of the ventricular wall most commonly results from a large transmural anteroseptal infarct.
35. Ans. (b) Necrotic myofibers with presence of neutrophils (Ref: Robbins 7th/578-581, 9/e p544)
The patient in the question succumbed to myocardial infarction after about 28 hours of the attack. After twenty-four hours
of the attack light microscopy shows coagulative necrosis of myofibrils with loss of nuclei and striations along with an
interstitial infiltrate of neutrophils. For details, see the table of morphological changes of MI in text.
36. Ans. (c) Nephrotic syndrome (Ref: Harrison 17th/272, Robbins 9/e p914)
Nephrotic syndrome is a clinical complex characterized by proteinuria (> 3.5 g/day), hypoalbuminemia, edema and
hyperlipidemia.
A hypercoagulable state frequently accompanies severe nephrotic syndrome due to urinary loss of AT-III, reduced
serum levels of protein C and S, hyperfibrinogenimia and enhanced platelet aggregation.
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Due to increased coagulation state, predisposition to CAD is present in patients with nephrotic syndrome.
Potential future questions
Among hyperlipoproteinemias type II, III and IV are associated with increased risk of CAD whereas Type I and V are not associated
with CAD.
37. Ans. (c) Within one week (Ref: Robbins 7th/579, 9/e 544, Chandrasoma Taylor 3rd/364)
38. Ans. (d) Myocardial infarction (Ref: Robbins 9/e 547, 8th/555, 7th/583, Harrison 17th/1534)
The preferred biomarkers for myocardial damage are cardiac-specific proteins, particularly Troponin-I (TnI) and Troponin-T.
39. Ans. (b) Coagulative necrosis (Ref: Robbins 7th/579, 9/e 545)
40. Ans. (d) Troponin-I (Ref: Cardiovascular Imaging ; Vol. 22, No. 2, April 2006, Robbins 9/th p547)
Hypothyroid patients have increased concentration of CPK that is mostly due to increased CPK MM. However CPK-MB
has also been reported to increase above reference value in hypothyroid patients without myocardial damage. This may
create confusion during the evaluation of myocardial injury in a hypothyroid patient presenting with chest pain.
Troponin I is considered superior, marker for the diagnosis of myocardial infarction in hypothyroid patient.
41. Ans. (c) CPK-MB (Ref: Harrison 17th/1535, Robbins 9/e 547)
Troponin levels remain elevated for 10-14 days after MI, therefore if there is reinfarction prior to that period, Tro-
ponin cannot be used for the diagnosis. As discussed is text, CPK-MB is better marker for diagnosis of reinfarction.
42. Ans. (a) Waviness of the fibers (Ref: Robbins 9/e p544, 8th/550-551; 7th/581)
43. Ans. (c) Left anterior descending coronary artery (Ref: Robbins 9/e p542, 8th/551; 7th/577)
44. Ans. (d) 3 months (Ref: Robbins 9/e p544, 8th/550, 7th/579)
45. Ans. (d) Autoimmune (Ref: Robbins 9/e p549, 8th/557, 7th/584)
46. Ans. (c) MM and MB (Ref: Robbins 8th/555, 9/e p547)
47. Ans. (a) CPK MB (Ref: Robbins 9/e p547, 8th/556; 7th/583)
48. Ans. (d) Stable angina (Ref: Robbins 9/e p539-540, 8th/545, also read the explanation below)
This patients history of hypertension, hyperlipidemia, coronary artery bypass surgery, and carotid endarterectomy all in-
dicate that he suffers from generalized atherosclerosis. When atherosclerosis involves intestinal arteries, the bowel suffers
from diminished blood supply. Intestinal hypoperfusion, which can be very painful, is especially pronounced after meals
when more blood is needed for the digestion and absorption of nutrients.
Chronic mesenteric ischemia is most often caused by atherosclerotic narrowing of the celiac trunk, superior mesenteric
artery and inferior mesenteric artery. This triad of symptoms characterizes the disease:
Epigastric or peri-umbilical abdominal pain occurs 30-60 minutes after food intake. Atherosclerotic arteries are not able to
dilate in response to increased blood flow requirements during the digestion and absorption of food.
Weight loss is common; many patients avoid the pain associated with eating. Patients report severe pain; but the phy-
sician examination will usually appear benign.
On light microscopy, hypo-perfused areas of intestine show mucosal atrophy and loss of villi. Atherosclerotic plaques
are found in the intestinal vessels.
Angiography is the gold standard but this method is invasive and expensive. Mesenteric duplex ultrasonography is a noninvasive
alternative in assessing intestinal blood flow.
(Choice C) Pulmonary emboli describe the lodging of emboli (usually a blood clot) in the branches of the pulmonary artery.
The most common source is blood clots in the veins of lower extremities. A similar pathogenesis accounts for acute mesenteric
ischemia associated with mural thrombus.
(Choices A and B) The pathogenesis of peptic ulcer disease and esophageal spasm are unrelated to blood supply.
49. Ans. (d) Myocardial rupture (Ref: Robbins 9/e p549, 8th/557)
Rupture of the left ventricle, a complication of acute myocardial infarction, usually occurs when the necrotic area has the
least tensile strength, about 4-7 days after an infarction, when repair is just beginning.
The anterior wall of the heart is the most frequent site of rupture, leading to fatal cardiac tamponade. Internal rupture
of the interventricular septum or of a papillary muscle may also be seen.
Arrhythmias are the most important early complication of acute myocardial infarction.
Pump failure, ventricular aneurysms and mural thrombosis are other complications that may develop as a result of
permanent damage to the heart after infarction.
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50. Ans. (c) Pericardial inflammation overlying the necrotic segment of myocardium (Ref: Robbins 9/e p549, 8th/557)
The sharp and pleuritic nature of this patients new pain suggests pericardial involvement. The exacerbation with swal-
lowing indicates that the posterior pericardium may be involved, and the radiation into the neck suggests involvement of
the inferior pericardium, which is adjacent to phrenic nerve afferents supplying the diaphragm. The patients low-grade
fever tells us that this is an inflammatory process.
A fibrinous or serofibrinous early onset pericarditis develops in about 10-20% of patients between days 2 and 4 following a transmural
myocardial infarction. This pericarditis is a reaction to the transmural necrosis.
The inflammation affects the adjacent visceral and parietal pericardium; in other words, the inflammation is usually local-
ized to the region of the pericardium overlying the necrotic myocardial segment. This type of early post-MI pericarditis is
generally short-lived and disappears with 1 to 3 days of aspirin therapy.
(Choices A and B) Thrombosis of a coronary vessel would be expected to reproduce the patients original, anginal type
pain. The pain of myocardial ischemia is not usually sharp or pleuritic in nature, but rather is constant, substernal, and
crushing.
(Choice D) This describes the late-onset post-myocardial infarction pericarditis (Dresslers syndrome). Dresslers syn-
drome typically begins one week to a few months after a myocardial infarction.
Typical features include fever, pleuritis, leukocytosis, pericardial friction rub, and chest radiograph evidence of new peri-
cardial or pleural effusions. Dresslers syndrome is thought to be an autoimmune polyserositis provoked by antigens
exposed or created by infarction of the cardiac muscle. Thus, the pericardium is usually diffusely inflamed. Other serosal
surfaces including the lung pleura may be involved. Dresslers syndrome generally responds to aspirin, NSAIDs, and/or
glucocorticoids.
51. Ans. (b) 7 days (Ref: Robbins 8th/550, 9/e p549)
A number of serious complications can occur between 5 and 10 days following infarction, due to marked weakening of the necrotic
myocardium. These include rupture of the ventricular wall leading to hemopericardium and cardiac tamponade (as this patient had),
rupture of the interventricular septum, and rupture of the papillary muscle.
Arrhythmias are the most common complication 2 days post-infarction (choice A).
Fibrinous pericarditis secondary to an autoimmune phenomenon (Dresslers syndrome) can be seen several weeks after
infarction (choices C and D).
52. Ans. (b) Fibrinous pericarditis (Ref: Robbins 8th/557, 9/e p549)
Different types of pericarditis can be seen in different settings. Fibrinous and serofibrinous pericarditis may follow acute myocardial
infarction (Dresslers syndrome) and can be seen in uremia, chest radiation, rheumatic fever, systemic lupus erythematosus and
following chest trauma (including chest surgery) or chest radiation.
52.1. Ans. (a)Troponin T (Ref: Robbins 8/e p555, 9/e p547)

Enzyme Initiation of rise Peak Return to baseline
CK-MB 2-4 hours 24 hours 48-72 hours
Troponin T and l (TnT, Tnl) 2-4 hours 48 hours 7-10 days
AST/SGOT In 12 hours 48 hours 4-5 days
LDH 24 hours 3-6 days 2 weeks
5 2.2. Ans. (c) LDH (Ref: Robbins 8/e p555, 9/e p547)
5 2.3. Ans. (c) Macrophages (Ref: Robbins 8/e p550, 9/e p544)
Evolution of changes in MI
Reversible injury
0-30 min None None
Irreversible injury
30 min to 4 hr. None Waviness of fibers at border (earliest change)

4-12 hr. Occasional dark mottling Beginning of coagulative necrosis, edema and hemorrhage
12-24 hr. Dark mottling Ongoing coagulative necrosis, marginal contraction band necrosis,
beginning of neutrophilic infiltration
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Reversible injury
1-3 days Mottling with yellow tan infarct center. Coagulation necrosis, interstitial neutrophilic infiltrate
3-7 days Hyperemic borders, central yellow Beginning of disintegration with dying neutrophils, early phagocytosis by
tan softening macrophages
7-10 days Maximum yellow tan and soft Early formation of fibrovascular granulation tissue at margins
depressed red-tan margin
10-14 days Red gray depressed infarct borders Well established granulation tissue and collagen deposition
2-8 weeks Gray-white scar progressive from Collagen deposition, Cellularity
border towards infarct core
> 2 months Scarring complete Dense collagenous scar
Have a close at the table given above, the answer is undoubtedly is macrophage.
5 2.4. Ans. (d) Free radicals (Ref: Robbins 8/e p553, 9/e p546)
Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured. However, under
certain circumstances, when blood flow is restored to cells that have been ischemic but have not died, injury is para-
doxically exacerbated and proceeds at an accelerated pace. This process is called ischemia-reperfusion injury. The following
mechanisms have been proposed for the reperfusion injury:
New damage may be initiated during reoxygenation by increased generation of reactive oxygen and nitrogen species
from parenchymal and endothelial cells and from infiltrating leukocytes.
Ischemic injury is associated with inflammation as a result of the production of cytokines and increased expression
of adhesion molecules by hypoxic parenchymal and endothelial cells, which recruit circulating neutrophils to reper-
fused tissue.
Activation of the complement system may contribute to ischemia-reperfusion injury. Some IgM antibodies have a pro-
pensity to deposit in ischemic tissues, for unknown reasons, and when blood flow is resumed, complement proteins
bind to the deposited antibodies, are activated, and cause more cell injury and inflammation.
5 2.5. Ans. (c) 1-3 days. See the table in text or details (Ref: Robbins 9/e p544, 8/e p550, 7/e p579)
5 2.6. Ans. (c) Coxsackie Virus (Ref: Robbins 7/e 610, 9/e p570)
53. Ans. (a) Bronchial carcinoma (Ref: Robbins 9/e p574, 8th/589, 7th/614)
5 3.1. Ans. (d) Myxoma (Ref: Robbins 9/e p575, 8/e p583-4)
Important information about NEET
Most common cardiac tumor: MetastasisQ
Most common benign cardiac tumor: atrial myxomaQ
Most common primary cardiac tumor in adults: atrial myxomaQ
Most common primary cardiac tumor in children: rhabdomyomaQ
53.2. Ans. (a) Myxoma (Ref: Robbind 8/e p583, 9/e 575)
Myxomas are the most common primary tumor of the heart in adults.
Though they may arise in any cavity of the heart but nearly 90% are located in the atria,
The left-to-right ratio of the myxoma is approximately 4:1
The region of the fossa ovalis in the atrial septum is the favored site of origin.
Histologically, myxomas are composed of stellate or globular myxoma (lepidic) cells,
Major clinical manifestations: fever, malaise, features due to valvular ball-valve obstruction or embolization
Familial cardiac myxoma syndrome (known as Carney syndrome) is characterized by autosomal dominant transmission,
multiple cardiac and often extracardiac (e.g. skin) myxomas, spotty pigmentation, and endocrine overactivity.
53.3. Ans. (b) Left atrium (Ref: Robbins 9/e 575, 8/e p583, 7/e p613)
Atrial myxoma is most commonly located on the left atrium. Other important points have discussed earlier.
54. Ans. (c) Lower limb ischemia (Ref: Robbins 8th/499, 1140)
Direct quote from Robbins... Gangrene of the lower extremities as a result of advanced vascular disease is about 100 times more
common in diabetics than in general population.
The risk of myocardial infarction (MI) is twice in a diabetic as compared to a non diabetic individual.
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55. Ans. (b) Atherosclerosis in less important in age more than 45 years age (Ref: Robbins 9/e p493, 8th/497)
Risk factors for atherosclerosis
Modifiable Non modifiable
Hyperlipidemia Increasing age
Hypertension Gender
Cigarette smoking Family history
Diabetes Genetics
C reactive protein
According to Robbins,
Age is a dominant influence on atherosclerosis. Between ages 40 and 60, the incidence of myocardial infarction increases fivefold.
Hyperlipidemia more specifically hypercholesterolemia; even in the absence of other risk factors is a major risk factor for
atherosclerosis. The major component of serum cholesterol associated with increased risk is low-density lipoprotein (LDL)
cholesterol. In contrast, higher levels of HDL correlate with reduced risk.
Dietary and pharmacologic approaches that lower LDL or total serum cholesterol, and/or raise serum HDL are all of considerable
interest. High dietary intake of cholesterol and saturated fats (present in egg yolks, animal fats, and butter, for example) raises
plasma cholesterol levels. Conversely, diets low in cholesterol and/or with higher ratios of polyunsaturated fats lower plasma
cholesterol levels.
Omega-3 fatty acids (abundant in fish oils) are beneficial, whereas (trans) unsaturated fats produced by artificial hydrogenation of
polyunsaturated oils (used in baked goods and margarine) adversely affect cholesterol profiles.
Cigarette smoking is a well-established risk factor in both men and women. Prolonged (years) smoking of one pack of cigarettes
or more daily increases the death rate from ischemic heart disease by 200%. Smoking cessation reduces that risk substantially.
C-reactive protein (CRP) is an acute-phase reactant synthesized primarily by the liver. When locally synthesized within atherosclerotic
intima, it can also regulate local endothelial adhesion and thrombotic states. Most importantly, it strongly and independently predicts
the risk of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death, even among apparently healthy
individuals
56. Ans. (c) Hyaline arteriosclerosis (Ref: Robbins 8th/495-6, 9/e p490)
Hyaline arteriosclerosis is characterized by the following:
Pink, hyaline thickening of arteriolar walls (due to leaking of plasma proteins) associated with luminal narrowing.
Seen in elderlyQ, more commonly in benign hypertensionQ, diabetes mellitusQ (DM) and benign nephrosclerosisQ.
57. Ans. (a) Insulin deficiency (Ref: Robbins 8th/1144-1146, 9/e p499)
All the mentioned features in the question are the macrovascular complications of diabetes mellitus which is caused due
to insulin deficiency.
58. Ans. (a) Atherosclerosis (Ref: Robbins 8th/507, Harrison 18th/2060-1)
Direct quote from Harrsion.atleast 90% of all abdominal aortic aneurysms >4.0 cm are related to atherosclerotic
disease and most are present just below the renal arteries.
59. Ans. (a) Hyaline arteriosclerosis (Ref: Robbins 8th/495; 507, 950, 9/e p490)
Hyaline arteriosclerosis is characterized by the following:
Pink, hyaline thickening of arteriolar walls (due to leaking of plasma proteins) associated with luminal narrowing.
Seen in elderly, more commonly in benign hypertension, diabetes mellitus (DM) and benign nephrosclerosis.
Other important points

The characteristic features seen in the kidney are called benign nephrosclerosis include:
Hyaline arterioslcerosis
Normal or small kidney size with leather grain appearanceQ.
Presence of fibroelastic hyperplasia (media hypertrophy, elastic lamina duplication and intimal thickening)
Presence of patchy ischemic atrophy and glomerular sclerosis
Malignant hypertension is discussed below.
60. Ans. (b) Hyaline arteriolosclerosis: (Ref: Robbins 7th/534, 8th/496, 949, 9/e p490)
Malignant hypertension is characterized by sudden elevation of BP (diastolic BP > 120 mmHg) accompanied by papillede-
ma, CNS manifestations, cardiac decompensation and acute progressive deterioration of renal function.
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The characteristic features include:

1. Fibrinoid necrosisQ of the small vessels particularly the arterioles
2. Necrotizing arteriolitisQ: Presence of inflammatory cells in the vessel wall
3. Hyperplastic arteriosclerosisQ: Proliferation of the internal smooth muscle cells seen in the interlobular arteries giving onion skin
like appearanceQ
Renal involvement is called malignant nephrosclerosis having the features like
a. Kidneys have a typical flea bitten appearanceQ (due to petechial hemorrhage on cortical surface)
b. Necrotizing glomerulonephritis: Necrotizing arteriolitis may involve the glomeruli also.
61. Ans. (c) Lipoprotein A (Ref: Robbins 7th/520-521)

In addition to a high cholesterol level there is a positive correlation between atherosclerosis of coronary artery and other
arteries and circulating levels of lipoprotein (a).
Lp (a) has structural similarity with plasminogen. It interferes with formation of plasmin and hence, fibrinolysis. This contributes to
atherosclerosis.
62. Ans. (b) Atherosclerosis (Ref: Harrison 17th/1563, 18th/2060-1, Robbins 7th/531, 9/e p503)
63. Ans. (a) Heart (Ref: Ultrastructural pathology/374, Robbins 8th/495-6)
Friends, trust me this seemed to be an easy one but as i found out to my surprise, the reference pages mentioned by all
MCQ books including our competitors (whom we expect to copy this info as well as has happened so many times earlier
!J) give page number from Robbins which dont have this info! But I managed to find something worthy as follows:
Ultrastructural pathology by Cheville NF page 374 mentions that . hyperplastic arteriosclerosis of the kidney has the
most serious effects but this lesion is also found in the artereioles of the intestine , gall bladder and pancreas. I was not
able to found anything relevant about pericardial fat. But after discussion with many senior faculty members, the answer
of consensus is option a i.e. Heart.
64. Ans. (a) Homocysteinemia; (c) Increased fibrinogen; (e) Increased plasminogen activator inhibitors. (Ref: Robbins
7th/520, 8th/498, 9/e p492)

65. Ans. (a) Concentric hypertrophy of LV; (b) Increased heart size; (c) Increased size of heart muscle; (d) Myohypertrophy:
(Ref: Robbins 7th/587, Harrison 17th/1552)
Features of essential hypertensions are:
Concentric hypertrophy of the left ventricles due to pressure overload of the heart.
Increase in weight of heart (>500 gm) is disproportionate to the increase in overall size of heart.
Thickening of the left ventricular wall increased the ratio of its wall thickness to radius.
Microscopically the earliest changes of systemic hypertensive heart disease is an increased transverse myocytes di-
ameter. In advanced stage the cellular and nuclear enlargement is prominent. Electron microscopy reveals increase in
number of myofilaments comprising myofibrils, mitochondrial changes and multiple intercalated disks.
Increase total RNA and ratio of RNA to DNA contents.
66. Ans. (c) Lipids in LDL gets auto-oxidized (Ref: Harrison 17th/1502 Robbins 7th/523, 9/e p496)
Scavenger receptors and not LDL receptors on macrophages result in uptake of oxidized LDL to form foam cells contribut-
ing to atherosclerosis.
67. Ans. (b) Pulmonary artery trunk (Ref: Robbins 8th/502, 9/e p498)
See mnemonic in text.
68. Ans. (b) Hyaline arteriosclerosis (Ref: Robbins 8th/495-496, 9/e p490)
69. Ans. (a) Fibrinoid necrosis of arteriolar wall (Ref: Robbins 7th/1007, 9/e p490)
Accelerated phase of hypertension is the other name for malignant hypertension.
70. Ans. (d) Abdominal aorta (Ref: Robbins 9/e p502, 8th/507, 7th/531)
71. Ans. (b) Media (Ref: Robbins 9/e p491, 8th/496; 7th/498)
72. Ans. (c) Platelets (Ref: Robbins 8th/501, 9/e p496)
The pathogenesis of atherosclerotic plaques (atheromas) begins with endothelial cell injury, which results in endothelial
cell dysfunction and/or exposure of subendothelial collagen (endothelial cell denudation). Exposure of subendothelial
collagen promotes platelet adhesion, aggregation, and release of factors that promote migration of smooth muscle cells
(SMC) from the media into the intima, as well as SMC proliferation. These factors include platelet-derived growth factor
(PDGF) and transforming growth factor beta (TGF-b).
396
PDGF is chemotactic and mitogenic for smooth muscle cells (SMC). TGF- is chemotactic for SMC.
(Choice A) Neutrophils do not appear to play a significant role in the chronic intimal inflammatory process that generates
atheromas, nor do they release growth factors.
(Choice B) Eosinophils are important in parasitic infections and IgE-mediated immune reactions.
73. Ans. (d) They show predominantly intracellular lipid accumulation. (Ref: Robbins 9/e p496, 8th/501-4)
The lesions in the stem of the question are fatty streaks. These are the earliest lesions in the progression to atherosclerosis. Fatty
streaks are composed of intimal lipid filled foam cells, derived from macrophages and smooth muscle cells (SMC) that have engulfed
lipoprotein (predominantly LDL) which has entered the intima through an injured leaky endothelium. The foamy appearance is due to
intracellular lipid containing phagolysosomes.
Fatty streaks begin as multiple yellow spots approximately 1 mm in diameter which join to form streaks approximately 1
cm long. They may contain a few lymphocytes, but foam cells are the predominant constituents. The fatty streaks are not
significantly raised, so, they do not disturb normal blood flow. They can be seen in the aortas of children less than 1 year
old and are present in the aortas of all children over 10. Whereas some fatty streaks maybe precursors of atheromatous
plaques not all fatty streaks progress to these more advanced atherosclerotic plaques.
(Choice B) Fatty streaks often occur on regions of the vasculature not particularly prone to atheroma development later in
life. Moreover, they frequently affect individuals in locations and populations with a low lifetime incidence of fully devel-
oped atheromatous plaques.
74. Ans. (c) Hyperplastic arteriolosclerosis (Ref: Robbins 8th/496, 9/e p490)
7 4.1. Ans. (b) Left anterior descending coronary artery (Ref: Robbins 8/e p551, 9/e p542)
The frequencies of involvement of each of the three main arterial trunks and the corresponding sites of myocardial lesions
resulting in infarction (in the typical right dominant heart) are as follows:
Left anterior descending coronary artery (40% to 50%): infarcts involving the anterior wall of left ventricle near the
apex; the anterior portion of ventricular septum; and the apex circumferentially
Right coronary artery (30% to 40%): infarcts involving the inferior/posterior wall of left ventricle; posterior portion of
ventricular septum; and the inferior/posterior right ventricular free wall in some cases
Left circumflex coronary artery (15% to 20%): infarcts involving the lateral wall of left ventricle except at the apex
7 4.2. Ans. (b) Flea bitten kidney (Ref: Robbins 8/e p950-1, 9/e p490)
In malignant hypertension, on gross inspection the kidney size depends on the duration and severity of the hypertensive
disease. Small, pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular
capillaries, giving the kidney a peculiar flea-bitten appearance.
Causes of contracted kidney
Symmetric Asymmetric
Chronic glomerulonephritis Chronic pyelonephritis
Benign nephrosclerosis
Causes of enlarged kidneys
Amyloidosis Diabetic renal disease [Kimmelstiel Wilson nodules are pathognomic]
Rapidly progressive glomerulonephritis (RPGN) Polycystic kidney disease
Myeloma kidney Bilateral obstruction (hydronephrosis)
7 4.3. Ans. (a) Marfan syndrome (Ref: Robbins 8/e p509, 9/e p502)
The vascular wall is weakened through loss of smooth muscle cells or the inappropriate synthesis of noncollagenous or nonelastic ECM.
Atherosclerosis and hypertension induced ischemia is reflected in degenerative changes of the aorta, whereby smooth
muscle cell loss leads to scarring (and loss of elastic fibers), inadequate ECM synthesis, and production of increasing
amounts of amorphous ground substance (glycosaminoglycan). Histologically these changes are collectively called cystic
medial degeneration. Though these are nonspecific, they can be seen with Marfan diseaseQ and scurvyQ
7 4.4. Ans. (a) Hypertension (Ref: Robbins 8/e p508, 9/e p504)
Aortic dissection occurs when blood splays apart the laminar planes of the media to form a blood-filled channel within the aortic wall;
this can be catastrophic if the dissection then ruptures through the adventitia and hemorrhages into adjacent spaces.
Aortic dissection occurs principally in two groups:
Men aged 40 to 60, with antecedent hypertension (more than 90% of cases of dissection);
Younger patients with systemic or localized abnormalities of connective tissue affecting the aorta (e.g., Marfan syndrome).
7 4.5. Ans. (b) Heart (Ref: Robbins 8/e p502, 9/e p498)
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Coronary arteries supply the heart. They are the second most common vessel (after abdominal aorta) to be affected in
atherosclerosis.
Significance of involved blood vessels in atherosclerosis
Abdominal Aorta Most common site of atherosclerotic aneurysm in body
Coronary Arteries Left Anterior Descending is MC coronary artery involved
Poplitial Artery MC peripheral vessel showing aneurysm formation
Descending Thoracic Aorta
Internal carotid artery
Circle of Willis
74.6. Ans. (c) Atherosclerosis (Ref: Robbins 8/e p507, 9/e 502)
The two most important disorders that predispose to aortic aneurysms are atherosclerosis and hypertension; atheroscle-
rosis is a greater factor in abdominal aortic aneurysms, while hypertension is the most common condition associated with
aneurysms of the ascending aorta.
An aneurysm is a localized abnormal dilation of a blood vessel or the heart); it can be congenital or acquired. When an aneurysm
involves an intact attenuated arterial wall or thinned ventricular wall of the heart, it is called a true aneurysm.
7 4.7. Ans. (a) Splenic (Ref: Peripheral Vascular Interventions chapter 15, pg 263)
The visceral arteries include the three main unpaired branches of the abdominal aorta namely celiac artery, superior
mesenteric and inferior meseneteric arteries.
The most common visceral vessel showing aneurysm formation is the splenic artery followed by the hepatic artery.
Q
7 4.8. Ans. (c) Monckebergs sclerosis (Ref: Robbins 8/e p496, 9/e p491)
Mnckeberg medial sclerosis is characterized by calcific deposits in muscular arteries in persons typically older than
age 50.
The deposits may undergo metaplastic change into bone.
Nevertheless, the lesions do not encroach on the vessel lumen and are usually not clinically significant.
7 4.9. Ans. (a) Syphilitic (Ref: Robbins 8 /e p507-508, 7/e p532)
Direct lines The obliterative endarteritis characteristic of late-stage syphilis shows a predilection for small vessels, in-
cluding those of the vasa vasorum of the thoracic aorta.
Atherosclerosis affects abdominal aorta most commonly. Traumatic aneurysm can affect any site of the aorta. Berry aneu-
rysm affects the circle of Willis.
7 4.10. Ans. (d) Hyperplastic arteriosclerosis (Ref: Robbins 9/e p490, 8/e p496, 7/e p530)
Hyperplastic arteriosclerosis is associated with malignant hypertension in which concentric thickening of the walls and
luminal narrowing leads to onion skin like lesions.
7 4.11. Ans (c) Chlamydia (Ref: Robbins 9/e 496, 8/e p500)
Robbins.. Herpes virus, cytomegalovirus and Chlamydia pneumoniae have all been detected in atherosclerotic plaques
but not in normal arteries, and seroepidemiologic studies find increased antibody titers to C. pneumoniae in patients with
more severe atherosclerosis.
Though the book also mentions that some of these observations are confounded by the fact that C. pneumoniae bron-
chitis is also associated with smoking which is a well-established IHD risk factor. Moreover, infections with these or-
ganisms are exceedingly common (as is atherosclerosis), so that distinguishing coincidence from causality is difficult.
Nevertheless, it is certainly possible that such organisms could infect sites of early atheroma formation; their foreign
antigens could potentiate atherogenesis by driving local immune responses, or infectious agents could contribute to
the local prothrombotic state.
7 4.12. Ans (c) Hyaline arteriosclerosis (Ref: Robbins 9/e p490, 8/e p495)
The following are the two patterns of vascular changes in hypertension
Hyaline Arteriolosclerosis Hyperplastic Arteriolosclerosis
Vascular lesion consists of a homogeneous, pink, hyaline Vascular lesion has onionskin, concentric, laminated
thickening of the walls of arterioles with loss of underlying thickening of the walls of arterioles with progressive narrowing
structural detail, and with narrowing of the lumen of the lumina
Seen in the elderly, hypertensive and diabetic Seen in but not exclusively in malignant hypertension,
Hyaline arteriolosclerosis is more generalized and more Frequently accompanied by deposits of fibrinoid and acute
severe in patients with hypertension. necrosis of the vessel walls referred to as necrotizing
arteriolitis (particularly in the kidney)
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75. Ans. (a)Giant cell arteritis (Ref: Robbins 9/e p508, 8th/512-3)
Giant-cell (temporal) arteritis is a chronic, typically granulomatous inflammation of large to small-sized arteries that
affects principally the arteries in the headespecially the temporal arteriesbut also the vertebral and ophthalmic
arteries
Histopathologically, the disease is a panarteritis with inflammatory mononuclear cell infiltrates within the vessel wall
with frequent giant cell formation.
Leukocytoclastic Vasculitis (also known as Microscopic Polyarteritis): it is a necrotizing vasculitis affecting arteri-
oles/capillaries/venules in which all lesions are of the same age. Granulomatous inflammation is absentQ
76. Ans. (d) Microscopic polyangiitis (Ref: Robbins 9/e p506, 8th/512, 515)
Its a direct question; we just need to keep in mind the classification of vasculitis. See text for details.
77. Ans. (a) Henoch-Schonlein Purpura (Ref: Robbins 8th/934, 9/e p926, Harrison 17th/2128, Wintrobes 12th/1343)
Henoch-Schonlein Purpura (HSP) is a syndrome seen in children (3-8 years of age) consisting of purpuric skin lesions
characteristically involving the extensor surfaces of arms and legs as well as buttocks; abdominal manifestations including pain,
vomiting, and intestinal bleeding; nonmigratory arthralgia; and renal abnormalities. It follows an upper respiratory infection.
A history of atopy is present.
The renal manifestations may include gross or microscopic hematuria, proteinuria, and nephrotic syndrome and is seen in 1/3rd of
the patients. IgA is deposited in the glomerular mesangium.
Microscopically
Kidney has deposition of IgA, sometimes with IgG and C3, in the mesangial region.
The skin lesions consist of subepidermal hemorrhages and a necrotizing vasculitis with IgA deposition involving the small vessels
of the dermis.
Vasculitis also occurs in other organs, such as the gastrointestinal tract, but is rare in the kidneyQ
Wegners granulomatosis and Giant cell Vasculitis are not seen in children. Options b and c are ruled out.
Kawasakis disease affects children but the presentation is fever, cervical lymphadenopathy, skin rash, oral ulcers, con-
junctivitis and edema of hands and feet. So, option d is also ruled out.
78. Ans. (d) Microscopic polyangiitis (Ref: Robbins 8th/513-517, 9/e p510)
Robbins clearly mentions that microscopic polyangiitis is characterized by segmental fibrinoid necrosis of the media with focal
transmural necrotizing lesions; granulomatous inflammation is absent.
79. Ans. (d) Wegeners granulomatosis (Ref: Robbins 8th/516-517, 9/e p507)
ANCA or antineutrophilic cytoplasmic antibodies are formed against certain proteins in the cytoplasm of neutro-
phils. Out of the given options, Wegeners granulomatosis is most strongly associated with ANCA.
80. Ans. (c) Kawasakis disease (Ref: Robbins 9/e p510, 8th/515, 7th/539, Harrison 17th/2130. 18th/2800)
Kawasakis disease (mucocutaneous lymph node syndrome) is an arteritis that often involves the coronary arteries,
usually in young children and infants (majority of the cases are seen in <5 years old). It is treated with intravenous
immunoglobulin and aspirin. (For details, see text.)
81. Ans. (b) Post-capillary venules (Ref: Harrison 17th/2128, 18th/2798, Robbins 8th/515, 9/e p510)
Hypersensitivity vasculitis is clearly mentioned in Harrison 18th/2798 as the other name for cutaneous vasculitis.
However, Robbins confuses the issue by mentioning that Hypersensitivity vasculitis is the other name of microscopic angiitis.
However, we would prefer to go with Harrison in this context.
Direct quote from Harrison 18th/2798 Post capillary venules are the most commonly involved vessels; capillaries and
arterioles may be involved less frequently.
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82. Ans. (c) Wegeners granulomatosis (Ref: Robbins illustrated 7th/541, 8th/516, 9/e p511-512)
Both Wegeners granulomatosis and Goodpastures syndrome can present similarly but presence of c-ANCA makes
a diagnosis of Wegeners granulomatosis.
83. Ans. (a) Buergers disease; (b) HSP; (d) Reiters disease; (e) Behcets syndrome. (Ref: Harrison 17th/2119, 1485,
Robbins 7th/535, 537)
Vasculitis syndromes
Primary vasculitis Secondary vasculitis syndrome
Wegeners granulomatosis Drug induced vasculitis
Churg-Strauss syndrome Serum sickness
PAN, HSP Infection
Microscopic polyangitis Malignancy
Giant cell arteritis, Takayasus arteritis Rheumatic disease
Idiopathic cutaneous vasculitis
Essential mixed cryoglobulinemia
Behcets syndrome, Cogans syndrome
Kawasaki disease
84. Ans. (a) Lung; (c) Kidney; (d) Upper respiratory tract; (e) Heart (Ref: Robbins 7th/541, 9/e p511)
85. Ans. (a) Involve lungs; (b) Involve nose; (c) Involve kidney; (d) Treated with cytotoxic agent and/or steroid.
(Ref: Robbins 7th/541, 9/e p511, Harrison 17th/2121)
Wegeners granulomatosis is treated with steroids and cyclophosphamide. They dramatically ameliorate glomerular
injury in pauci-immune glomerulonephritis.
86. Ans. (c) Seen in Henoch Schonlein purpura (Ref: Robbins 8th/920-921, 9/e p926)
87. Ans. (a) Kawasaki disease (Ref: Robbin 7th/537, 9/e p506)
Classification of vasculitis with important points
Large vessel vasculitis

(a) Giant cell (temporal) arteritis: in patients older than 50.
(b) Takayasus arteritis: in patients younger than 50.
Medium-sized vessel vasculitis:
(a) Polyarteritis nodosa: Glomerulonephritis is absent
(b) Kawasaki disease: coronary arteries are often involved, usually occurs in children.
Small vessel vasculitis:
(a) Wegner granulomatosis: Necrotizing glomerulonephritis is common
(b) Churg-strauss syndrome: Associated with asthma and blood eosinophilia
(c) Microscopic polyangitis: Necrotizing glomerulonephritis and pulmonary capillaritis
(d) Henoch-Schonlein purpura: Vasculitis with IgA- dominant immune deposits
(e) Essential cryoglobulinemic vasculitis: Skin and glomeruli are often involved.
(f) Cutaneous leukocytoclastic angiitis: Systemic vasculitis or glomerulonephritis is absent.
88. Ans. (a) Hypertension (Ref: Robbins 7th/539, 9/e p509-510)
Polyarteritis Nodosa
It is a systemic vasculitis manifested by transmural necrotizing inflammation of small or medium sized muscular arteries.
Renal artery is most commonly involved whereas Pulmonary circulation is spared.
Most common manifestations are malaise, fever of unknown cause, weight loss, hypertension (rapidly developing), abdominal pain,
melena, diffuse muscular pains, and peripheral neuritis (predominantly motor).
89. Ans. (c) Kawasaki disease (Ref: http://emedicine.medscape.com/article/1006838, Robbins 9/e p510)
Clinically, infantile polyarteritis nodosa (IPAN) often is part of the spectrum of Kawasaki disease (KD).
90. Ans. (b) Lung and kidney (Ref: Robbins 9/e p511-512, 8th/516; 7th/541-542)
91. Ans. (a) Pulmonary artery (Ref: Robbins 9/e p 509-510, 8th/514; 7 th/539)
92. Ans. (c) Wegeners granulomatosis (Ref: Robbins 9/e p511-512, 8th/516-517; 7 th/541)
93. Ans. (b) Henoch Schonlein purpura (Ref: Robbins 8th/920-921, 9/e p926)
94. Ans. (d) Segmental vasculitis extending into contiguous veins and nerves (Ref: Robbins 8th/517, 9/e p512)
400
Munish is most likely suffering from Buergers disease (Young male with hypersensitivity to tobacco). Microscopically
the condition shows. Segmental thrombosing vasculitis often extending into contiguous veins and nerves (a feature rarely
seen in other types of vasculitis), encasing them in fibrous tissue.
(Choice A) Lipid-filled intimal plaques that bulge into the arterial lumen are seen in atherosclerosis.
(Choice B) Onion-like concentric thickening of arteriolar walls as a result of laminated smooth muscle cells and redu-
plicated basement membranes is seen in hyperplastic arteriolosclerosis (seen in malignant hypertension)
(Choice C) Transmural inflammation of the arterial wall with fibrinoid necrosis is characteristic of polyarteritis nodosa.
95. Ans. (a) Blindness (Ref: Robbins 8th/512-31, 9/e p508)
Most likely diagnosis in this case is temporal (giant cell) arteritis. This is a pan-arteritis that can involve any of the branches of the
aortic arch. Temporal arteritis commonly produces visual disturbances including blindness due to involvement of the ophthalmic
artery. Biopsy of affected segments shows granulomatous lesions with giant cells.
Stroke may occur in temporal arteritis, but this would not likely produce loss of all tactile sensations (choice c).
Loss of the ability to speak (choice d) may result from stroke. Visual disturbances are more common than stroke in
temporal arteritis.
96. Ans. (b) Wegeners granulomatosis (Ref: Robbins 8th/516, 9/e p512)
9 6.1. Ans. (d) Involves large vessels (Ref: Robbins 8/e p516-7, 9/e p511
Wegeners granulomatosis is a small vessel necrotizing vasculitis which is characterized by triad of
Acute necrotizing granulomas of either upper (more commonly) or lower respiratory tract or both
Focal necrotizing or granulomatous vasculitis most commonly affecting lungs and upper airways.
Renal involvement in the form of focal necrotizing, often crescentic glomerulonephritis.
Clinical features include fever, weight loss, otitis media, nasal septal perforation , strawberry gums , cough,
Q Q
hemoptyis, palpable purpura , joint pain and ocular features (uveitis, conjunctivitis)
Q
Investigations show serum c-ANCA positivity, cavitatory lesions in the chest X ray and red cell casts (indica-
Q Q
tive of glomerulonephritis) in the urine.

9 6.2. Ans. (c) Polyarteritis nodosa (Ref: Robbins 8/e p512, 9/e p506)
Classfication based on vessel size
Large vessel vasculitis Medium vessel vasculitis Small vessel vasculitis

Giant cell (temporal) Classic PAN Wageners granulomatosis
arteritis Kawasakis disease Chung-strauss syndrome
Takayasu arteritis Buergers disease Henoch-schonlein pupura
Microscopic polyangitis
SLE, HSP, Goodpasture syndrome
9 6.3. Ans. (c) Most commonly involved artery is abdominal aorta (Robins 8/e p512-3, 9/e p507-508)
Salient features of temporal arteritis/ Giant cell arteritis
Large vessel vasculitis characterised by granulomatous arteritis of the aorta and its major branches particularly the
extracranial branches of the carotid artery.
Since the superficial temporal artery is the most commonly involved vessel, the giant cell arteritis is called as
Q
temporal arteritis.
Clinical features include constitutional symptoms like fever, fatigue, weight loss, jaw pain (most specific symptom),
Q
facial pain, localized headacheQ (commonest symptom; most intense along the anatomical course of the superficial
temporal artery) and sudden onset of blindness (due to involvement of ophthalmic artery).
Biopsy of temporal arteryQis the investigation of choice.
Since giant-cell arteritis is extremely segmental, adequate biopsy requires at least a 2- to 3-cm length of artery; even
then, a negative biopsy result does not exclude the diagnosis
Microscopically, there is presence of granulomatous inflammation with multinucleated giant cells and fragmentation
of internal elastic lamina.
96.4. Ans. (a) Lung (Ref: Robins 8/e p514-5, 9/e p509-510)
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Polyarteritis nodosa (PAN) is characterised by necrotizing inflammation typically involving renal arteries but sparing
pulmonary vessels.
96.5. Ans. (b)Takayasu arteritis (Ref: Internet, Robins 9/e p508)
Takayasu arteritis is the choosen answer as it is associated with involvement of superior mesenteric artery. So, it may be
associated with abdominal angiitis.
9 6.6. Ans. (a) No change (Ref: Robbins 8/e p518, 9/e p513)
Structural changes in the arterial walls are absent except late in the course, when intimal thickening can appear.
9 6.7. Ans. None or (c) 40-60% (Ref: Robbins 8/e p Heptinstalls Pathology of the Kidney, Volume 1 p463.)
I dont know why they frame these type of questions.
Heptinstall writesIn different series, the degree if renal involvement in children with HSP (defined by the presence of
hematuria) is 20-56% (overall 32%) whereas in adults, it is 49-78% (overall 59%).
You may choose your answer friends.
9 6.8. Ans. (a) Carotid body tumour (Ref: Robbins 8/e p522)
Before we discuss the answer friends, a simple clarification that is to be kept in mind;
Glomus tumor (also known as a glomangioma) is a rare benign neoplasm arising from the glomus body and mainly found
under the nail, on the fingertip or in the foot. It DOES NOTcontain glomus cells.
A glomus cell (type I) is a peripheral chemoreceptor mainly located in the carotid bodies and aortic bodies helping in regulation of
the breathing.
Neoplasms of glomus cells are known as paraganglioma.
The most common location of these tumors is within the adrenal medulla, where they give rise to pheochromocytomas,
Approximately 70% of extra-adrenal paragangliomas occur in the head and neck region. Paragangliomas typically develop in two
locations:
Paravertebral paraganglia (e.g., organs of Zuckerkandl and, rarely, bladder). Such tumors have sympathetic connections and are
chromaffin-positive, a stain that detects catecholamines.

Paraganglia related to the great vessels of the head and neck, the so-called aorticopulmonary chain, including the carotid bodies
(most common); aortic bodies; jugulotympanic ganglia; ganglion nodosum of the vagus nerve; and clusters located about the
oral cavity, nose, nasopharynx, larynx, and orbit. These are innervated by the parasympathetic nervous system and infrequently
release catecholamines
Important points about carotid body tumour

The carotid body tumor is a prototype of a parasympathetic paraganglioma.
Arisesclose to or envelops the bifurcation of the common carotid artery.
The microscopic features include presence of nests (Zellballen) of round to oval chief cells (neuroectodermal in origin) that are
surrounded by delicate vascular septae.
The chief cells stain strongly for neuroendocrine markers such as chromogranin, synaptophysin, neuron-specific enolase, CD56,
and CD57.
In addition, the supporting spindle-shaped stromal cells called sustentacular cells are positive for S-100 protein.
96.9. Ans. (c) Distal portion of digits (Ref: Robbins 8/e p522, 9/e p517)
Glomus tumor is a biologically benign tumor that arises from the modified smooth muscle cells of the glomus body
Q
Glomus body is a specialized arteriovenous anastomosis that is involved in thermoregulation . Q
It is an often exquisitely painful tumor

Glomus tumors are most commonly found in the distal portion of the digits , especially under the fingernails.
Q
Excision is curative.
Q
96.10. Ans (a)Port wine stain (Ref: Robbins 8/e p522, 9/e p516)
SturgeWeber syndrome is usually manifested at birth by a port-wine stain on the forehead and upper eyelid of one side
of the face.
96.11. Ans (a) Bacterial infection (Ref: Robbins 8/e p521, 9/e p516)
402
Pyogenic granuloma: Key points

It is a benign tumor Q
Type of capillary hemangioma which it bleeds easily and is often ulcerated.

Q Q
Is a rapidly growing pedunculated red nodule on the skin, or gingival or oral mucosa;
1/3 of the lesions develop after trauma
rd
Also know that;

Pregnancy tumor (granuloma gravidarum) is a pyogenic granuloma that occurs infrequently (1% of patients)
in the gingiva of pregnant women.
These lesions may spontaneously regress post pregnancy) or undergo fibrosis;
Some cases require surgical excision
Recurrence is rare.
Golden points For quick review / Updated information from 9th edition of robbins
(Cardiovascular System)
9th Robbins/ 507New Names of Antibodies
The c-ANCA antibody is now called as Anti-proteinase-3 or PR3-ANCA. It is produced against proteinase 3 (PR3)
which is a neutrophil azurophilic granule constituent. It is seen in patients having granulomatosis with polyangiitis
(Wegeners granulomatosis).
The p-ANCA antibody is called as Anti-myeloperoxidase or MPO-ANCA. It is produced against MPO which is
a lysosomal granule constituent involved in oxygen free radical generation. This antibody is seen in microscopic
polyangiitis and Churg-Strauss syndrome. It also develops after administration of many drugs including
propylthiouracil.
Wegeners granulomatosis is now called by the new name of granulomatosis with polyangiitis.
C
Myocardial vessel spasm (concept of ardiac Raynaud and Takotsubo cardiomyopathy)
Excessive constriction of coronary arteries or myocardial arterioles may cause ischemia, and persistent vasospasm can even cause
myocardial infarction. High levels of vasoactive mediators like endogenous epinephrine (in pheochromocytoma) or exogenous chemicals
(cocaine or phenylephrine) can precipitate prolonged myocardial vessel contraction.
Such agents can be endogenous (e.g, epinephrine released by pheochromocytomas) or exogenous (cocaine or phenylephrine).
Extreme psychological stress can also lead to pathologic vasospasm. When vasospasm of cardiac arterial or arteriolar beds (so-called cardiac
Raynaud) is of sufficient duration (20 to 30 minutes), myocardial infarction occurs. The increased catecholamines also increase heart rate and
myocardial contractility exacerbating the cardiac ischemia.

Takotsubo cardiomyopathy (also called broken heart syndrome) is an ischemic di;lated cardiomyopathy caused by emotional stress.
Robbins / 543..Apart from transmural and subendocardial myocardial infarction, there is a new entity called as Multifocal microinfarction.
This pattern is seen when there is pathology involving only smaller intramural vessels.
It is seen with microembolization, vasculitis, or vascular spasm, for example, due to endogenous catechols (epinephrine) or drugs (cocaine
or ephedrine).
This may even lead to by a fatal arrhythmia) or an ischemic dilated cardiomyopathy, so-called takotsubo cardiomyopathy (also called broken
heart syndrome described earlier).
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CHAPTER 10
ANATOMY OF RESPIRATORY TRACT
Respiratory System
Trachea

Principal Bronchi

Bronchi

Bronchioles do not have
Bronchiole
cartilage and submucosal glands
in wall like bronchiQ
Terminal Bronchiole

Respiratory Bronchiole
Acinus
Alveoli
Acinus is the functional unit of lung whereas alveoli are the chief sites of gaseous Terminal bronchiole contain
exchange.
um smooth muscle relative
maxim
to the wall thicknessQ
Lobule is composed of 3-5 terminal bronchioles with their acini.
Alveoli are lined by type I pneumocytes (forming 95% of alveolar surface) and type II
pneumocytes (responsible for secretion of surfactant and repair of alveoli after type I
pneumocyte destruction). The alveolar wall has the presence of pores of KohnQ for
allowing the passage of bacteria and exudate between adjacent alveoli.
The entire respiratory tract is lined by pseudostratified, tall, ciliated columnar epithelial
cells except vocal cords (these have stratified squamous epithelium).
Broadly, the diseases of lung may be divided into infectious, obstructive, restrictive,
vascular and neoplastic etiologies.
INFECTIVE LUNG DISEASES
1. Pneumonia
Infection of the lung parenchyma is called pneumonia. It can be of two types

Pneumonia
Commonest cause of community

Typical pneumonia Atypical pneumonia accquired pneumonia is Strep
Infection caused by extracellular organisms Infection caused by intracellular organisms tococcus pneumoniae
mainly bacteria like Mycoplasma, Chlamydia pneumoniae and
viruses like RSV, influenza virus, rhinovirus.
Characterized by neutrophilic infilration Characterized by lymphocytic infiltration
and presence of Intra-alveolar exudates and presence of alveolar septal and interstitial Commonest cause of nosoco-
(leading to consolidationQ). inflammation with absence of alveolar mial pneumonia is Staphylo
exudatesQ. coccus aureus
Clinical features include acute onset of high Clinical features include fever, headache,
grade fever and mucopurulent cough which dry cough and myalgia. Productive Cough
may also be associated with pleuritic pain. and pleural involvement is uncommonQ.
Viral pneumonia result in interstitial infiltrates (therefore called interstitial pneumonia) and may result Most common cause of atypical
in variety of cytopathic effects. e.g. RSV shows bronchiolitis and multinucleate giant cells and CMV pneumonia is Mycoplasma
and herpes show inclusion bodies. pneumoniae).
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Furthermore, typical pneumonia can be of two types:

Typical pneumonia
Lobar pneumonia Bronchopneumonia
Condolidation of entire lobe usually caused Patchy consolidation in the lobe of lung.
by Streptococcus pneumoniae. Usually bilateral basalQ in location due to
Following 4 stages of inflammation are gravitation of secretions.
present. Affects extremes of ageQ (infants or old).

1. Congestion: It is due to vasodilation.
There is bacteria rich intra-alveolar fluid.

2. Red hepatization: Exudate is rich in
RBC, neutrophils and fibrinQ.

3. Gray hepatization: Degradation of RBC
and fibrinosuppurative exudates

4. Resolution: Enzymatic degradation of
exudate and healing
Chest X-ray show opacification of the entire Chest X-ray shows patchy opacification of the
lobe. lobeQ.
2. Lung Abscess
Local suppurative process within the lung associated with necrosis of the lung tissue
Commonest etiological agent of
lung abscess is Anaerobic bac is called lung abscess.
It is most commonly caused by aspiration of infective material.
teria
Commonest etiological agent is Anaerobic bacteria of the oral cavity.Q
Causes of lung abscess
Respiratory System
Aspiration Post pneumonic infection Post Septic Miscellaneous

obstructive emboli
Most common Infection caused by Due to Direct hematog
causeQ. Staph aureus, kleb primary or enous spread to
Commonest cause of lung abs
Right lower siella or type 3 Pneu secondary lung from infec
cess is aspiration
lobe is the mococcus cancer. tion in esopha
most frequent Usually basal, multiple gus or pleural
ly affectedQ. and diffusely scattered. cavity.
Clinical features: Fever, productive cough with large amount of sputum, chest pain,
weight loss and presence of clubbing of the fingers and toes.
Characteristic histologic feature: Suppurative destruction of lung parenchyma within
the central area of cavitation.
Complications include empyema, brain abscess or meningitis, pulmonary hemorrhage
and secondary amyloidosisQ.
3. Tuberculosis (Kochs Disease)
Pulmonary tuberculosis spread Pulmonary tuberculosis is caused by droplet infection (coughing, sneezing etc) due to
by droplet infection Mycobacterium tuberculosis. It is a strict aerobic bacteria having mycolic acid in its cell wall
making it acid fast which means it resists decolourisation by a treatment with a mixture of
acid and alcohol.
The reservoir of infection is a human being with active tuberculosis. However, certain
clinical conditions can increase the risk of tuberculosis like diabetes mellitus, Hodgkins
lymphoma, chronic lung disease (particularly silicosis), chronic renal failure, malnutrition,
The reservoir of infection is alcoholism, and immunosuppression.
a human being with active

tuberculosis.
406
Respiratory System
Concept
Infection with M. tuberculosis is different from disease. Infection is the presence of organisms, which
may or may not cause clinically significant disease. In most of the people, primary tuberculosis is
asymptomatic though it may be associated with fever and pleural effusion. Infection with M. tubercu-
losis typically leads to the development of delayed hypersensitivity to M. tuberculosis antigens, which
can be detected by the tuberculin (Mantoux) test. A positive tuberculin test result signifies cell medi
ated hypersensitivity to tubercular antigens but does not differentiate between infection and disease.
False-negative Mantoux test False-positive Mantoux test Acid-fastness of the Mycobac

Sarcoidosis Infection by atypical mycobacteria terium is due to mycolic acid
Malnutrition Previous vaccination with BCG
Hodgkin disease
Immunosuppression
Fulminant tuberculosis
Cord factor is a virulence fac

tor for Mycobacterium tubercu
Pathogenesis losis
Macrophages are the primary cells infected by M. tuberculosis. The bacteria enter macrophages
by endocytosis. The bacterial cell wall glycolipid lipoarabinomannan blocks the fusion of the
phagosome and lysosome. This is followed by bacterial multiplication inside the macrophages.
Both ventilation as well as per
Thus, the initial stages of primary tuberculosis (<3 weeks) in a non-sensitized individual fusion per unit lung volume is
is characterized by bacterial multiplication in the pulmonary alveolar macrophages and maximum at the base of the
airspaces, with resulting bacteremia and spread to multiple sites in the body. After about lung.
However ventilation perfusion
3 weeks of infection, the TH1 cells are stimulated by mycobacterial antigens and these cells ratio is maximum at the apical
differentiate into mature TH1cells by the action of IL-12. regions of the lungs
The mature TH1 cells in the lymph nodes and lung produce IFN-g which activates
macrophages, stimulates formation of phagolysosome in them and causes nitric oxide induced
Respiratory System
oxidative damage to the mycobacteria. Activated macrophages produce TNF and recruit
monocytes which then differentiate into the epithelioid histiocytes, a characteristic feature
of granulomatous inflammation. So, immunity to M. tuberculosis is primarily mediated by
TH1 cells, which stimulate macrophages to kill the bacteria. The immune response is usually
accompanied by hypersensitivity and tissue destruction. Reactivation of the infection or re-
exposure to the bacilli in a previously sensitized host therefore causes activation of defense
mechanism and increased tissue necrosis.
Clinical Features
Primary tuberculosis
It develops in a previously unexposed and unsensitized individual. The source of the organism
is usually exogenous. Most patients with primary tuberculosis develop latent disease while a
minority develops progressive infection.
Primary tuberculosis almost always begins in the lungs. Typically, the inhaled bacilli implant in the
distal airspaces of the lower part of the upper lobe or the upper part of the lower lobe due to most
of the inspired air being distributed here and form a subpleural lesion. This subpleural lesion along
with the draining lymphatics and the lymph nodes is called as Ghons complexQ. During the first
few weeks, there is also lymphatic and hematogenous dissemination to other parts of the body.
At times, occult hematogenous spread occurs in primary TB where the focus is then called Simon
focus.
-
In majority of the people, development of cell mediated immunity controls the infection. The
Ghons complex undergoes progressive fibrosis and calcification (detected radiologically and Concept
called as Ranke complexQ).
Immunocompromised people
Histologically
do not form the characteristic
The sites of active disease show a characteristic granulomatous inflammatory reaction having the granulomas
presence of both caseating and non-caseating tubercles. There is also presence of Langhans giant
cells and lymphocytes.
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Secondary tuberculosis
Bronchial artery is the source It is the pattern of disease that arises in a previously sensitized host. It usually results from a
of hemoptysis in TB. reactivation of latent primary lesions after many years of an initial infection, particularly when host
immunity is decreased or uncommonly may follow primary tuberculosis. Secondary pulmonary
tuberculosis is classically localized to the apex of the upper lobes of the lungs called as Puhl
lesion. The right lung is affected more commonly as compared to left because of high oxygen
tension in the apices. Infraclavicular lesion of chronic pulmonary TB is called as Assman focus.
The preexistence of hypersensitivity contributes to an immediate and marked tissue response
Infectious aneurysms in a
leading to localization of the infection (the regional lymph nodes are less prominently involved in
pulmonary artery secondary
secondary tuberculosis) and cavitation followed by erosion into an airway (leading to spread of
to pulmonary tuberculosis ( B) T bacilli during coughing).
are referred to as Rasmussen
aneurysms. Histologically, the active lesions show characteristic coalescent tubercles composed of epithelioid
cells and Langhans cells with central caseation. The lesion of secondary pulmonary tuberculosis
may heal with fibrosis either by itself or after therapy, or it may progress along the following several
different pathways:
The most frequent form of Progressive pulmonary tuberculosis
extra pulmonary tuberculosis It is seen in the elderly and the immunosuppressed individuals. The apical lesion enlarges with
is lymphadenitis usually in the increase in the area of caseation. The erosion of blood vessels (particularly bronchial arteryQ) results
cervical region and is known as in hemoptysis. The pleural cavity is associated with pleural effusion or empyema. If the treatment is
scrofula.
adequate, the disease may be controlled but if it is inadequate, the infection may disseminate through
airways, lymphatics or the vascular system.
Miliary disease
It occurs when organisms drain through lymphatics and blood vessels to the different organs of the
-
body resulting in small yellow white consolidated lesions. Miliary tuberculosis is most prominent in the
Potts disease is define as liver, bone marrow, spleen, adrenals, meninges, kidneys, fallopian tubes, and epididymis.
tubercular involvement the vertebrae
Recent exam info: names of other healed foci
Respiratory System
Names Organs
Rich focus Cortex of brain Q
Simon focus Healed site of primary infection at apex of lungQ

Simmond focus LiverQ
Weigart focus Intima of blood vesselsQ
Important radiological info

Clinical features in TB are Early infraclavicular lesion - Assman Redeker SimonQ
drenching night sweats, fever, In post primary stage (late dissemination), coarse granular dissemination is called Aschoff Puhl
weight loss focus
The patients present with insidious onset of symptoms like low grade remittent fever
usually associated with night sweats, productive cough, weight loss, hemoptysis, dyspnea
and pleural effusion. The investigations usually reveal lymphocytosis and increased ESR (on
hemogram), hilar lymphadenopathy and pleural effusion (on chest X ray), presence of acid
fast bacilli with Ziehl Nielson staining. The treatment is provided with multiple drugs (for
details, refer to Review of Pharmacology by the same authors).
Most common cause of drug
resistant tuberculosis is Pulmonary diseases
previous A .TT
Obstructive lung disease Restrictive lung disease
Characterized by increased resistance Characterized by decreased expansion of the lung.
to airflow due to airway obstruction.
FEV 1
Spirometry reveals FVC
ratio is Spirometry reveals reduced total lung capacity and
decreasedQ. vital capacityQ.
Examples: Asthma, Emphysema, Examples:
Chronic bronchitis, Bronchiectasis. -
1. Chest wall disorder polio, obesity kyphoscoliosis.
2. Interstitial/infiltrative disease: Pneumoconiosis,
ARDS, Pulmonary fibrosis.
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Respiratory System
OBSTRUCTIVE LUNG DISEASES
1. Chronic Bronchitis
It is defined clinically as the presence of productive cough for at least 3 months in at least 2 Most important initiating agent
consecutive years in absence of any other identifiable cause. in chronic bronchitis is smoking
The most important initiating agent is smokingQ resulting in airway irritation leading to
mucus hyper secretion; the latter may cause airway obstruction. Infection plays a secondary
role particularly in maintaining chronic bronchitis and is also responsible for the acute
exacerbations.
Histologic features include chronic lymphocytic infiltration of the airways and submucosal
gland hypertrophy. There is also increase in Reid indexQ. The bronchial epithelium may also
have squamous metaplasia and dysplasia. Reid index is the ratio of the
mucus gland layer thickness to
Normal Reid index is 0.4 whereas its value increases in chronic bronchitis. the thickness of the wall between
epithelium and cartilage.
Clinical features: Late onset of dyspnea with productive cough (copious sputum),
recurrent infections, hypoxemia and mild cyanosis (BLUE BLOATERS). Long standing
chronic bronchitis can cause cor pulmonale (right sided heart failure due to pulmonary
hypertension).
2. Emphysema
It is abnormal permanent enlargement of the airspace distal to terminal bronchioles and is associated
with destruction of their walls. Most important etiological agent
Most important etiological agent for emphysema is smokingQ which causes inflam for emphysema is smoking
mation in airways resulting in increased neutrophils and macrophages. These
Respiratory System
inflammatory cells release elastase responsible for destruction of lung tissue resulting
in emphysema.
Normally, the pulmonary tissue destruction by elastase is prevented by the presence
of anti-elastase activity which is primarily due to 1-antitrypsin; a1-AT (with minor a1-AT deficiency is associated
contribution from secretory leukoprotease inhibitor in bronchial mucus and serum with panacinar emphysema
a1- macroglobulin). So, any increase in neutrophils (usually in smokers) or deficiency
of a1AT would contribute to development of emphysema. Characteristically, there
is loss or reduction of elastic recoil of the lung.
a1-AT is synthesized in the liver. The normal a1-AT phenotype is PiMM. The abnormal
phenotype is PiZZ which is associated with a1-AT deficiency and development of
emphysema at earlier age and greater severity.
Emphysema
Centriacinar Panacinar Distal acinar/Paraseptal Irregular

Involvement of Involvement of the Distal part of acinus is Irregular acinar in
central part of acinus entire acinusQ. affected with sparing volvement associ
with sparing of of proximal part of ated with fibrosis/
alveollQ. acinusQ. scarringQ.
Seen in smokersQ. Seen with a1 AT - Seen in smokersQ.
deficiency.
Usually more severe Occurs more Involvement of lung
in upper lobesQ (due severely in lower adjacent to pleura.
to relative deficiency lobes at base of
-
of serum a1 At to lungQ (due to lower
this less perfused lung distribution
region). of neutrophils emPhysema has letter P (and not
MC type of because of more Associated with Most common type B) so Pink Puffer.
emphysema seen perfusion of this the development of emphysema chronic Bronchitis has letter B
clinically. region). of spontaneous histologicallyQ. (and not P) so Blue Bloater.
pneumothorax.
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Clinical features: Progressively increasing dyspnea, weight loss, late onset of cough
with scanty sputum. The patient is non-cyanotic, uses accessory muscle of respiration and
shows pursed lip breathing. (PINK PUFFERS).
Management: Cessation of smoking and use of bronchodilators is the mainstay of the
management.
3. Asthma
Concept
Hyperactivity of the airways resulting in reversible bronchoconstriction and air flow
Virus induced inflammation
obstruction on exposure to some external stimuli is called asthma.
lowers the threshold of the
subepithelial vagal receptors to Pathogenesis: Primary exposure of an allergen causes TH2 cell dominated inflammatory
irritants. response resulting in IgE production and eosinophil recruitment (called sensitization).
Exposure to the same allergen causes cross linking of IgE bound to IgE receptors on mast
cells in the airways which cause opening up of epithelial cells due to released mediators.
Concept Antigens then cause activation of mucosal mast cells and eosinophils and this along with
Exercise causes loss of water neuronal reflexes (subepithelial vagal receptors) cause bronchospasm, increased vascular
and heat from the respiratory permeability and mucus production (Acute or Immediate response). Later on, leukocytic
tract. The water loss causes infiltration causes release of more mediators and damage to the epithelium (Late Phase
mucosal hyperosmolarity which Reaction). Eosinophils in airways release major basic protein which causes epithelial damage
stimulates release of media- and more airway constriction.
tors from the mast cells. This
Leukotrienes C4, D4, E4 and acetylcholine have definite role in bronchoconstriction
explains the pathogenesis of ex
ercise induced asthma whereas agents like histamine, PGD2 and platelet activating factor (PAF) may also have role
in the features of the disease. The following are the two variants of asthma.
Features Extrinsic asthma Intrinsic asthma
Concept Pathogenesis -
Type I hyper sensitivity reaction due -
Initiated by non immune mechanisms
to exposure to an extrinsic antigen with intrinsic body stimuli
Respiratory System
In intrinsic asthma, aspirin

causes shift of the arachidonic Age on presentation Child Adult
acid metabolism towards the li- Family history Present Q
AbsentQ
poxygenase pathway resulting Prior allergic reaction/ Positive history of rhinitis, Absent
in formation of the bronchocon
strictor leukotrienes. allergen exposure urticaria, eczema
Serum IgE levels IncreasedQ Normal Q
Skin test Positive Negative

Associated COPD Rare Usually present
Examples Atopic/allergic asthma, Occupational Drugs (most commonly aspirin), viral
Differential of asthma from COPD asthma, Allergic bronchopulmonary infections, cold exposure, exercise
is by Reversibility of FEV1 us aspergillosis induced asthma
ing bronchodilators/ oral steroids
I mportant fact
IL-13 gene polymorphism is strongly associated with bronchial asthma.
ADAM-33 is another gene causing proliferation of smooth muscle cells and fibroblasts in bronchi
resulting in bronchial hyper-reactivity and subepithelial fibrosis.
Clinical features: Acute asthmatic attack is characterized by wheezing, cough and

severe dyspnea.
Morphology: The most stroking macroscopic finding is occlusion of the bronchi and
3 Cs of sputum findings in bronchioles by mucus plugs. Histologically, there are numerous eosinophils, Charcot leyden
asthma; crystalsQ (composed of eosinophil membrane protein called as galectin-10) and Curschmann
Charcot leyden crystals spiralsQ (whorls of shed airway epithelium). Structural changes in the bronchial wall called
Curschmann spirals
airway remodelling is characterized by presence of eosinophilic inflammation and edema of
Creola bodies
bronchial walls, increased size of submucosal glands, hypertrophy of bronchial wall smooth
muscle and deposition of subepithelial collagen in the bronchial wall. Individual epithelial
cells present in the sputum of the patients are called Creola bodies.
Management is done with bronchodilators and corticosteroids (for details, refer to the
Review of Pharmacology by the same authors).
410
Respiratory System
4. Bronchiectasis
Abnormal permanent airway dilation resulting from chronic necrotizing infections is called
bronchiectasis.
Causes
Bronchial Congenital N ecrotizing Miscellaneous

obstruction pneumonias
Tumor Cystic fibrosis Mycobacterium SLE
Foreign body Kartagner syndromeQ Staph aureus Rheumatoid arthritis Bronchiectasis affects vertical
(Triad of Bronchiectasis + Aspergillus Post transplatation. air passages of the lower lobes
situs inversus + sinusitis). Influenza virus. bilaterally with involvement of
left side more frequent than
Obstruction and infection are the chief contributors to the damage of airway wall associated right.
with destruction of smooth muscle and elastic tissue fibrosis and further dilatation of bronchi.
Clinical features: Chronic cough, fever, foul smelling sputum production, recurrent

pulmonary infections, sinusitis and immune deficiencies.
It usually affects vertical air passages of the lower lobes bilaterally with involvement of
High Resolution C T Scan
left sideQ more frequent than right. The dilated bronchi can be followed directly out to the T
(HRC ) is the best inves
pleural surfaces. There is usually presence of inflammatory cells in the walls of bronchi and
tigation for the detection of
bronchioles which may also exhibit squamous metaplasia. bronchiectasis
Complications include massive hemoptysis, amyloidosis, visceral abscess and cor pulmonaleQ.
RESTRICTIVE LUNG DISEASE
Respiratory System
1. Interstitial Lung Disease
Interstitial lung disease (ILD) is a group of heterogeneous diseases characterized by chronic

inflammation and fibrosis of the interstitium and lung parenchymaQ. The interstitium of the lung
(supporting structure) is the area in and around the small blood vessels and alveoli where
the exchange of oxygen and carbon dioxide takes place. Inflammation and scarring of the
interstitium (and eventually extension into the alveoli) will disrupt normal gas exchange.
Usually, patients present with exertional dyspnea and non-productive cough.
The chest X-ray shows reticular or reticulonodular pattern (ground glass appearance).
Pulmonary function tests show evidence of intrapulmonary restrictive pattern.
Earliest manifestation of the disease is inflammation in the alveolar wall called Alveolitis.
The inflammatory cells release chemical mediators resulting in injury to parenchymal cells
and stimulation of fibrosis. In advanced stages of the disease, the gross destruction and
scarring of the lung results in end stage disease or honeycomb lung.Q
IL D
Fibrosis Granulomatous Associated with Miscellaneous

smoking
Idiopathic pulmonary fibrosis Sarcoidosis D e s q u a m a t i v e Pulmonary alveo
Collagen vascular disease asso Hypersensitivi interstitial pneu lar proteinosis.
ciated pulmonary fibrosis (SLE, ty pneumonitis. monia
RA, Scleroderma)
Pneumoconiosis
Drug reaction
Rediation pneumonitis
Fumes and gases (SO2 etc.)
We shall focus on each of the chief subtypes of interstitial lung disease:

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A. PNEUMOCONIOSIS
Non-neoplastic lung reaction (usually fibrosis) to inhalation of mineral dust, organic and
inorganic particles and chemicals and vapors is called pneumoconiosis.
The most dangerous particle size is 1-5 m which reaches the terminal small airways and
alveoli. These particles overwhelm the normal phagocytosis by alveolar macrophages to
The most dangerous par

ticle size for causation of evoke fibroblast proliferation and collagen deposition. Some of the important pneumoconiosis
pneumoconiosis is 1-5 microns. includes:
(1) Coal workers pneumoconiosis

It is due to inhalation of coal dust in coal miners and is usually present adjacent to respiratory
Dust cells are alveolar macro bronchiole. It is categorized into:
phages with anthracotic pig
ment. Simple CWP:
-
(i) Coal macules (carbon laden macrophages)
(ii) Coal nodules (upper lobes more heavily involved)
(iii) Centrilobular emphysema
Complicated CWP: Develops after many years
(i) Intense blackened scars larger than 2 cm in diameter
Caplan syndrome is the co

existence of pneumoconiosis (ii) Center of lesion is often necrotic

and cavitating rheumatoid nodules
(2) Silicosis
Nodular fibrosing diseaseQ due to inhalation of silica in workers engaged is sandblasting, hard
rock mining, foundry work, glass and pottery making.
Most common chronic occupational disease in the worldQ.
Respiratory System
Crystalline form of silica called quartz is most commonly implicated in silicosis.

-
Co inhalation of other mineral particles reducesQ the fibrogenic effect of silicosis.
Involvement of upper lobes of the lung.Q
Association with increased susceptibility to tuberculosisQ.
-
Chest X ray shows presence of Eggshell calcificationQ (thin sheet of calcification in the lymph
node surrounding a zone lacking calcification).
Polarized microscopy reveals presence of birefringent silica particlesQ.
(3) Asbestosis
Benign pleural plaques: most
Diffuse interstitial fibrotic disease due to inhalation of asbestos particles in workers
common lesions in asbestosis
engaged in mining, pipes, brakes, insulation and boilers.
Initially, involvement of lower lobes of the lung pleurallyQ.
In contrast to other dusts, can also act as a tumor initiator and tumor promoterQ.
Two types of fibers are:
Bronchogenic carcinoma: most
common asbestos related cancer
Serpentine (curly and flexible fibres, chrysotile): These account for most of the asbestos
used in industry.
Amphibole (straight, stiff and brittle fibres, crocidolite, amosite, actinolyte): These are more
pathogenic than chrysotiles, particularly with respect to induction of malignant
pleural tumors (mesotheliomas).
Lesions with asbestosis
Pleural plaqueQ:
It is the most common manifestation of asbestos exposure and is composed of well circumscribed
plaques of dense collagen containing calcium. They are usually asymptomatic and develop on anterior
and posterolateral parts of parietal pleura and over the diaphragm.
412
Respiratory System
Interstitial fibrosis
Pulmonary fibrosis with the presence of asbestos bodyQ (iron containing proteinaceous material The presence of asbestos
coating asbestos fiber) and ferruginous bodyQ (iron protein complex coating other inorganic particles bodies in or adjacent to the walls
of fibrotic respiratory bronchioles
like talc, mica, fibre, glass and other less common materials in the lung). True asbestos bodies are
is the hallmark of the disease.
clear whereas the core of these particles is dark).
Bronchogenic cancer
Most common cancer associated with asbestosQ whose risk is increased with concomitant smoking.
Mesothelioma
Localization of asbestos fibres in the lung close to the mesothelial layers increases the risk of
development of pleural and peritoneal mesothelioma. Concomitant smoking does not increase the
risk of mesothelioma. It is the most specific cancer associated with asbestos inhalation.
Pleural effusion, laryngeal and colon cancers.
Other important pneumoconiosis

Baritosis is caused by inhalation of Barium sulfate (in miners).
Stannosis is caused by inhalation of Tin oxide (in miners).
Siderosis is caused by inhalation of Iron oxide (in welders).
Byssinosis is caused by inhalation of cotton fibres (in textile workers).
Caplan syndrome: Coexistence of rheumatoid arthritis with pneumoconiosis
Clinical symptoms of pneumoconiosis include progressively increasing dyspnea,

productive cough, reduced exercise tolerance which may progress to respiratory failure, cor
pulmonale and ultimately death.
B. SARCOIDOSIS
Respiratory System
It is a systematic disease of unknown etiology characterized by the presence of non-caseating
granulomas in many organs. It is seen more commonly in females of 20-40 years of age. It is Sarcoidosis shows presence of
associated with HLA-A1 and HLA-B8. noncaseating granulomas
Immunological abnormalities associated with sarcoidosis
-
Intra alveolar and interstitial accumulation of CD4 + T cells resulting in CD4:CD8 T cell ratio ranging
from 5:1 to 15:1Q.
- -
Increased levels of IL 2 and IFN g causing T-cell expansion and macrophage activation
Concept
respectivelyQ.
Polyclonal hypergammaglobulinemiaQ. Sarcoidosis has elevated ACE
Anergy to skin antigens like purified protein derivative (PPD)Q.
levels. ACE enzyme is important

even for distinguishing sarcoi
Histologically, there is characteristically presence of non-caseating granulomaQ composed dosis from bronchogenic car
of aggregates of epithelioid cells and giant cells. There is also presence of Schaumann bodiesQ cinoma as the level of the ACE
(laminated concretions of calcium and protein) and asteroid bodiesQ (stellate or star shaped enzyme in the latter would be
normal.
inclusions in giant cells).
Organs Affected
Lungs
Most common site of organ involvement
-
There is presence of non caseating granuloma in the bronchial submucosa.
-
Bronchoalveolar lavageQ shows CD4:CD8 T lymphocytes ratio of > 2.5 is seen.
Lymph nodes
Involvement of hilar and mediastinal nodes is seen in almost all the cases. Sarcoidosis is a diagnosis of
Liver and spleen exclusion; rule out other granu
lomatous diseases.
Splenomegaly may be seen with sparing of capsule. Scattered granulomas are seen more in portal
triads as compared to globular parenchyma.
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Bone marrow
Favored site of localization having tendency to involve phalangeal bones of hands and feet showing
small areas of bone resorption, bony shaft widening and new bone formation.
Skin
Lesions include erythema nodosum, subcutaneous nodules, erythematous plaques and lupus
pernioQ.
Eye, lacrimal glands and salivary glands
Unilateral or bilateral ocular involvement resulting in iritis, glaucoma or corneal opacity may occur.
Causes lacrimal gland inflammation (causing dry eyesQ) and salivary gland involvement (dry
mouthQ).
Clinical features include shortness of breath, cough, chest pain, hemoptysis,
Lofgren syndrome (has ery constitutional signs and symptoms (fever, fatigue, weight loss) or it may be discovered on
thema nodosum, arthritis and routine X-ray as bilateral hilar lymphadenopathy. It can also manifest as Lofgren Syndrome
hilar adenopathy). and Heerfordt Waldenstrom Syndrome.
Heerfordt Waldenstrom syn Chest X-ray shows bilateral hilar and left paratracheal lymphadenopathy. There is
hypercalcemiaQ due to increased circulation of vitamin D by macrophages. Elevated
drome (fever, parotid enlarge
ment, uveitis and facial palsy) levels of ACEQ (Angiotensin Converting Enzyme) are seen in the disease. These
patients also demonstrate skin anergy and a restrictive pattern on pulmonary
function tests.
Management: It is done usually with corticosteroids.
C. PULMONARY ALVEOLAR PROTEINOSIS

It is a rare disease in which phospholipids accumulate within alveolar spaces. This is a
condition of unknown cause characterized by auto-antibodies against granulocyte macro
Respiratory System
phage-colony stimulating factor (GM-CSF).

Some (10%) PAP cases are congenital in nature secondary to mutations in the GM-CSF
gene leading to reduced or absent SP-B and intra alveolar accumulation of SP-A and SP-C.
Secondary PAP is associated with immunodeficiency, hematopoietic disorders,
malignancies, acute silicosis and other inhalational syndromes.
Clinical features: Progressive dyspnea is the usual presenting symptom. Chest X-ray
shows bilateral alveolar infiltrates suggestive of pulmonary edema. Bronchoalveolar lavage
shows characteristic milky appearance and PAS-positive lipoproteinaceous material. Lung
biopsy reveals amorphous intra-alveolar phospholipids.
2. Adult Respiratory Distress Syndrome (ARDS)
Also called as Shock lungQ, Diffuse alveolar damageQ or Acute lung injuryQ
Sepsis is most common cause Characterized by damage to alveolar cells and blood vessels resulting in oxygen
of ARDS refractory progressive respiratory insufficiency.
Conditions associated with AR S D
D
Features of AR S severe Infections Physical factors Chemical factors Miscellaneous
hypoxemia, PA wedge pressure Septicemia Drowning Drugs like aspirin Pancreatitis
< 18 mm Hg, increased A a - Aspiration Head injury Heroin/Methadone Uremia
-
(Alveolar arterial) gradient. Pulmonary infections Radiation expo Overdose of barbi Multiple transfu
(TB, viral, mycoplas sure turates sion
ma, etc.) Fat embolism Hypersensitivity by DIC.
Smoking organic solvents.
Irritant gases.
414
Respiratory System
Hyaline membrane is made up

of fibrin and necrotic cells.
Morphological features include Interstitial and intra-alveolar edema with lining of

alveoli with hyaline membrane composed of fibrin rich edema fluid and lipid remnants of
epithelial cells. Later on, there is intra-alveolar fibrosis.
Clinical features include Progressively increasing dyspnea (difficulty in breathing),
tachypnea resulting in respiratory failure, cyanosis and hypoxemia, chest x-ray shows
bilateral diffuse infiltration (white out lungQ). Management is done primarily with
treatment of underlying cause and mechanical ventilation.
Neonatal RDS/Hyaline membrane disease
Respiratory System
Prematurity Infants of diabetic mothers Cesarean section
Results from surfactant deficiency which is chemically composed of lecithin
(dipalmitoylphosphatidylcholine; DPPCQ). Due to reduced surfactant, surface tension
of alveoli increases. Increased alveolar surface tension causes atelectasis resulting
in hypoxemia responsible for damage to endothelial and epithelial cells. The latter
contributes to formation of hyaline membraneQ (fibrin + necrotic cells).
Clinical features include normal infant at birth but within 30 minutes, there is
development of progressively increasing respiratory effort and cyanosis. Chest X-ray
demonstrates multiple reticulogranular densities (ground glass appearanceQ).
Prevention of hyaline membrane disease is by delaying the onset of labor and administra
tion of glucocorticoids to the mother. Steroids increase the formation of surfactant lipids
T
and proteins thereby decreasing the respiratory distress. reatment is by administration of
artificial surfactant and oxygen using high frequency ventilation.
Deep vein thrombosis is the

VASCULAR LUNG DISEASES commonest cause of pulmonary
thromboembolism.
1. Pulmonary Emboli and Pulmonary Infarction
Most (90-95%) of the pulmonary emboli arise from deep vein thrombosis (DVT) in the leg and
only 10% of pulmonary emboli cause infarction. The infarcts occur in patients with underlying
cardiopulmonary disease. It is a wedge shaped hemorrhagic infarction. The diagnosis of T
Spiral C scan is the investi
gation of choice. (Ref Harrison
pulmonary embolism is made on ventilation/perfusion scan (V/Q lung scan) which shows a 18th/2173)
mismatch. The complications associated with this condition include pulmonary hypertension,
cor pulmonale, pulmonary abscess and even sudden death.
2. Pulmonary Hypertension
It is defined as increased pulmonary artery pressure, usually due to increased vascular

resistance or blood flow. It is seen in association with:
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COPD and interstitial disease (hypoxia induced vasoconstriction is seen).

Multiple ongoing pulmonary emboli.
Mitral stenosis and left sided heart failure.
Mutations in the bone morpho-
genetic protein receptor type Congenital heart disease with left to right shunts (ASD, VSD, PDA).
2 (BMPR2) signaling pathway Primary (idiopathic).
have been associated with pul-
monary hypertension. Recently mutations in the bone morphogenetic protein receptor type 2 (BMPR2) signaling path
way have been associated with pulmonary hypertension due to increased medial hypertrophy and
intimal fibrosis in small arteries.
The presence of plexogenic pulmonary arteriopathy may also be seen in primary

pulmonary hypertension or congenital heart disease with left to right shunts.
3. Pulmonary Edema
It is defined as the fluid accumulation within the lungs usually due to disruption of starling
forces or endothelial injury.
So, it can be due to:
Hemosiderin-laden 1. Increased hydrostatic pressure as in left-sided heart failure, mitral valve stenosis,
macrophages are also known fluid overload, etc.
as heart-failure cells 2. Decreased oncotic pressure as in nephrotic syndrome, or liver disease.
3. Increased capillary permeability as in infections, drugs (bleomycin, heroin), shock,
radiation.
The lungs are wet and heavy and the fluid accumulation is more in the lower lobes.
Microscopically, there is presence of intra-alveolar fluid, engorged capillaries and hemosiderin-
laden macrophages (heart-failure cells).
Respiratory System
NEOPLASTIC LUNG DISEASES
1. Bronchogenic Cancer
Metastasis/Secondaries are the
commonest malignant tumor of The lung is a common site of metastatic neoplasms. However, bronchogenic cancer is the most
the lung. common primary malignant tumor of the lung. It is most frequently diagnosed major cancer in
the world.
Risk factors
Non-genetic Genetic
Tobacco smoking (contain chemicals like Mutations affecting
benezophrene and polycyclic Tumor suppressor genes p53 and Rb
Air pollution gene
Occupational exposure (asbestosis, ura Oncogenes
nium mining, radiation, etc.) -
K ras Adenocarcinoma
-
L myc Small cell carcinoma.
Histological variants of lung cancer
Squamous cell Adenocarcinoma Small cell cancer or oat Large cell cancer
carcinoma cancer
MC type of lung Overall MC type of Associated with
cancer in smokersQ. cancerQ. smoking
MC type in malesQ. MC type in non - Commoner in
smokers and smokersQ.
femalesQ.
Cont...
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Respiratory System
Cont...
Usually central Usually peripheral in Central in location Peripheral in
in location (arise location (arise from location.
from the segmental terminal bronchiole)
bronchi)
Shows highest fre Associated with K - Immunohistochemistry
quency of p53 mu ras mutationQ. shows high expression
tationQ. of Bcl-2 geneQ in ma
jority of tumors.
Intercellular bridges Glandular pattern of Cells have scanty cy Cells have large
or junction is very growth of the tumor toplasm, small nucle nuclei, prominent
specific. is seen. oli, granular chromatin nucleoli and a mod
Histologically, the Cells are positive for (salt and peper pat- erate amount of cy
tumor has presence mucin and thyroid ternQ). toplasm. SVC syndrome is most
of keratinizationQ. -
transcription factor 1 Azzopardl effect (Ba commonly caused by small cell
-
(TTF 1)Q. sophilic staining of vas lung cancer
cular walls) is frequent
ly present.
Electron microscopy
shows presence of neu
rosecretory granules
chromogranin, synap
tophysis and leu 7Q. -
Has best response to
chemotherapy and ra
diotherapy.
Has the worst progno
sisQ.
Respiratory System
Most aggressive lung
cancerQ.
Diagnosis of bronchogenic can
H y p e r c a l c e m i a Q Associated with maxi Has gynecomas- cer is usually made with spu
due to PTHrP is the mum paraneoplastic tia as paraneoplas tum cytology and fibreopt ic
MC paraneoplastic syndromeQ (particularly tic syndromeQ. bronchoscopy
syndrome. D
SIA H and Cushing
syndrome).
Bronchoalveolar carcinoma is a subtype of adenocarcinoma having absence of stromal,

-
vascular or pleural invasion with growth of the tumor along the pre existing alveolar septa. Tumors
cells are present in the alveoli and tend to have aerogenous spreadQ. Due to involvement of the
airways, the patient usually dies by suffocation (not by metastatic spreadQ).
Clinical features: Cough is the most common symptom in these patients which is
followed by weight loss and dyspnea. They also have anorexia, fatigue, hemoptysis, and
chest pain.
Metastasis of the cancer causes involvement of adrenal (most commonlyQ) followed by
liver, brain and bone. Intrathoracic spread of the cancer causes enlargement of lymph nodes
(hilar, mediastinal, bronchial and tracheal), pleural involvement, hoarseness (recurrent
laryngeal nerve invasion), dysphagia (esophageal obstruction), diaphragmatic paralysis
(phrenic nerve paralysis), Horner syndrome and superior vena cava (SVC) syndrome.
Horner syndrome
Horner syndromeQ is caused due to compression of sympathetic nerve plexus by an apical tumor
called as Pancoast tumorQ. It is usually an adenocarcinoma. Its components include: (mnemonic:
Punjabi MEAL)

Punjabi Ptosis
M Miosis (small pupil)
E Enophthalmos (sunken eyes)
A Anhidrosis (absence of sweating)
L Loss of ciliospinal reflex (in this reflex, pinching of the skin on the nape of neck causes
dilatation of the pupil of the same side)
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Important paraneoplastic syndromes associated with bronchogenic cancer include:

1. Endocrinological syndrome
a. Cushing syndrome (Due to ACTH)
b. Syndrome of inappropriate ADH secretion (SIADH) [Due to anti-diuretic
Malignant Mesothelioma is not hormone]
associated with smoking. c. Hypercalcemia: Due to parathyroid hormone related peptide (PTH related
peptide).
d. Hypocalcemia: Due to calcitonin
e. Gynecomastia: Due to gonadotropins
2. Lambert eaton syndrome: Due to autoantibodies against neuronal calcium channel

3. Acanthosis nigricans: Hyperpigmentation of axillary region.

4. Hypertrophic pulmonary osteoarthropathy having clubbing and periosteal new
born formation.
2. Solitary (Localized) Fibrous Tumor
It was earlier referred to as benign mesothelioma. It has got no relationship with asbestosisQ.
Microscopically, there is presence of whorls of reticulin and collagen fibers with interspersed
spindle cells resembling fibroblasts. The tumor cells characteristically show immunostaining
pattern of CD34(+) and keratin-negativeQ.
3. Malignant Mesothelioma
It is a tumor arising from visceral or parietal pleura which is seen after prolonged duration
(after a latent period of 25-45 years) of asbestos inhalation. It is not associated with smoking.
Unlike bronchogenic cancer, it is less commonly associated with p53 mutation. It is associated
with extensive pleural effusion and local invasion of thoracic structures. Microscopically, the
Concept tumor can have the following patterns:

1. Sarcomatoid type: Mesenchymal stromal cell type
Respiratory System
The best marker to differentiate

benign and malignant mesothe
2. Epithelioid type: Consists of cuboidal, columnar or flattened cell forming tubular or
lioma is p53. Its mutation is papillary structure resembling adenocarcinoma.
present in malignant meso
3. Mixed type: It contains both epithelioid and sarcomatoid patterns.
thelioma and this mutation is
absent in benign mesothelioma. Concept: Epithelioid mesothelioma is differentiated from pulmonary adenocarcinoma by
-
Positive staining for acid muco polysaccharide
Lack of CEA and other epithelial glycoproteins (these are expressed by adenocarcinomas)
-
Keratin positive with accentuation of peri nuclear halo rather than peripheral staining
Electron microscopy demonstrates long, slender, numerous microvilli and tonofilaments but
absent microvillus rootlets and lamellar bodies. This is the gold standard of diagnosis
Clinical features include chest pain, dyspnea and recurrent pleural effusions. Right
lung is more commonly affected than left lung. It is usually unilateral at presentation. The
lung is invaded directly, and there is often metastatic spread to the hilar lymph nodes and,
eventually to the liver and other distant organs. It is associated with very poor prognosis.
ATELECTASIS
Incomplete expansion of the lungs or the collapse of previously inflated lung is known as
atelectasis.

1. Resorption Atelectasis:

Due to airway obstruction leading to resorption of oxygen trapped in the alveoli.

Causes mediastinal shift towards affected lung.

Associated with chronic bronchitis/asthma/aspiration of foreign body/
secretions.

2. Compression Atelectasis:

Due to presence of fluid, blood, air or tumor in pleural space.

Causes mediastinal shift away from the affected lung.

Most commonly associated with cardiac failureQ.

3. Contraction Atelectasis:

Fibrosis in the lung or pleura preventing full expansion of pulmonary tissue.

Only irreversible cause of atelectasisQ.
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Respiratory System

nfective lung disease: pneumonia, tb, lung
I (d) Wegeners granulomatosis
abscess (e) Hantan virus infection
1. Infraclavicular lesion of tuberculosis is known as: 9. Lung granuloma found in A/E: (PGI June 2004)
(a) Berylliosis
(a) Gohns focus (AIIMS May 2011) (b) Asbestosis
(b) Puhls focus (c) SLE
(c) Assmans focus (d) Sarcoidosis
(d) Simmons focus
2. Pulmonary tuberculosis is more common in following 10. True about Ghons focus:
(a) Left apical parenchymal lesion
(PGI Dec 2004)
associated diseases, except: (DPG 2011) (b) Right apical parenchymal lesion
(a) Acquired immune deficiency syndrome (c) Subpleural caseous lesion in right upper lobe
(b) Diabetes (d) Subpleural caseous lesion just above or below inter-
(c) Chronic renal failure lobar fissure
(d) Mitral stenosis (e) Caseous hilar lymphadenopathy
3. All of the following features are seen in the viral 11. Which of these is seen in primary tuberculosis:
pneumonia except (AI 2005) (a) Ghons focus (PGI Dec 2006)
(a) Presence of interstitial inflammation (b) Pleural effusion
(b) Predominance of alveolar exudate (c) Miliary mottling
(c) Bronchiolitis (d) Fibrosis
Respiratory System
(d) Multinucleate giant cells in the bronchiolar wall (e) Cavity
4. Atypical pneumonia can be caused by the following 12. Characteristic histopathological feature of pneumocystis
-
microbial agents except? (AI 2005) carinii pneumonia (PGI Dec 2000)
(a) Mycoplasma pneumoniae (a) Interstitial pneumonitis
(b) Legionella pneumophila (b) Increased eosinophils
(c) Human corona virus (c) Foamy vacuolated exudates
(d) Klebsiella pneumoniae (d) Mononuclear cell in bronchoalveolar lavage
(e) Neutrophil infiltration
5. In primary tuberculosis, all of the following may be 13. A 9 year old girl Bandhini developed a 10 mm area of
seen except: (AI 2002)
induration on the left forearm 72 hours after intradermal
(a) Cavitation
injection of 0.1 ml of purified protein derivative
(b) Caseation
(PPD). Though she appears healthy, a chest X ray was
(c) Calcification
performed. Which of the following is most likely to be
(d) Langhans giant cell
seen on the radiograph?
6. Lung granuloma with necrosis is seen in- (a) Marked hilar adenopathy
(a) PAN (PGI June 01) (b) Upper lobe calcifications
(b) TB (c) No abnormal findings
(c) Histoplasmosis (d) Reticulo-nodular densities
(d)
(e)
Cryptococcosis
Wegeners granulomatosis
14. A 60 year old smoker BD Thapa with inguinal hernia
undergoes surgery under general anaesthesia. On the
7. Predisposing factors of lung abscess are: third post operative day, he complains of increasing
difficulty in respiration. The finger probe reveals
(a) Altered sensorium (PGI Dec 2003)
(b) Dental sepsis presence of pO2 of 60 mm Hg but the patient is afebrile
(c) Aggressive treatment of pneumonia to touch. His vitals are as follows: pulse is regular
(d) Subpulmonic effusion and good volume at 76/min, respiratory rate is 17/min
(e) Endobronchial obstruction and BP is 130/84 mm Hg. Blood investigations reveal
hemoglobin is 14g/dL, TLC is 7300/mm3 and a normal
8. Pulmonary, renal syndrome is seen in: DLC. One evening the resident doctor notices that Mr
(a) Good pasture syndrome (PGI Dec 2003) Thapa coughs up copious mucoid sputum following
(b) Leptospirosis which his condition improves dramatically. What is the
(c) Legionella most likely diagnosis?
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(a) Compression atelectasis obstructive lung disease: bronchitis, asthma,

(b)
(c)
Microatelectasis
Resorption atelectasis
bronchiectasis, emphysema
(d) Contraction atelectasis 16. Increased Reids index is increased in which of the
15. Autopsy of a person reveals a small cluster of caseating following? (AI 2012)
granulomas in the right lung just above the interlobar (a) Bronchiectasis
fissure and similar granulomas in the hilar lymph (b) Bronchial asthma
nodes. Acid-fast staining demonstrates acid-fast bacilli (c) Chronic bronchitis
within these lesions. No other lesions were found in the (d) Emphysema
remaining organs and systems. Which of the following
is the most accurate interpretation of these findings?
17. True about alpha-1 antitrypsin deficiency, is/are -
(a) Autosomal dominant (PGI June 01)
(a) Cavitary tuberculosis (b) Pulmonary emphysema
(b) Ghon complex (c) Diastase resistant hepatic cells
(c) Remote healed tuberculosis (d) Hepatic cells are orcein stain positive
(d) Miliary tuberculosis (e) Associated with berry aneurysm
Most Recent Questions 18. Late response in bronchial asthma is due to:
(a) Mast cells (UP 2003)
15.1. Collapse of lung is called: (b)
(c)
Eosinophils
Neutrophils
(a) Emphysema (b) Bronchiactasis
(c) Atelectasis (d) Bronchitis (d) Macrophages
15.2. In the stage of Grey hepatisation, which of the following 19. Charcot-Leyden
seen in:
crystals and Curschmanns spirals are
(UP 2006)
is a finding?
(a) Bronchial asthma
(a) WBCs fill the alveoli
(b) Chronic bronchitis
(b) RBCs fill the alveoli (c) Bronchiectasis
(c) Organisms fill the alveoli (d) Emphysema
(d) Accumulation of fibrin
Respiratory System
15.3. Gray hepatization of lungs is seen on day: 20. Most common type of emphysema clinically is:
(a) Panacinar (RJ 2006)
(a) 1 (b) 2-3 (b) Centriacinar
(c) 3-4 (d) 5-7 (c) Paraseptal
15.4. The earliest feature of tuberculosis is: (d) Segmental
(a) Caseation 21. In a heavy smoker with chronic bronchiolitis, which of
(b) Recruitment of lymphocytes the following is likely to be seen:
(c) Formation of giant cells (Langhans) (a) Centrilobular emphysema (Kolkata 2003)
(d) Granuloma formation (b) Panacinar emphysema
(c) Paraseptal emphysema
15.5. Reactivated TB is most commonly located near: (d) None of the above
(a) Apex (b) Near bronchus
(c) Subpleurally (d) Base 22. A 37 year old male Ranjir Kapoor presents to the
hospital with progressive exertional dyspnea. His
15.6. Maximum smooth muscle relative to wall thickness is symptoms began insidiously but have progressed
seen in gradually to the extent that now he has a problem
(a) Terminal bronchiole
even in his daily activities. Dr. Gulaeria, a respiratory
(b) Trachea
medicine specialist decided to perform spirometry
(c) Bronchi
which shows decreased forced vital capacity (FVC).
(d) Respiratory bronchioles
His plasma protein electrophoresis shows a markedly
15.7. The alveoli are filled with exudates the air is displaced reduced alpha fraction. Mr Kapoors lower lung lobes
converting the lung into a solid organ this description are most likely to show which of the following?
suggests (a) Panacinar emphysema
(a) Chronic bronchitis (b) Bronchial asthma (b) Centriacinar emphysema
(c) Bronchiectasis (d) Lobar pneumonia (c) Compensatory hyperinflation
(d) Apical subpleural blebs
15.8. ESR is a very critical investigation is the diagnosis of
TB. Which of the following is true about ESR in TB? 23. A 30 year old woman Chinamma has had increasing
(a) No change is ESR (AIIMS May 2013) dyspnea with cough for the past week. Over the past
(b) Confirms recovery from TB 2 days she is having productive cough with copious
(c) ESR is raised because of increased RBC aggregate sputum. On examination, she is afebrile but has
(d) ESR is raised due to decreased RBC size extensive dullness to percussion over all the lung fields.
420
Respiratory System
Her chest X ray has B/L diffuse opacification. Electron Most Recent Questions
microscopic examination of the biopsy tissue shows

many lamellar bodies. The antibody is directed against 27.1. Creola bodies are seen in:
which of the following substances in the pathogenesis (a) Bronchial asthma
of the above described condition? (b) Chronic bronchitis
(a) CFTR (c) Emphysema
(d) Bronchiectatsis
(b) Granulocyte macrophage colony stimulating factor
(c) DNA topoisomerase 1
27.2. Alpha-1-antitrypsin deficiency occurs in:
(d) Glomerular basement membrane (a) Emphysem
(b) Bronchiectasis
24. A 50 year old man Shahid K. John has had increasing (c) Empyema
dyspnea for the past 3 years with associated occasional (d) Bronchogenic carcinoma
cough but little sputum production. Auscultation

reveals that his lungs are hyper-resonant and is 27.3. Thickening of pulmonary membrane is seen in:
associated with expiratory wheeze. Pulmonary function (a) Asthma
tests reveal increased total lung capacity (TLC) and (b) Emphysema
slightly increased FVC. There is decreased FEV1 and (c) Bronchitis
(d) Bronchiectasis
FEV1/FVC ratio also. ABG analysis reveals pH of 7.35,
pO2 of 60 mm Hg and pCO2 of 48 mm Hg. What is the
most likely diagnosis? restrictive lung disease ild ards pneumoconiosis
: , ,
(a) Sarcoidosis
(b) Centriacinar emphysema
28. Which of the following is the characteristic feature of
(c) Diffuse alveolar damage
adult respiratory distress syndrome? (AI 2012)
(d) Chronic pulmonary embolism
(a) Diffuse Alveolar Damage
25.
(b) Interstitial tissue inflammation
A 65-year-old smoker Sutta Ram with hemoptysis
(c) Alveolar exudates
and weight loss undergoes a left upper lobectomy for
Respiratory System
(d) Interstitial fibrosis
squamous cell carcinoma. The uninvolved lung tissue
shows destruction of the alveolar septae around the

29. All are true about phagocytosis except (AI 2011)
(a) Size of the particle ingested is less than 0.5 microm-
respiratory bronchioles, with marked enlargement of
eter
the airspaces. Anthracotic pigments deposited heavily
(b) Size of the particle ingested is more than 0.5 microm-
in the walls of these tissues. These findings are most eter
compatible with (c) Combines with lysosome forming phagolysosome
(a) Asthma (d) Amoeba and other unicellular organisms make their
(b) Chronic bronchitis living out of it
(c) Emphysema
(d) Pulmonary hypertension
30. The following does not occur with asbestosis:
(a) Methaemoglobinemia (DPG 2011)
26. A 52-year-old male smoker Naresh presents with fever (b) Pneumoconiosis
and a cough productive of greenish-yellow sputum. (c) Pleural mesothelioma
The patient states that he has had a morning cough with (d) Pleural calcification
excessive mucus production for the past 5 years. Which 31. Ferruginous bodies are seen in:
(AI 2008)
of the following abnormalities would most likely be (a) Silicosis (b) Byssinosis
found in this patient? (c) Asbestosis (d) Bagassosis
(a) Apical cavitary lesions on x-ray
(b) Curschmann spirals in his sputum
32. All of the following are seen in asbestosis except:
(a) Diffuse alveolar damage (AI 2002)
(c) Increased Reid index
(b) Calcify pleural plaques
(d) Enlarged hilar lymph nodes on x-ray
(c) Diffuse pulmonary interstitial fibrosis
27. In emphysema, the destruction of many alveolar walls (d) Mesothelioma
changes the compliance of the respiratory system. 33. Which of the following is characteristically not

Which of the following clinical observations is directly associated with the development of interstitial lung
related to this change in compliance?
(a) Barrel chest
disease? (AIIMS May 2006)
(a) Organic dusts
(b) Chronic cough (b) Inorganic dusts
(c) Pink face (c) Toxic gases, e.g. chlorine, sulphur dioxide
(d) Long, slow, deep breathing pattern (d) Inhalation of tobacco smoke
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34. All of the following features are seen in asbestosis 43. Predominant constituent of Hyaline membrane is:
except: (AIIMS Nov 2002) (a) Albumi (Delhi PG-2005)
(a) Diffuse pulmonary interstitial fibrosis (b) Anthracotic pigment
(b) Fibrous pleural thickening (c) Fibrin rich exudates
(c) Emphysema (d) None of the above
(d) Calcific pleural plaques 44. Egg-shell calcifications are seen in: (UP 2005)
35. Asbestosis of the lung is associated with all of the (a) Silicosis
following except: (AIIMS May 2002) (b) Berylliosis
(a) Mesothelioma (c) Asbestosis
(b) Progression of lesion even after stopping exposure to (d) Bronchial asthma
asbestos
(c) Nodular lesions involving upper lobe
45. Hyaline membrane disease is associated with:
(a) Respiratory distress syndrome (UP 2006)
(d) Asbestos bodies in sputum (b) Bronchopulmonary dysplasia
36. Which of the following is associated with hypersensitive (c) Sudden infant death syndrome
pneumonitis? (AIIMS May 2002) (d) Bronchiolitis obliterans
(a)
(b)
Silicosis
Asbestosis
46. Baggasosis is caused by: (RJ 2004)
(a) Cotton dust
(c) Byssinosis (b) Sugarcane
(d) Berylliosis (c) Asbestosis
37. End stage lung disease is seen in: (PGI June 2004) (d) None
(a) Sarcoidosis 47. Which interstitial lung disease is caused by organic
(b) Interstitial lung disease dust: (RJ 2005)
(c) Langerhans cell histiocytosis (a) Silicosis
(d) Aspergillosis (b) Asbestosis
(e) Asbestosis (c) Byssinosis
(d) Anthracosis
Respiratory System
38. Features seen in bronchiolitis obliterans with organi

zing pneumonia include: (PGI Dec 2001) 48. Lower lung involvement is common in:
(a) Polypoid plugs in bronchioles (a) TB (RJ 2005)
(b) Ulceration and exudation of epithelium into the lu- (b) Asbestosis
men (c) Silicosis
(c) Exudation of proteinaceous material in terminal air- (d) All
ways 49. Pleural calcification is found in all of the following
(d) Bronchoconstriction except: (Bihar 2003)
(e) Response to steroids (a) Asbestosis
39. Which of the following inhaled occupational pollutant (b) Hemothorax
produces extensive nodular pulmonary fibrosis? (c) Tuberculous pleural effusion
(a) Silica (Delhi 2009 RP) (d) Coal worker pneumoconiosis
(b) Asbestos
(c) Wood dust
50. Caplans syndrome is seen in: (Bihar 2004)
(a) COPD
(d) Carbon (b) Pneumoconiosis
40. Earliest lesion seen in asbestosis is: (c)
(d)
Pulmonary edema
Bronchial asthma
(a) Pleural plaques (Delhi PG-2007)
(b) Hilar lymphadenopathy 51. Acute pulmonary sarcoidosis is least likely to be asso
(c) Adenoma lung ciated with: (Bihar 2004)
(d) Mesothelioma (a) Uveitis
(b) Pleural effusion
41. Most dangerous particles causing pneumoconiosis are (c) Erythema nodosum
of size: (Delhi PG-2006)
(d) Lymphadenopathy
(a) 1-5 micron (b) < 1 micron
(c) 5-10 micron (d) 10-20 micron 52. A 40 year old air-hostess man has experienced increa
sing respiratory difficulty for the past 18 months.
42. Asbestos exposure can cause all except: She is unable to clear her annual physical fitness
(a) Arthralgia (Delhi PG-2006) examination. She therefore approaches a physician.
(b) Mesothelioma She has normal physical findings on examination but
(c) Carcinoma larynx pulmonary function tests reveal a normal FEV1 and
(d) Bronchogenic carcinoma reduced FVC. Her chest X-ray is highly suggestive of
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Respiratory System
diffuse interstitial disease without any abnormal mass (c) Silicosis

or hilar lymphadenopathy. Blood investigations reveal (d) Berylliosis
normal hemogram. Special investigations also have
negative results for antibodies like ANA and anti

55.4. All are recognized causes off Adult Respiratory Distress
Syndrome (ARDS), except:
DNA topoisomerase I. Which of the following is the
(a) Smoke inhalation
most likely diagnosis?
(b) Malignant hypertension
(a) Scleroderma
(c) Gastric aspiration
(b) Goodpastures syndrome
(d) Viral pneumonias
(c) Silicosis
(d) Idiopathic pulmonary fibrosis
vascular lung disease infarct pulmonary edema
: , ,
53. Just 24 hours after moving in to a new apartment in
Benagaluru, a 27 years old photographer Akki develops
pulmonary htn
acute onset of fever, cough, dyspnea, headache, and 56. The percentage of pulmonary emboli, that proceed to

malaise. Surprisingly his symptoms subside over next
infarction, is approximately: (AI 2006)
6 days when he visits a friend in South Gautham Nagar (a) 0-5%
(a new city). When he returns, he visits his physician, (b) 5-15%
Dr. Oja Jesu who finds that he is not having any (c) 20-30%
abnormality on physical examination. Mr. Akkis (d) 30-40%

chest X ray is also normal. Which of the following may

57. On sectioning of an organ at the time of autopsy, a
produce these findings?
(a) Antigen antibody complex formation focal, wedge-shaped firm area is seen accompanied
(b) Release of histamine by extensive hemorrhage, with a red appearance. The
(c) Release of leukotrienes lesion has a base on the surface of the organ. This fin
(d) Toxic injury to type I pneumocytes dings is typically of (AIIMS May 2003)
(a) Lung with pulmonary thromboembolism

54. A 44-year-old woman presents with insidious onset of (b) Heart with coronary thrombosis
Respiratory System
shortness of breath, chest pain, and fatigue. Chest x-ray (c) Liver with hypovolemic shock
films reveal bilateral pulmonary infiltrates and enlarged (d) Kidney with septic embolus

hilar lymph nodes. There is no history of occupational 58. All are the histological features of pulmonary hyper
exposure to mineral dusts or organic dusts. A biopsy of
one of these lesions shows non-necrotizing granulomas.
tension: (PGI June 2004)
(a) Capillaritis of alveolar septa
Special stains for fungi and mycobacteria are negative. (b) Saddle thrombi in pulmonary trunk
Which of the following is the most likely diagnosis? (c) Thrombi in pulmonary vasculature
(a) Asbestosis (b) Berylliosis (d) Veno-occlusive disease
(c) TB (d) Sarcoidosis (e) Thickened arterial wall
55. Which of the following would most likely be observed 59. Bilateral
(a) SLE
exudative pleural effusion is seen in:
(PGI Dec 2006)
in the lung during an autopsy of a 2-week-old infant
(b) Lymphoma
who died of neonatal respiratory distress syndrome?
(c) CCF
(a) Alveoli filled with neutrophils
(d) Nephrotic syndrome
(b) Dense fibrosis of the alveolar walls (e) Ascites
(c) Enlarged air space
(d) Hyaline membranes and collapsed alveoli 60. Sudden cardio pulmonary collapse occurring in pul
mon ary embolism is due to: (UP 2005)
(a) Peripheral embolism of the vessels
(b) 60% pulmonary circulation is obstructed by emboli
55.1. The commonest cause of death in ARDS is (c) Multiple small thrombi causes impaction
(d) Organization of the clot
(a) Hypoxemia
(b) Hypotension 61. Dr. Sushant Verma conducted a study in MAMC which
(c) Non pulmonary organ failure included admitted patients hospitalized for more than 10
(d) Respiratory failure days and are bedridden for more than 7 days. He carries
a battery of investigations on these patients including
55.2. Pneumoconiosis is seen with which particle size? Doppler venous ultrasound of the lower limbs, arterial
(a) 0.5-3 microns (b) 3.5-6 microns blood gas analysis, and radiographic ventilation and
(c) 6.5-8 microns (d) 10-20 microns perfusion scanning of the lungs. Dr. Verma finds that
a small number of patients have abnormal ultrasound
55.3. Which of the following increases tuberculosis? (suggestive of thrombosis in lower limbs), low pO2 and
(a) Asbestosis (b) Sarcoidosis pulmonary perfusion defects. Which of the following
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Review of Pathology
symptoms is most likely associated with these patients? (b) Small cell carcinoma
(a) Cor pulmonale (b) Hemoptysis (c) Large cell carcinoma
(c) Dyspnea (d) No symptoms (d) Bronchoalveolar carcinoma
(e) Squamo us cell carcinoma
67. Most common site of metastasis in lung carcinoma is:
61.1. Sequestrated lobe of lung is commonly supplied by (a) Brain (RJ 2000)
which of the following vessels? (b) Kidney
(a) Pulmonary artery (c) Adrenal
(b) Intercostal artery (d) Testes
(c) Descending aorta 68. True about oat cell carcinoma of lung is:
(d) Bronchial artery
(a) Secrete ectopic hormone (RJ 2001)
61.2. Bronchogenic sequestration is seen in which lobe: (b) Variant of small cell carcinoma
(a) Left lower lobe (c) Cause SIADH
(b) Right upper lobe (d) All
(c) Left middle lobe
(d) Left upper lobe 69. A 42 years old woman Sugahi Ramamurty has a 3 month
history of mild persistent left sided chest pain. She is a
61.3. Which of the folloowing is not true about pulmonary non-smoker. There is no physical finding but chest X ray
embolus? shows a left side pleural mass without pleural effusion.
(a) Saddle embolus may cause sudden death CT scan of the chest shows a localized, circumscribed
(b) Most lesions affect are in the lower lobes 2.5 6 cm mass confined to the surface of the lung. A
(c) Small arterioles are blocked biopsy taken after thoracotomy demonstrated the mass
(d) Most of the emboli cause infarction being composed of spindle cells resembling fibroblasts
with abundant collagenous stroma. These cells were
lung malignancies CD34 (+) but are cytokeratin negative. Which of the
following is the most likely diagnosis?
Respiratory System
62. All are true regarding mesothelioma except: (a) Hamartoma

(a) Bilaterally symmetrical (AIIMS May 2011) (b) Malignant mesothelioma
(b) Associated with asbestos exposure (c) Metastatic breast carcinoma
(c) Histopathalogy shows biphasic pattern (d) Solitary fibrous tumor
(d) Occurs in late middle age
63. A 67 yr male with history of chronic smoking hemoptysis 70. Asmoking
75-year-old man Sukhdev Singh with a significant
history presents to the emergency room
with cough. Bronchoscopic biopsy from centrally located
with complaints of dyspnea and truncal, arm, and
mass shows undifferentiated tumor histopathologically.
facial swelling for one week. Physical examination is
Most useful I.H.C. (immunohistochemical) marker to

make a proper diagnosis would be: (AIIMS Nov 2009) remarkable for facial erythema and facial, truncal, and
(a) Cytokeratin arm edema with prominence of thoracic and neck veins.
(b) Parvalbumin On chest x-ray, there is a mass in the right mediastinum
(c) HMB-45 with adenopathy. Which of the following is the most
(d) Hep-par1 likely diagnosis?
(a) Adenocarcinoma
64. Which of the following is a finding in biopsy of meso (b) Hodgkins lymphoma
thelioma of pleura - (PGI Dec 01)
(c) Large cell carcinoma
(a) Myelin figures
(d) Small cell carcinoma
(b) Desmosomes
(c) Weibel-Palade bodies 71. A patient Rasool is brought to the emergency room
(d) Microvilli invasion following a seizure. Serum electrolyte studies
(e) Intense fibrosis demonstrate serum sodium of 128 mEq/L. The urine
65. Neuroendocrine lesions of lung are: osmolarity is higher than the serum osmolarity. Chest
(a) Carcinoid hamartoma (PGI June 2004) x-ray demonstrates a lung mass. Which of the following
(b) Alveolar carcinoma forms of lung cancer is most likely to cause the described
(c) Hamartoma electrolyte imbalance?
(d) Asthma (a) Adenocarcinoma
66. Hypersecretory granules are seen in which carcinoma (b) Bronchioloalveolar carcinoma
of lung?: (PGI Dec 2006) (c) Large cell carcinoma
(a) Adenocarcinoma (d) Small cell carcinoma
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Respiratory System
72. A medical examination of a student reveals absence of 74.4. Cavity formation is observed in one of the following
cardiac sounds on left side of the chest but surprisingly bronchogenic carcinoma:
the normal heart beat on the right side of the chest. (a) Squamous cell
The liver edge can be palpated on the left but not the (b) Oat cell
right side of the abdomen. He also gives history of (c) Adenocarcinoma
bronchiectasis and sinusitis. Which of the following (d) Bronchoalveolar
should be suspected?
(a) Down syndrome
All give rise to malignancy except
74.5.
(a) Cholelithiasis (b) Bronchiectasis
(b) Kartagener syndrome (c) Ulcerative colitis (d) Pagets disease
(d) Marfan syndrome Indoor air pollution does not lead to:
74.6.
(a) Chronic lung disease (AIIMS Nov 2013)
73. A patient with small-cell carcinoma of the lung (b) Impaired neurological development
complains of muscle weakness, fatigue, confusion, and (c) Pneumonia in child
weight gain. Physical examination is unremarkable. (d) Adverse pregnancy outcome
Serum sodium is found to be 120 mEq/L. Which of the
following abnormal laboratory results would also be 74.7. In a 70 year old man who was working in asbestos
expected in this patient? factory for 10-15 years. On routine X ray, a mass was
(a) Decreased plasma atrial natriuretic peptide (ANP) seen in the right apical region of the lung. Biopsy was
concentration taken from the mass. Which of the following is seen on
(b) Decreased plasma vasopressin concentration electron microscopic examination? (AIIMS Nov 2013)
(c) Decreased serum osmolarity (a) Numerous long slender microvilli
(d) Decreased urinary sodium concentration (b) Melanosomes
(c) Desmososmes with secretory endoplasmic
74. Pleural mesothelioma is associated with: reticulum
(a) Asbestosis (PGI Dec 2005)
(d) Neurosecretory granules in the cytoplasm
(b) Berylliosis
(c) Silicosis 74.8. Which of the following is having the minimal chances
Respiratory System
(d) Berylliosis of causing a mesothelioma?
(e) Baggasosis (a) Amphibole
(b) Crysolite
Most Recent Questions (c) Amesolite
(d) Tremolite
74.1. APUD cells are seen in: 74.9. The most common lesions in the anterior mediastinum
(a) Bronchial adenoma are all except:
(b) Bronchial carcinoid (a) Thymomas
(c) Hepatic adenoma (b) Lymphomas
(d) Villous adenoma (c) Lymph node enlargement from metastasis
74.2. Which of the following can develop into lung cancer? (d) Teratomatous neoplasms
(a) Asbestosis
74.10. Least common cause of clubbing is:
(b) Silicosis (a) Adenocarcinoma
(c) Byssinosis (b) Squamous cell cancer
(d) Anthracosis (c) Small cell cancer
(d) Mesothelioma
74.3. Scar in lung tissue may get transformed into:
74.11. Lung cancer most commonly associated with?
(a) Adenocarcinoma
(a) Asbestosis
(b) Oat cell carcinoma
(b) Silicosis
(c) Squamous cell carcinoma
(c) Berylliosis
(d) Columnar cell carcinoma
(d) Coal worker pneumoconiosis
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E xplanations
1. Ans. (c) Assmans focus (Ref: Robbins 8th/370; OP Ghai 5th/2001-1, Radiology of chest diseases 2nd/77 Thieme)
Recent Advances in Pediatrics pulmonology by Suraj Gupte volume 10 page/165)
Most common lesion of chronic pulmonary TB is called as Puhl lesionQ.
The infraclavicular lesion is called Assman Redeker SimonQ focus.
In post primary stage (late dissemination), coarse granular dissemination is called Aschoff Puhl focus.
2. Ans. (d) Mitral Stenosis (Ref: Robbins 8th/367-72)

Disease states that increase the risk of tuberculosis are:
Diabetes mellitus Chronic lung disease (particularly silicosis) Malnutrition
Hodgkins lymphoma Chronic renal failure Alcoholism
Immunosuppression (e.g. seen in AIDS)
3. Ans. (b) Predominance of alveolar exudate (Ref: Robbins 7th/751, 8th/713-4, 9th/704; Harrisons 17th/1620)
Important points about viral pneumonias
Called as atypical because of moderate amount of sputumQ, moderate elevation of total white cell countQ, no finding of
consolidationQ and lack of alveolar exudateQ.
Characterized by inflammatory reaction predominantly restricted within the walls of alveoliQ within the interstitium.are clear
whereas the core of these particles is dark.

Respiratory System
4. Ans. (d) Klebsiella pneumonia (Ref: Harrison 17th/838, Robbins 7th/751, 9/e p703-705)
Klebsiella pneumonia presents as typical air space pneumonia with cough productive of purulent sputum.
Causes of atypical pneumonias
Mycoplasma
Chlamydia pneumonia
Viral infections (Influenza, RSV, Adenovirus),
Legionella
Coxiella burnetti
Pneumocystis carinii
MycoplasmaQ is the commonest cause of atypical pneumonia.
5. Ans. (a) Cavitation (Ref: Robbins 7th/3845, 9/e p373; Harrison 17th/1010)
Cavitation is seen when there has been a previous sensitization of the host resulting in caseous necrotic material being
present which is discharged through the cavities. So, it is associated with secondary tuberculosis more frequently.
Caseous granulomas with multinuclear giant cells are present in both primary and secondary tuberculosis.

6. Ans. (b) TB; (c) Histoplasmosis; (d) Cryptococcosis; (e) Wegeners granulomatosis
(Ref: Robbins 7th/399, 754, 9/e p98,709)
Granuloma with necrosis is seen in following conditions
Tuberculosis
Histoplasmosis
Wegeners granulomatosis
Cryptococcosis
Classical PAN does not involve the pulmonary arteryQ.
7. Ans. (a) Altered Sensorium; (b) Dental sepsis; (d) Subpulmonic effusion; (e) Endobronchial obstruction. (Ref: Robbins
7th/753, 8th/716-7, 9/e p708)
Predisposing factors of lung abscess
Aspiration of infective material: Seen in alcoholics, during general anesthesia, sinusitis, gingivodental sepsis, coma,
gastroesophageal reflux diseases.
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Respiratory System
Antecedent primary bacterial infection: Post pneumonic abscess.

Septic embolism: Thrombophlebitis, bacterial endocarditis, IV drug abusers.
Carcinoma bronchus: causing obstruction to bronchopulmonary segment.
Miscellaneous: Direct spread of infection from suppuration of subphrenic space, pleural cavity, esophagus, spine, etc.
8. Ans. (a) Goodpasture syndrome; (b) Leptospirosis; (d) Wegeners granulomatosis; (e) Hantana virus infection;
(Ref: Harrison 17th 1793)
Pulmonary renal syndrome is seen in:
Goodpastures syndrome: Pulmonary hemorrhage and renal failure
Leptospirosis: Renal and hepatic dysfunction, hemorrhagic pneumonia, bleeding diathesis
Hantan virus also cause pulmonary renal syndrome.
Wegeners granulomatosis: Lung and kidney involvement is common.

Note: Legionella does not affect kidneys. It causes atypical pneumonia, diarrhea and hyponatremia.
9. Ans. (b) Asbestosis; (c) SLE (Ref: Crofton and Douglas 5th/979,1043, 579,1437,611, Robbins 9/e p693)
Causes of Granulomatous lung response
Known cause Unknown cause
Hypersensitivity pneumonitis Sarcoidosis
Inorganic dust: beryllium, silica Langerhans cell granulomatosis
TB Granulomatous vasculitis
Coccidiodomycosis Wegeners granulomatosis
Schistosomiasis -
Churg Strauss syndrome
Bronchocentric granulomatosis
Lymphomatoid granulomatosis
10. Ans. (d) Subpleural caseous lesion just above or below the interlobar fissure. (Ref: Robbins 8th/370, 9/e p374)
Respiratory System
Inhaled tubercle bacilli implanted in the distal air spaces of the lower part of upper lobe or upper part of the lower lobe, close
to the pleura lead to formation of Ghons focus.
Primary complex or Ghons complex of tuberculosis consists of 3 components
Pulmonary compound or Ghons focus
Draining lymphatics
Caseating hilar lymph node
Caseous hilar lymphadenopathy is associated with Ghon complex and not Ghon focus.
11. Ans. (a) Ghons focus, (b) pleural efffusion (d) Fibrosis (Ref: Robbins 7th/384, 9/e p374-375)
12. Ans. (a) Interstitial pneumonitis; (c) Foamy vacuolated exudates; (d) Mononuclear cell in bronchoalveolar lav-
age; (e) Neutrophil infiltration: (Ref: Harrison 17th/1267-8, 18th/1671)
Pneumocystis carinii pneumonia
On lung sections stained with H and E, the alveoli are filled with typical foamy, vacuolated exudates.
Severe disease may include interstitial edema, fibrosis and hyaline membrane formation.
The host inflammatory to lung injury results in increasing neutrophil count in bronchoalveolar lavage fluid, hypertrophy of alveolar
type II cells and a mild mononuclear cell infiltrate.
Malnourished infants display an intense plasma cell infiltrate.
13. Ans. (c) No abnormal findings (Ref: Robbins 8th/368-9, 9/e p373)
Most Mycobacterium tuberculosis infections are asymptomatic and subclinical infections.
Calcifications and cavitation are more frequent after re-infection or reactivation of tuberculosis infections in adults.
Lymphadenopathy or subpleural granuloma formation is more frequent in primary tuberculosis infections.
A diffuse reticulo-nodular pattern is suggestive of miliary tuberculosis.

14. Ans. (c) Resorption atelectasis (Ref: Robbins 8th/679, 9/e p670-671)
Resorption atelectasis
It is the result of complete obstruction of the airway most often due to the excessive secretions or exudates in the airway wall. It may
occur postoperatively, or may complicate bronchial asthma, chronic bronchitis, aspiration of foreign body etc.
Mediastinum shifts towards the atelectatic lung.
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Compression atelectasis
It results when the pleural cavity is partially or completely filled with fluid exudates, tumor, air or fluid as in conditions like
pneumothorax, hemothorax, or pleural effusion.
Also known as Relaxation atelectasis.
Mediastinum shifts away from the atelectatic lung.
Microatelectasis
It can occur postoperatively, in diffuse alveolar damage, and in respiratory distress of the newborn from loss of surfactant.
Contraction atelectasis
It occurs when fibrous scar tissue surrounds the lung preventing its full expansion.
Atelectasis is a reversible disorder except for contraction atelectasis.

15. Ans. (b) Ghon complex (Ref: Robbins 8th/370, 9/e p374)
The Ghon complex is the most frequent pathologic form of primary pulmonary tuberculosis. Mycobacterium tuberculosis first
localizes in the lung parenchyma, then in the hilar lymph nodes. In both these locations, a granulomatous reaction takes place.
These lesions usually heal by fibrosis, leaving only small scars at the sites of remote tuberculous infection. Reactivation of dormant
-
bacilli in old lesions or additional re exposure leads to secondary tuberculosis, with progression of lesions.
Cavitary tuberculosis (choice A) and miliary tuberculosis (choice D) are expressions of secondary infection, following reactivation
of old, usually clinically silent, lesions.
The cavitary form is characterized by development of large areas of liquefactive necrosis that empty into the airspaces, leading to
cavities within the lung parenchyma.
The miliary form is due to lymphohematogenous dissemination and subsequent seeding of tubercle bacilli throughout the body.
1 5.1. Ans. (c) Atelectasis (Ref: Robins 8/e p679-680, 9/e 670-671)
Atelectasis refers either to incomplete expansion of the lungs (neonatal atelectasis) or to the collapse of previously
inflated lung, producing areas of relatively airless pulmonary parenchyma.
Respiratory System
Resorption Atelectasis Compression Atelectasis Contraction Atelectasis

Due to airway obstruction leading to resorption Due to presence of fluid, blood, Fibrosis in the lung or pleura preventing full
of oxygen trapped in the alveoli. air or tumor in pleural space. expansion of pulmonary tissue.
Causes mediastinal shift towards affected Causes mediastinal shift away Only irreversible cause of atelectasisQ.
lung. from the affected lung.
Associated with chronic bronchitis/asthma/ Most commonly associated with
aspiration of foreign body/ secretions cardiac failureQ.
15.2. Ans. (d)Accumulation of fibrin (Ref: Robbins 8/e p713, 9/e p704)
The following 4 stages of inflammation are present.
Congestion: It is due to vasodilation. There is bacteria rich intra-alveolar fluid.
Red hepatization: Exudate is rich in RBC, neutrophils and fibrinQ.
Grey hepatization: Degradation of RBC and fibrinosuppurative exudates
Resolution: Enzymatic degradation of exudate and healing
15.3. Ans. (d) 5-7 (Ref: Harsh Mohan 6/e p469)
Stages of pneumonia
-
Congestion: 1 2 days
Red hepatization: 2-4 days
Gray hepatization: 4-8 days
-
Resolution: by 8 9 days

15.4. Ans. (b) Recruitment of lymphocytes (Ref: Robbins 9/e p371-374, 8/e p74, 7/e p382)
Macrophages are the primary cells infected by M. tuberculosis. Early in infection, tuberculosis bacilli replicate
essentially unchecked, while later in infection, the cell response stimulates macrophages to contain the proliferation
of the bacteria.
About 3 weeks after infection, a T-helper 1 (TH1) response is mounted that activates macrophages to become
bactericidal.
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Respiratory System
The TH1 response orchestrates the formation of granulomas and caseous necrosis. Macrophages activated by IFN-
differentiate into the epithelioid histiocytes that characterize the granulomatous response, and may fuse to form
giant cells.
1 5.5. Ans. (a) Apex (Ref: Robbins 9/e p373, 8/e p370, 7/e p383)
Secondary pulmonary tuberculosis classically involves the apex of the upper lobes of one or both lungs
1 5.6. Ans. (a) Terminal bronchiole (Read below) (Ref: Robbins 9/e p373)
The largest amount of smooth muscle relative to the thickness of the wall is present in the terminal bronchioles . Q
1 5.7. Ans. (d) lobar pneumonia (Ref: Robbins 9/e p704)

Bacterial invasion of the lung parenchyma causes the alveoli to be filled with an inflammatory exudate, thus causing
consolidation (solidification) of the pulmonary tissue..Robbins definition of pneumonia
1 5.8. Ans. (c) ESR is raised because of increased RBC aggregate (Ref: Wintrobes hematology 13/e p16-7)
ESR is a non specific test which is used as an indicator of active disease. It increases in some disease states due to increase
in plasma fibrinogen, immunoglobulins and other acute phase reactants. In addition, change in red cell shape and number
affect ESR.
Decreased ESR: Sickle cell disease, polycythemia, and hereditary spherocytosis.
Increased ESR: Infections, anemia, liver disease, cancer, pregnancy, collagen vascular disease
So, in a patient with TB, ESR will increase due to aggregation of red cells called rouleaux whose formation is facilitated by
fibrinogen. Since, it is non specific; it cannot conform recovery from TB.
Additonal info for AIIMS
The ESR may be measured by Wintrobe or Westergrens tube but the readings need to be corrected for the patient anemia.
However, a variant of ESR called zeta sedimentation rate is developed which produced reproducible results and doesnot
require correction for anemia.
16. Ans. (c) Chronic bronchitis (Ref: Robbins 8th/688, 9/e p679)
Respiratory System
17. Ans. (b) Pulmonary emphysema; (c) Diastase resistant hepatic cells: (Ref: Robbins 7th/911-2, 8th/865-6, 9/e p675-676)
Alpha 1-anti-trypsin deficiency is an autosomal recessive disease marked by abnormally low serum levels of 1 AT
enzyme resulting in panacinar emphysema.
It is characterized by presence of round to oval, PAS positive and diastase resistant cytoplasmic inclusions in
hepatocytes which on H and E stain acidophilic and indistinctly demarcated from surrounding cytoplasm.
18. Ans. (b) Eosinophils (Ref: Robbins 9/e p680, 8th/690-691; 7th/724-726)
19. Ans. (a) Bronchial asthma (Ref: Robbins 9/e p682, 8th/691, 7th/726)
20. Ans. (b) Centriacinar (Ref: Robbins 9/e p675, 8th/684, 7th/718)
21. Ans. (a) Centrilobular emphysema (Ref: Robbins 9/e p675, 8th/684, 7th/719)
22. Ans. (a) Panacinar emphysema (Ref: Robbins 8th/368-9, 9/e p675)
Progressive exertional dyspnea with a reduction of FVC could be due to chronic obstructive or restrictive lung disease.
A key clue in the stem of the question is the plasma protein electrophoresis finding suggesting -l-antitrypsin deficiency.
Deficiency of -l-antitrypsin can cause panacinar emphysema (a form of COPD), which usually affects the lower lung lobes
most severely.
Compensatory hyperinflation refers to the expansion of normal lung parenchyma that occurs when adjacent lung
segments or lobes collapse or are surgically removed.
Rupture of apical blebs is thought to be the major cause of primary spontaneous pneumothorax.
a 1-antitrypsin deficiency is associated with chronic panacinar emphysema preferentially localized to the lower pulmonary
lobes.
Centriacinar emphysema has a predominantly upper lung lobe distribution and is strongly associated with chronic smoking.
23. Ans. (b) Granulocyte macrophage colony stimulating factor (Ref: Robbins 8th/705, 9/e p696)
The patient in the stem of the question has the acquired from of pulmonary alveolar proteinosis (PAP).
CFTR gene mutations lead to cystic fibrosis and widespread bronchiectasis.
Anti DNA topoisomerase I antibodies are seen in diffuse scleroderma, which produces interstitial fibrosis.
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Anti glomerular basement membrane antibody is present in Goodpastures syndrome with extensive alveolar hem-
orrhage.
PAP is associated with impaired surfactant clearance by alveolar macrophages.

-
Microscopically there is accumulation of acellular surfactant in intra alveolar and bronchiolar spaces.
24. Ans. (b) Centriacinar emphysema (Ref: Robbins 8th/684-5, 9/e p675)
The findings of Mr. John point to an obstructive lung disease like emphysema which occurs due to airway narrowing or
even from loss of elastic recoil. So, emphysema is the most likely diagnosis.
Sarcoidosis is a chronic restrictive lung disease with all lung volumes decreased, low FVC, and normal FEV1/FVC ratio.
Diffuse alveolar damage is an acute restrictive lung disease.
Chronic pulmonary embolism does not affect FVC because the airways are not affected. It is however associated with a
ventilation/perfusion mismatch.

25. Ans. (c) Emphysema (Ref: Robbins 8th/684, 9/e p675-676)
Emphysema is a pulmonary disease characterized by enlargement of the alveolar airspaces due to destruction of the septae
without consequent fibrosis.
Pulmonary hypertension (choice D) affects neither the airways nor the alveoli. It is characterized by thickening of the
arterial smooth muscle with intimal hyperplasia and fibrosis. Atherosclerotic changes in the normally plaque-free larger
pulmonary arteries may be seen.
26. Ans. (c) Increased Reid index (Ref: Robbins 8th/688, 9/e p679)
This patient has the presentation of acute infection (elevated temperature, greenish-yellow sputum) on a background of
chronic bronchitis, which is common in smokers. Hyperplasia and hypertrophy of mucous glands in chronic bronchitis
causes increased Reid index in these patient.
Apical cavitary lesions (choice A) might be indicative of cavitary tuberculosis. It is not associated with excessive mucus
production. Hemoptysis and weight loss might also be expected as clinical findings.
Curschmann spirals (choice B) are found in asthmatic patients and represent mucus casts of small airways. Enlarged hilar
Respiratory System
lymph nodes (choice D) might suggest bronchogenic carcinoma or a granulomatous process, which would be less likely
than chronic bronchitis. In addition, patients with carcinoma often present with hemoptysis and weight loss, rather than
excessive mucus production.

27. Ans. (a) Barrel chest (Ref: Robbins 8th/686, 9/e p677)
A barrel chest with increased anterior/posterior diameter is commonly observed in patients with long-standing, severe
emphysema. This change in chest shape occurs because these patients, who have high complianceQ of the lung proper,
tend to function with their lungs to some degree over-inflated compared to people with normal lung compliance. This
over-inflation limits their ability to take further deep breaths. Patients with moderately severe emphysema are able to
maintain an adequate lung ventilation by taking many short breathsQ (compare with choice D); this physiology is some-
times expressed by describing these patients as pink puffersQ (choice C). Chronic cough (choice B) in emphysema pa-
tients is not directly related to the change in compliance.
2 7.1. Ans. (a)Bronchial asthma (Ref: Robbins 8/e p691, 9/e p682)
Creola bodies are are clusters of ciliated epithelial cells sometimes seen in sputum samples of patients with asthma.
3 Cs of sputum findings in asthma
Charcot leyden crystals
Curschmann spirals
Creola bodies
2 7.2. Ans. (a) Emphysema (Ref: Robbins 9/e p675, 8/e p685, 7/e p719)
Alpha 1 anti trypsin deficiency is associated with panacinar emphysema.
2 7.3. Ans (a) Asthma (Ref: Robbins 9th/ 682)
Thickening of the airway wall is a feature of airway remodeling and is seen in asthma.
28. Ans. (a) Diffuse Alveolar Damage (Ref: Robbins 8th/680-1, 9/e p672)
29. Ans. (a) Size of the particle ingested is less than 0.5 micro meter (Ref: Robbins 8th/53, Pharmaceutical Research, Vol. 25,
No. 8, August 2008)
The article writes.Particles possessing diameters of 2-3 microns exhibits maximum phagocytosis and attachment.
30. Ans. (a) Methaemoglobinemia (Ref: Harrison 17th/1612-3, Robbins 9/e p691)
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Respiratory System
31. Ans. (c) Asbestosis (Ref: Robbins 8th/700, 9/e p691)

Robbins direct quote inorganic particles may become coated with iron protein complexes and are called ferruginous
bodies.
Asbestosis in its classical form is a diffuse fibrotic disease of the lung tissue. Typically, the fibrotic changes of asbestosis are
focal and are most prominent in the lower lung lobes. The presence of asbestos bodies in or adjacent to the walls of fibrotic
respiratory bronchioles is the hallmark of the disease. A characteristic of asbestos bodies is a core of asbestos coated by
ferroprotein. (So, c is the answer)
Asbestos bodies are mimicked by ferruginous bodies which are formed on particles of talc, mica, fibre, glass and other less common
materials in the lung. True asbestos bodies are clear whereas the core of these particles is dark.

32. Ans. (a) Diffuse alveolar damage (Ref: Robbins 7th/736, 8th/700, 9/e p672)
Diffuse alveolar damage is a characterstic feature of ARDs. As explained in the text, asbestos inhalation is associated with
pleural plaque, interstitial fibrosis, bronchogenic cancer and mesothelioma.
33. Ans. NONE (Ref: Harrison 17th/1643, Robbins 8th/694, 704, 9/e p685)
All the mentioned options are associated with interstitial lung disease. Following is a table adapted from Robbins and
Harrison for a quick reference.
Causes of Interstitial Lung Disease (ILD)
Fibrosing Granulomatous Smoking related Miscellaneous
Usual interstitial pneumonia (idiopathic Sarcoidosis Desquamative interstitial pneumonia Eosinophilic
pulmonary fibrosis)
Associated with collagen vascular Hypersensitivity -
Respiratory bronchiolitis associated Pulmonary alveolar
diseases, drugs and radiation pneumonitis interstitial lung disease proteinosis
Cryptogenic organizing pneumonia
Nonspecific interstitial pneumonia
Respiratory System
Pneumoconiosis
Directly quoting Pneumoconiosis as is given on page 696 of Robbins . the pneumoconiosis was originally coined to de-
scribe the non-neoplastic lung reaction to inhalation of mineral dusts encountered in the workplace. Now it also includes
diseases induced by organic as well as inorganic particulates and chemical fumes and vapors. Presented underneath is
an adapted classification from Robbins table 15-6;
Causes of pneumoconiosis
Mineral dusts Coal dust, silica, asbestos, iron oxide, barium sulfate
Organic dusts inducing hypersensitivity pneumonitis Moldy hay, bagasse, bird droppings
Chemical fumes and vapours Sulfur dioxide, ammonia, benzene, insecticides
Organic dusts inducing asthma Cotton, flax, hemp
As can be concluded from both the above tables, the answer should be none in the options provided. If the question would
have been containing pneumoconiosis and NOT ILD, then smoking would have been the answer of choice.
34. Ans. (c) Emphysema (Ref: Robbins 7th/735-6, 8th/699-700, 9/e p691)
35. Ans. (c) Nodular lesions involving upper lobes (Ref: Robbins 7th/734-6, 8th/700, 9/e p688)
In asbestosis, there is presence of lesions affecting lower lobes or base of the lungs
Nodular lesions involving upper lobes is a feature of silicosis. The lesions continue to progress even after exposure
to asbestos has stopped.
36. Ans. (c) Byssinosis (Ref: Robbins 7/e p733, 9/3 p688)
Hypersensitivity pneumonitis (also called allergic alveolitis) describes a spectrum of immunologically mediated,
predominantly interstitial lung disorders caused by intense, often prolonged exposure to inhaled organic antigensQ.
It is a type III + IV hypersensitivity reaction.
Table 15-6 on page 697/8th Robbins mentions- Byssinosis is an organic dust causing asthma; rest of the options silico-
sis, asbestosis and berylliosis are given as examples of mineral dusts. So, they can be easily excluded. The best answer
would therefore be option c i.e. Byssinosis.
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Other examples associated with hypersensitivity pneumonitis
Farmers lung: Thermopohilic actionomycete or mouldy hay or grain dust*.

Pigeon breeders lung: Proteins from serum, excreta or feathers of the birds.
Air conditioner lung (or Humidifier lung): Thermopohilic bacteria in heated water reservoirs.
37. Ans. (a) Sarcoidosis; (b) Interstitial lung disease; (c) Langerhans cell histiocytosis (e) Asbestosis.
Parenchymal causes of end stage lung disease: Pulmonary Langerhans cell histiocytosis is a progressive
Emphysema disease, and can lead to end stage lung disease.
Pneumoconiosis Sarcoidosis of the lung is an interstitial lung disease; which may
lead to progressive fibrosis and end stage lung disease.
Bronchitis
Aspergillosis causes extrinsic allergic alveolitis or
ARDS
hypersensitivity pneumonitis.
Asbestosis
Interstitial lung disease.
38. Ans. (a) Polypoid plugs in bronchioles; (c) Exudation of proteinaceous material in terminal airways; (d) Bronchocon-
striction; (e) Response to steroids (Ref: Robbins 7th/731, 8th/696, 9/e p687; CMDT 2010 243)
Cryptogenic organizing pneumonia (earlier called as Bronchiolitis obliterans with organizing pneumonia)
-
Affects men and woman equally, around 50 70 years
Etiology is unknownQ
-
Clinical features Dry cough and dyspnea
-
Chest X ray shows subpleural and peribronchialQ patchy area of airspace consolidation.
Histopathology: there is presence of polypoid plugs of loose organizing connective tissue (called as Masson bodiesQ) within
alveolar ducts, alveoli and often bronchiolesQ (all are of same age)
There is no interstitial fibrosis or honey comb lungQ.
Treatment is done with steroidsQ.
Respiratory System

39. Ans. (a) Silica (Ref: Robbins 8th/698-9, 9/e p690)
40. Ans. (a) Pleural plaques (Ref: Robbins 7th/735, 8th/700, 9/e p691)
Pleural plaqueQ:
It is the most common manifestation of asbestos exposure composed of plaques of dense collagen containing calcium. They are usu
ally asymptomatic and develop on anterior and posterolateral parts of parietal pleura and over the diaphragm.

41. Ans. (a) 1-5 micron (Ref: Robbins 7th/732, 8th/696, 9/e p688)
In pneumoconiosis, the most dangerous particles range from 1-5 micron in diameter, because they may reach the terminal
small airways and air sacs and settle in their linings.
Note:
The solubility and cytotoxicity of particles, modify the nature of pulmonary response.
In general, the smaller the particle, the higher the surface area-to-mass ratio, and the more likely and more rapidly toxic levels will
appear in the pulmonary fluids.
Larger particles resist dissolution and so may persist within lung parenchyma for years.
Larger particles tend to evoke fibrosing collagenous pneumoconiosis, such as characteristic of silicosis.
42. Ans. (a) Arthralgia (Ref: Robbins 7th/735, 8th/700, 9/e p691)
43. Ans. (c) Fibrin rich exudates (Ref: Robbins 7th/481, 8th/456-8, 9/e p457)
The membranes (in hyaline membrane disease) are largely made up of fibrinogen and fibrin admixed with cell debris
derived chiefly from necrotic type-II pneumocytes.
There is a remarkable paucity of neutrophilic inflammatory reaction associated with these membranes.
The lesions of hyaline membrane disease are never seen in still born infants or in live-born infants who die within a
few hours of birth.
44. Ans. (a) Silicosis (Ref: Robbins 9/e p690, 8th/699, 7th/734)
45. Ans. (a) Respiratory distress syndrome (Ref: Robbins 9/e p457, 8th/680, 7th/715)
46. Ans. (b) Sugarcane (Ref: Robbins 9/e 688, 8th/697, 7th/733)
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Respiratory System
47. Ans. (c) Byssinosis (Ref: Robbins 9/e 688, 8th/697, 7th/733)
48. Ans. (b) Asbestosis (Ref: Robbins 9/e 691, 8th/700, 7th/736)
49. Ans. (b) Hemothorax (Ref: Robbins 8th/732, 9/e 722)
50. Ans. (b) Pneumoconiosis (Ref: Harrison 17th/1625, 9/e 688)
51. Ans. (b) Pleural effusion (Ref. Robbins 9/e 693, 8th/702-703, 7th/738)
52. Ans. (d) Idiopathic pulmonary fibrosis (Ref: Robbins 8th/694-5, 9/e 685)
Needless to tell you the name of the airline employing a 40 year old airhostess friends, we understand that the lady
has chronic restrictive lung disease. The etiology in this lady is unknown. This has to be differentiated from patients
having an identifiable cause like infection, collagen vascular disease, drug use, and pneumoconiosis.
Scleroderma is ruled out because there is no history of skin involvement and in these, the ANA test result typically
is positive.
Goodpastures syndrome is a rare cause of sudden onset of severe hemoptysis but no mention of anti glomerular
basement antibody is present.
Silicosis is due to inhalation of dust but the profession of the lady excludes that.
53. Ans. (a) Antigen antibody complex formation (Ref: Robbins 8th/703 -4, 9/e p694)
Mr. Akki is likely suffering from hypersensitivity pneumonitis. In this condition, the symptoms appear acutely soon after
exposure to an antigen like a fungus (mould) present in ventilation or AC ducts. However, the symptoms improve if the
affected individual leaves the environment having the antigen. There are minimal pathologic pulmonary changes. It is
mainly a type III hypersensitivity reaction, but with more chronic exposure to the antigen, there may be a component of
type IV hypersensitivity with granulomatous inflammation. Histamine release is characteristic of a type I hypersensitivity
reaction that more typically occurs in allergic disease.
Leukotrienes are important mediators in asthma produced by the lipoxygenase pathway.
A toxic injury is more typical of inhalation of a toxic gas like sulfur dioxide (known as silo fillers disease).

54. Ans. (d) Sarcoidosis (Ref: Robbins 8th/702-703, 9/e 693)
Respiratory System
The correct answer is D. The diagnosis of sarcoidosis is usually made by exclusion. This disease is characterized by non-
necrotizing granulomas developing most frequently in the lungs, lymph nodes, retina, heart, spleen, skin, and liver. Non-
necrotizing granulomas may be seen in a number of other conditions, however, such as infections and certain forms of
pneumoconiosis, which must be ruled out before making a diagnosis of sarcoidosis.
55. Ans. (d) Hyaline membranes and collapsed alveoli (Ref: Robbins 8th/680, 9/e 457)
Neonatal respiratory distress syndrome is a disease of immaturity. The immature lung is not able to produce sufficient
surfactant to prevent collapse of many alveoli. Severe diffuse damage to alveoli causes precipitation of protein (hyaline
membranes) adjacent to many alveolar walls.
Abundant neutrophils (choice A) are seen in pneumonia.
Fibrosis (choice B) is a late, not early, feature of respiratory distress syndrome whereas the air spaces are collapsed, not
enlarged (choice C), in this condition.
55.1 Ans (c) Non pulmonary organ failure (Ref: Robbins 9th/ 674)
In ARDS, most of the deaths are attributable to sepsis or multiorgan failure and, in some cases, direct lung injury.
55.2 Ans (a) 0.5-3 microns (Ref: Robbins 9th/ 688)
55.3 Ans (c) Silicosis (Ref: Robbins 9/e p 690)
5 5.4. Ans (b) Malignant hypertension (Ref: Robbins 9th/ 672)
See the table of causes of acute respiratory distress syndrome. ARDS is associated with non cardiogenic pulmonary edema.
Malignant hypertension will cause development of cardiogenic pulmonary edema.
The four most important causes of ARDS:
Sepsis, diffuse pulmonary infections, gastric aspiration and head injuries.

56. Ans. (b) 5-15% (Ref: Robbins 7th/742, 8th/706, 9/e 698)
Robbins direct quote. Only about 10% of pulmonary artery emboli actually cause infarction.
57. Ans. (a) Lung with pulmonary thromboembolism (Ref: Robbins 9/e p129-130, 8th/128, 7th/138)
The morphology is characteristically present as red (hemorrhagic) infarct. The red infarcts are seen in lung, liver and
intestine.
White infarcts are seen in brain, spleen, kidney and heart.
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58. Ans. (c) Thrombi in pulmonary vasculature; (d) Vaso-occlusive disease; (e) Thickened arterial wall (Ref: Robbins
8th/708, 9/e p699-700, Harsh Mohan 6th/466)
In pulmonary hypertension pathological changes are seen from main pulmonary arteries to arterioles. They are:
Arterioles and small pulmonary arteries (most Medium sized pulmonary arteries Large pulmonary arteries
prominently affected)
(i) Medial hypertrophy (i) Medial hypertrophy; which is not marked in (i) Atheromatous deposits
secondary pulmonary hypertension
(ii) Thickening and reduplication of elastic lamina. (ii) Concentric intimal thickening
(iii) Plexiform pulmonary arteriopathy in which (iii) Adventitial fibrosis
intraluminal tuft of capillary formation occurs in
dilated thin walled arteriolar branches.
(iv) Thickening and reduplication of elastic lamina.
The presence of many organizing or recanalizing thrombi favors recurrent pulmonary emboli as the cause and the coexistence of
diffuse pulmonary fibrosis or severe emphysema and chronic bronchitis points to chronic hypoxia as the initiating event.
59. Ans. (a) SLE; (Ref: Harrison 17th/1660)

Transudative and exudative pleural effusion (PE) are differentiated by measuring the LDH and protein level in the pleural fluid.
Exudative PE meets at least one of the following criteria:
1. Pleural fluid protein/serum protein > 0.5.
2. Pleural fluid LDH by serum LDH > 0.6.
3. Pleural fluid LDH more than 2/3rd of the normal upper limit of serum.

Transudative PE is caused by:
CCF, cirrhosis, pulmonary embolism
Respiratory System
Nephrotic syndrome, peritoneal dialysis, superior vena cava obstruction

Myxoedema
Causes of exudative pleural effusion
Neoplastic disease Pericardial disease Asbestos exposure Yellow nail syndrome
Hemothorax Chylothorax Uremia Radiation therapy
Pulmonary emboli Sarcoidosis Meigs syndrome Ovarian hyperstimulation syndrome
GI disease Collagen vascular disease Drugs Infections
Esophageal perforation Rheumatoid pleuritis Nitrofurantoin Bacterial infections
Pancreatic disease SLE Dantrolene TB
-
Intra abdominal abscess Drug induced lupus Methysergide Fungal infections
Diaphragmatic hernia Sjogrens syndrome Bromocriptine Viral infections
Wegeners granulomatosis Amiodarone Parasitic infections
Churg Strauss syndrome Procarbazine
60. Ans. (b) 60% pulmonary circulation is obstructed by emboli (Ref: Robbins 9/e p127, 8th/126; 7th/136)
61. Ans. (d) No symptoms (Ref: Robbins 8th/698, 706-7)
The stem of the question suggests that Dr. Vermas clinical study is being done on patients with pulmonary thromboem-
bolism, and most pulmonary emboli are small and clinically silent. Cor pulmonale may result from repeated emboliza-
tion which is associated with reduction in the pulmonary vascular bed. Hemoptysis is a rare manifestation of pulmonary
embolism. It occurs usually with hemorrhagic infarction of the lung. Dyspnea occurs with medium to large emboli.
61.1. Ans. (c) Descending aorta (Ref: Robbins 8/e p679, 9/e 670)
Pulmonary sequestration refers to the presence of a discrete mass of lung tissue without normal connection to the airway
system.
The blood supply to the sequestered area arises not from the pulmonary arteries but from the aorta or its branches
6 1.2. Ans. (a) Left lower lobe (Ref: Fetal and Neonatal Physiology 4/e p872; Robbins 9/e p670 8/e p679; www.uptodate.com)
Pulmonary sequestrationcan be either:
Extralobar sequestrations are external to the lung and may be located anywhere in the thorax or mediastinum. They are
seen in infants. They occur in the lower left side of the thorax between the left lower lobe ad the diaphragm.
Intralobar sequestrations occur within the lung substance usually in older children and are often associated with recur-
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Respiratory System
rent localized infection or bronchiectasis. These are seen most commonly in the posterior basal segment of left lower
lobeQ (Ref. Fetal and Neonatal Physiology).
61.3. Ans. (d) Most of the emboli cause infarction (Ref: Robbins 8/e p706, 9/e p127)
Large emboli lodge in the main pulmonary artery or its major branches or at the bifurcation as a saddle embolus. It
may lead to sudden death.
Smaller emboli travel out into the more peripheral vessels, where they may cause hemorrhage or infarction. In patients with
adequate cardiovascular function, the bronchial arterial supply can sustain the lung parenchyma. Hemorrhages may
occur, but there is no infarction. The underlying pulmonary architecture is preserved, and resorption of the blood
permits reconstitution of the preexisting architecture.
Also know: NEET points
Only about 10%Q of emboli actually cause infarction, which occurs when the circulation is already inadequate, as in
patients with heart or lung disease.
Pulmonaryinfarcts tend to be uncommon in the young.
About 3/4thof all infarcts affect the lower lobes Q
Inmore than half, multiple lesions occur.
Typically, they extend to the periphery of the lung substance as a wedge with the apex pointing toward the hilusQof the lung.
62. Ans. (a) Bilaterally symmetrical (Ref: Robbins 8th/733-4, Malignant Pleural Mesothelioma 1st/65, DeVitas Cancer
8th/1840, 9/e p723-724)
Mesothelioma is an asbestos exposure releated tumor having Mean age of presentation as 50-70 years. Microscopically it
may have both epithelioid and sarcomatoid patterns (biphasic pattern).
Option a. Pleural mesotheliomas are more commonly right sided (R:L ratio is 3:2) may be because of greater size of
right sided pleural cavity. Although usually unilateral at presentation, it is not infrequent to find histological evidence
of mesothelioma in the contralateral pleura. Macroscopic evidence of synchronous bilateral pleural tumors is rare.
Malignant Pleural Mesothelioma 1st/65.
Respiratory System
63. Ans. (a) Cytokeratin (Ref: Harsh Mohan 6th/16, Robbins 8th/35, 725-726, 9/e p716)
The presence of chronic smoking, cough and hemoptysis in old man is a pointer towards a diagnosis of bronchogenic
cancer. The central location suggests the possibility of a squamous cell cancer.
Robbins writes Histologically, this tumor is characterized by the presence of keratinization and/or intercellular
bridges.
Other options
HMB-45 is a specific tumor marker for melanoma.

Parvalbumin is low molecular calcium binding albumin protein localised in fast-contracting muscles. It is also present in the brain
(in GABAergic interneurons) and some endocrine tissues. Decreased PV and GAD67 expression was found in PV+ GABAergic
interneurons in schizophrenia.
Hep-par 1 is hepatocyte paraffin 1 and is a well known marker for hepatocellular carcinoma.
64. Ans. (d) Microvilli invasion, (e) Intense fibrosis: (Ref: Robbins 7th/768-9, 8th/734, 9/e p723-724)
Benign mesothelioma Malignant mesothelioma
Nature Solitary fibrous tumor Diffuse thick and fleshy tumor
Prior asbestos exposure No Q
relationship Definitive associationQ is present
Microscopic feature Whorls of reticulin and collagen fibers among Epithelioid type: cuboidal/columnar cells form tubular/
which interspersed spindle cells resembling papillary structures
fibroblasts are present Sarcomatoid type: appear as spindle cell carcinoma
Mixed type
Immunotyping -
Cells are CD34(+) and keratin ( )Q -
Cells are CD34( ) and keratin (+)Q
65. Ans. (a) Carcinoid hamartoma (Ref: Robbin 7th/764, 9/e p719)
Neoplasms of neuroendocrine cells in the lung include:
Benign tumorlets (small tumors in areas of scarring and inflammation)
Carcinoid
Small cell carcinoma
Large cell neuroendocrine carcinoma of lung.
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66. Ans. (b) Small cell carcinoma (Ref: Robbins 7th/762, 8th/727, 9/e p717)
Small cell carcinoma of lung shows dense core neurosecretory granules. The granules are similar to those found in
neuroendocrine argentaffin cells present along the bronchial epithelium.
Some of these tumors secrete polypeptide hormones. Presence of neuroendocrine markers such as chromogranin,
synaptophysin and Leu-7 is seen.
It also secretes PTH like substance. They are most common pattern associated with ectopic hormone production.
67. Ans. (c) Adrenal (Ref: Robbins 9/e p717, 8th/723, 7th/763)
68. Ans. (d) All (Ref: Robbins 9/e p717, 8th/728, 7th/762)
69. Ans. (d) Solitary fibrous tumor (Ref: Robbins 8th/732-3 9/e p723)
The solitary fibrous tumor (or localized benign mesothelioma) of pleura is rare neoplasm appearing as a pedunculated mass.
It is not associated with asbestos exposure/environmental pathogens.
A hamartoma is a peripheral intra-parenchymal mass with cartilage tissue and a significant component of fibrous
connective tissue.
Metastases are typically multiple and often produce bloody effusions.
The tumor cells in solitary fibrous tumor characteristically show immunostaining pattern of CD 34(+) and keratin-negativeQ.
A malignant mesothelioma forms a non circumscribed pleural mass. It has atypical cells which are cytokeratin positive.

70. Ans. (d) Small cell carcinoma (Ref: Robbins 8th/728-729, 9/e p718)
Superior vena cava (SVC) syndrome is characterized by obstruction of venous return from the head, neck, and upper
extremities. Over 85% of cases of SVC syndrome are related to malignancy. Bronchogenic carcinomas (most commonly
small cell cancer and squamous cell cancer) account for over 80% of these cases. Lymphomas such as Hodgkins disease
(option B) and non-Hodgkins lymphoma are uncommon causes of SVC syndrome.
71. Ans. (d) Small cell carcinoma (Ref: Robbins 8th/728-729, 9/e p717)
The patient has SIADH (syndrome of inappropriate antidiuretic hormone secretion), which can be caused by ectopic ADH
Respiratory System
secretion by small cell carcinomas of the lung, CNS disorders, chronic pulmonary disease, and certain drugs. Features
of SIADH include excessive water retention, hyponatremia (which can lead to seizures when severe), and serum hypo-
osmolarity with urine osmolarity greater than serum osmolarity.
Bronchioloalveolar carcinoma (option B) is associated with alveolar-like spaces and no link to smoking.
72. Ans. (b) Kartagener syndrome (Ref: Robbins 8th/692, 9/e p683)
Isolated inversion of the heart (dextrocardia) is almost always associated with cardiac defects that may include
transposition of the atria and transposition of the great arteries.
However, dextrocardia as part of situs inversus totalis, with reversal of the thoracic and abdominal organs, is usually
associated with a physiologically normal heart. The cluster of situs inversus, sinusitis, and bronchiectasis is called
Kartagener syndrome, which is caused by defective ciliary function.
Association of cardiac defects with syndromes
-
Down syndrome ostium primum type of atrial septal defect.
-
Kawasaki disease coronary artery aneurysms.
Marfan syndrome - aortic dissection.
-
Turner syndrome coarctation of the aorta.

73. Ans. (c) Decreased serum osmolarity (Ref: Robbins 8th/728-729, 9/e p719)
74. Ans. (a) Asbestosis (Ref: Robbins 7th/768, 8th/700, 9/e p723)
7 4.1. Ans. (b) Bronchial carcinoid (Ref: Robbins 8/e p729-730, 9/e p719)
Amine Precursor Uptake and Decarboxylation (APUD) cells are also known as neuroendocrine cells. These cells are the
cell of origin of the carcinoid tumour.
7 4.2. Ans. (a) Asbestosis (Ref: Robbins 8/e p699-700, 7/e p735, 9/e p691)
Direct lines.. In contrast to other inorganic dusts, asbestos an also act as a tumour initiator and promoter.
7 4.3. Ans. (a) Adenocarcinoma (Ref: Robbins 9/e p714-715, 8/e p724, 7/e p760-761)
Peripheral adenocarcinomas with a small central invasive component associated with scarring and a predominantly
peripheral bronchioloalveolar growth pattern may have a better outcome than invasive carcinomas of the same size...
Robbins
436
Respiratory System
7 4.4. Ans. (a) Squamous cell (Ref: Robbins 9/e p716-717)

Important points about Squamous cell carcinoma of lung
MC type of lung cancer in smokersQ
MC type in malesQ
Usually central in location (arise from the segmental bronchi)
Intercellular bridges or junction is very specific.
HypercalcemiaQ due to PTHrP is the MC paraneoplastic syndrome
74.5. Ans. (b). Bronchiectasis (Ref: Robbins 9/e p684)

Bronchiectasis cannot cause malignancy. The complications which may be associated with bronchiectasis are: Cor
pulmonale, metastatic brain abscesses, and amyloidosis.
To be considered bronchiectasis, the dilation should be permanent; reversible bronchial dilation often accompanies
viral and bacterial pneumonia.
74.6. Ans. (b) Impaired neurological development (Ref: Robbin 8/e p 403)
Concept: Please note friends that impaired neurological development can result from lead exposure but lead is an
outdoor air pollutant.
Impaired lung function, lung inflammation, reduced exercise capacity; increased respiratory symptoms are associated
with air pollution.
Indoor air pollution contributes to acute respiratory infections in young children, chronic lung disease and cancer in
adults, and adverse pregnancy outcomes (such as stillbirths) for women exposed during pregnancy. Acute respiratory
infections, principally pneumonia, are the chief killers of young children.Park
7 4.7. Ans. (c) Desmososmes with secretory endoplasmic reticulum (Ref: Robbins 8/e p 669, Thurlbecks Pathology of the Lung
3/e p428-435)
Tough one friends.AIIMS guys laid the trap beautifully! Lets analyze the question
Respiratory System
The exposure to asbestos brings the first malignancy to our mind which is mesothelioma. However, this is not the answer
for the current question because:
Period of exposure is 10-15 years in question. However, as per Robbins.. there is a long latent period of 25 to 45 years
for the development of asbestos-related mesothelioma.
More importantly, mesothelioma is a pleural tumor whereas the question clearly mentioned that the mass was seen in
the right apical region. Considering that there is no history of smoking, this is more likely to an adenocarcinoma (and
not squamous cancer) which is also the most common type of lung cancer associated with asbestos exposure.
Desmososmes with secretory endoplasmic reticulum is a feature of electrom microscopic finding of adenocarcino-
ma.. Thurlbecks Pathology table 17-7
Type Desmosomes/Tonofilament Microvllll Tight Lumina Secretory Neuro-secretory

Bundles Junctions RER Granules
Squamous carcinomas Many, wellformed +
Small cell carcinoma Small, poorly formed Rare +
Adenocarcinoma Many, small well formed + + + +
For future AIIMS question!

Napsin A is a more sensitive and specific marker than TTF-1 for adenocarcinoma of the lung.
Features of mesothelioma
On electron microscopy, the presence of long microvilli and abundant tonofilaments but absent microvillous
rootlets and lamellar bodies.
Lack of staining for carcinoembryonic antigen (it is positive in adenocarcinoma)
Positive staining for calretinin, Wilms tumor 1 (WT-1), cytokeratin 5/6, and D240
7 4.8. Ans (b) Crysolite (Ref: Robbins 9/e p 691)

The serpentine chrysotile form accounts for 90% of the asbestos used in industry. Amphiboles even though less prevalent,
are more pathogenic than chrysotiles with respect to induction of mesothelioma.
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74.9. Ans (c) Lymph node enlargement from metastasis (Ref: Robbins 9/e p 721)
Anterior Mediastinum Middle Mediastinum Posterior Mediastinum
Thymoma Bronchogenic cyst Neurogenic tumors (schwannoma, neurofibroma)
Teratoma Pericardial cyst Lymphoma
Lymphoma Lymphoma Metastatic tumor (most are from the lung)
Thyroid lesions Bronchogenic cyst

Parathyroid tumors Gastroenteric hernia
Metastatic carcinoma
74.10. Ans (c) Small cell cancer

Principles and practice of lung cancer page 348
Clubbing is most common with adenocarcinoma and is least common with small cell lung cancer.direct quote
74.11.Ans: (a) Asbestosis (Ref: Robbins 9/e p 713)
(Lungs)
Airway remodeling is associated with bronchial asthma.
Pulmonary hypertension is defined as a mean pulmonary artery pressure greater than or equal to 25 mm Hg at rest.
Cough is the most common symptom of the bronchogenic carcinoma.
The lung is the most common site of metastatic neoplasms. (Robbins 9th/721)
The NAB2- STAT6 fusion gene is virtually unique to solitary fibrous tumor.
In about 80% of mesotheliomas, the most common is homozygous deletion of the tumor suppressor gene CDKN2A/
INK4a. The demonstration of this deletion (usually by FISH) involving chromosome 9p can be very helpful in
Respiratory System
distinguishing mesothelioma from reactive mesothelial proliferations.
U pdated information from 9th edition of robbins

Acute lung injury (ALI)
Acute lung injury (ALI) (also called noncardiogenic pulmonary edema) is characterized by the abrupt onset of
significant hypoxemia and bilateral pulmonary infiltrates in the absence of cardiac failure. Acute respiratory distress
syndrome (ARDS) is a manifestation of severe ALI.
It is associated with sepsis, severe trauma, or diffuse pulmonary infection.
The histologic manifestation of these diseases is diffuse alveolar damage (DAD). There is also the presence of hyaline
membranes lining alveolar walls.
Pulmonary Langerhans Cell Histiocytosis
Pulmonary Langerhans cell histiocytosis is a rare reactive inflammatory disease characterized by focal collections
of Langerhans cells (often accompanied by eosinophils). It results in scarring and the appearance of irregular cystic
spaces.
Langerhans cells are immature dendritic cells with grooved, indented nuclei and abundant cytoplasm. They are
positive for S100, CD1a, and CD207 (langerin) and are negative for CD68.
Most of the affected patients are relatively young adult smokers. It is associated with acquired activating mutations
in the serine/ threonine kinase BRAF.
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis is a pulmonary disorder that primarily affects young woman of childbearing age. It is characterized
by a proliferation of perivascular epithelioid cells that express markers of both melanocytes and smooth muscle cells. The
proliferation distorts the involved lung, leading to cystic, emphysema-like dilation of terminal airspaces, thickening of the
interstitium, and obstruction of lymphatic vessels. The condition is characterized by TSC2 mutations. The condition affects
young women mainly and the presenting features include dyspnea or spontaneous pneumothorax. The condition is treated with
lung transplantation.
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CHAPTER 11 Kidney and Urinary Bladder

Kidney is the organ of the body responsible for the removal of nitrogenous products from
the blood.
Azotemia refers to an elevation
Some important definition : s of Blood Urea Nitrogen (BUN)
and creatinine levels.
Azotemia It refers to an elevation of Blood Urea Nitrogen (BUN) and creatinine
1.
levels due to reduced glomerular filtration rate. It can be due to:
a. Pre-renal cause Associated with decreased perfusion as in shock, hemorrhage
and heart failure.
b. Renal cause Due to intrinsic defect in the kidney. Uremia = Azotemia + Clinical
signs and symptoms + Biochem-
c. Post renal cause Associated with obstruction to urine outflow. ical abnormalities
Patients do not require dialysis at this stage.
2. Uremia Azotemia + Clinical signs and symptoms + Biochemical abnormalities
There is secondary presence of uremic gastroenteritis, peripheral neuropathy
and uremic pericarditis.
Patients require dialysis at this stage.
Countercurrent mechanism
CYSTIC DISEASES OF THE KIDNEY of the kidney is responsible
for maintenance of osmotic
Polycystic Kidney Disease (PKD) gradient in the medulla.
Adult PKD Childhood PKD

Autosomal dominantQ inheritance Autosomal recessiveQ inheritance.
Mutations in PKD1, PKD2 and PKD3 genes Mutation in PKHD1 gene which produces Major source of erythropoietin is
(PKD1 produces Polycystin proteinQ). fibrocystin proteinQ. Interstitial cells in peritubular
Asymptomatic till middle age Presents in infancy with renal insufficiency. capillaries and tubular epithe-
Clinical features include hematuria, Associated with multiple hepatic cysts and lial cellsQ. It is also produced in
hypertension, UTI and renal stones. congenital hepatic fibrosisQ. perisinusoidal cells in the liver
Extra renal manifestations Grossly, bilaterally enlarged kidney with small
1. Cysts in other organs like liverQ (most cysts in cortex and medulla having their long
commonly), pancreas, spleen and ovary. axis at right angle to capsule.
2. Berry aneurysmQ.
3. Colonic diverticulaQ.
Major source of renin is JG cell
4. Mitral valve prolapse and aortic regurgi-
of the kidneyQ
tationQ.
Grossly, bilaterally enlarged kidneys
with multiple cysts containing serous or
hemorrhagic fluidQ.
Genetics
Mnemonic for APKD: ADult Polycystic Kidney Disease
1. Clinical Features: (11 Bs) is Autosomal Dominant
Signs: Bloody urine Also; Polycystic kidney has 16
letters and is due to a defect on
Bilateral pain [vs. stones, which are usually unilateral pain] chromosome 16.
Blood pressure up
Bigger kidneys
Complications
Berry aneurysm
Biliary cysts
Bicuspid valve [prolapse and other problems]
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Accelerators:
Boys
Blacks
Blood pressure high.
GLOMERULAR DISEASES
Pathogenesis of glomerular injury

1. In Situ immune complex disease
1. Anti-GBM antibody induced nephritis
The antibodies are directed against intrinsic fixed antigens that are normal
components of the glomerular basement membrane (GBM) proper resulting
in a diffuse linear pattern of staining for the antibodies by immunofluorescence
techniques. This is the model of anti-GBM disease (Goodpasture syndrome)
which is caused by antibodies against non-collagenous domain of the alpha 3
Heymann antigen or megalin chain of collagen type IV.
is located on visceral epithelial
2. Heymann nephritis
cells The antibodies are directed against intrinsic fixed antigen called Heymann
antigen or megalin located on visceral epithelial cells resulting in complement
activation and the formation of subepithelial deposits and a granular pattern of
staining for the antibodies by immunofluorescence techniques.

3. Antibodies against planted antigens
Antibodies can react with antigens that are not normally present in the
Kidney and Urinary Bladder
glomerulus but are planted there. These antigens include cationic molecules
like DNA, nuclear proteins, bacterial, viral and parasitic products and drugs. A
granular pattern of staining is observed by immunofluorescence techniques.
2. Circulating immune complex disease
The glomerular injury is caused by entrapment of circulating antigen-antibody
complex within the glomeruli. This results in complement activation, leukocytic
infiltration and proliferation of glomerular and mesangial cells. The endogenous
Concept antigens include DNA and tumor antigens whereas the exogenous antigens include
Anionic antigens form infectious products. Electron microscopy reveals the presence of immune complexes
subendothelial deposits. as electron dense deposits lying in the mesangium, between endothelial cells and the
Cationic antigens form sub- GBM (subendothelial deposits) or between the GBM and the podocytes (subepithelial
epithelial deposits. deposits). By immunofluorescence microscopy, the immune complexes can be seen
Neutral antigens form as granular deposits along the basement membrane, in the mesangium or both.
mesangial deposits.
Nephritic syndrome Nephrotic syndrome

1. Proteinuria (1-2g/d) 1. Severe proteinuria (>3.5g/d)
2. Hematuria 2. Hypoalbuminemia (<3g/dl)
3. Hypertension 3. Edema
4. Azotemia, Oliguria 4. Hyperlipidemia, lipiduria
Dehydration is the commonest

cause of primary renal vein Thrombotic and thromboembolic complications are common in nephrotic syndrome
thrombosis in children. due to loss of anticoagulant factor (e.g. antithrombin III, protein C and S) combined with
increased platelet activation. Renal vein thrombosis is most often a consequence of this
hypercoagulative state specially in case of nephrotic syndrome associated with membranous
nephropathy in adults. There is also increased synthesis of fibrinogen in the liver.
Terminology in glomerular diseases

Each region of a renal biopsy is assessed separately. By light microscopy, glomeruli (at least
10 and ideally 20) are reviewed individually for discrete lesions.
440
According to percentage of glomeruli affected

Focal (Less than 50%)
Diffuse (>50%)
Injury in each glomerular tuft can be
Segmental (involving a portion of the tuft)
Global (involving most of the glomerulus)
According to characteristic of lesion
Proliferative when showing increased cellularity.
Endocapillary (Proliferation of cells in the capillary tuft)
Extracapillary (Extension of proliferation into Bowmans space)
Synechiae (Epithelial podocytes attach to Bowmans capsule)
Crescents (when fibrocellular/fibrin collections fill all or part of Bowmans space)
Sclerosis (Acellular, amorphous accumulations of proteinaceous material throughout the tuft with
loss of functional capillaries and normal mesangium)
Nephritic syndrome
Acute Proliferative (Post Streptococcal) Glomerulonephritis
It is seen 1-4 weeks after a skin or pharyngeal infection caused by group A hemolytic
New Data 9/e 910
streptococci (particularly strains 12, 4 and 1) usually in children. Activation of complement Streptococcal pyrogenic exotoxin
system results in consumption of complement proteins leading to transiently low complement B (Spe B) is the principal
levels (for 6-8 weeks). The antigen responsible for the development of this condition is a antigenic determinant in most
cytoplasmic antigen called endostreptosin and a cationic proteinase antigen called nephritis cases.

strain associated protein or NSAP Q.
Clinical features
Malaise, fever, nausea, oliguria and hematuria leading to smoky or cocoa colored urine, periorbital
edema and mild to moderate hypertension. Concept
Microscopic findings There is a transient reduction
Presence of hypercellular glomeruli due to leukocytic infiltration, proliferation of endothelial and in complement proteins in post
mesangial cells. Immunofluorescence microscopy shows the presence of IgG, IgM and C3 deposits streptococcal glomerulonephritis.
in the mesangium and along the basement membrane giving starry sky appearance. The complement levels return
to normal in 6-8 weeks. If the
Investigations levels persist to be reduced, it is
There is elevated levels of antistreptolysin O or ASO and anti DNAase antibodiesQ (indicative of suggestive of another disease.
streptococcal infection) and reduced levels of serum C3.
Management
It is done with fluid restriction. The majority of the patients recover and only a small fraction may
progress to chronic glomerulonephritis.
Rapidly Progressive (Crescentic) Glomerulonephritis

It is characterized by rapid and progressive loss of renal function associated with rapid
development of renal failure in weeks or months.
It is of the following three types with the common feature of severe glomerular injury.
Crescentic Glomerulonephritis
Type I RPGN (Anti-GBM Type II RPGN (Immune Type III RPGN (Pauci immune) Crescents are composed of
antibody) complex) parietal cells, leukocytes and
Idiopathic Idiopathic Idiopathic. macrophage
Goodpastures syndrome. Post infectious ANCA associated.
SLE, Henoch Schonlein Wegeners granulomatosis.
Purpura. Microscopic polyangitis.
Immunofluorescence finding Immunofluorescence finding Immunofluorescence finding
Linear GBM deposits of IgG Lumpy bumpy granular No immunoglobulin or
and C3 pattern of staining. complement deposits in GBM.
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The characteristic histologic feature is the presence of glomerular crescents (in > 50%
of glomeruli seen on biopsy) which are composed of proliferation of parietal cells, leukocytic
infiltration, and monocyte and macrophage movement in the urinary space. The fibrin is prominent
within the cellular layers of the crescents. Electron microscopy shows the presence of ruptures
in the glomerular basement membrane and subepithelial deposits.
Clinical features include hematuria with RBC casts in the urine, subnephrotic proteinuria,
hypertension and edema. The prognostic features are mentioned as follows:
Poor prognostic factors Good prognostic factors
Oliguria and azotemia at presentation Pauci immune RPGN has best prognosis
Prognosis in RPGN is related More than 80% circumferential Non- circumferential crescents in less than 50%
to the number of crescents as it crescents have poor response to therapy glomeruli have indolent course.
corelates with oliguria. Glomerular tuft necrosis, global glomerular Associated endocapillary proliferation is a good
sclerosis, gaps in Bowman capsule and prognostic factor
interstitial fibrosis
Nephrotic syndrome
Membranoproliferative (Mesangiocapillary) Glomerulonephritis
It is characterized by the presence of basement membrane alterations, proliferation of
glomerular cells (particularly in the mesangium) and leukocytic infiltration. These patients
may have a nephritic or nephrotic picture.
In type I MPGN, the immune complexes are present in the glomeruli and they cause activation of
both complement and alternate pathway.
In type II MPGN, the immune complexes present in the glomeruli cause activation of alternate
complement pathway. The serum of these patients contain C3 nephritic factor (C3NeF) which
causes stabilization of alternate C3 convertase thereby causing persistent degradation of C3 and
resulting hypocomplementenemia.
Light microscopy shows the lobular appearance of glomeruli which are hypercellular
(due to leukocytic infiltration and proliferation of capillary endothelial cells and mesangial
cells). The GBM is thickened and the synthesis of new basement membrane causes tram-
track or double contour appearance appreciated with silver or PAS stains.
Electron microscopically, type I MPGN is having the presence of subendothelial
electron dense deposits. Immunofluorescence studies demonstrate the deposition of C3,
IgG and early complement proteins (C1q and C4) in the glomeruli. In type II disease, there
Glomerular basement mem- is presence of dense deposits within the GBM, so it is also called as dense deposit disease.
brane tram-track or double
Immunofluorescence studies demonstrate the linear or granular deposition of C3 whereas
contour appearance in MPGN.
IgG and early complement proteins are absent. C3 may also be present in mesangial rings.
442
Clinical presentation of the patient is nephrotic syndrome with the nephritic component
of hematuria. There is high incidence of recurrence in transplant patients.
NPHS1 contains 1, which
Secondary MPGN is invariably type I but the exact mechanism is unknown. suggest first letter (means
N) that stands for Nephrin
P
Genetic Basis of roteinuria whereas NPHS2 contains 2,
which suggest second letter
NPHS1 gene encodes for the protein nephrin (component of podocyte foot process controlling (means P) that stands for
Podocin.
glomerular permeability) and its mutation causes a hereditary form of congenital nephrotic
syndrome (Finnish type). 1 comes first, so NPHS1
NPHS2 gene encodes for the protein podocin (also a component of podocyte foot process) and mutations cause congenital
nephrotic syndrome whereas
its mutation results in the development of steroid resistant nephrotic syndrome of childhood
onset or autosomal recessive focal segmental glomerulosclerosis (FSG). 2 comes later, so NPHS2
mutations cause acquired
A mutation in the gene encoding podocyte actin-binding protein (a-actinin 4) results in autosomal
disease (steroid resistant
dominant focal segmental glomerulosclerosis (FSG). nephrotic syndrome).
Mutations in gene encoding for TRPC6 is implicated in adult-onset FSGS
L IPOID NEPHROSIS (MINIMAL CHANGE DISEASE)

It is the commonest cause of nephrotic syndrome in the children (peak incidence in 2-6
years) characterized by the diffuse effacement of the foot processes of epithelial cells of the
glomeruli which appear normal by light microscopy. So, the other name of the disease is minimal
change disease.
There is absence of immune deposits but presence of visceral epithelial injury due to
abnormal secretion of lymphokines by T cells resulting in the loss of glomerular polyanions
responsible for low molecular weight proteinuria (selective proteinuria). Mutation of the

protein nephrin causes a hereditary form of congenital nephrotic syndrome (Finnish typeQ).
Microscopy
Light microscopy shows the normal glomeruli with lipid accumulation in proximal tubular cells (lipoid
nephrosis) whereas the electron microscope reveals the presence of effacement of foot processes
of podocytes.
The patients of lipoid nephrosis
Clinical features with lipoid nephrosis have an
There is massive proteinuria particularly loss of albumin (highly selective proteinuriaQ) in the absence excellent response to steroids
of hypertension or hematuria.
MEMBRANOUS GLOMERULOPATHY
It is a common cause of nephrotic syndrome in the adults characterized by the diffuse
thickening of the glomerular capillary wall and accumulation of electron dense,
immunoglobulin-containing deposits along the subepithelial side of the basement membrane.
Its causes include:
Idiopathic Secondary
Seen in most of the Drugs (penicillamine, captopril, NSAIDs)
patients (in 85% Malignancies like carcinoma of colon and lung, melanoma
patients) Infections like hepatitis B and C, syphilis, malaria, schistosomiasis
Systemic diseases like SLE, diabetes mellitus, thyroiditis
The disease has resemblance to the Heymann nephritis modelQ of glomerular injury
mediated by immune complex formation against a visceral epithelial antigen called Heymann
antigen or megalin. The immune complex mediated formation of membrane attack complex
C5b-C9 causes activation of glomerular epithelial and mesangial cells which release oxidants
and proteases that cause vessel wall injury and protein leakage.
Microscopy
Light microscopy shows the diffuse membrane-like thickening of the glomerular capillary wall.
Basement membrane projections as spikesQ are seen on silver stains. Electron microscopy reveals
effacement of the foot process of podocytes and presence of subepithelial deposits.
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Immunofluorescence
It demonstrates the linear and granular deposition of C3 and IgG.
Clinical presentation
It is nephrotic syndrome with the excretion of higher weight globulins along with albumin (non selective
proteinuria) which is poorly responsive to steroids.
FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSG)

This is now the commonest cause of nephrotic syndrome and is characterized by the presence
of focal (only some glomeruli are affected) and segmental (only a part of the glomerulus is
affected) sclerosis of the glomeruli.
Causes
Degeneration and
disruption of the visceral
focal 1. Idiopathic
epithelial cells is the hallmark
2. Secondary:
feature of focal segmental Associated with loss of renal tissue as unilateral renal agenesis or advanced
glomerulosclerosis. stages of reflux nephropathy or hypertensive nephropathy.
Associated with conditions like Sickle cell anemia, HIV infection, Heroin abuse,
Obesity.
Inherited due to mutations in genes like nephrin, podocin and a-actinin 4.
Degeneration and focal disruption of the visceral epithelial cells is the hallmark
feature of focal segmental glomerulosclerosis. The hyalinosis and sclerosis are due to protein
The NOS variant is the most entrapment. Mutation of the protein podocin and -actinin 4 results in the development of autosomal
common subtype and collapsing recessive and autosomal dominant forms of focal segmental glomerulosclerosis respectively.
FSGS has worst prognosis.
Microscopy
Light microscopy reveals the focal segmental sclerosis and hyalinization of the glomeruli. Electron
microscopy demonstrates the diffuse effacement of the podocytes, focal detachment of the epithelial
cells and increased mesangial matrix in the sclerotic areas. Five mutually exclusive variants of FSGS
may be distinguished by the pathological findings seen on renal biopsy
Concept Collapsing variant
HIVAN may present clinically Glomerular tip lesion variant

with nephrotic range proteinuria Cellular variant
but is NOT associated with Perihilar variant
Hypertension (HTN), edema
or hyperlipidemia. (Harrison Not otherwise specified variant (NOS)
17th/1796) Immunofluorescence
It demonstrates C3 and IgM deposits in the sclerotic areas and the mesangium.
It affects all age groups and is characterized by the clinical features of non-selective
proteinuria, reduction in GFR and presence of hypertension and poor response to
corticosteroids. There is high incidence of recurrence in transplant patients. Children have
better prognosis than adults.
c
Con ept
A variant of FSG is seen in HIV associated nephropathy called collapsing glomerulopathy.Q It
is characterized by the collapse and sclerosis of the entire glomerular tuft with the formation of
microcysts in the renal tubules. This should be visible in atleast one glomerulus. The glomerular
lesion is most specifically the result of podocyte expression of vpr and nef genes. Electron
microscopy demonstrates the presence of tubuloreticular inclusions in the endothelial cells which

are induced by interferon (similar lesions are also seen in SLE). It carries a poor prognosis.
Most common cause of collapsing glomerulopathy in children is cystinosis.
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IgA NEPHROPATHY (BERGER DISEASE)

This is the commonest glomerulonephritis in the world. Q It is characterized by the presence
of prominent IgA deposits in the mesangial regions and clinically by gross or microscopic
hematuria. It can occur either alone or secondary to liver or intestinal disease.
Pathogenesis: The patient usually develops an initial respiratory or gastrointestinal
infection resulting in increased synthesis of IgA1 which gets trapped in the mesangium.
Here, these immunoglobulins cause activation of alternate pathway of complement system
resulting in glomerular injury. Any liver disease causes reduced clearance of IgA whereas
intestinal disease causes increased mucosal production of IgA.
Microscopic examination reveals the mesangial widening and proliferation which on
immunofluorescence reveals the presence of the mesangial deposition of IgA usually with C3 and
properdin. Mesangioproliferative glomerulonephritis is seen more commonly than focal proliferative
and crescentic (least) glomerulonephritis.
Clinical features: Any age group of the patients (more in children and young adults) may
be affected who present with gross hematuria 3-4 days after an infection of the respiratory,
GI or urinary tract. Almost 1/3rd of the patients have microscopic hematuria. This hematuria
lasts for some days to subside and recur every few months. Recurrence of the disease in the
transplanted kidneys is frequent.
Alport Syndrome
This is a nephritic disorder characterized by the involvement of the triad of kidney, ear and
eye. There is a fundamental defect in the a5-chain of collagen type IV resulting in defective GBM

synthesis responsible for the involvement of the organs where this collagen is found.
Microscopically
Electron microscopy is diagnostic
Light microscopy glomerular involvement in the form of the presence of foam cells in the for Alport syndrome. It shows
interstitial cells. basket weave appearance of
Electron microscopy (Diagnostic for this disorderQ) the GBM.
It shows the presence of irregular foci of thickening and thinning in the GBM with splitting and
lamination of lamina densa called as basket weave appearance. Absence of a5 staining is
seen even on skin biopsy apart from glomerular and tubular basement membrane.
Clinical features
Males in the age group of 5-20 years are more frequently affected presenting with gross or
microscopic hematuria, nerve deafness and ocular features (posterior cataract, lens dislocation
and corneal dystrophy).
Thin basement membrane dis-
Thin Membrane Disease (Benign Familial Hematuria) ease is the most common cause
of benign familial hematuria.
This is a disease characterized by the presence of familial asymptomatic hematuria and
thinning of the basement membrane to 150-250 nm (normal GBM thickness is 300-400 nm).
There is a defect in the 3 and 4 chains of collagen type IV.
Goodpasture Syndrome
It is an autoimmune disorder (type II hypersensitivity reaction) having the presence of Uremia is the cause of death in
antibodies against non-collagenous domain of a3 chain of collagen IV causing destruction of Goodpasture Syndrome.
basement membrane in renal glomeruli and pulmonary alveoli.
The disease affects young men more commonly and is associated with smoking, viral
infections or exposure to hydrocarbon solvents (workers in dry cleaning industry).
Histologically, the alveoli show focal necrosis, intra-alveolar hemorrhage, presence
of hemosiderin laden macrophages and hypertrophy of type II Pneumocytes. The renal
involvement is in the form of either focal proliferative or crescentic glomerulonephritis.
Immunofluorescence studies show linear deposits of immunoglobulins along alveolar
septa and GBM.
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Clinical features: Interstitial hemorrhagic inflammation leads to the predominant symptoms

of hemoptysis and hematuria. Management is done by plasmapheresis.
Goodpasture syndrome Goodpasture disease
Concept

Affects young males
Lungs are affected
Affects elderly females
Lungs are not affected
Goodpasture Syndrome and
Goodpasture Disease are different!
Poor prognosis Good prognosis
SU MMARY OF GLOMERULAR DEPOSITS

Subepithelial Subendothelial Basement membrane Mesangial
*Acute GN (like PSGN) *MPGN (Type I) *MPGN (Type II) *IgA nephropathy
*Membranous GN *SLE *Membranous *HSP
*Heyman GN *Acute GN Glomerulopathy *Anti-GBM
*RPGN (some cases) diseases like
*MPGN (Type I) rarely RPGN and
Goodpasture
syndrome
Concept: Proliferative Glomerulonephritis

Glomerular lesions with increased cells in the tufts are often known as proliferative glomerulonephritis.
It is seen in the following conditions:
SLE (particularly class II, mesangial hypercellularity defined as >3 cells in mesangial regions)
HIV
Membranoproliferative glomerulonephritis
Neoplasia (particularly CLL and MALT lymphoma)
Post streptococcal glomerulonephritis.
h c l
C roni G omer ulonephritis
It is the final stage of many forms of glomerular disease and is characterized by progressive
renal failure, uremia and ultimately death.
Clinical features include anemia, anorexia, malaise, proteinuria, hypertension and
azotemia.
Grossly there is presence of small, shrunken kidneys. There is fine and symmetrical scars.
Microscopically, there is hyalinization of glomeruli, interstitial fibrosis, atrophy of tubules,
and a lymphocytic infiltrate. Management is done by dialysis and renal transplantation.
The urinalysis in Chronic Glo-
merulonephritis shows broad
waxy casts. Diabetic Nephropathy
It is a disorder characterized by hyperglycemia resulting in formation of advanced
glycosylation end products responsible for GBM thickening and increased mesangial
matrix. There is also concomitant presence of hemodynamic changes resulting in glomerular
Concept hypertrophy with increased glomerular filtration area. Both of these contribute to the
development of proteinuria.
In uncontrolled diabetes there is
presence of glucosuria resulting Morphological features include:
in glycogen accumulation in
Capillary Basement Membrane Thickening
Proximal Tubular cells (called as
Armani Ebstein cells). It is the earliest morphological abnormality which is seen in virtually all diabetics irrespective of
proteinuria. It is best detected with electron microscopy and is associated with thickening of the tubular
basement membrane.
Diffuse Mesangiosclerosis
There is diffuse increase in the mesangial matrix usually consisting of PAS positive material associated
with GBM thickening.
Nodular Glomerulosclerosis
Microalbuminuria means urinary
excretion of 30-300 mg of It is a highly specific lesion of diabetes and is also known as intercapillary glomerulosclerosis or
albumin per 24 hours. Kimmelsteil Wilson lesion. It consists of PAS positive nodules of matrix situated in the periphery of
the glomeruli. It is associated with prominent accumulation of hyaline material in capillary loops and
Bowmans capsule known as fibrin caps and capsular drops respectively.
446
There is also presence of hyalinizing arteriolar sclerosis (affects characteristically bothQ Concept
afferent and efferent arterioles), pyelonephritis and papillary necrosis.
Clinical features: The increased GFR is associated with microalbuminuria.It is very Proteinuria in most adults with
important clinical predictor of development of diabetic nephropathy later on. The protein glomerular disease is non-
selective, containing albumin
excretion then reaches subnephrotic proteinuria followed by nephrotic proteinuria. Patients and a mixture of other serum
of type I diabetes may also have hypertension which further aggravates the renal disease. proteins while in children with
minimal change disease; protein-
Differences between Benign nephrosclerosis and Malignant nephrosclerosis uria is selective and largely
composed of albumin.
Features Benign nephrosclerosis Malignant nephrosclerosis
Condition Benign hypertension, DM, elderly age Malignant hypertension
Gross appearance Leather grain appearance Flea bitten appearance due to
of kidneys tiny petechial hemorrhage
Small or reduced kidneys Variable size of the kidney
Microscopy 1. Narrowing of the lumens of arterioles (i) Hyperplastic arteriolitis (onion
caused by thickening and hyalinization of skinning) due to proliferation and
the walls (hyaline arteriolosclerosis) elongation of smooth muscle cells.
2. Fibroelastic hyperplasia of arteries and (ii) Necrotizing glomerulitis
arterioles (neutrophils infiltration and
thrombosed capillaries)
(iii) Fibrinoid necrosis of arterioles
(iv) Necrotizing arteriolitis
Activity of renin Normal ed

angiotensin system
Proteinuria Mild Marked

Sign of malignant Absent Present such as retinopathy
hypertension encephalopathy
Renal failure Rare More common
TUBULAR DISEASES
Acute Tubular Necrosis (Atn)/Acute Kidney Injury (AKI)
It is a disorder characterized by destruction of tubular epithelial cells resulting in
loss of renal function. Acute Kidney Injury is the most
It is the most common cause of acute renal failure (ARF). ARF is defined as rapid and common cause of acute renal
reversible deterioration of renal function leading to reduction of urine outflow to failure (ARF).
less than 400 ml per day within 24 hours.
ATN
Ischemic ATN Nephrotoxic ATN

Most common cause of ATNQ. Due to drugs (gentamicin, methicillin, radio
Due to decreased blood flow (in shock, contrast agents, organic solvents, ethylene
hemorrhage, hypotension or dehydration). glycol, phenol, pesticides, myoglobin).
Presence of focal tubular necrosis affecting Diffuse necrosis of proximal convoluted
proximal straight tubule and ascending limb tubular segments and ascending Henles
of loop of HenleQ. loopQ occur.
Specific features in certain poisonings

Poisoning Features in tubular cells
Mercuric chloride Large acidopathic inclusionsQ
Carbon tetrachloride Accumulation of neutral lipidsQ
Ethylene glycol Ballooning and vacuolar degeneration of PCT, Calcium oxalate crystals in
tubular lumenQ
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In both ischemic and nephrotoxic ATN, there is rupture of tubular basement

membranes (tubulorrhexis) and occlusions of lumen by a cast mostly seen in distal
convoluted tubule and collecting ducts.
Pathogenesis of ATN
l c l u s ATN
C ini a feat re of
1. Initiation phaseLasts for about 36 hours and is characterized by slight decline in
urine output with a rise in blood urea nitrogen (BUN).
2. Maintenance phaseOliguria, salt and water overload, hyperkalemia, metabolic
acidosis and rising BUN concentration.
3. Recovery phase Steady increase in urine volume (upto 3L/d), hypokalemia and
increased vulnerability to infections.
PYELONEPHRITIS
It is the infection involving the renal pelvis, tubules and interstitium. It can be of two types:

Acute Pyelonephritis is the renal lesion associated with bacterial urinary tract infection
(UTI)
Ascending infection is the
most common route of pyelo-

Chronic pyelonephritis, bacterial infection is associated with other factors including
nephritis caused by most bac- vesicoureteral reflex and obstruction.
teria except TB which involves
the kidney by hemtogenous E. coli is the commonest bacteria causing UTIQ followed by Proteus, Klebsiella, Enterobacter and
spread. Strep. fecalis etc.
There is initial colonization of the distal urethra followed by movement in to the
bladder due to frequent instrumentation or catheterization. Bladder dysfunction or outflow
obstruction causes stasis of urine promoting the bacterial multiplication. From the bladder,
WBC casts are suggestive of it is the incompetence of the vesicoureteral valve allowing retrograde urine flow in to the
renal involvement because casts ureters (vesicoureteral reflux). The infected urine enters the renal pelvis more commonly in
are formed only in tubules. the upper and lower poles of the kidney (intrarenal reflux).
Predisposing factors include Vesicourethral reflux, urethral instrumentation, diabetes
mellitus, pregnancy, urinary obstruction, benign prostatic hypertrophy and other renal
pathology.
Clinical features: Females more commonly affected than males (because of shorter
urethra, hormonal changes favoring bacterial adhesion to mucosa, absence of antibacterial
448
property as in prostatic fluid and urethral trauma during sexual intercourse). There is
presence of fever with chills, dysuria (painful micturition), increased frequency and urgency
along with costovertebral angle tenderness.
Urinalysis reveals presence of leukocytes particularly neutrophils (pyuria) and WBC
castsQ suggestive of renal involvement (because casts are formed only in tubules).
Complications include papillary necrosis (usually bilateral), pyonephrosis and
perinephric abscess.
P
Concept of Sterile yuria: Causes
Recently treated UTI Sterile pyuria is defined as

TB, fungal infection white cells in the urine in the
Perinephric abscess absence of significant bacterial
Chronic prostatitis growth.
Acute interstitial nephritis
Chronic interstitial nephritis (including analgesic nephropathy)
Chronic pyelonephritis
Differences between Chronic glomerulonephritis and Chronic pyelonephritis In chronic glomerulonephritis

Traits Chronic glomerulonephritis Chronic pyelonephritis kidneys are diffusely and sym-
metrically scarred whereas
Causes Various glomerulonephritis Reflux nephropathy or chronic obstructive
in chronic pyelonephritis;
pyelonephritis
the kidneys are irregularly and
Pathogenesis End stage glomerular disease Chronic tubulo-interstitial inflammation and asymmetrically scarred.

due to specific glomerulone- scarring associated with renal disorder
phritis
Gross appearance of Diffusely, granular, cortical sur- Depressed area on dilated and blunted
surface faces calyx
Scar Fine and Symmetrical Coarse and Asymmetrical
Glomeruli Reduced in number with oblit- Normal; may show periglomerular fibrosis
eration
Tubules Atrophied Atrophy in some and hypertrophy in others
filled with colloid casts (thyroidisation)
Renal pelvis and calyx Normal Dilated
Interstitial and periglo- Mild More marked
merular fibrosis
Clinical features Insidious in onset May be asymptomatic or present with back
Proteinuria, azotemia, hyper- pain, fever, polyuria, nocturia, pyuria, bac-
tension, edema teriuria with gradual onset of hypertension
Urinary frequency is often the
and renal insufficiency earliest symptom and may be
the only manifestation of renal
Xanthogranulomatous pyelonephritis (X PN) tuberculosis
Unusual variant of chronic pyelonephritis. Most cases occur in the setting of obstruction due to infected
renal stones.
Grossly
Yellow, lobulated masses diffusely replace the renal architecture.
Microscopically
There is massive destruction of the kidney due to granulomatous tissue containing lipid-laden
macrophages; the appearance may be confused with renal malignancy.
Clinical features
It most often occurs in middle-aged women with a history of recurrent urinary tract infections.
Typical presenting symptoms include flank pain, fever, malaise, anorexia and weight loss.
A unilateral renal mass can usually be palpated on physical examination.
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Diagnosis
Examination of the urine confirms the presence of urinary tract infection. Urine culture typically
demonstrates Enterobacteriaceae. The most common organisms associated with XPN are E. coli,
Proteus mirabilis, Pseudomonas, Streptococcus faecalis and Klebsiella.
Renal Stones/Urinary Calculi

In the urinary tract, the most common site of origin of stone is the kidney. Males between the age
group of 20-30 years are most commonly affected. Renal stones are formed either due to
Patients with calcium oxalate supersaturation of urine (constituent concentration exceeding the solubility) or deficiency
stone are advised to maintain a of crystal formation inhibitors like pyrophosphate, diphosphonate, citrate, osteopontin and
low sodium, low protein but nephrocalcin.
normal calcium diet to reduce
the recurrence renal stone. Renal stones
Calcium oxalate Uric acid Magnesium Cystine

ammonium phosphate
Struvite (triple) stone: Coffin lid Most common Seen with hyper- Also called stru- Due to genetic
shapedQ. stoneQ. uricemia (gout, leu- vite stones or defect in the ab-
Calcium oxalate: Needle shaped/ Idiopathic hyper- kemias)Q. triple stonesQ. sorption of cys-
square envelope shapeQ calciuria is the tine resulting in
commonest causeQ. cystinuriaQ.
Seen in acidic urine. Seen in acidic urine Formed in alkaline Formed in acid-
Also associated (pH < 5.5)Q. urine particularty in ic urine
with hypocitraturiaQ. infection with pro-
teusQ.
Cystine stone: Hexagonal Q

Radiopaque stoneQ. Radiolucent stoneQ. Occupy large part Change color
from initial yel-
of renal pelvis, so,
Uric acid: diamond / barrel shapeQ called as staghom low to green on
calculiQ. air exposureQ.
Note: Uncommon renal stones can be composed of xanthine (due to xanthine oxidase deficiency),
indinavir (in AIDS patients taking this drug) or triamterene (Patients on this antihypertensive medica-
Concept tion). All these are radiolucent stonesQ.
Stones are usually unilateral (80% of patients) and are deposited in renal pelvis and
Reasons why low calcium
bladder. If the developing stone takes the shape of the pelvicalyceal system, it is called
is avoided in patients with
calcium oxalate are: staghorn calculi.
Clinical symptoms include hematuria, urinary obstruction, renal colic (if they pass
Low calcium diet increases
into the ureters) and increased chances of infection. Most of the renal stones are managed
risk of stone formation
by reducing calcium in the surgically.
intestine to bind with oxalate
thereby increasing oxalate U RINARY CASTS
levels in the urine.
Hyaline casts
Low calcium increases the
risk of reduced bone density. This is a normal constituent of urine and has no attached significance.
Tamm Horsfall protein is a protein secreted by epithelial cells of loop of HenleQ.
This protein may be exerted as Hyaline cast.
May be seen in concentrated urine, febrile disease, after heavy exercise
RBC cast
Is suggestive of glomerular injury.Q
White cell casts
Are suggestive of interstitial injury and may be seen in interstitial nephritis. WBC cast with bacteria
indicate Pyelonephritis.Q
Broad granular casts
Arise in the dilated tubules of enlarged nephrons that have undergone compensatory hypertrophy in
response to reduced renal mass i.e. chronic renal failure.Q
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Pigmented muddy brown granular casts

Are suggestive of ischemic or nephrotoxic injury i.e. Tubular NecrosisQ.
Lipid cast
Seen when there is fatty degeneration of the tubular epithelium.
Also seen in nephrotic syndrome, lupus and toxic renal poisoningQ.
RENAL TUMORS
Benign Tumors
Angiomyolipoma It is a hamartoma composed of fat, smooth muscle and blood

vessels and is associated with tuberous sclerosis.
Oncocytoma- Tumor arising from intercalated cells of collecting ducts having large,
eosinophilic cells which have numerous mitochondria. The cells have expression of
carbonic anhydrase C and band 3 protein.
T N
Wilms umor ( ephroblastoma)
Wilms tumor is the most common primary renal tumor of childhood in USA. This tumors
peak age is 2-5years. The risk of Wilms tumor is increased in association with at least three
recognizable groups of congenital malformations:
WAGR syndrome
It is characterized by aniridia, genital anomalies, and mental retardation and a 33% chance of

developing Wilms tumor. Patients with WAGR syndrome carry constitutional (germline) deletions of
two genes WT1 and PAX6 both located at chromosome 11p13Q.
Denys-Drash syndrome
It is characterized by gonadal dysgenesis (male pseudohermaphroditism) and early-onset nephropathy

leading to renal failure. The characteristic glomerular lesion in these patients is a diffuse mesangial
sclerosis. These patients also have germline abnormalities in WT1. In addition to Wilms tumors these
individuals are also at increased risk for developing germ-cell tumors called gonadoblastomas.
Beckwith-Wiedemann syndrome Concept
It characterized by enlargement of body organs (organomegaly), macroglossia, hemihypertrophy, Anaplasia is an indicator of
omphalocele and abnormal large cells in adrenal cortex (adrenal cytomegaly). The genetic locus adverse prognosis because
involved in these patients is in band p15.5 of chromosome 11 called WT2. In addition to Wilms it is associated with p53 gene
tumors patients with Beckwith-Wiedemann syndrome are also at increased risk for developing mutation and resistance to anti-
hepatoblastoma, adrenocortical tumors, rhabdomyosarcomas and pancreatic tumors. cancer drugs.
Morphology
Grossly, Wilms tumor tends to present as a large, solitary, well-circumscribed mass and on cut
section, the tumor is soft, homogeneous, and tan to grey with occasional foci of hemorrhage,
cyst formation, and necrosis.
Microscopically, Wilms tumors are characterized by the classic triphasic combination of blastemal,
stromal, and epithelial cell types (immature glomeruli and tubules) seen in majority of lesions.
The tumor usually presents as a large abdominal mass, which may extend across the
midline and down into the pelvis. The patient may also present with fever and abdominal
pain, with hematuria, or rarely, with intestinal obstruction as a result of pressure from the
tumor.
The prognosis for Wilms tumor is generally very good, and excellent results are obtained
with a combination of nephrectomy and chemotherapy.
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Renal Cell Carcinoma (Hypernephroma/Grawitz Tumor)

It is the most common malignant cancer of the kidney affecting the poles of the kidney
Triad of VHL syndrome =
Cerebellar hemangioblastoma
(more commonly upper pole). Males are more frequently affected (M:F ratio is 2 to 3:1) in the
+ Bilateral renal cell cancer + age group of 6-7th decade.
Retinal angiomatosis.
Risk factors
Non genetic factors

Tobacco (most important risk factor)Q
HypertensionQ
ObesityQ
Tuberous sclerosisQ
Estrogen therapyQ
Asbestos exposureQ
Chronic renal failure and acquired cystic diseaseQ
Von Hippel Lindau syndrome
Genetic factors
Trisomy 7 shows increased expression of MET which is a proto-oncogene having tyrosine kinase
receptor activity thereby resulting in development of papillary type of renal cancer.
t(X; 1) causes translocation of PRCC gene to fuse with TFE-3 gene on X chromosome and fusion
gene increases the risk of papillary renal cell carcinoma (PRCC) particularly in children.
Clinical features include the classical triadQ of hematuria (earliest and most common
Sarcomatoid change in any symptomQ; usually intermittent), palpable mass and flank pain.
renal cancer causes worsening Paraneoplastic syndromes associated with RCC
of prognosis.
Elevation of erythrocyte sedimentation rate
Polycythemia (Due to erythropoietin)
Stauffer syndrome (non metastatic hepatic dysfunction)
Papillary cancer is associated
Hypertension (Due to renin)
with a strong tendency to
invade the renal vein and Anemia and fever
grow as solid column of cells. Hypercalcemia (Due to PTH related peptide)
The tumor may even extend to
inferior vena cava and right side Cushing syndrome (Due to corticosteroid synthesis)
of the heart. Feminization or masculinization (Due to gonadotropin release)
May also cause amyloidosis, eosinophilia or leukemoid reactionQ
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Metastasis is usually by the hemotogenous route and the organs affected include lungsQ
(most common), bones, regional lymph nodes, liver, adrenals and brain.
Management: Partial/total nephrectomy is the treatment of choice.
U RINARY BLADDER
It is the organ (lined by transitional epithelium) responsible for the collection of urine formed
by the kidney and its removal by intermittent voiding.
Inflammation of urinary bladder is called cystitis and it is more common in females as
compared to males. It is usually due to:

1. Bacterial cause: E.coli, Proteus, Klebsiella, Mycobacterium tuberculosis

2. Fungal cause: Candida albicans, seen with immunosuppression

3. Hemorrhagic cystitis: Due to cytotoxic antitumor drugs like cyclophosphamide and
Adenovirus.

4. Radiation cystitis: Due to radiation exposure.
Clinical features:

1. Frequency Requirement of urination every 15-20 minutes

2. Suprapubic pain Pain in anatomical location of the bladder

3. Dysuria - Painful or burning sensation or urination
This triad may be associated with fever and malaise.
Special cystitis

Hunner ulcer Malacoplakia
Painful chronic cystitis associated Chronic bacterial cystitis having presence of soft,
with hemorrhagic inflammation yellow mucosal plaques.
and fibrosis of the layers of bladder Most commonly associated with E. coli or uncommonly
wallQ. proteus.
Seen frequently in females. Microscopically, there is presence of infiltration with
Usually idiopathic but may be lymphocytes and abundant epithelioid histiocytes (Von
associated with SLE. Hansemann Histiocytes) having PAS positive granules
Mast cellsQ are characteristically and characteristics 3-10m rounded intracytoplasmic
present. inclusions (called Michaelis-Gutmann bodies)Q that
contain iron (demonstrated by prussian blue stain) and
calcium (demonstrated by Von Kossa stain).
Similar lesions are also seen in colon, lungs, bones,
kidneys and prostate etc.
y l
Urinar B adder eop a m N ls s
The urinary bladder cancers usually are of epithelial origin. The commonest histological
variant is the transitional cell tumors (urothelial tumors).
Risk factors of urinary bladder cancers
Transitional cell cancers Squamous cell cancer Adenocarcinoma

Cigarette smoking .
Q
Infection with Schistosoma Usually arises from
Industrial exposure to arylamines hematobiumQ. urachal remnantsQ
as 2-napthylamine, benzidine, Chronic bladder infection or in association with
aniline in textile workers, dye and irradiationQ. intestinal metaplasiaQ.
workers and leather workersQ. Diverticula in the bladderQ.
Pelvic irradiation for other pelvic
cancerQ.
Long term use of analgesics.
Exposure to drugs like cyclo-
phosphamideQ.
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Genetic risk factors include:

9 p gene deletions- Present in superficial papillary tumors.
17p gene deletion- Invasive urothelial cancers.
9p and 9q have tumor suppressor gene, 17 p has the location of p53 (again tumor
Involvement of the detrusor suppressor gene). So, any deletion of these genes increases the risk of bladder cancers.
muscle is associated with the
worst prognosis. l cl
C ini a feat re u s
Painless hematuriaQ (most common symptom), features of bladder irritability (frequency,
urgency and dysuria) or uncommonly, hydronephrosis and pyelonephritis may also be seen.
The prognostic markers include grade of tumor, presence of lamina propria invasion and
associated carcinoma in situ.
The worst prognosis is associated with tumor invading the muscularis mucosa (detrusor
muscle)Q.
Investigations:
Cystoscopy and biopsy (Best investigation)
Q
Urine cytology of urine markers like telomerase, human complement factor H

related protein, mucins, CEA, hyaluronic acid, hyaluronidase, fibrin- fibrinogen
degradation products, nuclear matrix proteins and DNA content.
ISUP (International Society of Urological Pathology) Classification of Transitional Cell Tumors

Urothelial Papilloma Seen in young patients, finger like papillae covered with normal looking
urothelium.
Urothelial neoplasm of low malignant potential Similar to papilloma but with thicker urothelium
with diffuse nuclear enlargement.
Papillary urothelial carcinoma, low grade Almost always papillary having limited cell/nuclear
pleomorphism and limited chromosomal/gene abnormalities.
Papillary urothelial carcinoma; high grade May be papillary/nodular or both having
considerable anaplasia and high frequency of chromosomal/gene abnormalities.
Management:
1. Intravesical BCG Q
Presence of lamina propria invasion

Carcinoma in situ (CIS)
2. Radical cystectomy
CIS refractory to BCG
Invasion of muscularis propria
CIS extending to prostatic urethra or down
3. Chemotherapy (Mitomycin, thiotepa etc.)
Advanced bladder cancer
Information about commonest mesenchymal tumors of urinary bladder:

The most common benign tumor is LeiomyomaQ
The most common sarcoma in infants/children is embryonal rhabdomyosarcomaQ
The most common sarcoma in adults is LeiomyosarcomaQ.
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yg l s c s lycystic kidney disease 8. A 42-year-old man Kumaran is having flank pain and
Kidne : enera a pe t , po
hypertension. He has increased blood urea nitrogen
1. A 28 year old man has lenticonus and end stage renal and creatinine with hematuria. Ultrasound studies
disease now. His maternal uncle also died of the same demonstrate markedly enlarged kidneys with irregular
illness. What is the most likely diagnosis? margins and many fluid-filled spaces of different sizes.
(a) Autosomal dominant polycystic kidney disease Excessive secretion of which of the following hormones
(b) Autosomal recessive polycystic kidney disease would be most likely responsible for the patients
(c) Oxalosis (AIIMS Nov 2012) hypertension?
(d) Alport syndrome
(a) ACTH (b) Cortisol
2. Which one of the following is not associated with adult
(c) Parathormone (d) Renin
polycystic kidney disease? (DPG 2011)
(a) Autosomal dominant inheritance
(b) Mutations involving gene affecting cell-cell matrix 8.1. Podocytes are seen in:
interactions (a) Proximal convoluted tubule
(c) Intracranial berry aneurysm may be present (b) Distal convoluted tubule
(d) Tricuspid valve prolapse (c) Collecting tubule of the kidney

3. Which of the following is associated with adult (d) Bowmans capsule
polycystic kidney disease? 8.2. Adult polycystic kidney disease is inherited by:
(a) Berry aneurysms of Circle of Willis
(a) Autosomal dominant
(b) Saccular aneurysms of aorta
(c) Fusiform aneurysms of aorta
(c) X-linked
(d) Leutic aneurysms
(d) Mitochondrial
4. True about adult polycystic kidney disease is all, 8.3. Major cause of death in End Stage Renal Disease
patients on display is which one of the following?
(a) Autosomal dominant inheritance
(b) Hypertension is rare (a) Cardiovascular disease
(c) Can be associated with cysts in liver, lungs and (b) Infections
pancreas (c) Uremia
(d) Pyelonephritis is common (d) Respiratory Failure
5. True about autosomal dominant type of APKD: 8.4. What is oliguria

(a) Small kidney (PGI June 2004) (a) Excretion of less than 300 ml in 24 hrs
(b) Bilateral medullary cysts (b) Excretion of less than 500 ml in 24 hrs
(c) Mutation of polycystin 1and 2 gene (c) Excretion of less than 300 ml in 12 hrs
(d) Renal transplantation is contraindicated (d) Excretion of less than 100 ml in 24 hrs
(e) Pathogenesis starts early and renal failure seen in 8.5. What is the minimum number of red blood cells per
middle life. microliter of urine required for diagnosis of hematuria?
6. Chromosomes involved in adult polycystic kidney (a) 3
disease (APKD) are: (PGI June 01) (b) 5
(a) 6 and 11 (b) 4 and 16 (c) 8
(c) 7 and 17 (d) 4 and 12 (d) 10
(e) 4 and 17
8.6. Polycystic kidney may be associated with cysts in all
7. Acquired cystic disease of kidney is associated with: the sites, except:
(a) Xanthogranulomatous pyelonephritis (UP 2004) (a) Lung
(b) Dialysis (b) Liver
(c) Renal stones (c) Pancreas
(d) Renal dysplasia (d) Brain
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glomerular disease: nephritic syndrome, 16. Pathological changes of diabetic nephropathy are all
nephrotic syndrome, glomerulonephritis except: (DPG 2011)
(a) Fibrin caps and capsular drops
9. In a specimen of kidney, fibrinoid necrosis is seen and (b) Kimmelstein-Wilson lesion
onion peel appearance is also present. Most probable (c) Basement membrane thickening
pathology is: (AIIMS Nov 2012) (d) Focal glomerular sclerosis
(a) Hyaline degeneration 17. What is the cause of hypercoagulation in nephrotic
(b) Hyperplastic arteriosclerosis syndrome: (AI 2010)
(c) Glomerulosclerosis (a) Loss of antithrombin III (AT III)
(d) Fibrillary glomerulonephritis (b) Decreased fibrinogen
10. Which of the following is the diagnosis for a condition (c) Decreased metabolism of vitamin K
having mutation in COL4A5 chain? (AIIMS Nov 2012) (d) Increase in Protein C
(a) Alports syndrome 18. Finnish type of nephrotic syndrome is associated with:
(b) Good pastures syndrome
(a) Nephrin (AI 09, 06)
(c) Thin membrane disease
(b) Podocin
(d) Nodular glomerulosclerosis
(c) Alpha actinin
11. The most common gene defect in idiopathic steroid (d) CD2 activated protein
resistance nephrotic syndrome (AIIMS Nov 2011)
(a) ACE
19. Pauci-immune crescentic glomerulonephritis is
associated with: (AI 2009)
(b) NPHS 2
(a) Microscopic polyangiitis
(c) HOX11
(b) SLE
(d) PAX
(c) H S Purpura
12. A person with radiologically confirmed reflux (d) PAN
nephropathy develops nephritic range proteinuria.

Which of the following would be the most likely
20. Most common mutation seen in congenital nephrotic
syndrome is: (AI 2008)

histological finding in this patient? (AIIMS Nov 2011)
(a) Nephrin

(a) Focal segmental glomerulosclerosis
(b) Podocin

(b) Nodular glomerulosclerosis
(c) a 4 actinin

(c) Membranous glomerulopathy
(d) Megalin

(d) Proliferative glomerulonephritis with crescents
13. A 7 yrs old girl is brought with complaints of
21. Which of these does not cause crescentic glomerulone-
phritis? (AI 2008)
generalised swelling of the body. Urinary examination
(a) Rapidly progressive glomerulonephritis
reveals grade 3 proteinuria and the presence of hyaline
(b) Alport syndrome
and fatty casts. She has no history of hematuria. Which
of the following statements about her condition is true? (c) Goodpastures syndrome
(AIIMS May 2011) (d) Henoch-Schnlein purpura

(a) IgA nephropathy is likely diagnosis 22. All are non-proliferative glomerulonephritis, except:

(b) Her C3 levels will be low (a) Membranous glomerulonephritis (AI 2008)

(c) No IgG deposits or C3 deposition on renal biopsy (b) Mesangiocapillary glomerulonephritis

(d) Alport syndrome is likely diagnosis (c) Diabetic glomerulosclerosis
14. The pathological feature in Wegeners granulomatosis (d) Amyloidosis
on renal biopsy is (AIIMS Nov 2010) 23. Kidney biopsy from a child with hemolytic uremic
(a) Nodular glomerulosclerosis syndrome characteristically most likely presents
(b) Focal necrotizing glomerulonephritis features of: (AI 2005)
(c) Granulomas in the vascular wall (a) Thrombotic microangiopathy
(d) Granuloma of parenchyma of kidney (b) Proliferative glomerulonephritis
15. Fibronectin nephropathy has all of the following (c) Focal segmental glomerulosclerosis
features except (AIIMS Nov 2010) (d) Minimal change disease
(a) Autosomal recessive inheritance 24. Serum C3 is persistently low in the following except:
(b) Associated with mesangial expansion (a) Post streptococcal glomerulonephritis
(c) Glomeruli do not stain for immunoglobulin or com- (b) Membranoproliferative glomerulonephritis
plement (c) Lupus nephritis (AI 04, DNB 07)
(d) PAS- positive amyloid negative deposits. (d) Glomerulonephritis related to bacterial endocarditis
456
25. All of the following are associated with low complement (c) Parietal epithelial proliferation
levels except: (AI 2004) (d) Hypertrophy and necrosis of visceral epithelium
(a) Lupus nephritis
(b) Mesangiocapillary glomerulonephritis
34. The most common gene defect in idiopathic steroid
resistant nephrotic syndrome (AIIMS May 2007)
(c) Diarrhea-associated hemolytic uremic syndrome (a) ACE
(d) Post-infections glomerulonephritis (b) NPHS 2
26. All of the following are associated with low C3 level (c) HOX 11
except: (AI 2003) (d) PAX
(a) Post streptococcal glomerulonephritis 35. HIV associated nephropathy is a type of:
(b) Membranoproliferative Glomerulonephritis (a) Membranous glomerulonephritis (AIIMS Nov 2004)
(c) Goodpastures disease (b) Immunotaetoid glomerulopathy
(d) Systemic lupus erythematosus (c) Collapsing glomerulopathy
27. Which of the following is not true about Bergers (d) Fibrillary glomerulopathy
disease? (AI 2003) 36. Mesangial deposits of monoclonal kappa/Lambda light
(a) The pathological changes are proliferative and usu- chains in indicative of (AIIMS May 2004)
ally confined to mesangial cells; usually focal and (a) Mesangioproliferative glomerulonephritis
segmental (b) Focal and segmental glomerulosclerosis
(b) Hematuria may be gross or microscopic (c) Kimmelstiel-Wilson lesions
(c) On immunofluorescence deposits contain with IgA (d) Amyloidosis
and IgG
(d) Absence of associated proteinuria is pathognomic
37. In renal disease, Albumin is first to appear in urine
because (AIIMS May 2004)
28. Crescent formation is characteristic of which of the (a) Of its high concentration in plasma
following glomerular disease: (AI 2002) (b) Has molecular weight slightly greater than the mol-
(a) Minimal change disease ecules normally getting filtered

(b) Rapidly progressive glomerulonephritis (c) High Albumin Globulin ratio
(d) Tubular epithelial cells are sensitive to albumin
(c) Focal and segmental glomerulosclerosis
(d) Rapidly non progressive glomerulonephritis 38. A 7 year old boy presented with generalized edema.
Urine examination revealed marked albuminuria. Serum
29. In Wegeners granulomatosis, kidney has which of the biochemical examinations showed hypoalbuminemia
following lesions? (AIIMS Nov 2009) with hyperlipidemia. Kidney biopsy was undertaken.
(a) Glomerular granuloma On light microscopic examination, the kidney appeared
(b) Interstitial granuloma normal. Electron microscopic examination is most
(c) Crescentic glomerulonephritis likely to reveal: (AIIMS Nov 2003)
(d) Glomerulosclerosis (a) Fusion of foot processes of the glomerular epithelial
30. The Electron Microscopy is virtually diagnostic in renal (b)
cells
Rarefaction of glomerular basement membrane
biopsy study of: (AIIMS May 2008)
(a) Goodpastures syndrome (c) Deposition of electron dense material in the basement
(b) Churg-Strauss syndrome membrane
(d) Thin basement membrane
(c) Alport syndrome
(d) Wegners granulomatosis 39. The prognosis of rapidly proliferating glomerulo
nephritis (Crescentic GN) depends upon
31. Which type of FSGS has worst prognosis? (a) Number of crescents (AIIMS Nov 2001)
(a) Tip variant (AIIMS May 2008)
(b) Size of crescents
(b) Collapsing
(c) Shape of crescents
(c) NOS
(d) Cellularity of crescents
(d) Perihilar
32. Steroid resistant nephrotic syndrome is caused due to 40. Trueis:
about light microscopy in minimal change disease
(AIIMS Nov 2001)
mutation in the gene encoding for? (a) Loss of foot process seen
(a) Nephrin (AIIMS May 2008, Nov 2006) (b) Anti-GBM antibodies are seen
(b) Alpha-actinin-4 (c) IgA deposits seen
(c) Podocin (d) No change seen
(d) Transient Receptor Potential 6
33. Which of the following is a feature of Collapsing 41. A(minimal child had hematuria and nephrotic syndrome
change disease) was diagnosed. True about it
glomerulopathy? (AIIMS Nov 07) is: (AIIMS Nov 2001)
(a) Tuft necrosis (a) A type of focal segmental GN
(b) Mesangiolysis (b) IgA deposition on basement membrane
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(c) Foot process of glomerular membrane normal
(c) Electron dense deposits in mesangium

(d) Glomerular function is lost due to loss of polyanionic
(d) Subepithelial aspect of basement membrane have
charge on both sites of glomerular foot process deposits
42. Mutation in alpha 5 chain of collagen type IV is seen in:
(e) Antigen against bacterial and viral proteins
(a) Alport syndrome (AIIMS Nov 2006) 50. Malignant hypertension is associated with:
(b) Thin membrane disease (a) RPGN (PGI Dec 2004)
(c) Nodular glomerulosclerosis (b) Malignant nephrosclerosis
(d) Good pasture syndrome (c) Membranous GN
(d) IgA nephropathy
43. Persistent low C3 complement level is not found in: (e) Acute pyelonephritis
(AIIMS Nov 2006)
(a) Post streptococcal glomerulonephritis 51. Histology of Alport syndrome: (PGI June 2005)
(b) Mesangiocapillary glomerulonephritis (a) Foamy cells in interstitium
(c) Cryoglobulinemia (b) Foamy cells in tubular epithelial cells
(d) SLE (c) Thickening of GBM > 100 nm
(d) Thinning of GBM < 100 nm
44. Low complement levels are seen in: (e) Intimal proliferation.
(a) PSGN (PGI Dec 2006)
(b) MPGN 52. RPGN is caused by: (PGI June 2005)
(c) Goodpastures syndrome (a) FSGS
(d) Wegeners granulomatosis (b) Wegeners granulomatosis
(e) Infective endocarditis. (c) Goodpastures syndrome
(d) PAN
45. Subepithelial deposits in kidney are seen in: (e) Microscopic polyangitis
(a) MPGN-1
(PGI June 2001)

(b) Goodpastures syndrome 53. Post streptococcal glomerulonephritis is associated
(c) PSGN with: (PGI Dec 2006)
(d) Membranous GN (a) Subepithelial deposit
(e) RPGN (b) Nephritis along with acute renal failure
(c) Low complement levels
46. Nephrotic syndrome is characterized by: (d) HTN and proteinuria
(a) Proteinuria (PGI Dec 2002) (e) Normal complement levels
(b) Hyperlipidemia
(c) Edema 54. Pauci-immune glomerulonephritis is seen in:
(d) Haematuria (a) RPGN (Delhi PG-2007)
(e) Lipiduria (b) IgA nephropathy
(c) Microscopic polyangitis
47. In glomerular disease which of the following is mainly (d) FSGS
excreted in urine: (PGI Dec 2003)
(a) Albumin 55. Kimmelstiel Wilson lesions are characteristic of:
(b) Globulin (a) Diabetic Nephropathy (Delhi PG-2007)
(c) Light chain (b) Analgesic nephropathy
(d) Heavy chain (c) RPGN
(e) Tamm-Horsfall protein (d) Post streptococcal glomerulonephritis
48. Which of the following is included in definition of 56. Anti-glomerular basement membrane nephritis is seen
Nephrotic syndrome? (PGI June 2004) in: (Delhi PG-2005)
(a) Microalbuminuria (a) Goodpastures syndrome
(b) Massive Proteinuria (b) SLE associated glomerulopathy
(c) Microscopic hematuria (c) MGN
(d) Edema (d) MPGN
(e) Hyperlipidemia. 57. Kimmelstiel Wilson disease is diagnostic of:
(a) Diabetic Glomerulosclerosis (Delhi PG-2005)
49. True about Heymann rat glomerulonephritis is: (b) Benign Hypertension
(a) Heymann antigen is called megalin (PGI Dec 2004)
(c) Malignant Hypertension
(b) Electron dense deposits in subendothelial space
(d) Amyloidosis
458
58. The following is not a feature of acute post streptococcal

(b) Hemorrhage inflammation
glomerulonephritis: (Karnataka 2007)
(c) Anti-GBM antibody
(a) Normal C 3

(d) Diffuse alveolar involvement
(b) Hypertension 68. All of the following are True about minimal change
(c) Elevated blood urea and creatinine nephrotic disease except: (PGI-1999)
(d) Increased ASO titre (a) Respond to steroids (UP 2004)
59. Visceral leishmaniasis causes (Karnataka 2005) (b) Selective proteinuria
(a) Membranous glomerulonephritis (c) IgG deposition in mesangium
(d) Common in the age group of 2-9 years
(b) Mesangioproliferative glomerulonephritis
(c) Focal segmental glomerulonephritis 69. IgA depositions in mesangial cells are seen in
(d) Rapidly progressive glomerulonephritis (a) Goodpastures syndrome (UP 2005)
(b) Berger disease
60. Histological hallmark of rapidly progressive (c) Cresenteric glomerulonephritis
glomerulonephritis is (Karnataka 2004) (d) Alport syndrome
(a) Crescents in most of the glomeruli
(b) Loss of foot processes of epithelial cells 70. All are causes of rapidly progressive glomerulonephritis
except: (UP 2002, 2007)
(c) Subendothelial electron dense deposits
(a) SLE
(d) The thickening of glomerular capillary wall
(b) Polyarteritis nodosa
61. ANCA is most specific and sensitive marker for (c) Post streptococcal GN
(UP 2000) (d) Rheumatoid arthritis
(a) Idiopathic cresenteric glomerulonephritis 71. The cause of edema in nephritic syndrome is:
(b) Post streptococcal glomerulonephritis (a) Decrease in plasma protein concentration (UP 2007)
(c) Membranoproliferative glomerulonephritis (b) Increase in plasma protein concentration
(d) Focal segmental glomerulosclerosis (c) Reduced plasma osmotic pressure

(d) Sodium and water retention
62. True about post streptococcal glomerulonephritis is:
(a) Linear deposition (UP 2001) 72. Hall mark of the IgA nephropathy is: (UP 2007)
(b) Diffuse involvement (a) Oedema
(c) Tram track appearance (b) Hematuria
(d) Global sclerosis (c) Hypertension
(d) Proteinuria
63. Most common in diabetic nephropathy is: 73. Electron dense deposits in the region of hyalinosis and
(a) Diffuse glomerulosclerosis (UP 2002)
sclerosis, with diffuse loss of foot processes, seen in
(b) Diffuse cortical sclerosis electron microscopy are features of: (UP 2007)
(c) Nodular glomerulosclerosis (a) Minimal change disease
(d) Renal atherosclerosis (b) Membranous glomerulonephritis
64. Steroid responsive glomerulonephritis are all except: (c) Membranoproliferative GN
(a) Post streptococcal glomerulonephritis (UP 2002) (d) Focal segmental glomerulosclerosis
(b) Minimal change disease 74. In hemolytic uremic syndrome there is:
(c) Membranoproliferative glomerulonephritis (a) Thrombocytopenia + Renal failure (AP 2000)
(d) Focal segmental glomerulosclerosis (b) Normal coagulative profile
(c) Microangiopathic hemolytic anemia
65. All conditions lead to CRF except: (UP 2002) (d) All of the above
(a) Post streptococcal GN
(b) Membranoproliferative GN 75. Subepithelial deposits with M spike is seen in:
(c) Minimal change GN (a) Membranous glomerulonephritis (AP 2001)
(d) Focal glomerulosclerosis (b) Membranoproliferative glomerulonephritis
(c) Minimal change disease
66. Most characteristic finding in diabetic nephropathy is: (d) RPGN
(a) Diffuse glomerulosclerosis (UP-2002, 2004)
76. Crescentic glomerulonephritis with pauci-immune
glomerulonephritis is associated with:
(c) Diffuse cortical sclerosis
(d) Renal atherosclerosis
(Mahe 2001, TN 1990, 1991) (AP 2002)
(a) Post infectious glomerulonephritis
67. All of the following are seen in Goodpastures syndrome (b) Goodpastures syndrome
except: (PGI-1999)(UP 2004) (c) Wegeners glomerulonephritis
(a) Cresenteric glomerulonephritis (d) Membranous glomerulonephritis
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77. Tram track appearance on histopathology of kidney is (c) Nests of cells with abundant clear cytoplasm
seen in: (AP 2005) (d) Ovoid, periodic acid-Schiff (PAS)-positive, hyaline
(a) Membranous nephropathy masses
(b) Membranoproliferative glomerulonephritis
(c) IgA nephropathy
82. A 60-year-old man develops oliguria and peripheral
edema over a period of weeks. Urinalysis reveals
(d) Crescentic glomerulonephritis
hematuria and proteinuria; examination of the
78. On electron microscopy, in most of the cases, urinary sediment reveals red cell casts. Radiologic and
characteristic splitting of GBM with sub-epithelial ultrasound studies fail to demonstrate an obstructive
deposits in few cases is seen in: (AP 2008) lesion. Renal biopsy shows many glomerular crescents.
(a) RPGN This presentation is most suggestive of which of the
(b) Membranous nephropathy following conditions?
(c) FSGS (a) Anti-glomerular basement membrane disease
(d) Minimal change disease (b) Diabetic nephropathy
79. An old man from a village Ram Khilavan has (c) Hypertensive nephropathy
progressively increasing back pain for last 6 months. He (d) Lupus nephritis
also had repeated bouts respiratory tract infections with 83. An IV drug abuser Chulbul develops an aggressive
Streptococcus pneumonia within past 10 months. He
form of nephrotic syndrome that does not respond to
ignored these thinking they are associated with his age.
steroids. A renal biopsy is performed. Which of the
However, he then notices the development of an edema
following histological diagnoses will most likely be
on his lower limbs. He rushes to a physician in the city
made from the biopsy tissue?
hospital. On examination, apart from pitting edema,
his investigations reveal total serum protein 9.8 g/dL,

(a) Focal segmental glomerulosclerosis
albumin 3.6 g/dl, creatinine, 3.5 mg/dL; urea nitrogen,
(b) IgA nephropathy
30 mg/dL; and glucose is 80 mg/dL. There is absence of
(c) Membranous glomerulonephritis

(d) Membranoproliferative glomerulonephritis
glucosouria and hematuria but presence of proteinuria

(4.5 g/24 hr). Biopsy of the kidney followed by staining
reveals the amorphous pink material deposited within M Rost ecent Questions
glomeruli, interstitium, and arteries. What is the most
probable diagnosis of the old man?

83.1. All of the following decrease in Nephrotic syndrome
except:

(a) Analgesic nephropathy

(a) Thyroxin
(b) Transferrin

(b) Goodpasture syndrome

(c) Fibrinogen
(d) Albumin

(c) Diabetes mellitus

(d) Multiple myeloma
83.2. Crescents are derived from which of the following?

80. A 6 year old child Devanand presented to the skin

(a) Epithelial cells + fibrin + macrophage
OPD with some honey-colored crusts on his face. Dr

(b) Mesangial cell + fibrin + macrophage
Priyanka sends a microbiological culture which comes

(c) Tubular cell + mesangial cell + fibrin
out to be positive for group A b hemolytic streptococci.

(d) Neutrophil + tubular cell + fibrin

Antibiotics are initiated in the child. However, he returns 83.3. Flea bitten appearance of the kidney is seen in:
to the hospital with his mother after 15 days with mild
(a) Malignant hypertension
fever, malaise and a history of passage of smoky urine.
(b) Benign hypertension
His investigations reveal a serum antistreptolysin O
(c) Chronic pyelonephritis
titer of 1:1024. Which of the following is the most likely
(d) Diabetes mellitus
outcome in this child?

83.4. Most common cause of nephritic syndrome in adults is:
(a) Development of rheumatic heart disease

(a) Rapidly progressive glomerulonephritis
(b) Chronic renal failure

(b) Focal segmental glomerulosclerosis
(c) Complete recovery without treatment

(c) Membranous glomerulonephritis
(d) Progression to crescentic glomerulonephritis
(d) Minimal change disease

81. A 35-year-old woman Sumitra has had type 1 diabetes 83.5. Most common cause of nephrotic syndrome in adults is:
mellitus for 20 years. She is now developing advanced
(a) Membranous glomerulonephritis
disease with visual complaints, foot ulcers, and renal
(b) Minimal change disease
disease. Which of the following features that might
(c) Acute GN
be seen on renal biopsy is most specific for diabetic
glomerulosclerosis?

(d) Focal segmental glomerulosclerosis

(a) Mesangial IgA deposits
83.6. The crescent forming glomerulonephritis is:

(b) Necrotic epithelial cells in tubules
(a) Acute GN

(b) Rapidly progressive glomerulonephritis
460

(c) Membranous GN 85. Urine analysis of a patient with haematuria and

(d) Membranoproliferative GN hypercalciuria is most likely to reveal which of the
following? (AIIMS Nov 2011)
83.7. Microalbuminuria is defined as protein levels of: (a) Isomorphic RBCs
(a) 100-150 mg/d (b) 151-200 mg/d (b) RBC casts
(c) 30-300 mg/d (d) 301-600 mg/d
(c) Nephrotic range proteinuria
83.8. Post streptococcal glomerulonephritis in children is (d) Eosinophiluria
diagnosed by:
(a) Heavy protienuria, high cholesterol, high ASO titre
86. All of the following about xanthogranulomatous
pyelonephritis are true except : (AI 2011, AIIMS May 2010)
(b) Heavy protienuria, hematuria, low ASO titre
(a) On cut section yellowish nodules are seen
(c) Mild proteinuria, hematuria, high ASO titre
(b) Associated with tuberculosis.
(d) Mild protienuria, high cholesterol, normal ASO titre
(c) Foam cells are seen
8 3.9. IgA nephropathy is characterized by all of the following (d) Giant cells are seen
except: 87. In which of the following conditions bilateral contracted
(a) Hypertension kidneys are characteristically seen?
(b) Hematuria
(a) Amyloidosis (AI 2005)
(c) Nephritic syndrome
(b) Diabetes mellitus
(d) Renal biopsy having thin basement membrane
(c) Rapidly progressive glomerulonephritis
83.10.In which one of the primary glomerulonephritis the (d) Benign nephrosclerosis
glomeruli are normal by light microscopy but shows
loss of foot processes of the visceral epithelial cells and
88. Necrotizing papillitis may be seen in all of the following
conditions except: (AI 2002)
no deposits by electron microscopy
(a) Sickle cell disease
(a) Poststreptococcal glomerulonephritis
(b) Tuberculous pyelonephritis
(b) Membrano-proliferative glomerulonephritis type I

(c) IgA nephropathy
(d) Minimal change disease (d) Analgesic nephropathy
83.11. Type I membranoproliferative glomerulonephritis is 89. Mercury affects which part of the kidney?
commonly associated with all except: (a) PCT (AIIMS May 2007)
(a) SLE (b) DCT
(b) Persistent hepatitis C infections (c) Collecting duct
(c) Partial lipodystrophy (d) Loop of Henle
(d) Neoplastic diseases 90. Nephrocalcinosis is seen in all except:
83.12. RBC cast seen in: (a) Sarcoidosis (AIIMS May 2007)
(a) Minimal change disease (b) Distal RTA
(b) Renal vein thrombosis (c) Milk alkali syndrome
(c) Bladder schistomiasis (d) Medullary cystic kidney
(d) Rapidly progressive glomerulonephritis 91. Pulmonary, renal syndrome is seen in:
83.13. Most common glomerulonephritis associated with HIV (a) Goodpastures syndrome. (PGI Dec 2003)
is which of the following? (b) Leptospirosis.
(a) Focal segmental glomerulonephritis (c) Legionella.
(b) Diffuse glomerulosclerosis (d) Wegeners granulomatosis.
(c) Membrano-proliferative glomerulonephritis (e) Hanta virus infection
(d) Crescentic glomerulonephritis 92. Renal papillary necrosis is seen in:
(a) Thalassemia (PGI June 2001)
tubular disease and renal calculi (b) DM
(c) Phenacetin abuse
84. A lady presents with complaints of abdominal pain. (d) Alcoholism
Contrast enhanced CT scan shows bilateral papillary (e) Cortical necrosis
necrosis. Which of the following test shall not be done 93. Causes of Nephrocalcinosis are: (PGI June 2001)
to investigate the cause of her papillary necrosis? (a) Hyperparathyroidism
(a) Culture for bacteria (AIIMS Nov 2011) (b) T.B. Kidney
(b) Sickling test (c) Hypercalcemia
(c) Urine acidification (d) Glomerulonephritis
(d) Urine PCR for TB (e) MCD
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94. Bilaterally enlarged kidneys are seen in:

(b) Lupus nephritis
(a) Chronic glomerulonephritis (PGI Dec 2002)
(c) Hypercalcemic nephropathy
(b) Chronic pyelonephritis
(d) Analgesic nephropathy
(c) Benign nephrosclerosis 105. Renal pathology in SLE includes all except:
(d) Polycystic Kidney disease (a) Focal glomerulonephritis (UP 2008)
(e) Amyloidosis (b) Diffuse glomerulonephritis
95. Hereditary nephritis is seen in: (c) Diffuse membranous glomerulonephritis
(a) Analgesic nephropathy (PGI Dec 2003) (d) Lipoid nephrosis
(b) Balkan nephropathy 106. Pathologic feature of malignant hypertension is:
(c) Alport syndrome. (a) Fibrinoid necrosis (RJ 2004)
(d) Eosinophilic nephritis (b) Papillary necrosis
96. Nephrocalcinosis is seen in: (PGI June 2004) (c) Hard exudate
(a) Hypoparathyroidism (d) All
(b) Medullary sponge kidney 107. Contracted kidneys are seen in all of the following
(c) DM diseases except: (RJ 2006)
(d) RTA (a) Chronic glomerulonephritis
(b) Chronic renal failure
97. Histology of acute rejection of renal transplant are: (c) Amyloidosis
(a) Arteriolar hyalinosis (PGI June 2005)
(d) Analgesic nephropathy
(b) Eosinophilic infiltration
(c) Glomerular vasodilatation 108. Hematuria with dysmorphic RBC are seen in:
(d) Neutrophilic infiltration (a) Acute glomerulonephritis (RJ 2006)
(e) Necrotizing vasculitis. (b) Renal TB
98. Which of the following is seen in hemolytic uremic (c) Renal Calculi
(d) Chronic renal failure
syndrome? (Delhi PG-2007)

(a) Spherocytes (b) Schistocytes 109. Birefringent crystals in urine is seen with: (Bihar 2004)
(c) Target cells (d) Heinz bodies (a) Calcium oxalate stone (b) Uric acid stone
99. All are true about nephronophthisis except: (c) Struvite stones (d) None
(a) Interstitial fibrosis (Delhi PG-2006) 110. Anti-GBM antibodies are seen in: (Kolkata 2005)
(b) Cortical tubular hypertrophy (a) Goodpastures syndrome
(c) Cysts in the medulla (b) RPGN
(d) 20% cases are non-familial
(c) Membranous GN
100. Most common cause of papillary necrosis is: (d) Minimal change disease
(a) Diabetes Mellitus (Delhi PG-2005)
(b) Acute Pyelonephritis
111. A 30 year old company executive gets up at night with
(c) Sickle cell disease severe waxing and waning abdominal pain on right
(d) Analgesic Nephropathy side radiating to the groin and rushes to his physician
Dr. Shiv Narayan at RG Clinic. On examination, he is
101. Renal calculi are commonly made up of afebrile and has a blood pressure of 118/74 mm Hg. His
(a) Calcium oxalate (Karnataka 2006)
blood and urine samples are sent for investigations.
(b) Magnesium ammonium phosphate
Reports show serum Na+, 140 mmol/L; K+, 4.2 mmol/L;
(c) Uric acid
(d) Cystine glucose, 80 mg/dL: creatinine, 1.0 mg/dL; calcium, 8.9
mg/dL; and phosphorus, 2.4 mg/dL. Urine had pH of 7.1;
102. Salt losing nephritis is due to (UP 2000) specific gravity of 1.018 and absence of protein, glucose
(a) Lupus nephritis or ketones. He is advised to drink plenty of water but
(b) Streptococcal infection
even after following this advice, he continues to have
(c) Interstitial nephritis
similar episodes. Which of the following is most likely
(d) Goodpastures syndrome
substance to be increased in his urine?
103. Most common cause of renal papillary necrosis is:
(a) Mucoprotein
(a) Analgesic nephropathy (UP 2000)
(b) Calcium oxalate
(b) Sickle cell disease
(c) Magnesium ammonium phosphate
(d) Uric acid
(d) Chronic pyelonephritis
104. Tubulo-interstitial disease are all except: 112. A 28 year young female Katrina present to your OPD
(a) Hypokalemic nephropathy (UP 2002) with complaints of suprapubic pain, urinary frequency
and dysuria. She also passed blood in last voided urine
462
about 30 minutes ago. Her urinanalysis demonstrate perihilar infiltrates. Which of the following most likely
the presence of pyuria but no white cell casts. On accounts for his BUN and creatinine levels?
physical examination, she has suprapubic tenderness
(a) Decreased renal perfusion
on palpation. Which of the following is the likely
(b) Distal urinary tract obstruction
diagnosis in this patient?
(c) Increased synthesis of urea

(a) Acute pyelonephritis
(d) Renal tubulointerstitial disease

(b) Chronic pyelonephritis

(c) Cystitis M R
ost ecent Questions

(d) Fanconi syndrome
117.1. Alports syndrome is inherited by al the following

113. A 27 year old female Kareena presents to your office inheritances except
(a) X linked
with urinary frequency, urgency, and burning during
urination. She has also noticed a scant vaginal
(b) Co-dominant
discharge. The symptoms started two days ago. Which (c) AD
of the following additional findings would be most (d) AR
suggestive of pyelonephritis in this patient? 117.2. Renal papillary necrosis is almost always associated

(a) Fever with one of the following conditions:

(b) Bacteriuria (a) Diabetes mellitus

(c) White blood cell casts (b) Analgesicnephropathy

(d) Sterile pyuria (c) Chronic pyelonephritis
(d) Post streptococcal GN
114. A female patient Nargis comes to your OPD with
117.3. All are causes of granular contracted kidneys except:
complaints of fever, malaise, increased frequency,
urgency and painful micturition. Further investigations (a) Benign nephrosclerosis
reveal that she is suffering from acute urinary tract (b) Diabetes mellitus
(c) Chronic Pyelonephritis

infection. Which of the following is not a risk factor for
the increased predisposition of females for development (d) Chronic glomerulonephritis
of UTI? 1 17.4. Periglomerular fibrosis is considered typical of:

(a) Shorter urethra in females (a) Chronic pyelonephritis

(b) Absence of antibacterial properties in vaginal fluid (b) Chronic glomerulonephritis

(c) Hormonal changes affecting adherence of bacteria to (c) Arterionephrosclerosis
the mucosa (d) Malignant hypertension

(d) Urethral trauma during sexual intercourse 1 17.5. Nephrocalcinosis is seen in which one of the following?
115. At autopsy, a patient who had died with acute anuria and (a) Hyperparathyroidism
uremia is found to have ischemic necrosis of the cortex (b) Diabetes mellitus
of both kidneys with relative sparing of the medulla. (c) Amyloidosis kidney
These pathological findings are most likely related to (d) End stage kidney
which of the following underlying conditions? 1 17.6. Thimble bladder is typically seen in which one of the

(a) Disseminated intravascular coagulation following?

(b) Multiple myeloma (a) Acute bacterial cystitis

(c) Sickle cell anemia (b) Tuberculous cystitis

(d) Pyelonephritis (c) Bilharziasis
(d) Transitional cell carcinoma
116. A 51-year-old man Sonu with a history of recurrent 1 17.7. Marker of acute kidney injury includes all of the
calcium-containing renal stones presents to the
emergency room with excruciating flank pain and blood following except: (AIIMS Nov 2013)
in the urine. This patient is likely to have which of the (a) Cystatin C (b) N gal
following underlying disorders? (c) Kim 1 (d) Micro RNA -122

(a) Anemia of chronic disease 117.8. Which of the following increases tuberculosis?

(b) Chronic Proteus infection (a) Asbestosis (b) Sarcoidosis

(c) Hyperparathyroidism (c) Silicosis (d) Berylliosis

(d) Hyperaldosteronism 117.9. Which one of the following statements is incorrect
117. A 54 old man Girish is admitted to the hospital because regarding uric acid stones?
of shortness of breath. He has severe pedal edema and (a) They are radiolucent
his blood pressure is 75/50 mm Hg. His serum urea (b) Crystals are hexagonal
nitrogen (BUN) 36 mg/dL and serum creatinine 1.0 (c) Formed in acidic urine
mg/dL. A chest x-ray shows cardiac enlargement and (d) Can be seen with normouricemia
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117.10. Characteristic histopathological feature of kidney in
(b) Medullary
DM?

(c) Papillary
(a) Nodular glomerulosclerosis

(b) Fibrin cap

(d) Mixed type

(c) Papillary necrosis 126. A 60 year old security guard Dharam Chaudhary

(d) Diffuse glomerulosclerosis presents to the his physician because he is having
malaise, fever and weakness. On taking history, a
positive history of multiple episodes of passage of
renal tumours: rcc, wilms tumour altered colored urine is present. However, this is not
associated with urinary frequency, dysuria, or nocturia.
118. Which of the following is not associated with renal cell Physical examination is insignificant but his urine
carcinoma? (AIIMS May 2011) analysis reveals 4 + hematuria; 1 + proteinuria and
(a) Polycythemia absence of glucose or ketones by the dips stick method.
(b) Amyloidosis Which of the following is the next most appropriate
(c) Cushings syndrome step for the management of this patient?
(d) Hypertension
(a) Straining of urine for calculi
119. Wilms tumor is associated with all of the following
(b) Abdominal CT scan for renal mass
except (AIIMS May 2010)

(c) Collection of a 24 hour urine specimen for protein
(a) Hemihypertrophy

(d) Percutaneous renal biopsy
(b) Aniridia 127. A pediatrician Dr. Jyoti Jain discovers a large mass in the
(c) Hypertension abdomen of a 3-year-old child. Ultrasound examination
(d) Bilateral polycystic kidney demonstrates that the mass appears to arise from the
right kidney. Which of the following tumors is most
120. The cytogenetics of chromophilic renal cell carcinoma likely present?
is characterized by: (AI 2010)
(a) Cortical adenoma
(a) Mutant VHL gene
(b) Hemangioma
(b) Loss of 3p
(c) Nephroblastoma
(c) Trisomy 7/17
(d) Oncocytoma
(d) Loss of 5q 3
128. An anxious couple brings in a 18 month boy with
121. The most common histological variant of renal cell gonadal dysgenesis to a pediatric clinic for a follow-
carcinoma is (AIIMS Nov 2005) up visit. The physician Dr. Mayank Dhamija notices a
(a) Clear cell type large abdominal mass during his physical examination.
(b) Chromophobe type Which of the following disorders does the patient most
(c) Papillary type likely have?
(d) Tubular type
122. In which of the following conditions, Aniridia and
(b) Renal hamartoma
Hemi-hypertrophy are most likely present

(c) Wilms tumor
(a) Neuroblastoma (AIIMS May 2004)

(d) Transitional cell carcinoma of the bladder
(b) Wilms tumor Most Recent Questions

(c) Non-Hodgkins lymphoma
(d) Germ cell tumor 1 28.1. Most important prognostic factor of wilms tumour:
(a) Histopathology and ploidy of cells
123. In Wilms tumor the following leads to emergence of (b) Tumour stage
resistance to chemotherapy: (Delhi 2009 RP) (c) Age of patient
(a) Nephrogenic rests (d) Mutation of chromosome 1p
(b) Monophasic morphology
(c) Anaplasia 1 28.2. Oncocytic carcinoma arises from:
(d) Capsular infiltration (a) Perivascular tissue
(b) Glomerulus
124. True statement regarding Wilms tumour is: (c) Loop of henle
(a) Common in adult (UP 2004) (d) Collecting duct
(b) Associated with deletion of chromosome 11p13
(c) Associated with MIC-2 genes 1 28.3. Gene for Wilms tumour is located on which of the
(d) Commonest presentation is hematuria following?
(a) Chromosome 1
125. Most common histological type of renal cell carcinoma (b) Chromosome 10
is: (AP 2003) (c) Chromosome 11
(a) Clear cell (d) Chromosome 12
464
128.4. Deletion of short arm of chromosome 11 is seen in: 131. Michaelis Guttmann bodies are present in:
(a) Osteosarcoma (a) Analgesic nephropathy (RJ 2001,2003)
(b) Meningioma (b) Hommans ulcer
(c) Wilms tumor (c) Malacoplakia
(d) Colon Carcinoma (d) Erythroplasia
132. Bence Jones proteins are: (RJ 2001)
urinary bladder disease (a) Light chain
(b) Heavy chain
129. Michaelis Gutmann bodies are seen in (c) Medium chain
(AIIMS May 2007) (d) All
(a) Xanthogranulomatous pyelonephritis
(b) Malacoplakia Most Recent Questions
(c) Nail patella syndrome
(d) Tubercular cystitis 132.1. Transitional cell carcinoma bladder is associated with
130. Chronic urethral obstruction due to benign prostatic (a) Schistosomiasis (b) Ascariasis
hyperplasia can lead to the following change in kidney (c) Malaria (d) Any of the above
parenchyma (Karnataka 2007)
(a) Hyperplasia 132.2. Metabolic complication in CRF include all of the
(b) Hypertrophy following except
(c) Atrophy (a) Hyperkalemia (b) Hypophosphatemia
(d) Dysplasia (c) Hypocalcemia (d) Hypokalemia
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E xplanations
1. Ans. (d) Alports syndrome (Ref: Robbins 8th/931-2)
Presentation of male patient with lenticonus and end stage renal disease with a family history of renal disease is highly
suggestive of Alport syndrome.
AR polycystic kidney is ruled out because the age of presentation in ARPKD is childhood and most of the affected
children do not survive beyond their childhood.
AD polycystic kidney is ruled out because there is no association of ADPKD with lenticonus as is mentioned in our
question.
Alport syndrome is manifest by hematuria with progression to chronic renal failure, accompanied by nerve deafness and
various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.
In about 85% cases, it is inherited as an X-linked trait. So, males express the full syndrome, and females are carriers
in whom manifestations of disease are typically limited to hematuria.
Autosomal recessive and autosomal dominant forms also exist in which both the sexes are equally susceptible.
In Alport syndrome, Hematuria is the earliest manifestation and the sensorineural deafness is the commonest extra
renal abnormality.
2. Ans. (d) Tricuspid valve prolapse (Ref: Robbins 8th/959 9/e p947)
Mitral valve prolapse (and not tricuspid valve prolapse) and other cardiac valvular anomalies occur in 20% to 25% of
patients.
Adult polycystic kidney disease (APKD) is a hereditary disorder characterized by multiple expanding cysts of both kid-
neys that ultimately destroy the renal parenchyma and cause renal failure. It is an autosomal dominant condition caused by
mutation in PKD1 gene encoding for polycystin-1. This protein is present on distal tubular epithelial cells. It is involved in
cell-cell and cell-matrix interactions. The PKD2 gene product polycystin-2 is localized to all segments of the renal tubules
and may act as a Ca2+-permeable cation channel for regulatoring intracellular Ca2+ levels.
3. Ans. (a) Berry Aneurysm in Circle of Willis (Ref: Robbins 7th/964 9/e p947)
4. Ans. (b) Hypertension is rare (Ref: Robbins 7th/964, 9/e p 947)
Hypertension is common in patients with autosomal dominant polycystic kidney disease. It is present in 75% of adult
patients and 25% of children.
5. Ans. (e) Renal failure seen in middle life (Ref: Robbins 7th/963-64, 9/e p947, Harrison 17th/1797-1798)
Salient points about Adult polycystic kidney disease
Due to mutation of PKD 1 gene (Chromosome 16) and PKD 2 gene (on chromosome 4).
PKD 1 and 2 genes encode for polycystin 1 and 2 proteins (and not genes) respectively.
Autosomal dominant
Kidneys are enlarged bilaterally.
Disease may present at any age but most frequently produces symptoms in the 3rd or 4th decade
Leads to CRF at 40-60 years of life.
Other than kidney, cysts are found in Liver (most commonly), Pancreas, Spleen Ovaries, and Lung.
Other associated lesions include berry aneurysm, mitral valve prolapsed and colonic diverticula
The goals of treatment are to slow the rate of progression of renal disease and to minimize the symptoms.
There is no contraindication to renal transplantation.
6. Ans. (b) 4 and 16. (Ref: Robbins 8th/960; 9/e p946)

7. Ans. (b) Dialysis (Ref: Robbins 9/e p949, 8th/960; 7th/962, 966)
8. Ans. (d) Renin (Ref: Robbins 8th/957-958, 9/e p 946-47)
The disease is adult polycystic kidney disease, which is an autosomal dominant condition that typically manifests in middle
age. The kidneys appear very badly deformed but they function surprisingly well because the cystic spaces actually only
affect 10% or less of the nephrons. Pressure exerted by the cysts can compromise blood flow to some glomeruli, increasing
renin secretion followed by hypertension.
466
ACTH (choice A) can stimulate cortisol (choice B) secretion, and the cortisol (in high amounts) can have enough
mineralocorticoid activity to cause hypertension. However, this is associated with a pituitary tumor, adrenal tumor, or
with exogenous corticosteroid use.
8.1. Ans. (d) Bowmans capsule (Ref: Robbins 8/e p910, 9/e p900)

Podocytes (or visceral epithelial cells) are cells in the Bowmans capsule in the kidneys that wrap around the capillaries
of the glomerulus.
8.2. Ans. (a) Autosomal dominant.. Too obvious at this stage friend...For details, read text.
8.3. Ans. (a) Cardiovascular disease (Ref: Cambells Urology, 8/e p346,349)
Principal causes of death in renal transplant patients (in decreasing order)

Heart diseaseQ Infection
Stroke
8.4. Ans. (b) Excretion of less than 500 ml in 24 hrs
As per Harrisonrefers to a 24-h urine output of <500 mL , and
Oliguria Q Q
Anuria is the complete absence of urine formation (<50 mL) .

Q Q
8.5 Ans. (a) 3 (Ref: Harrison 18/e p 339; CMDT 2014/e p879)
The minimum number of red blood cells per microliter of urine required for diagnosis of hematuria is >3 RBC/HPF of
centrifuged specimen.
Persistent or significant hematuria (>3 RBCs/ HPF on three urinalyses, a single urinalysis with >100 RBCs, or gross hema-
turia) is associated with significant renal or urologic lesionsHarrison
8.6. Ans (d) Brain (Ref: Robbbins 9/e p947)
About 40% have one to several cysts in the liver (polycystic liver disease) that are usually asymptomatic. Cysts occur much
less frequently in the spleen, pancreas, and lungs.
9. Ans. (b) Hyperplastic arteriosclerosis (Ref: Robbins 8th/950-951, 9/e p939)
Histological alterations characterizing blood vessels in malignant hypertension
Fibrinoid necrosis of arterioles: This appears as an eosinophilic granular change in the blood vessel wall, which

stains positively for fibrin by histochemical or immunofluorescence techniques.
In the interlobular arteries and arterioles, there is intimal thickening caused by a proliferation of elongated and con-
centrically arranged smooth muscle cells with deposition of collagen. This alteration has been referred to as onion-
skinning because of its concentric appearance. The lesion, also called hyperplastic arteriolitis, correlates well with
renal failure in malignant hypertension.
Malignant nephrosclerosis is the form of renal disease associated with the malignant or accelerated phase of hypertension. Small,
pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular capillar-
ies, giving the kidney a peculiar flea-bitten appearance.
Hyaline arteriolosclerosis is narrowing of the lumens of arterioles and small arteries, caused by thickening and hya-
linization of the walls. It is seen with Benign nephrosclerosis. Nephrosclerosis is associated with increasing age, more
frequent in blacks than whites, and may be seen in the absence of hypertension. Hypertension and diabetes mellitus,
however, increase the incidence and severity of the lesions.
10. Ans. (a) Alports syndrome (Ref: Robbins 8th/931-2, 9/e p924)
COL4A5 chain represents the a5 chain of collagen type IV. It is associated with the development of Alport syndrome.
Genetic Mutation in Chain Disease
Gene encoding a5 chain of collagen type IV Alport syndrome
Gene encoding a4 chain of collagen type IV Benign familial hematuria/Thin membrane disease
Gene encoding a3 chain of collagen type IV Goodpasture syndrome
Alport syndrome
Nephritic disorder characterized by the involvement of the triad of kidney, ear and eye.
Fundamental defect in the 5-chain of collagen type IV
Light microscopy glomerular involvement in the form of the presence of foam cells in the interstitial cells.
Electron microscopy (Diagnostic for this disorderQ)
It shows the presence of irregular foci of thickening and thinning in the GBM with splitting and lamination of lam-
ina densa called as basket weave appearance. Absence of 5 staining is seen even on skin biopsy apart from glomerular
and tubular basement membrane.
11. Ans. (b) NPHS 2 (Ref: Robbins 8th/927, 9/e p918)

Gene Chromosome Protein Location Disease
NPHS 1 19q13 Nephrin Slit diaphragm Steroid sensitive/Finnish type of nephrotic syndrome
NPHS 2 1q25 Podocin Slit diaphragm Steroid resistant nephrotic syndrome
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12. Ans. (a) Focal segmental glomerulosclerosis (Ref Robbins 8th/926, 9/e p918)
Direct quote Robbins 8 /926. Focal segmental glomerulosclerosis occurs as a component of the adaptive response to loss
th
of renal tissue in advanced stage of other renal disorders such as reflux nephropathy, hypertensive nephropathy and unilateral
renal agenesis.
13. Ans. (c) No IgG deposits or C3 deposition on renal biopsy (Ref: Robbins 8th/925-6, 9/e 910)
The clinical symptoms and the findings in the stem of the question (child with generalised swelling because of reduced
serum protein secondary to massive proteinuria with urinary lipid casts) are suggestive of nephrotic syndrome. The
commonest cause in a child of nephrotic syndrome is lipoid nephrosis or minimal change disease. So option a and d are
ruled out. Both cause hematuria as a finding.
Electron microscopic examination in minimal change disease show the presence of effacement of foot processes of
podocytesQ.
Summary of salient features of some diseases causing nephrotic syndrome
Glomerular microscopic findings
Disease Clinical presentation Light Microscopy Fluorescence Electron Microscopy
Membranous Nephrotic syndrome Diffuse capillary wall Granular IgG and Subepithelial deposits
glomerulopathy thickening C3; diffuse
Minimal change disease Nephrotic syndrome Normal; lipid in tubules Negative Loss of foot processes; no
deposits
Focal segmental Nephrotic syndrome; non- Focal and segmental Focal; IgM and C3 Loss of foot processes;
glomerulosclerosis nephrotic proteinuria sclerosis and hyalinosis epithelial denudation
Membranoproliferative Nephrotic syndrome Mesangial proliferation; (I) IgG + C3; C1q (I) Subendothelial deposits
glomerulonephritis basement membrane + C4
(MPGN) Type I
thickening; splitting
Note: MPGN Type II (Dense deposit disease) is associated with hematuria.

14. Ans. (b) Focal necrotizing glomerulonephritis (Ref: Robbins 9/e p511-512, 8th/516-7, 7th/541, Harrison 17th/2121-3)
Robbins .....The renal lesions range from a mild/early disease, where glomeruli show acute focal necrosis with
thrombosis of isolated glomerular capillary loops (focal and segmental necrotizing glomerulonephritis) whereas
advanced glomerular lesions are characterized by diffuse necrosis and parietal cell proliferation to form crescents
(crescentic glomerulonephritis).
Direct quote from Harrison.. Necrotizing vasculitis of small arteries and veins with granuloma formation is seen
in pulmonary tissue whereas granuloma formation is rarely seen on renal biopsy.
15. Ans. (a) Autosomal recessive inheritance (Ref: Heptinstalls pathology of kidney vol 1/931)
Fibronectin nephropathy is a disease with the following features:
Autosomal dominantQ mode of inheritance.
Presents with proteinuria and slowly progressive loss of renal function.
Proteinuria is the most common presentation with patients also having microscopic hematuria and mild hypertension.
The fibronectin levels in serum are normal.
The principal light microscopic change is glomerular enlargement and lobulation resulting from PAS and trichrome-positive
mesangial deposits and mild mesangial proliferation
Special stains for amyloid are negative
By immunofluorescence microscopy, the glomeruli do not stain for immunoglobulin or complement components
The most consistent ultrastructural finding is large (giant), mesangial and subendothelial electron-dense deposits that mirror the
location of the PAS-positive, fibronectin deposits.
16. Ans. (d) Focal glomerular sclerosis (Ref: Robbins 9/e p1118-1119, 8th/1141-1142)
Diabetes may cause nodular and diffuse glomerulosclerosis but not focal glomerular sclerosis.
17. Ans. (a) Loss of antithrombin III (AT III) (Ref: Robbins 9/e p914, 8th/922, 7th/978 CMDT 2010)
Thrombotic and thromboembolic complications are common in nephrotic syndrome due to loss of anticoagulant factor
(e.g. antithrombin III, protein C and S) combined with increased platelet activation. Renal vein thrombosis is most often a
consequence of this hypercoagulative state. There is also increased synthesis of fibrinogen in the liver.
18. Ans. (a) Nephrin (Ref: Robbins 9/e p918, 8th/927)
Direct quote RobbinsA mutation in the Nephrin (NPHS 1) gene causes a hereditary form of congenital Nephrotic syndrome
(Finnish type) with minimal change glomerular morphology whereas mutations in NPHS2 coding for podocin results in steroid
resistant nephrotic syndrome.
468
Gene Chromosome Protein Location Disease

NPHS 1 19q13 Nephrin Slit diaphragm Steroid sensitive/Finnish type of nephrotic syndrome
NPHS 2 1q25 Podocin Slit diaphragm Steroid resistant nephrotic syndrome
19. Ans. (a) Microscopic polyangiitis (Ref: Robbins 9/e p912, 8th/920)
Crescentic Glomerulonephritis
Type I RPGN (Anti-GBM antibody) Type II RPGN (Immune complex) Type III RPGN (Pauci immune)
Idiopathic Idiopathic Idiopathic.
Goodpastures syndrome. Post infectious ANCA associated.
SLE, Henoch Schonlein Purpura. Wegeners granulomatosis.
Microscopic polyangitis.
Immunofluorescence finding Immunofluorescence finding Immunofluorescence finding
Linear GBM deposits of IgG and C3 Lumpy bumpy granular pattern of No immunoglobulin or complement
staining. deposits in GBM.
20. Ans. (A) Nephrin (Ref: Robbins 9/e p912, 8th/918, Nelson 17th/1757)
Lipoid nephrosis or nephrotic syndrome is also called as minimal change disease. Congenital nephrotic syndrome
occurs as a result of mutation in the nephrin gene. (Finnish type of nephrotic syndrome)
Also now
Megalin in involved is the pathogenesis of membranous glomerulonephritis
Podocin and a4 actinin can also result in congenital nephrotic syndrome.
21. Ans. (b) Alport syndrome (Ref: Robbins 9/e p912, 8th/920, 7th/523-4)

As discussed earlier, crescentic glomerulonephritis is the alternative name of RPGN.
Alport syndrome is a hereditary nephritis characterized by associated nerve deafness and eye disorders like lens dislocation,
posterior cataracts and corneal dystrophy. Histologically foam cells (interstitial cells having fats and mucopolysaccharides) are seen.
22. Ans. (b) Mesangiocapillary GN (Ref: Anderson 10th/2076; Robbins 7th/979)

Glomerular lesions with increased cells in the tufts are often known as proliferative glomerulonephritis.
Conditions with Proliferative Glomerulonephritis
SLE (particularly class II, mesangial hypercellularity defined as >3 cells in mesangial regions)
HIV
Membranoproliferative/Mesangiocapillary glomerulonephritis
Neoplasia (particularly CLL and MALT lymphoma)
Post streptococcal glomerulonephritis
Rest all options are non proliferative glomerulonephritis.
23. Ans. (a) Thrombotic microangiopathy (Ref: Robbins 9/e p941, 8th/952, 7th/1009, 612, Harrison 17th/1813-4)
The term thrombotic microangiopathy encompasses a spectrum of clinical syndromes that include TTP and HUS. DIC
is not included because these disorders (TTP and Hus) are associated with normal coagulation times and normal fibrin
degradation products.
Microthrombi are demonstrated in renal arterioles and capillaries. In HUS, microthrombi mainly contain fibrin whereas in
TTP, these are composed of platelet aggregates, fibrin and VWF. More than 90% patients with HUS have significant renal
failure whereas < 10% cases of classic TTP have anuria.
24. Ans. (a) Post streptococcal glomerulonephritis (Ref: Robbins 9/e p918, 8th/919, Harrisons 17th/1786)
Although all conditions mentioned in the question are associated with low complement levels. Persistently depressed
levels are not seen in post streptococcal glomerulonephritis.
In post streptococcal glomerulonephritis: serum C levels are depressed within 2 weeks, however, these usually
3
return to normal levels within 6 to 8 weeks.
Persistently depressed levels after this period should suggest another cause such as presence of C3 nephritic factor
(Membranoproliferative glomerulonephritis).
25. Ans. (c) Diarrhea associated hemolytic uremic syndrome (Ref: Harrison 17th/1813-1814, 9/e p942)
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Nephritic syndrome associated with low C3

Immune complex glomerulonephritis
Post streptococcal glomerulonephritis Crescenteric glomerulonephritis
Lupus nephritis Idiopathic proliferative glomerulonephritis
Cryoglobulinemia Atheroembolic renal disease
Bacterial endocarditis Sepsis
Shunt nephritis Acute Pancreatitis/advanced liver disease
Membranoproliferative glomerulonephritis
*Hemolytic uremic syndrome is associated with normal C levels. 3
26. Ans. (c) Goodpastures disease (Ref: Harrisons 17th/1788)

27. Ans. (d) Absence of associated proteinuria is pathognomic (Ref: Robbins 7th/986-988, 9/e p923)
Bergers disease (IgA nephropathy) is a frequent cause of gross or microscopic hematuria. Mild proteinuria is frequently present and
occassionally nephrotic syndrome may develop.
Microscopically, mesangioproliferative glomerulonephritis is seen more commonly than focal proliferative and crescentic (least)
glomerulonephritis.
Immunofluorescence shows deposition of IgA with C3 and properdin.
Electron dense deposits are seen in mesangium on electron microscopy.
28. Ans. (b) Rapidly progressive glomerulonephritis (Ref: Robbins 9/e p912, 8/e p920-921)
Rapidly progressive glomerulonephritis, also known as crescentic glomerulonephritis is characterized by the pres-
ence of crescents in most of the glomeruli.
Crescents are produced by proliferation of the parietal epithelial cells of Bowmans capsule and by infiltration of
monocytes and macrophages.
29. Ans. (c) Crescentic glomerulonephritis (Ref: Robbins 9/e p912, 8th/516-7, 7th/541, Harrison 17th/2121-3)
Discussed earlier.
30. Ans. (c) Alport syndrome (Ref: Robbins 9/e p924, 8th/932, 7th/988, Rubin pathology/361)
Alport syndrome is the commmest type of Hereditary nephritis (refers to a group of heterogenous familial renal diseases associ-
ated primarily with glomerular injury). The other important intity is thin basement membrane disease.
Rubins mentions The most diagnostic morphologic lesion is seen only by electron microscopy as an irregularly thickened
GBM, with splitting of the lamina densa into interlacing lamellae that surround electron-lucent areas
Robbins 8 . The characteristic electron microscopic finding of Alport syndrome is that the glomerular basement mem-
th
brane shows irregular foci of thickening alternating with attenuation (thinning), with pronounced splitting and lamination
of the lamina densa, often with a distinctive basket-weave appearance.
Important info
Thin basement membrane disease is the most common cause of benign familial hematuria.
31. Ans. (b) Collapsing (Ref: Robbins 8th/926, 9th/p 920, 7th/985)
Five mutually exclusive variants of focal segmental glomerulosclerosis (FSGS) may be distinguished by the path-
ological findings seen on renal biopsy
Collapsing variant
Glomerular tip lesion variant
Cellular variant
Perihilar variant
Not otherwise specified variant (NOS)
The NOS variant is the most common subtype and collapsing FSGS has worst prognosis.
32. Ans. (c) Podocin (Ref: Robbins 9/e p918, 8th/927, 7th/983-4)
Mutations in NPHS1 gene that codes for nephrin results in congenital nephrotic syndrome of Finnish type.
NPHS2 gene coding for podocin mutation result in steroid resistant nephrotic syndrome.
Mnemonic:
NPHS1 contains 1, which suggest first letter (means N) that stands for Nephrin whereas NPHS2 contains 2, which suggest
second letter (means P) that stands for Podocin.
1 comes first, so NPHS1 mutations cause congenital nephrotic syndrome whereas 2 comes later, so NPHS2 mutations cause
acquired disease (steroid resistant nephrotic syndrome)
33. Ans. (d) Hypertrophy and necrosis of visceral epithelium (Ref. Robbins 9/e p920, 8th/926, 7th/983-4)
470
Collapsing Glomerulopathy is characterised by

A characteristic feature is proliferation and hypertrophy of glomerular visceral epithelial cells.
The minimum diagnostic criteria for defining a collapsing variant of FSGS is the presence by light microscopy of at least one
glomerulus showing segmental or global obliteration of the glomerular capillary lumen by wrinkling and collapse of glomerular
basement membrane in association with hypertrophy and hyperplasia of overlying visceral epithelial cells.
34. Ans. (b) NPHS-2 (Ref: Robbin 9/e p918, 8th/927, 7th/983-4)
35. Ans. (c) Collapsing glomerulopathy (Ref: Harrison 17th/1796, Robbins, 9/e p920, 8th/928,7th/982- 3)
36. Ans. (d) Amyloidosis (Ref: Robbins 9/e p926, 8th/252,610-1,927-8)
Mesangial deposits of monoclonal kappa/lambda light chains suggest the diagnosis of Amyloidosis. In primary
Amyloidosis AL protein is deposited in the organs, which is made of light chains (usually lambda type) of immuno-
globulins. Renal amyloidosis is the most common cause of death due to amyloidosis (including both primary and
secondary amyloidosis).
Other options:
Mesangioproliferative glomerulonephritis shows mesangial deposits of IgG, IgA and C3.
Focal and segmental glomerulosclerosis shows hyaline deposits of IgM, C3 and IgA and fibrinogen in juxtamedullary
capillaries.
In Kimmelstiel-Wilson disease (or nodular glomerulosclerosis), the hyaline masses are deposited in the mesangial core of the
glomerular lobules consist of lipids and fibrin.
37. Ans. (b) Has molecular weight slightly greater than the molecules normally getting filtered (Ref: Robbins 9/e p914,
8th/910, Harrison 18th/2334, Ganong 21st/709-10; Guyton 10th/373)
There are three main types of plasma proteins which include Albumin, Globulin and Fibrinogen
Normally, the glomerular filtration layer does not allow any plasma protein to pass through it. However, in any renal
disease, it allows protein molecules to pass through it and albumin is the first protein to appear in the urine.

The filtration of any substance through glomerular filtration layer depends on two factors as described below:
Size of the substance
The glomerular filtration layer is thick and porous membrane. Any neutral substance < 4A diameter freely filters through this layer.
However, the filterability of any neutral substance with diameter between 4 nm and 8 nm is inversely proportional to its size. The
filterability of substances of diameter more than 8 nm is zero.
Charge of the substance
The sialoproteins contained in the glomerular filtration layer are negatively charged causing repulsion of all negatively
charged particles including proteins. This explains the negligible filtration of albumin anion which has diameter of 7 nm
In some renal diseases, the anionic charge of the filtration membrane is lost and this allows negatively charged particles
of diameter 8nm to pass through it resulting in proteinuria. Albumin has a diameter of 7nm and it starts appearing in urine
as soon as the negative charge of filtration layer disappears.
38. Ans. (a) Fusion of foot process of the glomerular epithelial cells (Ref: Robbins 9/e p917, 8th/925)
The child is presenting with features likely of Nephrotic syndrome whose most frequent cause in children is minimal
change disease or lipoid nephrosis.
Light microscopy there is no abnormality whereas on electron microscopy there is fusion of foot processes of the
glomerular epithelial cells with normal glomeruli.
39. Ans. (a) Number of crescents (Ref: Robbins 6th/453, Essential of nephrology by K visweswaran 2nd/102 )
As discussed in text the prognosis in RPGN is related to the number of crescents. However, this point is not mentioned in
the 7th, 8th and 9th editions of Robbins.
Poor prognostic factors Good prognostic factors
Oliguria and azotemia at presentation Pauci immune RPGN has best prognosis
More than 80% circumferential crescents have poor Non- circumferential crescents in less than 50% glomeruli have
response to therapy indolent course.
Glomerular tuft necrosis, global glomerular sclerosis, gaps Associated endocapillary proliferation is a good prognostic factor
in Bowman capsule and interstitial fibrosis
Essential of nephrology writes that oliguria is related to crescent formation.
40. Ans. (d) No change seen (Ref: Robbins 9/e p917, 7th/981-982)
41. Ans. (d) Glomerular function is lost due to loss of polyanionic charge on both sites of glomerular foot process.
(Ref: Harrison 17th/1790, Robbins 9/e p900)
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As discussed earlier, Glomerular barrier function depends on the molecular size (the larger, the less permeable) and charge
(the more cationic, the more permeable) is done. The anionic moieties present within the capillary wall including the acidic
proteoglycans of the GBM and the sialoglycoproteins of epithelial and endothelial cells are responsible for the virtually
complete exclusion of albumin (also having anionic charge) from the filtrate. In addition, the visceral epithelial cell (or po-
docyte) is important for the maintenance of glomerular barrier function. The slit diaphragm of the podocyte is composed
of nephrin, actin and podocin, so, any defect in any of these is responsible for increased protein excretion from the kidney.
In a patient of minimal change disease, there is presence of visceral epithelial injury leading to the loss of glomerular poly-
anions resulting in low molecular weight proteinuria (selective proteinuria).
Clarifying Option c; Foot process of the podocyte is effaced. However, it appears to be normal on light microscopy.
42. Ans. (a) Alports syndrome (Ref: Robbins 9/e p924, 8th/931-2, 7th/988-9)
Genetic Mutation in Chain Disease

Mutation in the gene encoding 5 chain of collagen type IV Alport syndrome
Mutation in the gene encoding 4 chain of collagen type IV Benign familial hematuria
Mutation in the gene encoding 3 chain of collagen type IV Goodpasture syndrome
Alports syndrome is a hereditary nephritis, characterized by microscopic hematuria (first symptom) and deafness.
43. Ans. (a) Post streptococcal glomerulonephritis (Ref: Robbins 9/e p910, Harrison 17th/1786-1787)
44. Ans. (a) PSGN; (b) MPGN; (e) Infective endocarditis: (Ref: Robbins 9/e p910, Harrison 17th/1788)
45. Ans. (a) MPGN-l; (c) PSGN; (d) Membranous GN; (e) RPGN (Ref: Robbins 9/e p910, 7th-975)
Summary of Glomerular Deposits
Subepithelial Subendothelial Basement membrane Mesangial
Acute GN (like PSGN) MPGN (Type I) MPGN (Type II) IgA nephropathy
Membranous GN SLE Membranous HSP

Heyman GN Acute GN Glomerulopathy Anti-GBM diseases like
RPGN (some cases) RPGN and Goodpasture syndrome
MPGN (Type I) rarely
46. Ans. (a) Proteinuria; (b) Hyperlipidemia; (c) Oedema; (e) Lipiduria (Ref: Robbins 9/e p914, 8th/907, 7th/978)
47. Ans. (a) Albumin (Ref: Robbins 9/e p914, 7th/958, Vasudevan-Sreekumari 4th/224)
Albuminuria is seen in nephrotic syndrome.
48. Ans. (b) Massive proteinuria; (d) Edema; (e) Hyperlipidemia. (Ref: Robbins 7th/978, 9/e p914)
49. Ans. (a) Heymann antigen is called megalin; (d) Subepithelial aspect of basement membrane has deposit.
(Ref: Robbins 7th/968 970, 9/e p903, 915)
The Heyman model of rat glomerulonephritis is induced by immunizing rat with an antigen containing preparation
of proximal tubular brush border.
The rats develop antibodies to this antigen and a membranous glomerulopathy, resembling human membranous
glomerulopathy. The antigen is called megalin and has homology to LDL receptor.
On electron microscopy, the glomerulopathy is characterized by presence of numerous electron dense deposits along
the subepithelial aspect of basement membrane. Immunofluorescence microscopy shows granular deposits.
50. Ans. (b) Malignant nephrosclerosis. (Ref: Robbins 7th/1008, 9/e p939)
51. Ans. (a) Foamy cells in interstitium; (d) Thinning of GBM < 100 nm: (Ref: Robbins 7th/988, 9/e p924)
Histological characteristics of Alports syndrome:
Diffuse basement membrane thinning Vascular sclerosis
Foam cells in interstitium Tubular atrophy
In advanced stage there is focal or global glomerulosclerosis Interstitial fibrosis
On electron microscopy (diagnostic of this disorder), GBM shows
Irregular foci of thickening alternating with thinning
Pronounced splitting and lamination of lamina densa (basket weave appearance)Q.
Info: Immunohistochemistry shows failure to stain a-3, 4, 5 collagen.
52. Ans. (b) Wegeners granulomatosis (c) Goodpastures syndrome (e) Microscopic polyangitis (Ref: Robbins 9/e p912,
7th/977)
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53. Ans. (a) Subepithelial deposits; (b) Nephritis along with acute renal failure; (c) Low complement levels; (d) HTN and
proteinuria: (Ref: Robbins 7th/974-5, 9/e p910-911)
54. Ans. (c) Microscopic polyangitis (Ref: Robbin 7th/540, 9/e p912, Harrison 17th/1789)
In microscopic polyangitis, there is a paucity of immunoglobulin demonstrable by immunofluorescence microscopy
(pauci-immune injury). There are few or no immune deposits in this type of vasculitis.
Pauci immune injury is also seen in Churg Strauss syndrome and Wegener granulomatosis.
55. Ans. (a) Diabetic Nephropathy (Ref: Robbin 7th/991, 9/e p1118)
56. Ans. (a) Goodpastures syndrome (Ref: Robbins 7th/745-746, 9/e p912)
57. Ans. (a) Diabetic glomerulosclerosis (Ref: Robbins 7th/991, 9/e p1118)
58. Ans. (a) Normal C3 (Ref: Robbins 7th/974-5, 9/e p910-911)
59. Ans. (b) Mesangioproliferative glomerulonephritis (Ref: Robbins 7th/403-405 , 9/e p393)
Visceral leishmaniasis is caused by L. donovani
Mucocutaneous leishmaniasis is caused by L. braziliensis.
Visceral leishmaniasis is characterized by the clinical features of hepatosplenomegaly, lymphadenopathy, pancytopenia, fever and
weight loss. There is hyperpigmentation of the skin, so it is also called as Kala azar.
In the renal involvement in this disease, there is presence of mesangioproliferative glomerulonephritis and in advanced cases,
there is presence of amyloidosis.
60. Ans. (a) Crescents in most of glomeruli (Ref: Robbins 975 7th/20-6, 9/e p910)
61. Ans. (a) Idiopathic cresenteric glomerulonephritis (Ref: Robbins 9/e p910-911, 8th/920; 7th/977)
62. Ans. (b) Diffuse involvement (Ref: Robbins 9/e p911, 8th/919; 7th/975)

63. Ans. (a) Diffuse glomerulosclerosis (Ref: Robbins 9/e p1118, 8th/934; 7th/990-992)
64. Ans. (c) Membranoproliferative glomerulonephritis (Ref: Robbins 8th/929; 7th/985)
65. Ans. (a) Post streptococcal GN (Ref: Robbins 8th/920; 7th/975)
66. Ans. (b) Nodular glomerulosclerosis (Ref: Robbins 9/e p1118, 8th/934; 7th/991)
67. Ans. (d) Diffuse alveolar involvement (Ref: Robbins 8th/709-710, 9/e p913)
68. Ans. (c) IgG deposition in mesangium (Ref: Robbins 9/e p923, 8th/925-926; 7th/981)
69. Ans. (b) Berger disease (Ref: Robbins 9/e p923, 8th/929-930; 7th/986)
70. Ans. (d) Rheumatoid arthritis (Ref: Robbins 9/e p912, 8th/920; 7th/977)
71. Ans. (d) Sodium and water retention (Ref: Robbins 9/e p922, 8th/407-408; 7th/522)
72. Ans. (b) Hematuria (Ref: Robbins 9/e p923, 8th/930, 7th/986)
73. Ans. (d) Focal segmental glomerulosclerosis (Ref: Robbins 9/e p919, 8th/926, 7th/983)
74. Ans. (d) All of the above (Ref: Robbins 9/e p942, 8th/669-670; 7th/1009-1010 )
75. Ans. (a) Membranous glomerulonephritis (Ref: Robbins 9/e p915, 8th/918, 923; 7th/984,979-981)
76. Ans. (c) Wegeners glomerulonephritis (Ref: Robbins 9/e p903, 8th/920; 7th/993,997)
77. Ans. (b) Membranoproliferative glomerulonephritis (Ref: Robbins 9/e p920, 8th/929; 7th/984)
78. Ans. (b) Membranous nephropathy (Ref: Robbins 9/e p915, 8th/918,920; 7th/975, 979)
79. Ans. (d) Multiple myeloma (Ref: Robbins 9/e p937, 8th/948)
Elevated total serum protein with normal albumin point towards the large amount of serum globulin. This is combination with other
features like back pain (from lytic lesions), immunosuppression (manifesting as recurrent infections), and amyloid deposition
enlarging the kidneys are all pointing towards the likely diagnosis of multiple myeloma.
Analgesic nephropathy can lead to tubulointerstitial nephritis and papillary necrosis.
Absence of both hemoptysis and history of anti glomerular basement antibodies rules out option b
The serum glucose is normal so, diabetes mellitus is ruled out. Glomerulosclerosis is not the same as amyloid.
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80. Ans. (c) Complete recovery without treatment (Ref: Robbins 9/e p911, 8th/917-9)
The findings in the stem of the question are characteristic of poststreptococcal glomerulonephritis. There are different
strains of streptococci which cause glomerulonephritis and rheumatic fever. Majority of the children with post streptococ-
cal glomerulonephritis recover without treatment. Rarely, few children develop a rapidly progressive glomerulonephritis.
The progression to chronic renal failure is more common in affected adults.
81. Ans. (d) Ovoid, periodic acid-Schiff (PAS)-positive, hyaline masses (Ref: Robbins 8th/142, 9/e p1118)
The most specific lesion (pathognomonic) of diabetic glomerulosclerosis is the Kimmelstiel-Wilson nodule. These are
ovoid, hyaline, PAS-positive structures found in the mesangial core at the edge of the glomerulus.
Mesangial IgA deposits (option A) are a feature of Berger disease (IgA nephropathy).
Necrotic epithelial cells in tubules (option B) are a feature of acute tubular necrosis.
Nests of cells with abundant clear cytoplasm (option C) are a feature of renal cell carcinoma.
82. Ans. (a) Anti-glomerular basement membrane disease (Ref: Robbins 8th/920-921, 9/e p912)
The two principal causes of rapidly progressive glomerulonephritis are anti-glomerular basement membrane (including
both Goodpastures syndrome and isolated anti-glomerular basement disease) and primary systemic vasculitis (including
Wegeners granulomatosis, microscopic polyarteritis, idiopathic rapidly progressive glomerulonephritis, Churg-Strauss
syndrome, polyarteritis nodosa, giant-cell arteritis, and Takayasus arteritis).
Diabetic nephropathy (choice B) typically begins with microalbuminuria and hypertension and progresses to renal failure. Hypertensive
nephropathy (choice C) due to essential hypertension typically presents with slowly rising BUN and creatinine; hypertensive nephropathy
due to malignant hypertension presents with more rapidly rising BUN and creatinine. Lupus nephritis (choice D) has the most typical
presentation as proteinuria.
83. Ans. (a) Focal segmental glomerulosclerosis (Ref: Robbins 8th/928, 9/e p920)
There is a specific association between focal segmental glomerulosclerosis and both IV drug abuse and HIV nephropathy.
This disorder usually presents as an aggressive form of nephrotic syndrome with poor prognosis and non responsive to
steroid therapy (called as collapsing variant).
8 3.1. Ans. (c) Fibrinogen (Ref: Robbins 8/e p922, Heptinstalls Pathology of the Kidney 6/e p131)
Direct quote from Heptinstalls Pathology.. Many factors increase in nephrotic syndrome usually due to lowering of se-
rum albumin to which they are usually bound. These factors include fibrinogen, factors V, VII, VIII and von Willebrand
factor. On the other hand, substances like factors XI and XII, plasminogen an anti-thrombin III.
Thrombotic and thromboembolic complications are common in nephrotic syndrome due to loss of anticoagulant factor
(e.g. antithrombin III, protein C and S) combined with increased platelet activation. Renal vein thrombosis is most often a
consequence of this hypercoagulative state. There is also increased synthesis of fibrinogen in the liver.
Figure: Mechanisms of edema formation in the nephrotic syndrome left. The classic view of edema formation, in which a low blood volume
(underfill) serves as the signal for secondary renal sodium retention Right. The mechanism of edema formation in most patient with the nephrotic
syndrome who have normal or slightly elevated blood volumes (overfill). The blunted response to atrial natriuretic peptide observed in patients
with the nephrotic syndrome may be the stimulus for primary renal sodium retention that plays a central role in edema formation. ANP, atrial
natriuretic peptide.
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Edema in nephrotic syndrome is attributed to the following:

Underfill hypothesis/classical hypothesis:
Seen in patients with low plasma volume
Hypovolemia is the primary stimulus leading to sodium and water retention leading to edema by alteration of
Starling forces
Overfill hypothesis/classical hypothesis:
Seen in patients with normal or increased plasma volume
Sodium retention is the primary mechanism leading to increased blood pressure and then alteration in Starling
forces and edema formation.
8 3.2. Ans. (a) Epithelial cells + fibrin + macrophage (Ref: Robbins 8/e p921, 9/e p913)
Crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into the urinary
space. Neutrophils and lymphocytes may be present. Fibrin strands are frequently prominent between the cellular layers
in the crescents. The escape of fibrinogen into Bowman space and its conversion to fibrin are an important contributor to
crescent formation.
Rapidly progressive glomerulonephritis is characterized histologically by domination of distinctive crescents. It is also
known as Crescentic glomerulonephritis. The crescents eventually obliterate Bowman space and compress the glomerular
tuft. So, the prognosis is dependent on the number of crescents in the kidney biopsy.
8 3.3. Ans. (a) Malignant hypertension (Ref: Robbins 8/e p950, 9/e p939)
Mnemonic for differential diagnosis of flea bitten kidney: We HaTe PSM
We: Wegeners granulomatosis
HaTe Henoch schonlein purpura; HUS;TTP
P- Poststreptococcal glomerulonephritis (PSGN); Polyarteritis nodosa (PAN)
S-Sub acute bacterial endocarditis (SABE)
M- Malignant hypertension

8 3.4. Ans. (a) Rapidly progressive glomerulonephritis (Ref: Robbins 8/e p920, 9/e p912-913)
Easy question friends given the fact that all the other options b, c and d are associated with nephrotic syndrome.
Just brush up!
IgA nephropathy is a frequent cause of recurrent gross or microscopic hematuria and is probably the most
common type of primary glomerulonephritis worldwide.
MC primary cause of nephritic syndrome in children: post streptococcal glomerulonephritis Q
MC primary cause of nephrotic syndrome in children: minimal change disease Q
MC primary cause of nephrotic syndrome in adults: focal segmental glomerulosclerosis Q
MC overall/ secondary cause of nephrotic syndrome in adults: diabetes mellitus Q
8 3.5. Ans. (d) Focal segmental glomerulosclerosis (Ref: Robbins 8/e p926, 9/e p 918)
Focal segmental glomerulosclerosis is the commonest cause of nephrotic syndrome in the adults in the World. It is
characterized by
NEET Points to be brushed up!
Associated with loss of renal tissue as unilateral renal agenesis or advanced stages of reflux nephropathy
Q
or hypertensive nephropathy.
Also seen with with conditions like Sickle cell anemia , HIV infection , Heroin abuse, Obesity
Q Q
Degeneration and focal disruption of the visceral epithelial cells is the hallmark feature of focal segmental
glomerulosclerosis.
Is chief renal lesion in HIV associated nephropathy (especially collapsing variant)
Q
8 3.6. Ans. (b) Rapidly progressive glomerulonephritis discussed earlier (Ref: Robbins 7/e p976-977, 9/e p912)
8 3.7. Ans. (c) 30-300 mg/d (Ref: Robbins 8/e p1145, 9/e p1120)
The earliest manifestation of diabetic nephropathy is the appearance of low amounts of albumin in the urine (>30
mg/day, but <300 mg/day), that is, microalbuminuria.
Microalbuminuria is also a marker for greatly increased cardiovascular morbidity and mortality for persons with either type
1 or type 2 diabetes
8 3.8. Ans. (c) Mild proteinuria, hematuria, high ASO titre (Ref: Robbins 9/e p910-911)
In post streptococcal glomerulonephritis, there elevated levels of antistreptolysin O or ASO and anti DNAase antibodies Q
(indicative of streptococcal infection) and reduced levels of serum C3

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Glomerular Syndromes
Acute nephritic syndrome Hematuria, azotemia, variable proteinuria, oliguria, edema, and hypertension
Rapidly prog. glomerulonephritis Acute nephritis, proteinuria, and acute renal failure
Nephrotic syndrome >3.5 gm proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria
Chronic renal failure Azotemia uremia progressing for years

83.9 Ans. (d) Renal biopsy having thin basement membrane (Ref: Robbins 9/e p925)
Benign familial hematuria is common hereditary entity manifested clinically by familial asymptomatic hematuriausually
uncovered on routine urinalysisand morphologically by diffuse thinning of the GBM to widths between 150 and 225 nm
(compared with 300 to 400 nm in healthy adults).

83.10. Ans (d) Minimal change disease (Ref: Robbins 9/e p 917)
The glomeruli are normal by light microscopy. By electron microscopy the GBM appears normal, and no electrondense
material is deposited. The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement
of foot processes.
Foot process effacement is also present in other proteinuric states (e.g., membranous glomerulopathy, diabetic nephropathy);
it is only when effacement is associated with normal glomeruli by light microscopy that the diagnosis of minimal-change
disease can be made.

83.11. Ans (c) Partial lipodystrophy (Ref: Robbins 9/e p 922)
Secondary MPGN (invariably type I) is more common in adults and arises in the following:
Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia;
endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis
1-Antitrypsin deficiency
Malignant diseases particularly CLL which have formation of autoantibodies
Robbins 8th mentioned that partial lipodystrophy is associated with C3 nephritic factor (C3NeF). It is associated with type
II membranoproliferative glomerulonephritis.

83.12. Ans. (d) Rapidly progressive glomerulonephritis (Ref: Robbins 9/e p912)
RBC casts are a feature of glomerular damage. Normally < 3 RBC/HPF are going to leak. But in case of glomerular dam-
age the number of RBC in the urine will exceed the limit mentioned above and these RBC get impinged on Tamm Horsfall
protein. The resultant RBC casts can be seen under microscopic examination of urine.

83.13. Ans. (a) Focal segmental glomerulonephritis (Ref: Robbins 9/e p919)
A morphologic variant of FSGS is called collapsing glomerulopathy and is the most characteristic lesion of HIV-associated
nephropathy.
84. Ans. (d) Urine PCR for TB (Ref: Robbins 9/e p943, 8th/947, Harrisons 18th/2372)
Major causes of Papillary necrosis are:
Analgesic nephropathy Sickle cell nephropathy Diabetes with urinary tract infection
Option a can detect urinary tract infection which may be associated with UTI.
Option b is helpful for detecting sickle cell disease.
Option c can detect renal tubular acidosis. Analgesic nephropathy is an important cause of distal tubular acidosis.
Renal TB is least likely cause of papillary necrosis and therefore, urine PCR for B is the answer of exclusion. Please note that TB
can cause focal papillary necrosis of the kidney rarely.
85. Ans. (a) Isomorphic RBC (Ref: Paediatric Nephrology 5th/141, 190 by R.N. Srivastava, Arvind Bagga (senior faculty from AIIMS)
Approach to patient with hematuria to determine source of bleeding
Parenchymal Intrarenal Collecting system Extrarenal
Appearance of urine Tea colored Bright red, blood clots
Pattern of hematuria Total hematuria (throughout the stream) Initial, terminal hematuria
Urinary symptoms Painless Dysuria, urgency, frequency
Associated features Sore throat, HTN, edema Fever, colicky pain
Family history Deafness, renal failure Renal stones, urinary infection
Proteinuria High grade (urine protein: creatinine ratio >1) Low grade
Other urinary findings RBC casts (highly specific less sensitive) Crystals
RBC morphology Dysmorphic Eumorphic
Page 141 mentions Eosinophiluria (>1% WBCs) is observed in acute interstitial nephritis.
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86. Ans. (b) Associated with tuberculosis (Ref: Robbins 8th/943, 9/e p934)
As discussed in text, Xanthogranulomatous pyelonephritis is associated with E. coli Proteus mirabilis, Pseudomonas,
Streptococcus faecalis and Klebsiella.
87. Ans. (d) Benign Nephrosclerosis (Ref: Robbins 9/e p938, 8th/949, 7th/992, 1006; Chandrasoma taylor 3rd/275)
Direct quote Robbins.. In benign nephrosclerosis, kidneys are either normal or moderately reduced in size on gross appearance. The
loss of mass is due mainly to cortical scarring and shrinking.
Causes of contracted kidneys
Amyloidosis Diabetic renal disease [Kimmelstiel Wilson nodules are pathognomic]
Important info
Contracted kidneys:Less than 8 cm length of kidney is taken as chronic contracted kidney. Normal size corresponds to 3 times the
length of L1 vertebrae or 2/3rd of additive length of T11, T12 and L1 vertebrae.
Note: In some patients of diabetes (especially in late stages), kidney may be reduced in size.
88. Ans. (b) Tuberculous pyelonephritis (Ref: Robbins 7th/1004, 9/e p936, Harrison 17th/1825 1826)
Necrotizing papillitis is the other name of acute papillary necrosis. When infection of renal pyramids develop in
association with vascular diseases of the kidney or with urinary tract obstruction, renal papillary necrosis is likely to result.

In the given options, DM is the commonest and TB is the rarest cause of papillary necrosis
Diabetes mellitus
Sickle cell disease
Chronic alcoholism
Vascular disease
Analgesic abuse nephropathy
89. Ans. (a) PCT (Ref: Robbins 9/e p928, 8th/937-8, 7th/918)
ATN
Ischemic ATN Nephrotoxic ATN

Most common cause of ATNQ. Due to drugs (gentamicin, methicillin, radio
Due to decreased blood flow (in shock, contrast agents, organic solvents, ethylene
hemorrhage, hypotension or dehydration). glycol, phenol, pesticides, myoglobin).
Pressence of focal tubular necrosis affecting Diffuse necrosis of proximal convoluted
proximal straight tubule and ascending limb tubular segments and ascending Henles
of loop of HenleQ. loopQ occur.
Clinical info:Harrison 18th

It is the most common cause of acute renal failure (ARF). ARF is defined as rapid and reversible deterioration of renal function leading
to reduction of urine outflow to less than 400 ml per day within 24 hours.
90. Ans. (d) Medullary cystic kidney (Ref: Harrison 18th/2383, 16th/1807, Robbins 9/e p948, 8th/947, 7th/1005)
Nephrocalcinosis is a diffuse deposition of calcium salts in the interstitium of the kidney.
Conditions associated with nephrocalcinosis are:
Hyperoxaluria Hyperthyroidism
Hyperparathyroidism Hyperuricosuria
Prolonged immobilization Renal candidiasis
Hypervitaminosis D Excessive calcium intake (milk alkali syndrome)
Hypophosphatemic rickets Sarcoidosis
Excessive bone destruction in metastasis Renal tubular acidosis (distal)
Cortical necrosis malignancies (such as multiple myeloma) Medullary sponge kidney
Cushing syndrome
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91. Ans. (a) Goodpastures syndrome; (b) Leptospirosis; (d) Wegeners granulomatosis; (e) Hantan virus infection; (Ref:
Harrison 17th/1793)
Pulmonary renal syndrome is seen in
Goodpastures syndrome: pulmonary hemorrhage and renal failure
Leptospirosis: Renal and hepatic dysfunction, Hemorrhagic pneumonia, bleeding diathesis
Hantan virus also cause pulmonary renal syndrome.
Wegeners granulomatosis: Lung and kidney involvement common.
Other causes of pulmonary renal syndrome include Henoch Schonlein purpura, Churg Strauss vasculitis, microscopic polyangiitis
and cryoglobulinemia.
Please note that Legionella does not affect kidneys. It causes atypical pneumonia, diarrhea and hyponatremia.*
92. Ans. (b) DM, (c) Phenacetin abuse, (d) Alcoholism (Ref: Harrison 17th/1826, Robbins 9/e p936, 8th/947, 7th-1004)
Causes of papillary necrosis
Diabetes mellitus Analgesic nephropathy Sickle cell disease Obstruction
M:F 1:3 1:5 1:1 9:1
Time course 10 years 7 years of abuse Variable Variable
Infection 80% 25% + or 90%
Calcification Rare Frequent Rare Frequent
Number of papillae Several; all of same Almost all; all in different Few Variable
affected stage stages of necrosis
93. Ans. (a) Hyperparathyroidism; (b) T.B. Kidney; (c) Hypercalcemia (Ref: Harsh Mohan 6th/685, Robbins 9/e p937, 7th/l005)
Causes of Nephrocalcinosis
Distal RTA Hyperparathyroidism Multiple myeloma
Severe hypercalcemia Hypercalcemia Vitamin D intoxication
Medullary sponge kidney TB kidney Metastatic bone disease

94. Ans. (d) Polycystic kidney disease; (e) Amyloidosis: (Ref: Robbins 7th/964, 992, 989, 9/e 947)
Causes of bilaterally enlarged kidneys Causes of small contracted kidney
Polycystic kidney diseases Benign nephrosclerosis
Amyloidosis of kidney Chronic glomerulonephritis
DM Chronic Pyelonephritis
95. Ans. (c) Alports syndrome (Ref: Robbins 7th/988, 9/e p924, Harrison 17th/1794)
Hereditary Nephritis refers to a group of heterogenous hereditary familial diseases associated primarily with glomerular
injury. These are: Alports syndrome and Thin membrane disease.
96. Ans. (b) Medullary sponge kidney; (D) RTA (Ref: Robbins 7th/1005, 9/e p937,948)
97. Ans. (d) Neutrophilic infiltration; (e) Necrotizing vasculitis: (Ref: Robbins 7th/220)
Acute rejection can be caused by either cellular or humoral mechanisms
The histologic features of acute humoral rejection (within days) in renal transplants are:
Necrotizing vasculitis
Endothelial cell necrosis
Neutrophilic infiltration
Deposition of immunoglobulins
Complement and fibrin deposition and thrombosis.
There is extensive necrosis of renal parenchyma.
In acute cellular rejection
Extensive interstitial mononuclear cell infiltration
Edema
Interstitial hemorrhage is seen.
In hyper acute rejection (within minutes or hours)
Fibrinoid reactions are seen
In chronic rejection (over period of 4-6 months)
Vascular changes consisting of dense, obliterative intimal fibrosis, principally in the cortical arteries seen. It clinically
presents with progressive rise in serum creatinine.
98. Ans. (b) Schistocytes (Ref: Harrison 17th/723, Robbin 9/e p644)
478
The presence of a severe hemolytic anemia with schistocytes or fragmented red blood cells in the peripheral blood smear
is characteristic of microangiopathic hemolytic anemia such as in Hemolytic uremic syndrome and Thrombotic thrombo-
cytopenic purpura.
99. Ans. (b) Cortical tubular hypertrophy (Ref: Robbins 8th/959, 7th/966)
Cortical tubulo-interstitial damage occurs in nephronophthisis.
Nephronophthisis (Uremic Medullary Cystic Disease Complex)
It is a group of progressive renal disorders that usually have onset in childhood.
Common characteristic is the presence of a variable number of cysts in the medulla, usually concentrated at the
cortico-medullary junction.
Cortical tubulo-interstitial damage occurs.
4 variants of this disease are:
Sporadic/non familial (20%)
Familial juvenile nephronophthisis (40-50% autosomal recessive).
Renal-retinal dysplasia (15% autosomal recessive)
Adult-onset medullary cystic disease (15% autosomal dominant).
Affected children present first with polyuria and polydipsia which reflect a marked tubular defect in concentrating
ability.
Sodium wasting and tubular acidosis are also prominent.
Renal failure occurs in a period of 5-10 years.
In gross appearance, the kidneys are small, have contracted granular surfaces and show cysts in the medulla, most
prominently at the cortico-medullary junction.
Small cysts are also seen in the cortices and are lined by flattened or cuboidal epithelium.
In the cortex, there is widespread atrophy and thickening of the basement membranes of proximal and distal tubules
together with interstitial fibrosis.

In general, glomerular structure is preserved.
100. Ans. (a) Diabetes Mellitus (Ref. Robbins 7th/991, 1004, 9/e p936)
101. Ans. (a) Calcium oxalate (Ref: Robbins 7th/1014, 9/e p951)
102. Ans. (c) Interstitial nephritis (Ref: Robbins 9/e p930, 8th/938-939, 7th/1002-1003)
103. Ans. (c) Diabetes mellitus (Ref: Robbins 9/e p936, 8th/934; 7th/1003)
104. Ans. (b) Lupus nephritis (Ref: Robbins 8th/939, 9/e p929)
105. Ans. (d) Lipoid nephrosis (Ref: Robbins 9/e p222-223, 8th/218, 7th/231-232)
106. Ans. (a) Fibrinoid necrosis (Ref: Robbins 9/e p939, 8th/950, 7th/1007)
107. Ans. (c) Amyloidosis (Ref: Robbins 8th/254, 7th/263) Harsh Mohan
108. Ans. (a) Acute glomerulonephritis (Ref: Robbins 9/e p911, 8th/936)
109. Ans. (a) Calcium oxalate stone (Ref: Robbins 9/e p951, 8th/962, 7th/1014)
110. Ans. (a) Goodpastures syndrome (Ref: Robbins 9/e p912, 8th/920, 7th/745)
111. Ans. (b) Calcium oxalate (Ref: Robbins 9/e p951, 8th/962)
The patient has typical features suggestive of a ureteric colic. Most of the renal stones are composed of calcium oxalate
crystals. Patients with these stones tend to have hypercalciuria without hypercalcemia. Uric acid stones and cystine stone
are radiolucent and tend to form in acidic urine. Triple phosphate (magnesium ammonium phosphate) stones occur more
frequently with UTI caused by urease positive bacteria like Proteus sp. Mucoproteins may fuse together to form hyaline
casts which are asymptomatic because they are very small.
112. Ans. (c) Cystitis (Ref: Robbins 8th/974-5, 9/e p962)
The clinical presentation of the patient in the stem of the question is of cystitis, which is characterized by pyuria and
hematuria but absence of white cell casts in the urine.
Patients with acute pyelonephritis present with fever, leucocytosis, flank tenderness, urinary white cells, and white cell
casts in the urine. Chronic pyelonephritis is almost always the result of chornic urinary tract obstruction and repeated
bouts of acute inflammation in the kidneys.
113. Ans. (c) White blood cell casts (Ref: Robbins 9/e p933, 8th/942)
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WBC casts are pathognomonic for pyelonephritis when UTI is present. They are formed only in tubules, where
leukocytes are precipitated by the Tamm Horsfall protein secreted by tubular epithelial cells. Urethritis and cystitis are
both characterized by the clinical features of dysuria, frequency, urgency, pyuria, and bacterium, but suprapubic pressure
and tenderness is more specific to cystitis. If pathogens ascend via the ureter to penetrate kidney parenchyma, systemic
signs of the disease become prominent. Symptoms of acute pyelonephritis include fever, chills, nausea, vomiting, flank/
abdominal pain, and costovertebral angle (CVA) tenderness. Urine sediment microscopy reveals WBCs, WBC casts, and
bacteria.
(Choice A) Abdominal pain is a non-specific symptom. It can be seen in acute pyelonephritis and in a large number of other
conditions, like pelvic inflammatory disease.
(Choice B) Fever is a sign of any systemic infection. In acute pyelonephritis, it may also be accompanied by shaking chills,
nausea, vomiting, diarrhea, muscle aches, and anorexia.
(Choices C and D) Bacteriuria is found in both upper (acute pyelonephritis) and lower (cystitis, urethritis) UTIs.
114. Ans. (b) Absence of antibacterial properties in vaginal fluid (Ref: Robbins 8th/939, 9/e p931)
Females are more susceptible to UTIs due to having urethras that are both closer to the rectum and shorter than in males.
Sexual intercourse is often a precipitating factor for UTI. The increased predisposition is also attributed to the absence of
antibacterial substances which are present in prostatic fluid. Moreover, thinking logically, the anti infective substances in
vaginal fluid will prevent vaginal infection. They cannot prevent UTI.
115. Ans. (a) Disseminated intravascular coagulation (Ref: Robbins 8th/954, 9/e p944)
Diffuse cortical necrosis is usually seen in the setting of disseminated intravascular coagulation, typically associated with
overwhelming sepsis. It can also be seen following hypotension combined with vasoconstriction.
Multiple myeloma (option B) is associated with renal deposition of amyloid protein and damage to both glomeruli and
tubules.
Pyelonephritis (option D) would produce inflammation, often most severe in the renal pelvis. Sickle cell anemia (option c)
usually affects the medulla most severely, and can cause papillary necrosis.
116. Ans. (c) Hyperparathyroidism (Ref: Robbins 8th/962, 9/e p951)
The patients history of recurrent urolithiasis with calcium-containing stones implies a disorder in the regulation of cal-
cium concentration. Hyperparathyroidism is associated with increased parathormone (PTH) levels, which can produce
hypercalcemia, hypercalciuria, and, ultimately, renal stones.
Anemia of chronic disease (option A) does not produce calcium stones. The patient presents with a chronic condition and hematuria
but the urinary blood loss is not usually significant enough to produce an anemic state.
Hyperaldosteronism (option D) results in potassium depletion, sodium retention, and hypertension. Primary hyperaldosteronism
(Conns syndrome) is associated with adrenocortical adenomas in 90% of patients and is characterized by decreased renin.
Secondary hyperaldosteronism results from excessive stimulation by angiotensin II that is caused by excess renin production
(plasma renin-angiotensin levels are high). Neither condition is associated with renal stones.

117. Ans. (a) Decreased renal perfusion (Ref: Robbins 8th/906, 9/e p898)
The patients ankle edema, shortness of breath, and relatively low blood pressure suggest the development of congestive
heart failure (confirmed by the cardiac enlargement and perihilar infiltrates). This is an important prerenal cause for the
azotemia resulting in elevated serum urea nitrogen with normal serum creatinine.
Postrenal causes of azotemia are typically due to urinary tract obstruction distal to the kidney (option B), and usually cause
a rise in both urea and creatinine, with the rise in urea being larger than that in creatinine.
Increased synthesis of urea (option C) is seen in severe burns and prolonged high fever.
Renal tubulointerstitial disease (option D) severe enough to cause renal failure will cause both urea and creatinine to rise;
the creatinine may rise out of proportion to the urea, particularly in acute tubular necrosis.
1 17.1. Ans. (b) Co-dominant (Ref: Robbins 8/e p931-2, 9/e p924)
Friends, read the following lines from Robbins carefully.
Alport syndrome is manifested by hematuria with progression to chronic renal failure, accompanied by nerve deafness and vari-
ous eye disorders, including lens dislocation,posterior cataracts, and corneal dystrophy.
The disease is inherited as an X-linked trait in approximately 85% of cases. In this X-linked form, males express the full
syndrome and females are carriers in whom manifestations of disease are typically limited to hematuria.
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Autosomal recessive and autosomal dominant pedigrees also exist, in which males and females are equally suscep-
tible to the full syndrome
1 17.2. Ans. (a) Diabetes mellitus (Ref: Robbins 8/e p947, 9/e p 936, Top 3 Differentials in Radiology: A Case Review Thieme pg
121)
The most common cause of papillary necrosis is diabetes mellitus ..Top 3 Differentials in Radiology
Q
Encyclopedia of Imaging, Vol 2; pg 1192.. diabetes mellitus is the most common condition associated with renal papillary necrosis
accounting for >50% of all cases.
Clinical Pathology Oxford press pg220.. acute papillary necrosis is most often a complication of acute pyelonephritis in
diabetes. Chronic papillary necrosis is seen most often in association with analgesic nephropathy.
Conditions with papillary necrosis: Mnemonic is Postcards
Pyelonephritis
Obstruction of the urinary tract
Sickle cell hemoglobinopathies, including sickle cell trait
Tuberculosis
Cirrhosis of the liver, Chronic alcoholism
Analgesic abuse
Renal transplant rejection, Radiation
Diabetes mellitus
Systemic vasculitis
117.3. Ans. (b) Diabetes mellitus (Ref: Robbins 8/e p934, 7/e p991-992)
Causes of contracted kidneys

Amyloidosis Diabetic renal disease [Kimmelstiel winos nodules are pathognomonic]
117.4. Ans. (a) Chronic pyelonephritis (Ref: Robbins 9/e p934, 8/e p943, 7/e p989)
In the morphology of chronic pyelonephritis, glomeruli may appear normal except for periglomerular fibrosis.
117.5. Ans. (a) Hyperparathyroidism (Ref: Robbins 9/e p937)
Disorders characterized by hypercalcemia, such as hyperparathyroidism, multiple myeloma, vitamin D intoxication,
metastatic bone disease, or excess calcium intake (milk-alkali syndrome), may induce the formation of calcium stones and
deposition of calcium in the kidney (nephrocalcinosis).
1 17.6. Ans. (b) Tuberculous cystitis (Ref: Bailey 25/e p1108)
TB Urinary Bladder
Bladder tuberculosis is almost always secondary to renal tuberculosisQ.
The disease starts at the ureteric opening, the earliest evidence being pallor of the mucosa due to submucosal edema.
Subsequently tiny white transluscent tubercles develop all over. Gradually these tubercles enlarge and may ulcerate (but do
not cause bladder perforationQ).
These tubercles lend cobblestone appearanceQ on cystoscopy.
There is considerable suhmucous fibrosis which causes diminished capacity of bladder. Scarred & ftbrosed, small capacity
bladder is known as thimble bladderQ.
The fibrosis which usually starts around the ureter, contracts to cause a pull at the ureters. This either leads to a stricture or
displaced, dilated and rigid wide mouthed ureter called as golf hole uretersQ (this almost always leads to ureteral reflux.)
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117.7. Ans. (d) Micro RNA -122 (Ref: Harrison 18/e p2304-5)
New question friends and highly likely to be repeated..
Name of marker Significance
Kidney injury molecule-1 * Type-1 cell membrane glycoprotein upregulated in de differentiated proximal tubule epithelial cells
(KIM-1) and Clusterin * Elevated urinary levels are highly sensitive and specific for AKI
Cystatin C * Important extracellular inhibitor of cysteineproteases
* Elevated urinary levels reflect tubular dysfunction; high levels may predict poorer outcome
NGAL * Expression upregulated in kidney proximal tubule cells and urine following ischemic or cisplatin induced
renal injury
* Found to be an early indicator of AKI following cardiopulmonary bypass
IL-18 * Constitutively expressed in distal tubules; strong immunoreactivity in proximal tubules with transplant rejec-
tion
* Elevated urinary levels found to be early marker of AKI and independent predictor of mortality in critically
ill patients
Na+/H+ exchanger 3 (NHE 3) * For discrimination between prerenal azotemia and AKI in ICU patients
L-FABP Biomarker in CKD and diabetic nephropathy
Osteopontin * Correlates with inflammation and tubulointerstitial fibrosis
2-Microglobulin * Light chain of the MHC I molecule;
* An early marker of tubular dysfunction
1-Microglobulin * Synthesized by the liver; tubular dysfunction marker
Microalbumin Marker for monitoring progression of chronic kidney disease
NGAL is Neutrophil gelatinase associated lipocalin, Liver fatty acidbinding protein (L-FABP);
In addition, N-Acetyl--(D) glucosaminidase (NAG), Retinol-binding protein, Cysteine-rich protein CYR 61, Exosomal
fetuin-A and enzymes like Alanine aminopeptidase (AAP), alkaline phosphatase (AP), Glutathione-S-transferase

(-GST) Glutamyl transpeptidase (-GT) are other markers of acute kidney injury (AKI).

117.8. Ans (c) Silicosis (Ref: Robbins 9/e p690)
117.9. Ans (b) Crystals are hexagonal (Ref: Robbins 9/e p 952)
Hexagonal stones are seen in cystine stones whereas uric acid stones are barrel or diamond shaped.
Uric acid stones are common in individuals with hyperuricemia, such as patients with gout, and diseases involving rapid
cell turnover, such as the leukemias.
A tendency to excrete urine of pH below 5.5 may predispose to uric acid stones, because uric acid is insoluble in acidic
urine. In contrast to the radiopaque calcium stones, uric acid stones are radiolucent.
117.10. Ans (a) Nodular glomerulosclerosis (Ref: Harsh Mohan 6/e p678)
Nodular lesions of diabetic glomerulosclerosis are also called as Kimmelstiel-Wilson (KW) lesions or intercapillary glomeru-
losclerosis. These lesions are specific for type 1 diabetes.
118. Ans. None or c Cushing syndrome. (Ref: Robbins 8th/966, Kidney Cancer: Principles and Practice (2012) pg 71, Springer,
Harrison 17th/592: 618)
Friends, ideal answer of this question would be none. Robbins 8th/966. renal cell carcinomas produce a number of
paraneoplastic syndromes, ascribed to abnormal hormone production, including polycythemia, hypercalcemia, hyperten-
sion, hepatic dysfunction, feminization or masculinization, Cushing syndrome, eosinophilia, leukemoid reactions, and
amyloidosis.
However, a table from Kidney Cancer: Principles and Practice is given underneath to help you decide the fact that if we
have to compulsorily mark one option as the answer, then it has to be Cushing syndrome (option c) because it has the
rarest incidence.
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Paraneoplastic manifestations of renal cell cancer syndromes with their incidence

Paraneoplastic syndrome Incidence
Endocrinological
Hypercalcemia 13-20%
Hypertension 40%
Polycythemia 1-8%
Stauffer syndrome 3-20%
Elevated Alkaline phosphatase 10%
Cushing syndrome 2%
Thrombocytosis -
Cachexia 30%
Non endocrine
Amyloidosis 3-8%
Anemia 20%
Neuromyopathy 3%
Vasculopathy -
Nephropathy -
Fever 20%
Stauffer syndrome is the name give to non metastatic hepatic dysfunction.
119. Ans. (d) Bilateral polycystic kidney (Ref: Robbins 8th/479-480, 9/e p479-480)
Wilms tumor (Nephroblastoma) is the most common primary renal tumor of childhood in USA. It is associated with the
following:

WAGR syndrome
It is characterized by aniridia, genital anomalies, and mental retardation and increased choice of developing Wilms tumor. Patients with
WAGR syndrome carry constitutional (germline) deletions of two genes WT1 and PAX6 both located at chromosome 11p13Q.
Denys-Drash syndrome
It is characterized by gonadal dysgenesis (male pseudohermaphroditism) and early-onset nephropathy leading to renal failure.
Beckwith-Wiedemann syndrome
It characterized by enlargement of body organs (organomegaly), macroglossia, hemihypertrophy, omphalocele and abnormal large cells
in adrenal cortex (adrenal cytomegaly).
Clinical features include presentation as a large abdominal mass extending across the midlineQ and down into the pelvis.
The patient may also present with fever and abdominal pain, with hematuria, intestinal obstruction or hypertensionQ as a
result of pressure from the tumor.
120. Ans. (c) Trisomy 7/17 (Ref: Robbins 8th/964-964, 9/e p953-954, Harrison 17th/592)
Friends, answer to the question is very easy for us to understand provided we are aware of the fact that chromophilic renal
cell cancer is the other name of papillary renal cell cancer because 80% of chromophilic renal cell cancers show a tubu-
lopapillary architecture. (source.British Journal of Cancer 1996,74; 1605-1614.). As discussed in text, Papillary cancer is
associated with trisomy 7, 16, 17.
121. Ans. (a) Clear cell type (Ref: Robbins 7th/1016, 1017, 9/e p953)
122. Ans. (b) Wilms tumor (Ref. Robbins 8th/479, 9/e p479)
Wilms tumor is increased in WAGR syndrome, Dennys-Drash syndrome and Beckwith- iedemann syndrome. w
The features mentioned in the question point to a diagnosis of WAGR syndrome. The components of this syndrome are
W Wilms tumor
A Aniridia
G Genital anomalies
R Mental retardation
123. Ans. (C) Anaplasia (Ref: Robbins 8th/481, 9/e p481)

5% of tumors reveal anaplasia, defined as the presence of cells with large, hyperchromatic, pleomorphic nuclei and abnor-
mal mitoses and the presence of anaplasia correlates with underlying p53 mutations and the emergence of resistance to
chemotherapy.
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124. Ans. (b) Associated with deletion of chromosome 11p13 (Ref: Robbins 9/e p479, 8th/479-481; 7th/504-506)
125. Ans. (a) Clear cell (Ref: Robbins 9/e p953, 8th/964; 7th/1016)
126. Ans. (b) Abdominal CT scan for renal mass (Ref: Robbins 9/e p955, 8th/964-6)
Painless hematuria in an old patient is highly suggestive of a renal malignancy. Moreover, additional presence of consti-
tutional symptoms, such as fever and weakness, increase the suspicion of a renal cell carcinoma.
Urinary tract calculi usually cause severe, colicky pain when they are passed.
Nephrotic syndrome, which manifests with proteinuria, typically is not associated with hematuria,
A renal biopsy has a less diagnostic yield in a condition without an acute onset renal disease, and it is not very effective for
diagnosing neoplasms.
127. Ans. (c) Nephroblastoma (Ref: Robbins 8th/481, 9/e p481)

Nephroblastoma (Wilms tumor) characteristically affects children between 2 and 4 years of age and can form large
spherical masses composed of variegated tissues including primitive renal epithelial elements, a sarcomatous-ap-
pearing stroma, abortive glomeruli and tubules, and heterologous tissues such as muscle, cartilage, fat, and bone.
Cortical adenoma (option A) is a small (under 2 cm) benign tumor that is usually found incidentally at autopsy.
Hemangiomas (option B) can occur in the kidney, but would not usually produce a large mass.
Oncocytomas (option D) are benign tumors that can be large but do not usually affect young children.
128. Ans. (c) Wilms tumor (Ref: Robbins 8th/481, 9/e p479-481)
The only childhood malignancy in the given options is Wilms tumor, which commonly presents in a toddler as a large
abdominal mass. There is now a 90% survival rate for this tumor with combined therapy with surgery, chemotherapy, and
radiotherapy.
Renal cell carcinoma (choice A) and transitional cell carcinoma of the bladder (choice D) are malignant tumors of adults. Renal
hamartoma (fibroma; choice B) causes a small, gray, benign module in the renal pyramids and is usually only identified as an incidental
finding.
1 28.1. Ans. (b) Tumour stage (Ref: Robbins 8/e p, Rudolph Pediatrics; Robbins 9/e p481)
Also revise that anaplsia is an adverse prognostic factor because it increases the resistance to chemotherapy and increased
chances of recurrence.
Good prognostic factors Poor prognostic factors
Age < 2 years Age > 2 years
Early stage disease (stage I,II) Late stage disease (stage III,IV)
Favourable histology Anaplasia (unfavourable histology)
Tumour < 500 gms Tumour > 500 gms
Loss of genetic material on 11q,16q
Gain of material on 1q
Renal vessel and capsule invasion
1 28.2. Ans. (d) Collecting duct (Ref: Robbins 8/e p964, 9/e p953)
Oncocytoma
Arises from the intercalated cells of collecting ducts . Q
Epithelial tumor composed of large eosinophilic cells having small, round, benign-appearing nuclei that
have large nucleoli.
Ultrastructurally the eosinophilic cells have numerous mitochondria . Q
128.3. Ans. (c) Chromosome 11 (Ref: Robbins 8/e p479-80, 9/e p479-480)
Easiest way to remember that info.. count the number of letters in Wilms tumour..yea it is exactly 11the location of
both genes associated with Wilms tumour
So, the two genes associated with Wilms tumour WT1 gene (located on chr 11p13)and WT2 gene (located on chr 11p15).
128.4. Ans. (c) Wilms tumor. Discussed in a separate question (Ref: Robbins 8/e p479-480, 9/e p479-480)
129. Ans. (b) Malacoplakia (Ref: Robbins, 9/e p963, 8th/975, 7th/1027-8)
Michaelis-Gutmann bodies are laminated mineralized concretions typically present within the macrophages resulting from
deposition of calcium in enlarged lysosomes. It is seen in malacoplakia. Similar lesions are also seen in the colon, lungs,
bones, kidneys, prostate, and epididymis. In this conditions, there is presence of PAS+ macrophages.
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130. Ans. (c) Atrophy (Ref: Robbins 7th/9, 1012, 9/e p950)
Chronic urethral obstruction because of urinary calculi, prostatic hypertrophy, tumors, normal pregnancy, uterine pro-
lapse or functional disorders cause hydronephrosis which by definition is used to describe dilatation of renal pelvis and
calyces associated with progressive atrophy of the kidney due to obstruction to the outflow of urine.
Concept
Atrophy is shrinkage in size of the cell by loss of cell substance.Atrophied cells are only decreased in size; they are not dead
131. Ans. (c) Malacoplakia (Ref: Robbins 9/e p963, 8th/975, 7th/1027)
132. Ans. (a) Light chain (Ref: Robbins 9/e p937-938, 8th/948, 7th/1005)
132.1. Ans. (a) Schistosomiasis (Ref: Robbins 8/e p979, 9/e p965)
Direct lines from Robbins...
Schistosoma haematobium infections in endemic areas like Egypt and Sudan are an established risk. The ova are deposited
in the bladder wall and incite a brisk chronic inflammatory response that induces progressive mucosal squamous metapla-
sia and dysplasia and, in some instances, neoplasia.
Most of these cancers are squamous cellQ carcinomas.
132.2. Ans. (b) Hypophosphatemia (Ref: Harrison 18/e)
Hyponatremia
Hyperkalemia
Hyperphosphatemia
Golden Points For quick revision / Updated information from 9th edition of robbins
(KIDNEY and Urinary Bladder)
Robbins 9th/898.Chronic kidney disease is elaborated

Chronic kidney disease (previously called chronic renal failure) is defined as the presence of a diminished GFR that is persistently less than
60 mL/minute/1.73 m2 for at least 3 months, from any cause, and/or persistent albuminuria.
Robbins 9th/915.Membranous nephropathy with new autoantigen

Primary (also called idiopathic) membranous nephropathy is now considered to be an autoimmune disease linked to certain HLA
alleles such as HLA-DQA1 and caused in most cases by antibodies to a renal autoantigen. In many adult cases the autoantigen is the

phospholipase A2 receptor. This antigen is the counterpart of the megalin antigen complex in the rats.
Robbins 9th/938Bile Cast Nephropathy

Hepatorenal syndrome refers to impairment of renal function in patients with acute or chronic liver disease with advanced liver failure.
This can be associated with highly elevated bilirubin levels with bile cast formation (also known as cholemic nephrosis) in distal nephron
segments. The casts can extend to proximal tubules, resulting in both direct toxic effects on tubular epithelial cells and obstruction of the
involved nephron. The tubular bile casts can range from yellowish-green to pink. The reversibility of the renal injury depends upon the
severity and duration of the liver dysfunction.
Robbins 9th/953.additional risk factor of renal cell cancer

Hereditary leiomyomatosis and renal cell cancer syndrome: This autosomal dominant disease is caused by mutations of the FH gene,
which expresses fumarate hydratase, and is characterized by cutaneous and uterine leiomyomata and an aggressive type of papillary
carcinoma with increased propensity for metastatic spread.
Birt-Hogg-Dub syndrome: The autosomal dominant inheritance pattern of this disease is due to mutations involving the BHD gene, which
expresses folliculin. The syndrome features a constellation of skin (fibrofolliculomas, trichodiscomas, and acrochordons), pulmonary (cysts
or blebs), and renal tumors with varing histologies.
Additional variant of renal cell cancer (as if clear cell, papillary, chromophobe and collecting duct were not enough!!!)
Robbins 9th/954
Xp11 translocation carcinoma is a genetically distinct subtype of renal cell carcinoma. It often occurs in young patients and is defined by
translocations of the TFE3 gene located at Xp11.2 with other genes resulting in over expression of TFE3. The neoplastic cells consist of
clear cytoplasm with a papillary architecture.
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CHAPTER 12
The normal layers present in the gastrointestinal tract are:
Gastrointestinal Tract

1. Mucosa consisting of epithelial layer, lamina propria and muscularis mucosae Serosa is absent in the esopha-

2. Submucosa having submucosal glands and Meissners plexus gus except for intra-abdominal

3. Muscularis propria consisting of inner circular layer, outer longitudinal layer and portion.
having Auerbachs plexus in between these two layers.

4. Serosa.
The submucosa is the strong-

ESOPHAGUS est layer of the gut. Surgically,
it provides strength to intestinal
It is a muscular tube almost 25 cm in length in adults (it is about 10 cm in a newborn) taking
anastomosis
the food from the oral cavity into the stomach. The esophagus is having the following four
constrictions in it:
Cricopharyngeus constriction: present at 15 cm (6 inches) from the incisor teethQ.
Aortic arch constriction: present at 22.5 cm (9 inches) from the incisor teethQ.
Left bronchus constriction: present at 27.5 cm (11 inches) from the incisor teethQ.
Diaphragmatic and lower esophageal sphincter constriction: present at 40 cm (16 inches) from
the incisor teethQ.
Calcifying epithelial odonto-
There is presence of a functional sphincter at the lower end of the esophagus (LES) which genic tumour is called as
prevents the reflux of the gastric contents back into the esophagus. Pindborg tumour.
ACHALASIA CARDIA
It is a disease characterized by loss of ganglion cells in the Auerbachs plexus the cause
of which may be unknown (Primary achalasia) or it may be due to secondary cause like
Chagas disease (caused by T. cruzi) or Varicella zoster infection. This result in the incomplete
relaxation of the LES and its increased resting tone. There is selective loss of function of
inhibitory neurons like those secreting vasoactive intestinal peptide and nitric oxide whereas CCK test causes paradoxical
cholinergic innervation is intact. It is characterized by the triad of incomplete LES relaxation, increase in LES tone in achalasia
increased LES tone and aperistalsis of the esophagus. cardia
Clinical features include progressive dysphagia (difficulty in swallowing increases with
time as the disease progresses) for food though usually dysphagia is more for the liquid food
as compared to solid food particles.
Screening test
CholecystokininQ (CCK) test: CCK normally causes a fall in the sphincter pressure (because of the
relaxant effect of inhibitory neurotransmitters like VIP and nitric oxide) but in achalasia cardia it causes
paradoxical increase in LES tone (loss of inhibitory neurons).
Diagnosis
Barium swallow shows bird beakQ or rat tailQ appearance of the esophagus (due to normal
upper esophagus with tapering in the lower part). The gastric bubble is usually
absent in chest X-ray.
Manometry is the most confirmatory investigation. Q
Treatment
It is medically managed with botulinum toxin but the treatment of choice is surgical excision of the
muscle of the lower esophagus and cardia (Heller myotomyQ).
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HIATAL HERNIA
It is characterized by the separation of the diaphragmatic crura and increased space between
the muscular crura and the esophageal wall. It can be of two types:

1. Sliding hernia (95%): Characterized by upward dislocation of cardioesophageal
junction. Esophagitis resulting from the reflux is commonly seen.

2. Paraesophageal/Rolling hernia (5%): A part of the stomach enters the thorax
without any displacement of the cardioesophageal junction. Dysphagia is common
and chest pain may also be present (usually relieved by a loud belch).
Treatment is achieved only with surgical repair of the defect.
MALLORY-WEISS TEARS
Mallory-Weiss tears are mucosal tears in the esophagogastric junction or the gastric cardiac
Most of the cases (90%), the
tear is present at the cardia
mucosa caused due to vigorous vomiting usually seen in alcoholics. In most of the cases (90%), the
tear is present immediately below the squamocolumnar junction at the cardia Q whereas in
10% cases, it is present in the esophagus. These tears never involve the muscular layer of the
esophagus whereas, in contrast, in Boerhaave syndrome, rupture of all the esophageal layers is
seen including the muscle layer. Most common location of the perforation in this syndrome
is in left posterolateral part 3-5 cm above the gastroesophageal junction.
ESOPHAGITIS
Inflammation of the esophageal mucosa is known as esophagitis and reflux of the gastric
contents into the lower esophagus is its most important cause. Gold standard for the diagnosis of
Barretts esophagus is the most reflux esophagitis is 24 hours pH study Q. The reflux is associated with obesity, alcohol intake,
important risk factor for the smoking, pregnancy and overeating.

development of esophageal
adenocarcinoma.
BARRETTS ESOPHAGUS
Concept Barretts esophagus is the metaplastic change in the esophageal lining in which the normal
squamous epithelium is changed to columnar epithelium due to prolonged gastroesophageal
Intestinal goblet cells differ reflux disease (GERD). It is classified as long segment (if >3 cm is involved) or short segment
from normal mucus secreting
(if <3 cm is involved). Microscopically, esophageal squamous epithelium is replaced by
foveolar cells of the stomach by
the fact that in the former, there columnar epithelium. Definite diagnosis is made only when columnar mucosa contains the intestinal
is presence of distinct mucous goblet cells.Q
vacuoles (not present in gastric
Note: Barretts ulcer is the ulcer in the columnar lined portion of Barretts esophagus.
foveolar cells).
CARCINOMA OF THE ESOPHAGUS
It is a cancer affecting individuals of mid to late adulthood which is of two main types:
Triad of Plummer Vinson squamous cell cancer and adenocarcinoma.
syndrome = iron deficiency
anemia + esophageal webs + Risk factors for squamous cell cancer
glossitis Tobacco and alcohol consumption
Hot beverages or food
Longstanding esophagitis
Achalasia
Plummer Vinson syndrome (also known as Patterson Kelly syndrome)
Ingestion of nitrites in diet
Nutritional deficiency of vitamins A, vitamin C, riboflavin, zinc, molybdenum
The investigation of choice Tylosis et palmaris (hyperkeratosis and pitting of palms and soles)
in esophageal cancer is Longstanding celiac disease
endoscopy and biopsy. Other conditions like ectodermal dysplasia and epidermolysis bullosa
Genetic alterations include amplification of cyclin D1, c-MYC and Epithelial Growth Factor
Receptor (EGFR)
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Most of the cancers are well differentiated and the morphological patterns include:
i. Exophytic protruding lesion in the lumen (60%)
ii. Flat, diffuse infiltrative form spreading in the esophageal wall (15%)
Barium swallow in esophageal
iii. Ulcerative lesion (25%)
cancer shows rat tail
Risk factors for Adenocarcinoma appearance of the esophagus.

Barretts esophagusQ (Most important)

Tobacco exposure

Obesity

Genetic alterations include over expression of p53, amplification of c-ERB-B2 and
nuclear translocation of b-catenin (biomarkers of disease progression).
Microscopically, most of the cancers are mucin producing glandular tumors exhibiting
MC type of esophageal
intestinal type features. Multiple foci of dysplastic epithelium are present adjacent to the
cancer in India: Squamous
mucosa. cell cancerQ
Clinical features include progressive dysphagia (more for solids as compared to MC type of esophageal
liquids), weight loss, chest pain and vomiting. The lymph node metastasis is dependent on cancer in upper 1/3rd of
the anatomic site of the primary tumor. esophagus: Squamous cell

Cancer in the upper 1/3rd of the esophagus: metastasis to cervical lymph nodes. cancerQ

Cancer in the middle 1/3rd of the esophagus: metastasis to paratracheal, mediastinal MC type of esophageal
cancer in middle 1/3rd of
and tracheobronchial lymph nodes. esophagus: Squamous cell

Cancer in the lower 1/3rd of the esophagus: metastasis to gastric and celiac lymph cancerQ
nodes. MC type of esophageal cancer
in lower 1/3rd of esophagus:
Treatment: It is mainly surgical with partial or total esophagectomy. AdenocarcinomaQ.
STOMACH
C ells and their Secretions

Parietal (Oxyntic) cells Secrete acid (from the proton pump, H+-K+ ATPase)
Secrete intrinsic factor (required for vitamin B12 absorption)
Chief (Zymogenic) cells Secrete the proenzymes pepsinogen I and II (activated to pepsin)
Endocrine cells Secrete gastrin in antrum (by G cells), histamine in the body
Foveolar cells Secrete mucin layer over the mucosal cells
GASTRITIS
Gastritis is the inflammation of the gastric mucosa. It can either be acute gastritis or chronic
gastritis.
Risk factors of acute gastritis

Heavy smoking and alcohol consumption

Excessive NSAID use (particularly aspirin)

Uremia

Ischemia and shock

Stress (trauma, burns, surgery)

Others (nasogastric intubation, distal gastrectomy, systemic infections) Humans are the only known
Microscopically host of H.pylori.
Presence of neutrophils above the basement membrane in direct contact with the epithelial cells is
indicative of active inflammation Q.
Risk factors of chronic gastritis

Chronic infection with H. pylori
H.pylori. gastritis causes involve-

Autoimmune cause (pernicious anemia) ment of the antrum

Alcohol and smoking

Radiation
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Antrectomy with gastroenterostomy

Others (amyloidosis, graft-versus-host disease, uremia, Crohns disease).

Microscopically
Chronic gastritis has the presence of lymphocytes and plasma cells associated with intestinal
metaplasia and mucosal atrophy.
Chronic gastritis can be of the following two types:
Autoimmune gastritis causes
involvement of the fundus and

1. Associated with H. pylori (in 90% patients)
body. H. pylori is a gram-negative flagellated bacteria producing enzymes like
phospholipase and urease, adhesion molecules like BabA (responsible for enhanced
binding in people having blood group O) and toxins like CagA and VacA. It causes
gastritis in two patterns:
a. Antral predominant gastritis: Seen in individuals having lower IL-1 production and
associated with high acid production and increased risk of duodenal ulcer.
b. Pangastritis followed by multifocal atrophic gastritisSeen in individuals having
higher IL-1 production and lower gastric acid production and increased risk of
adenocarcinoma.
Histology remains the gold
standard for detection of H.
Intraepithelial neutrophils and subepithelial plasma cells (meaning plasma cells in the
pylori. The special stains used lamina propria) are characteristic of H. pylori gastritis. H. pylori is also associated with
for H. pylori include non-silver peptic ulcer disease, gastric cancer and gastric mucosa associated lymphoma Q.
stains (like Giemsa, Diff-Quick,
Gimenez, Acridine orange) and 2. Autoimmune gastritis (in 10% patients)
silver stains (like Warthin- It is caused due to formation of autoantibodies against the proton pump, gastrin
Starry, Steiner etc.) receptor and intrinsic factor and is associated with pernicious anemia, Hashimotos
thyroiditis, Addisons disease, type 1 diabetes, gastric cancer and carcinoid tumor.
This is particularly associated with damage to the mucosa of the body and fundus with
less involvement of the antrum. Hyperplasia of gastrin producing G cells in the antral
mucosa may result in gastric carcinoid tumor formation.
The histologic features of chronic gastritis include regenerative change, intestinal
metaplasia (columnar absorptive cells and goblet cells of intestinal type), atrophy and
dysplasia. In autoimmune gastritis, there is presence of inflammatory infiltrate having
lymphocytes, macrophages in the deeper layers. Plasma cells in the superficial lamina propria
are characteristically absent.
Clinical features include nausea, vomiting and epigastric pain. Autoimmune gastritis
maybe associated with symptoms seen in pernicious anemia (beefy tongue, paresthesia,
numbness, sensory ataxia, loss of vibration and position sense).
PEPTIC ULCER DISEASE
Any breach in the mucosa of the GIT that involves the submucosa or deeper due to exposure
to gastric acid is called peptic ulcer. It is usually a chronic and solitary lesion less than 4 cm
caused due to imbalance between gastroduodenal protective and damaging factors:
Damaging factors Protective factors
Gastric acid Mucus and bicarbonate secretion
Pepsin Mucosal blood flow
Smoking, alcohol Prostaglandin production
Drugs like NSAIDs Epithelial regenerative capacity
H. pylori is the most important H. pylori
cause of peptic ulcer.
Ischemia and shock
Delayed gastric emptying
Duodenal gastric reflux or gastric hyperacidity
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The location of the peptic ulcer (in decreasing order of frequency) is:
Duodenum (first part)Q
Stomach (lesser curvature near the junction of body and antrumQ)
Gastroesophageal junction in GERD or Barretts esophagus
Margins of jejunostomy
Stomach, duodenum and/or jejunum of patients with Zollinger-Ellison syndrome
In ileal Meckels diverticulum containing ectopic gastric mucosa.
Males are more commonly affected than females

Duodenal ulcers are located near the pyloric ring and gastric ulcers are predominantly located near
the lesser curvature and the antrum. More commonly, there is involvement of the anterior wall
of the duodenum as compared to the posterior wall. Benign peptic ulcer is classically punched
with margins of the ulcer usually at level with the surrounding mucosa whereas heaping up
of the margins is more frequently associated with malignancy. Histologically the zones in
peptic ulcer are:

i. Base and margins having necrotic fibrinoid debris

ii. Zone of neutrophil predominant infiltrate

iii. Base having active granulation tissue with mononuclear cells

iv. Zone of fibrous or collagenous scar
Clinical features include burning epigastric pain (usually getting worse at night),
nausea, vomiting and bloating.
Complications of Peptic Ulcer
Gastroduodenal artery is the
Bleeding source of the bleeding in duo-
Most frequent complicationQ. denal ulcer whereas left gastric
More common in posterior wall duodenal ulcersQ artery bleeds in gastric ulcer
Perforation
Most common cause of death in peptic ulcerQ
More common in anterior wall duodenal ulcersQ
Gastric outlet obstruction (GOO)
Results in persistent vomiting leading to fluid and electrolyte imbalance (metabolic alkalosis due
to loss of acid in vomitus)
Malignancy
Associated with gastric ulcer but never with duodenal ulcer.
Duodenal and Gastric peptic ulcer

Features Duodenal ulcer Gastric ulcer
Site 1st part of duodenum Along lesser curvature
Incidence More common Less common
Age 25 50 yrs, M>F Beyond 6th decade, M>F
Etiology Almost all patients have H. pylori infection Less stronger association
Acid level High Usually normal; if hypergastrinemia
Pain after food Relieved Aggravated
intake
Clinical Night pain and melena more common No night pain, hematemesis more
features common
No vomiting/no weight loss Vomiting common/weight loss is
present
Complications No malignant change Malignant change present (though
rarely)
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Investigations
Screening test: Serum ELISA for antibodies against H. pylori
Concept Urea breath test (radiolabeled urea is broken down to radiolabeled CO2 by urease enzyme which
Urea breath test is used to ensure is detected by breath analyzer, thus suggesting presence of H. pylori infection)
the efficacy of the treatment for Gold standard: Staining of H. pylori with silver stain or Warthin starry stainQ
peptic ulcer disease. Most specific investigation: Culture of bacteriaQ (done on Skirrows medium)
Treatment: with triple drug therapyQ (combination of lansoprazole, clarithromycin

and metronidazole) for 2 weeks.
Vital Information
Cushing ulcer is seen in esophagus, stomach or the duodenum and is associated with intracranial
disease or head injury. It is caused by gastric acid hypersecretion due to vagal nuclei stimulation.
Menetrier disease: It is char- Curling ulcer is seen in proximal duodenum and is associated with burns or trauma. It is caused
acterized by diffuse foveolar cell due to reduced blood supply and systemic acidosis in burns or trauma.
hyperplasia due to excessive
secretion of TGF-a. It is as-
sociated with enlarged gastric GASTRIC CANCER
rugae and protein losing en-
teropathy. Gastric cancer is the most common gastric malignancy. The risk factors for this cancer are:
Environmental factors Genetic factors Host factors
H. pylori infection Family history of gastric cancer Chronic gastritis
Nitrites in diet Blood group A Intestinal metaplasia
Nutritional (vitamin C, E) Hereditary nonpolyosis colon Partial gastrectomy
deficiency cancer syndrome (HNPCC) Gastric adenoma
Concept Smoking Familial gastric cancer syndrome Barretts esophagus
(due to E-cadherin mutation) Menetrier disease
Infection with H. pylori is

associated with distal intestinal Classification of gastric cancer
type and not with diffuse,
1. Based on Laurens histological classification
proximal carcinoma.
i. Intestinal type: This is localized type of cancer composed of the neoplastic
intestinal glands which exhibit an expanding sheet pattern of spread due to
cohesion of the cells.

ii. Diffuse type: Poorly differentiated non-cohesive cells which do not form glands.
The appearance of the cells is signet ring appearance Q (because mucin in
the cell pushes the nucleus to the periphery). It is seen more frequently with
E-cadherin mutation.
Diffuse involvement of the
stomach in cancer is called linitis
2. Based on Depth of invasion
plastica or leather bottle
i. Early gastric cancer: Characterized by the involvement of mucosa and the
appearance of the stomach. It submucosa irrespective of the involvement of perigastric lymph nodes and is
is also seen in metastasis from associated with better prognosis.
cancers of breast and lung.
ii. Late gastric cancer: Characterized by the involvement of the muscle layerQ of the
stomach and is associated with poor prognosis.

3. Based on Macroscopic pattern

i. Protruding mass or exophytic (type I lesion)
H. pylori is a Type 1 carcinogen
for gastric cancer.

ii. Flat or depressed: No obvious mass in the mucosa (type II lesion)

iii. Excavated: Erosion is present in stomach wall (type III lesion).
Clinical features
The most common location of the gastric cancer is the antrum of the stomachQ
Symptoms include postprandial heaviness in the abdomen (earliest symptom), weight loss
(most common symptom), vomiting and anorexia.
Metatasis to anterior left axillary
Investigation of choice: Endoscopy with biopsy and brush cytologyQ.
lymph node is called as Irish
Nodes Metastasis occurs to the liver (first organ to be affected) followed by lungs, bone, ovary
(where it is known as Krukenbergs tumor), periumbilical lymph nodes (Sister Mary Joseph
nodule), peritoneal cul-de-sac (Blumers shelf palpable on rectal or vaginal examination) and
left supraclavicular lymph node (Virchows lymph node Q).
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Treatment: Surgical resection is the only curative treatment in gastric cancer.

Chemotherapy may be given in advanced cancers with ECF regime (Epirubacin, Cisplatin
and 5-Fluorouracil).
GASTROINTESTINAL STROMAL TUMOR (GIST)
The cells controlling the gastrointestinal peristalsis are present in the muscularis propria
and are called as interstitial cells of Cajal. Q Gastrointestinal stromal tumor (GIST) is the most
common mesenchymal tumor of the abdomen and majority is present in the stomach. These Interstitial cells of Cajal are
tumors arise from interstitial cells of Cajal. Increased incidence of GIST is seen in NF-1. The known as the pacemaker cells of
the GIT.
most useful diagnostic marker is c-kit (CD117) detectable in 95% of the patients. Other
markers like CD34 and vimentin can also be expressed by some tumor cells.
Microscopically the tumor may show either epithelioid cells, spindle cells or mixed (both
the epithelioid cells and spindle cells). Carneys triad is gastric GIST
+ paraganglioma + pulmonary
Diagnosis: CT scan either alone or with PET scan (preferable) is the investigation of choice.
chondroma.
Treatment: The localized tumors are surgically resected and the metastatic or non-
excisable tumors are managed with tyrosine kinase inhibitors called imatinib mesylate or
sunitinib.
INTESTINE
Infectious Diseases
The important causes of infections in the intestine are as follows:

I. Enteric fever (typhoid)
It is caused because of infection with Salmonella species usually affecting the ileum
and the colon.

It is associated with ulceration of the Peyers patches in the terminal ileum and
presence of longitudinal ulcers Q (oval ulcers with long axis along the long axis
of the ileum). Microscopic examination reveals the presence of macrophages
having bacteria and red blood cells (erythrophagocytosis Q)

In the liver, the hepatocytes are replaced by an aggregation of macrophages
called as typhoid nodule Q. Involvement of gallbladder results in development
of chronic carrier state. Healing in ulcer is uncommonly associated with fibrosis or Erythrophagocytosis is a char-
stricture formation. acteristic feature of enteric fever.

Clinically, the patient develops step-ladder pyrexia, rose spots (erythematous
macular lesions on chest and abdomen), abdominal pain, vomiting and diarrhea.
Salmonella osteomyelitis is particularly common in patients having sickle cell
disease.

Complications include hemorrhage and perforation.

Blood culture is the mainstay of diagnosis and Widal test is use for measuring Hemorrhage occurs in 3rd week
the antibody titer. of typhoid infection.

Drug of choice for the treatment is ciprofloxacin/ceftriaxone and for carriers, it
is ampicillin + probenecid.

II. Tuberculosis: It can present itself in two of the following forms:
Primary infection
Caused by infection due to Mycobacterium bovis (due to intake of infected/non pasteurised
milk ) and results in the development of hyperplastic tuberculosis. The infection is present
in the lymphoid follicles of the intestine and associated with thickening and narrowing of
the lumen of the intestine. It usually affects the ileocecal region and is associated with
subacute intestinal obstruction. The mesenteric lymph nodes are enlarged; matted and
caseous. This is known as tabes mesenterica. Unlike typhoid, stricture formation
Clinical features of the patient include acute abdominal pain and intermittent diarrhea. is common in intestinal tuber-
Investigations show widening of the ileocecal angle (known as pulled up cecum) on culosis
barium radiography.
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Secondary infection
Caused by Mycobacterium tuberculosis secondary to swallowing of infected sputum in
a patient of pulmonary tuberculosis. It is characterized by presence of the transverse
ulcers in the intestine particularly the ileum.
Clinical features of the patient include weight loss and intermittent diarrhea.
Investigations show filling defect in the ileum, cecum and ascending colon on barium
radiography. Complications include perforation of the intestine and fistula formation.
Treatment is by administration of antitubercular therapy (conservative management)
or surgical resection of the affected part of the intestine (in case of obstruction or
fistula formation).

III. Amoebiasis
The drug of choice for amoebia- It is caused by infection with an anaerobic protozoa E. histolytica and results in the
sis is metronidazole. development of flask shaped ulcersQ (ulcer with a broad base but narrow neck).
The disease affects the cecum and ascending colon followed by sigmoid colon,
rectum and appendix. The ulcers usually involve the mucosa and the submucosa
(not the muscle layer) and have the presence of liquefactive necrosis. Liver is another
important organ affected by the disease resulting in the development of hepatic
abscess having necrotic material and hemorrhage (called as anchovy sauce pus Q).
The invasive disease is diagnosed with ELISA.
Microbiology link!
Rotavirus is the most common cause of diarrhea in children of age 6-24 months.
Giardia lamblia is the most common pathogenic parasitic infection in the humans.
Cholera is caused by Vibrio cholerae resulting in the passage of rice water stools.
PSEUDOMEMBRANOUS COLITIS (ANTIBIOTIC ASSOCIATED COLITIS)
It is a condition most commonly caused by Clostridium difficile and is characterized by

inflammation in the colon associated with the formation of a pseudomembrane (layer of
inflammatory cells and necrotic material overlying the sites of mucosal injury). In normal
individuals, the normal flora of the gut is responsible for the production of chemicals
called bacteriocins in the intestine. On administration of broad spectrum antibiotics (most
commonly, IIIrd generation cephalosporins), the normal bacteria are destroyed resulting
Treatment of Pseudomembra-
nous colitis is done with either met- in increased proliferation of the Clostridium bacteria which then produces large amounts
ronidazole (drug of choice) or of two toxins, toxin A and toxin B. These toxins induce cytokine production and host cell
vancomycin. apoptosis resulting in diarrhea. The disease is diagnosed with the demonstration of C.
difficile cytotoxin in stool.
Malabsorption Syndromes
Defective absorption of fats, vitamins, proteins, carbohydrates and fats is called

malabsorption. Its hallmark feature is steatorrhea and chronic diarrhea is the most common
clinical presentation. The important causes are as follows:

1. Celiac Disease (Celiac Sprue or Gluten Sensitive Enteropathy or Non-troical sprue)
It is a disease characterized by increased sensitivity to a protein called gluten or its
alcohol soluble fraction -gliadin Q present in the grains like wheat, oat, barley and
rye resulting in a T-cell mediated chronic inflammatory reaction in the small intestine
and impaired absorption. It is associated with HLA-DQ2 or HLA-DQ8. Clinical
Dapsone is the drug of choice for features include diarrhea, flatulence, weight loss and fatigue and a characteristic
dermatitis herpetiformis.
skin lesion called dermatitis herpetiformis.
Biopsy of the intestine shows the diffuse enteritis (lymphocytes and plasma cells in
lamina propria) with marked atrophy of the villi and elongated and hyperplastic
crypts (overall mucosal thickness is unalteredQ). The disease also demonstrates
the presence of antigliadin, antiendomysialQ (most useful) or antitransglutaminase
antibodiesQ (useful for screening test) whereas definitive diagnosis is made by the
following three features:
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Clinical documentation of malabsorption

Demonstration of small intestinal lesion by biopsy
Improvement in clinical features and mucosal histology on gluten withdrawal from the
diet.
Treatment is intake of the gluten-free diet and substitution by rice, millet, tapioca,
potato and maize in the diet.
2. Tropical Sprue (Post Infectious Sprue) is now called as Environmental Enteropathy
It is a disease similar in features to celiac sprue but present in the tropical region. Concept
Though the exact cause is unknown, but bacterial overgrowth particularly E. coli and
Hemophilus have been implicated. Biopsy of the intestine shows the diffuse enteritis In tropical sprue, the features in
with atrophy of the villi. Treatment is done with the help of antibiotics. the intestine do not reverse on
gluten free diet
Note:
There is characteristically involvement of the proximal intestine in celiac sprue resulting in iron
deficiency anemia whereas in tropical sprue, there is generalized involvement of the small
intestine (resulting in megaloblastic anemia because B12 and folic acid are absorbed from the
terminal ileum).
Another important difference between the two is that tropical sprue is not associated with
cancer development whereas celiac sprue is associated with cancers like non Hodgkins
lymphoma, small intestine adenocarcinoma and esophageal squamous cell cancer.
3. Whipples Disease

It is a systemic infectious disease caused by an actinomycete, Tropheryma
whippelii affecting the triad of small intestine, CNS and jointsQ. The bacteria
characteristically proliferate inside the macrophages without getting destroyed.
Concept
The presence of T. whipplei

The hallmark feature of the disease is small intestinal mucosa having macrophages outside of macrophages is
in the lamina propria and these macrophages show the presence of PAS positive, more important indicator of active
diastase resistant granulesQ and rod shaped bacteria on electron microscopy. There disease than is their presence
is mucosal edema, dilation of the lymphatics and involvement of mesenteric inside the macrophages.
lymph nodes. The macrophages having the bacteria can also be found in the
joints, brain, cardiac valves etc with absence of inflammation being a typical feature.

Clinical features include arthropathy (initial presentation), diarrhea, weight
loss, hyperpigmentation and dementia. The diarrhea is due to impaired lymphatic
transport.

Diagnosis is confirmed by identification of T. whipplei by polymerase chain
reaction (PCR). Treatment is done with cotrimoxazole (drug of choice) for one
year.
Note:
Hallmark of Whipples disease had been presence of PAS positive macrophages containing the
characteristic small bacilli. But, similar picture (PAS +ve macrophages with bacilli) can also be
seen with M. avium complex (cause of diarrhea in AIDS). However, these organisms are acid fast
whereas Tropheryma is not.
The organs in which these foamy macrophages can be seen are Liver, Small intestine, Lymph
nodes, Heart, Eyes, CNS and synovial membranes of joints.
Disorders Associated with Abnormalities in Small-Bowel Biopsy Specimens

Biopsy has diagnostic value (Diffuse Lesions)
Whipples disease: Lamina propria infiltrated with macrophages containing PAS-positive
glycoproteins
Abetalipoproteinemia: Villus structure normal; epithelial cells vacuolated due to excess fat
Agammaglobulinemia: Flattened or absent villi; increased lymphocytic infiltration; absence of
plasma cells
Mycobacterium avium complex
contd...
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contd...
Biopsy may have diagnostic value (Patchy lesions)
Intestinal lymphoma: Infiltration of lamina propria and submucosa with malignant cells
Intestinal lymphangiectasia: Dilated lacteals and lymphatics in lamina propria; clubbed villi
Eosinophilic enteritis: Diffuse or patchy eosinophilic infiltration in lamina propria and mucosa
Amyloidosis: Presence of amyloid confirmed by special stains
Regional enteritis: Noncaseating granulomas
Parasitic infestations: Parasitic invasion of mucosa; adherence of trophozoites to mucosal
surface, as in Giardiasis
Systemic mastocytosis: Mast cell infiltration of lamina propria
Biopsy is abnormal but not diagnostic
Celiac sprue Collagenous sprue Tropical sprue
Folate deficiency Vitamin B12 deficiency Acute radiation enteritis
Systemic scleroderma Bacterial overgrowth syndromes
Inflammatory Bowel Disease (IBD)
It is a group of chronic inflammatory conditions as a result of unregulated and persistent

activation of the immune system in genetically susceptible persons. It is primarily of two
types: Crohns disease and ulcerative colitis.
C rohns Disease
It is a chronic granulomatous disease which can affect any part of the gut from the esophagus
Skip lesions and non- to the large intestine but the most commonly affected part is small intestine particularly the ileum.
caseating granulomas are So, it is also called as terminal ileitis or granulomatous colitis Q. It is associated with HLA-
characteristic features of . DR1/DQw5 and NOD2 genes and an abnormal T-cell response particularly, CD4+ T cells
Crohns disease (TH1 cells Q).
M orphology:
The earliest lesion in Crohns disease is the aphthous ulcer. Many such ulcers may
fuse together to from serpentine ulcers arranged longitudinally.
Grossly, involved bowel segment typically has a rigid, strictured or thickened wall
with creeping fat. Q
Full thickness of the intestine is affected in the disease i.e. there is transmural
inflammation Q. This causes weakness in the wall thereby leading to fissure and fistula
formation in Crohns disease. Fibrosis is also commoner in this type of IBD. Perianal
fistula is the most common fistula seen.
Radiological appearance on There is patchy involvement of the intestine which is known as presence of skip
barium meal follow-through lesions. The intervening area between two affected portions is absolutely normal.
is known as String Sign So, the mucosa appears to be irregular which is known as cobblestone mucosaQ
of Kantor because of the
decreased lumen in the affected
There is a presence of non-caseatingQ granulomas.
part of the intestine. Clinical features are intermittent attacks of abdominal pain, blood in stools, fever,
steatorrhea and megaloblastic anemia (the last two features result because there is
impairment in the absorption of bile acids and vitamin B12 respectively from the
ileum).
Screening test is presence of ASCA (Anti-Saccharomyces cerevisae AntibodyQ).
Antibody formation is common against cell wall of yeast, Saccharomyces cerevisae in
The mnemonic for important patients of Crohns disease. The investigation done in these patients to confirm the
features of Crohns disease is
diagnosis is endoscopy and colonoscopy so that direct visualization of the lesions
SISTER
can be done and even a biopsy can be taken if needed.
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Important features of Crohns disease

S Skip lesions
I Ileum (MC affected site)
S Saccharomyces cerevisae antibody present
T Transmural involvement
E Extra fibrosis and fistula formation (as compared to ulcerative colitis)
R Radiological sign- String sign of Kantor, Rectum is usually spared.
U lcerative Colitis
It is a chronic inflammatory condition affecting the colon. It most commonly starts from
the rectum and affects the superficial layers, the mucosa and the submucosaQ (muscularis
propria is rarely affected). It is associated with HLA-DR2, polymorphism in IL-10 gene and an
abnormal T-cell response particularly of CD4+ T cells (TH2 cellsQ).
M orphology:
The disease involves the entire colon (pancolitis)Q starting from the rectum
(retrograde involvement). There is presence of regenerating mucosa which projects
in the lumen and is called pseudopolypsQ

In extreme cases, there is involvement of the nerve plexus in the muscularis layer
resulting in decrease in the motility of the colon and increase in its size over a period
of time giving rise to toxic megacolonQ

The characteristic feature of the disease is mucosal damage continuously from the Radiological appearance on
rectum and extending proximally. This may also lead to backwash ileitis. This type barium meal follow-through
of IBD is more commonly associated with progression to the development of cancer. is known as lead pipe

There is absence of granulomas Q. appearance.

Clinical features are intermittent attacks of abdominal pain, bloody mucoid stools
and fever.

There is presence of p-ANCAQ (perinuclear antineutrophil cytoplasmic antibodies).
Important features of ulcerative colitis
The mnemonic for important
Ulcerative Ulcers in mucosa and submucosa (Muscle layer not effected) features of Ulcerative colitis is
C - Continuous retrograde involvement (No skip lesions) Ulcerative COLITIS
O - Originates in the rectum
L - Lead pipe appearance
I - Increased chances of cancer (More than that in Crohns disease)
T - Toxic megacolon (Due to involvement of transverse colon) Concept
I - Increased growth from the mucosa (Pseudopolyps)
S - Symptoms are severe (As compared to Crohns disease) Polymorphism of the IL-23
receptor is protective in both
The extraintestinal manifestations in the IBD are uveitis, iritis, ankylosing spondylitis, the types of inflammatory bowel
clubbing, migratory polyarthritis, sacroilitis, primary sclerosing cholangitis, pyoderma disease.
gangrenosum, erythema nodosum etc. Smoking is a strong exogenous
risk factor for development of CD
The disease is treated with sulfasalazine (5-aminosalicylic acid is the principal therapeutic
whereas smoking partly relieves
moiety), infliximab (TNF- antagonist) and steroids.
symptoms in UC.
IBD is a precancerous condition and can increase the risk of development of cancer
of the colon.
CARCINOID TUMOR Concept

Carcinoid tumor arises from the endocrine cells called as argentaffin tissue (also called as The cardiac changes are largely
right sided due to inactivation
Kulchitzsky cells of crypts of Lieberkuhn) with the GIT and the lungs as the main sites of
of both serotonin and bradykinin
origin of this cancer. The clinical features are due to release of peptide and non-peptide in the blood during passage
hormones from these cells. The gastrointestinal carcinoid tumors can be of the following through the lungs by the
types: monoamine oxidase present

1. Foregut carcinoid tumors: Arise from the esophagus, stomach and the duodenum in the pulmonary vascular
endothelium.
proximal to the ligament of Treitz, these are usually benign.
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2. Midgut carcinoid tumors: Arise from the jejunum and ileum; these are aggressive
and metastasize frequently.
Alphabet M: Midgut carcinoid
3. Hindgut carcinoid tumors: Arise from the appendix, colon and rectum; usually
tumors are Malignant tumors
benign.
Morphology:
On section, the tumors show a characteristic solid, yellow tan appearance and on electron
microscopy, the tumor cells show dense core granules in the cytoplasm which stain positively
Clinical features of carcinoid with chromogranin A, neuron-specific enolase and synaptophysin Q on immunocytochemistry.
syndrome are Carcinoid syndrome is present in 1% patients of carcinoid tumor and it is due to excessive

S - Systemic fibrosis (Affects
release of serotonin (5-HT)Q It is strongly associated with metastatic disease.
cardiac valves, endocar-
dium, retroperitoneal and Cardiac lesions are present in 50% of the patients with the carcinoid syndrome. They
pelvic fibrosis) consist of fibrous intimal thickenings on the inside surfaces of the cardiac chambers and

H - Hepatomegaly (Because of valvular leaflets. And are located mainly in the right ventricle, tricuspid and pulmonic
metastasis) valves, and occasionally in the major blood vessels. The commonest cardiac manifestation is the

I - Intestinal hypermotility (Vom- tricuspid regurgitation (tricuspid stenosis is relatively uncommon) followed by pulmonary
iting, diarrhea, cramps, nau-
sea)
regurgitation.

V - Vasomotor symptoms like Hepatic metastasis is usually present in this tumor. The most sensitive screening test for
small intestine carcinoids is the plasma level of chromogranin A. The levels of 5-HT and its
flushing and cyanosis of
the skin metabolite 5-hydroxyindoleacetic acidQ (5-HIAA) is elevated in the urine.

A - Asthma like features (Cough,
wheezing, dyspnea) POLYPS
Polyps are seen most commonly in colon but can also be seen in other parts of GIT.
Polyps
Non-Inflammantory Neoplastic polyps

Inflammatory polyp Adenomatous polyp
The size of the adenoma is the Hyperplastic polyps
Tubular adenoma (most common)
most important characteristic
which correlates with the risk of
Hamartomatous polyps: they of 2 types
Villous adenomas (maximum malignant
Juvenile polyp (MC in rectum) potential)
malignancy. Peutz jegher polyp (MC in jejunum)
Tubulovillous adenoma
Concept
Dysplasia may be seen in a small number of juvenile polyps and the juvenile polyposis syndrome
is associated with increased risk of colonic cancer.
Peutz Jegher polyp is a benign polyp but Peutz Jeghers syndrome is characterized by multiple
hamartomatous polyps scattered throughout the GIT and melanotic mucosal and cutaneous
pigmentation around the lips, oral mucosa, face, genitalia and palmar surface of the hands.
Peutz Jeghers syndrome is
associated with increased
Adenomatous polyps are usually asymptomatic.
risk of developing carcinoma
Also Know
of pancreas, colon, breast,
uterus, lung and ovary. The GIT Hamartomatous polyps can occur sporadically or as a part of syndromes such as Juvenile polyposis,
malignancy in these patients Peutz-Jegher syndrome, Cowden syndrome and Cronkhite-Canada syndrome. All these syndromes
arises independently of the have autosomal dominant inheritance except Cronkhite-Canada syndrome, which is a non-
hamartomatous polyps. hereditary disorder.
CARCINOMA OF THE COLON
The cancer of the colon is seen frequently in old age (peak age 60-79 years). It is an
adenocarcinoma in almost all the patients. The risk factors for the colon cancer are:
A. G enetic factors
i. Hereditary Non-polyposis Colon Cancer (HNPCC) syndrome (also called as Lynch
syndromeQ)
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It is an autosomal dominant condition characterized by the increased incidence of

colon cancer and extraintestinal cancer particularly the ovarian and endometrial
cancer. The hallmark is the mutation in the DNA repair genes (MSH2 and MLH1) leading
to microsatellite instability. Colon cancers in these patients affect right or ascending
colon and occurs at younger age (<50 years). The proximal colon tumors in HNPCC
have a better prognosis than sporadic tumors from patients of similar age.

ii. Familial Adenomatous Polyposis (FAP)
It is caused by the mutation of adenomatous polyposis coli (APC) gene present on
the long arm of chromosome 5 Q (5q21). Some FAP patients without APC mutation
have a mutation in the nucleotide base excision repair gene called MUTYH.
Colorectal carcinoma develop in 100% of untreated FAP patients often before age
30. As a result, prophylactic colectomy is the standard therapy in patients with APC
mutations.
Subtypes of FAP
Classic FAP syndrome
The patient has a large number of adenomatous polyps and retinal pigment epithelial hypertrophy. Concept
There should be a minimum of 100 polypsQ to make a diagnosis of this syndrome. Most of the
adenomatous polyps are tubular polyps. Prophylactic colectomy in FAP
does not decrease risk for
Attenuated FAP syndrome
cancer due to adenomas at
The patient has a lower number of adenomatous polyps (around 30) which are located in proximal other sites specially ampulla of
colon. Vater and stomach.
Gardener syndromeQ
Intestinal polyps + epidermal cysts + fibromatosis + osteomas (of the mandible, long bones and
skull).
Turcot syndromeQ
Adenomatous colon polyposis + CNS tumors (medulloblastoma in 2/3rd and gliomas in 1/3rd
patients).

iii. Mutations affecting p53 and K-RAS genes
B. Environmental factors
Factors increasing risk Factors decreasing risk
Increased calorie intake and obesity Q
Increased intake of dietary fiberQ
Decreased intake of micronutrients Intake of w-3 fatty acids (fish)Q
Smoking and alcoholQ NSAID use (especially Aspirin)Q
Streptococcus bovis septicemia or endocarditis Intake of folic acid and calciumQ
UreterosigmoidostomyQ Hormone replacement therapy
Inflammatory bowel disease Q
Acromegaly
Pelvis irradiation
Molecular pathogenesis
1. APC/b-catenin pathway (also called adenoma-carcinoma sequence): Loss of tumor
suppressor APC gene is followed by increased b-catenin transcriptional activity
(normal APC protein degrades b-catenin) leading to localized colon epithelial
proliferation and formation of small adenoma. This is followed by dysplastic change
due to activating mutation in K-ras and inhibition of tumor suppressor genes like
SMAD2, SMAD4 and p53 leads ultimately to cancer.
2. Microsatellite instability pathway: Genetic lesions in 90% cases involve MSH2 and
MLH1 genes which are DNA mismatch repair genes. These genes correct any genetic
disruption which may arise whenever the colonic cells are multiplying rapidly. Any
mutation in these genes causes activation of BRAF and inhibition of BAX protein
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and TGF-b type II gene thereby increasing the chances of development of colonic
cancer. Kras and p53 are not typically mutated.
Colon cancer exemplifies the concept of Multi-step carcinogenesis
M orphology
Most of the cancers arise from the rectumQ followed by the sigmoid colon. Microscopically, it is
an adenocarcinoma and invasive cancers invoke a strong desmoplastic response. Cancers in
the anorectal region are squamous cell cancers.
C linical features of colorectal carcinoma

Features Right sided/proximal Left sided/distal
Sites in colon Caecum and ascending colon Descending colon and sigmoid colon
Gross Fungating/ulcerative type Obstructive type Carcinomatous ulcers have
Napkin ring configuration ulcers appearance polypoid carcinoma Large Napkin ring configuration
have increased fibrous tissue cauliflower-like soft friable mass
forming annular ring and have projecting into lumen
central ulceration with slightly Infiltration Absent Present
elevated margins
Clinical features Fatigue, weakness, Iron Occult bleeding change in bowel habits
deficiency anemia, bleed readily carmpy lower left quadrant discomfort,
Melena, diarrhea, constipation
Diagnosis Later Early stage (theoretically) due to symptoms
Prognosis Good Poor
Metastasis occurs in order of preference, to regional lymph nodes, liver, lungs and bones.
The occult blood loss in the Diagnosis

stool can be detected with the
help of Guaiac test. Tumor markers: Colonic cancer is associated with the elevated levels of tumor markers CEA
(carcinoembryonic antigen) and CA 19-9.
Colonoscopy may also be done which helps in the direct visualization of the cancer and may also
be used to take a biopsy. Gross appearance of the colon is called as napkin ringQ appearance
(caused by annular and constricting lesions in distal colon).
Most important prognostic indicator of colon cancer is the stage which means the extent
of tumor at the time of diagnosis. Dukes staging was used for colon cancer which has now
Double contrast barium
enema is the radiological been replaced by the TNM staging.
investigation of choice which
characteristically shows apple T reatment
core appearance of the
cancer.
Right colon cancer is surgically treated with resection and ileocolic anastomosis
whereas for Left sided colon cancer, Hartmans procedure (surgical resection of the
affected lesion and proximal diversion with the help of colostomy) is done.
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esophagus an upper GI endoscopy is performed to rule out Barrett
esophagus. However, the results reveal that Barrett
1. Barretts esophagus shows (AIIMS May 2010) esophagus, is indeed present. Which of the following is
(a) Intestinal dysplasia true of Barrett esophagus?
(b) Intestinal metaplasia
(a) A biopsy will show a histologic finding of columnar
(c) Columnar cell metaplasia to squamous metaplasia.
(d) Columnar cell dysplasia
(b) It is a known precursor of carcinoma of the stomach.
2. Predisposing factor for esophageal cancer is all except
(c) The most common location is the proximal (upper)
third of the esophagus.
(a) Mediastinal fibrosis (AIIMS May 2009)
(d) It is a known precursor of adenocarcinoma of the
(b) Diverticula esopohagus.
(c) Caustic alkali burn
(d) HPV 10. A 50 year old male Grisham who complains of nocturnal
cough undergoes an esophageal biopsy which shows
3. Most common cause of esophagitis is elongation of the lamina propriae, many eosinophils,
(a) Smoking (AIIMS May 2009) and occasional neutrophils within the squamous
(b) Alcohol epithelium. He takes metformin and enalapril for his
(c) Reflux disease diabetes and hypertension. He is started on omeprazole:
(d) Increased intake of spices after 2 weeks, his coughing symptoms resolve. Which of
4. Best site for taking biopsy for viral esophagitis is
the following is the most likely cause of his symptoms?
(a) Edge of ulcer (AIIMS Nov 2001)
(a) Pill-induced esophageal mucosa damage
(b) Base of ulcer
(b) Gastroesophageal junction incompetence
(c) Adjacent indurated area around ulcer
(c) Mucosal disruption from fungal infection
(d) Surrounding normal mucosa
(d) Absent esophageal peristaltic movements
5. Which of the following viruses does not produce viral 11. A 80 year old man Baba complains of pain in the upper
esophagitis? (Delhi PG 2009) portion of his neck on swallowing. He occasionally
(a) Herpes (b) Adenovirus regurgitates undigested food shortly after eating.
(c) Varicella (d) Cytomegalovirus Which of the following is the most likely etiology of
his problems?
6. Which of the following is true about Barrets esophagus?
(a) Mallory-Weiss tears
(a) Squamous to columnar metaplasia (Delhi PG-2007)
(b) Zenkers diverticulum
(b) Columnar to squamous metaplasia
(c) Schatzki rings
(c) Does not increase risk of malignancy
(d) Traction diverticula
12. A 43-year-old female Divya with chronic dysphagia
7. Barrett esophagus can result from: (UP 2004) undergoes an upper endoscopy that reveals massive
(a) H. pylori infection dilation of the distal esophagus. The esophagus is
(b) H. simplex infection kinked and tortuous and partly filled with undigested
(c) Gastroesophageal reflux foods. What is the most likely diagnosis for this patient?
(d) Varices
(a) Achalasia
8. Plummer-Vinson syndrome is characterized by all
(b) Barretts esophagus
except: (UP 2006)

(c) Hiatal hernia
(a) Glossitis

(d) Plummer-Vinson syndrome
(b) Esophageal webs 13. Which of the following locations is most likely for the
(c) Megaloblastic anemia development of carcinoma in a 50-year-old mason who
(d) Esophageal dysphagia has chewed tobacco for 25 years?
9. A 60- year-old man Jivan Kumar with a 4-year history of
(a) Floor of the mouth
GERD presents with persistent pyrosis (hearburn) and

(b) Lower lip
acid regurgitation. He has had similar symptoms for

(c) Tongue
the past 4years. Considering the long history of GERD,

(d) Buccal mucosa
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14. A middle aged man Nitesh complains of increasing 19. Which one of the following is the most significant risk
difficulty in swallowing over the past 3 years. He factor for development of gastric carcinoma? (AI 2006)
reports a feeling of pressure in his chest occurring (a) Paneth cell metaplasia
2-3 seconds after swallowing a solid bolus. He also (b) Pyloric metaplasia
experiences regurgitation of undigested food eaten (c) Intestinal metaplasia
hours previously. Manometry shows the absence of (d) Ciliated metaplasia
esophageal peristalsis with swallowing and a lower 20. When carcinoma of stomach develops secondarily to
esophageal sphincter that fails to relax. What is the pernicious anemia, it is usually situated in the:
most likely diagnosis? (a) Prepyloric region (AI 2006)
(a) Achalasia (b) Pylorus
(b) Diffuse esophageal spasm (c) Body
(c) Incompetent lower esophageal sphincter (d) Fundus
(d) Oropharyngeal dysphagia
21. Sister Mary Joseph nodules are found in:
Most Recent Questions (a) Gastric carcinoma (AIIMS May 2009)
(b) Pancreatic carcinoma
1 4.1. Most common anatomical location of tongue cancer is: (c) Lung carcinoma
(a) Anterior third (d) Ovary carcinoma
(b) Lateral margin
(c) Dorsum
22. Gastrointestinal stromal malignancy arises from which
of the following: (AIIMS May 2002)
(d) Posterior third
(a) Smooth muscle
14.2. All are precancerous for carcinoma of esophagus except: (b) Nerve cells
(a) Achalasia (c) Interstitial cells of Cajal
(b) Peterson Kelly syndrome (d) Vascular endothelium
(c) Zenker diverticulum
(d) Ectodermal dysplasia
23. Histologic examination of the lesion in stomach reveal
fat-laden cells, likely cause is:

(a) Lymphoma (AIIMS Nov 2001)
(b) Postgastrectomy
stomach: gastritis, pud, gist, gastric cancer (c) Signet-cell carcinoma stomach
(d) Atrophic gastritis
15. A 50 years old male presents with obstructive symptoms.
Biopsy of stomach reveals the likely diagnosis to be 24. The following have strong causal association with H.
gastrointestinal stromal tumour (GIST). The most pylori infection except (Karnataka 2008)
appropriate marker for this tumor would be which of (a) Chronic gastritis
the following? (AIIMS May 2011) (b) Peptic ulcerdisease
(a) CD 34 (c) Gastric carcinoma
(b) CD 117 (d) Gastric adenoma
(c) CD 30 25. In early gastric carcinoma malignancy is confined to
(d) CD 10 (a) Mucosa (Karnataka 2004)
16. Sister Mary Joseph nodule is most commonly seen in (b) Mucosa and submucosa
with which of the following? (AIIMS May 2010) (c) Gastric wall without lymph node metastasis
(a) Ovarian cancer (d) Gastric glands
(b) Stomach cancer 26. In pernicious anemia, antibody is formed against:
(c) Colon cancer (a) G-cell (Bihar 2006)
(d) Pancreatic cancer (b) Parietal cell
(c) Stem cell
17. Most appropriate marker of GIST: (d) All
(a) CD117 (AI 2010, AIIMS Nov 09)
(b) CD 34 27. A 60 years old fashion photographer and smoker Alok
(c) CK Nath complaints of severe nausea, vomiting, early
(d) Vimentin satiety, and a 10 kg weight loss over the past 5 months.
His physical examination reveals the presence of mild
18. Which of the following is a specific marker for GIST? muscle wasting. An upper GI endoscopy reveals the
(a) CD 117 (AI 2009)
erosion of entire gastric mucosa. In addition, there is
(b) CD34
presence of erythematous cobblestone appearance of
(c) CD23
the mucosa. The stomach is also found to be shrunken
(d) S-100 and reduced in size. Upper gastrointestinal radiographs
502
show that the stomach is small and shrunken. Which of 31.3.

the following is the likely microscopic finding in this
One of the following can have malignant transforma-
tion:
man? (a) Gastric ulcer

(a) Early gastric carcinoma (b) Duodenal ulcer

(b) Gastrointestinal stromal tumor (c) Stomal ulcer

(c) Signet ring cell adenocarcinoma (d) Stress ulcer

(d) Chronic atrophic gastritis
31.4. Gastrointestinal stromal tumor originates in which of

28. A 56-year-old man with a history of glomerulonephritis the following?
is diagnosed with renal failure. The man subsequently (a) Parietal cells
complains of heartburn and nausea, and gives a history (b) Chief cells
that he has been vomiting each morning for the last few (c) Neuroendocrine cells
days. Which of the following forms of gastritis would (d) Interstitial cells of Cajal
most likely be found in this patient?

(a) Acute gastritis 31.5. Which of the following artery is responsible for

(b) Chronic antral gastritis duodenal ulcer hemorrhage?

(c) Lymphocytic gastritis (a) Superior pancreaticoduodenal artery

(d) Hypertrophic gastritis (b) Inferior pancreaticodudenal artery
(c) Gastroduodenal artery
29. Which of the following conditions would mostly likely (d) Left gastric artery
be associated with chronic gastritis (Type A) resulting
from autoimmune destruction of parietal cells? 31.6. The best prognosis is gastric carcinoma is in type:

(a) Decreased growth of luminal bacteria (a) Linitis plastic

(b) Decreased likelihood of developing gastric carcino- (b) Polypoidal growth
ma (c) Ulcerative

(c) Decreased plasma concentration of gastrin (d) Superficial spreading

(d) Increased production of macrocytic red blood cells
30. Which of the following sites contains striated muscle intestine: infections, malabsorption diseases
that is not under voluntary control?
(a) Bladder 32. Which of the following is a histological feature of
(b) Colon Whipples disease? (AI 2008)
(c) Esophagus (a) Infiltration of histiocytes in the lamina propria
(d) Gallbladder (b) Granuloma in the lamina
31. An old man being evaluated for abdominal pain and (c) Macrophages with PAS (+) material inside the
weight loss undergoes endoscopy showing a broad lamina propria
region of the gastric wall in which the rugae are flattened. (d) Eosinophils in the lamina propria
Biopsy of this area shows infiltration by numerous
polygonal tumor cells with small, dark, round or ovoid
33. Gluten sensitive enteropathy is most strongly associated
with: (AI 2003)
nuclei pushed to the margin of the cell by large, clear,
(a) HLA-DQ2 (b) HLA-DR4
cytoplasmic structures. These cells might be expected to
have which of the following properties? (c) HLA-DQ3 (d) Blood group B

(a) Keratohyalin granules observed by electron micros- 34. In the intra-epithelial region of the mucosa of intestine
copy the predominant cell population is that of (AI 2002)

(b) Melanosomes and premelanosomes by electron mi- (a) B cell (b) T-cells
croscopy (c) Plasma cells (d) Basophils

(c) Positive staining for gastrin by light microscopy
35. Macrophages containing large quantities of undigested

(d) Positive staining for mucin by light microscopy
and partial digested bacteria in intestine are seen in
Most Recent Questions (a) Whipples disease (AI 2002)
(b) Amyloidosis
31.1. Most common site of GIST is: (c) Immunoproliferative small intestinal disease
(a) Ileum (b) Esophagus (d) Vibrio cholerae infection
(c) Colon (d) Stomach
36. The histological features of celiac disease include all of
3 1.2. Which of the following is not true about GIST? the following, except: (AI 2002)
(a) Stomach is the most common site (a) Crypt hyperplasia
(b) High propensity of malignant change (b) Increase in thickness of the mucosa
(c) Associated with c-KIT mutation (c) Increase in intraepithelial lymphocytes
(d) Histology shows spindle shaped cells (d) Increase in inflammatory cells in lamina propria
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37. Type of anemia caused by Ileocecal TB: and investigations do not reveal occult blood, ova, or
(a) Iron deficiency (AIIMS Nov 2009) parasites in the stool. An endoscopy is performed and
(b) Megaloblastic after thorough microscopic examination, her diet is
(c) Sideroblastic modified. She is started on a special diet with no wheat
(d) Normocytic Normochromic or barley grain products. The dietary substitution
causes marked improvement in her symptoms. Which
38. The following cereals should be avoided in patients of the following is the most likely microscopic finding
with celiac diseases, except: (AIIMS Nov 2003)
to be seen in the biopsy specimen?
(a) Wheat (b) Barley
(c) Maize (d) Rye

(a) Lymphatic obstruction

(b) Noncaseating granulomas
39. Which of the following organs is not involved in
(c) Atrophy of the villi with blunting and flatterning
Whipples disease? (Delhi PG 2009)
(d) Foamy macrophages within the lamina propria
(a) Heart (b) CNS
(c) Lungs (d) GI Tract
49. A middle aged man Humesh was cooking in his
kitchen when there was an accidental cooking gas
40. Morphological features of celiac disease include all cylinder bursting episode. He suffered extensive burns
except: (Delhi PG 2009 RP) for which he is admitted to Burns Care Hospital. The
(a) Increase in intraepithelial lymphocytes patient was stabilized by the health care team but after
(b) Increase in crypt: villous ratio 15 days, he passed altered colored (black) stools. His
(c) Distended macrophages with PAS positive granules blood pressure also dropped and his hematocrit just
in lamina propria is 20%. The patient worsened within a short time and
(d) Elongated hyperplastic and tortuous crypts eventually expired. If an autopsy is conducted, which
41. All are true about amoebic ulcer except: (UP 2002) of the following organs would show the presence of
(a) Commonest site is ascending colon and cecum gastrointestinal ulcerations?
(b) Flask shaped ulcer
(a) Esophagus
(b) Stomach
(c) Perforation is common
(c) Duodenum
(d) Ileum
(d) Paucity of inflammatory cells 50. A complete endoscopic examination is performed on a
42. Intestinal biopsy in not diagnostic in (UP 2002) middle aged female Bebo having abdominal pain and
(a) Abetalipoproteinemia alteration in the bowel habits. She was reassured by her
(b) Tropical sprue gastroenterologist Dr. S. Sarin that her lesions were non
(c) Agammaglobulinemia malignant in nature. Which of the following is most
(d) Intestinal lymphangiectasis likely to have been picked up by her physician?

(a) Colorectal villous adenoma
43. Transverse ulcers are seen in: (UP 2004)
(b) Crohn disease
(a) Typhoid (b) Tuberculosis
(c) Duodenal peptic ulcer
(c) Amoebiasis (d) Ulcerative colitis
(d) Familial multiple polyposis
44. Aphthous ulcers are also known as (UP 2007) 51. A woman Mallika Sehrawat presents to the medicine
(a) Canker sores (b) Marjolins ulcer OPD with complaint of low volume watery diarrhea
(c) Curlings ulcer (d) Cushings ulcer associated with flatulence. The symptoms occur off
45. All are complication of typhoid ulcers except:(UP 2008) and on and have been present since 10 months. She has
(a) Perforation (b) Stricture formation no fever, nausea, vomiting or abdominal pain but has
(c) Hemorrhage (d) Sepsis lost 3.5 kg weight during this period. Her stool test is
negative for occult blood, ova, and parasites, and a stool
46. Which one of the following tumors is most commonly culture. Endoscopy is performed and the biopsy from
associated with pseudomyxoma peritonei? (AP 2006) the duodenum shows villous atrophy with a chronic
(a) Appendix (b) Gall bladder inflammatory infiltrate in the lamina propria. Which
(c) Stomach (d) Pancreas of the following antibodies is likely to be seen in this
47. All are true about typhoid ulcer except: patient?

(a) Mainly affects ileum (Kolkata 2005) (a) Anticentromeric antibody
(b) Multiple ulcer and transverse
(b) Anti-DNA topoisomerase I antibody
(c) Perforation occurs at 3rd week
(c) Antimitochondrial antibody
(d) Perforation treated by surgery
(d) Antigliadin antibody
48. A 28 year old lady Kulraj Kandhawa presents to 52. Over the last 6 months, a 40 year old lady has noticed
the medicine OPD with complaints of diarrhea and gradual yellowing of her skin. She visits her physician
fatigue. She also had weight loss of 4 kg over last 5 who observes that she is afebrile and has scleral icterus
months. Her physical examination is non significant and generalized jaundice. Her blood investigations
504
reveal total serum bilirubin of 9.2 mg.dL; direct Most Recent Questions
bilirubin of 7.0 mg/dL, serum ALT of 120 U/L, and serum

AST of 110 U/L. A liver biopsy is performed which on 57.1. Diverticulum most common site is:
microscopic examination shows sclerosing cholangitis.
(a) Sigmoid colon
(b) Ileum
Which of the following disease of the gastrointestinal
(c) Ascending colon (d) Transverse colon
tract may coexist in this lady? 57.2. Which of the followingis the commonest site of

(a) Chronic pancreatitis intestinal tuberculosis?

(b) Diverticulosis
(a) Stomach
(b) Jejunum

(c) Celiac sprue
(c) Ileum (d) Colon

(d) Ulcerative colitis
57.3. The most common site for amoebiasis:
53. A patient who recently underwent a gastrectomy
(a) Sigmoid colon
(b) Transverse colon
procedure complains of nausea, diarrhea, sweating,
(c) Cecum (d) Liver
palpitations, and flushing soon after eating a meal. This 57.4. Anti-gliadin antibodies are detectable in:

patient should be instructed to
(a) Tropical sprue

(a) eat less frequent, larger meals that are high in carbo-
(b) Whipples disease

hydrates
(c) Celiac disease
(b) eat more frequent, smaller meals that are high in

fat

(d) Intestinal lymphoma

(c) eat more frequent, larger meals that are high in protein 57.5. Which of the following is not associated with celiac

(d) eat more frequent, smaller meals that are high in car- sprue?

(a) Turner syndrome
bohydrates

(b) Down syndrome
54. A female patient has severe arthritis involving the
(c) Klinefleter syndrome
lower back. Before making a diagnosis of ankylosing
(d) Type 1 diabetes
spondylitis, the patient should be questioned by the
57.6. Paneth cells contain:
physician about which of the following diseases?

(a) Carcinoid syndrome

(a) Zinc (b) Copper

(b) Celiac disease

(c) Molybdenum
(d) Selenium

(c) Crohns disease 57.7. Which is incorrect of typhoid ulcers:

(d) Whipples disease
(a) Hemorrhage is common
55. A patient with intestinal malabsorption is found to

(b) Occurs on lymphoid aggregation
markedly improve when flour products (bread, noodles,

(c) Horizontal ulcers
etc.) are removed from his diet. At the height of the

(d) Longitudinal ulcers

patients disease, marked histologic changes would be 57.8. Perforation of typhoid ulcer usually occurs during
seen at which of the following sites? which week?

(a) Distal large bowel
(a) 1st (b) 2nd

(b) Distal small bowel (c)
3rd (d) 4th

(c) Proximal small bowel 57.9. Serum amylase level are raised in all of the following

(d) Entire small bowel EXCEPT:
56. A 25-year-old man presents to a rheumatologist with
(a) Duodeneal ulcer perforation
complaints of joint pain involving the large joints of

(b) Pancreatitis
the legs which exacerbates frequently accompanied

(c) Appendicitis
by diarrhea. Which of the following gastrointestinal

(d) Small Bowel Strangulation

diseases is most likely to be implicated as the cause of 57.10. Which of the following is not considered a pre-
the patients joint problems? malignant lesion:

(a) Amebic colitis
(a) Leukoplakia

(b) Chronic appendicitis
(b) Erythroplakia

(c) Diverticulosis
(c) Chronic hyperplastic candidiasis

(d) Oral lichen planus
57. Based
on epidemiological studies, which of the 57.11. Diagnosis of typhoid in first week is by:
following has been found to be most protective against (a) Widal test
colon cancer? (AIIMS May 2011)
(b) Stool culture

(a) High fiber diet
(b) Low fat diet
(c) Urine culture

(c) Low selenium diet (d) Low protein diet
(d) Blood culture
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57.12. Purtschers retinopathy is seen in: 65. Which of the following statements about Crohns

(a) Meningitis disease is incorrect? (Delhi PG 2009)

(b) Pancreatitis (a) Granulomas present frequently

(c) Uncontrolled hypertension (b) It is separate and distinct from ulcerative colitis

(d) Unilateral carotid artery occlusion (c) Cigarette smoking is a risk factor
(d) Rectum spared in 50% patients with large bowel

57.13. Usually, gall stones consists of these types, except: involvement

(a) Oxalate

(b) Bile salts 66. Commonest endocrine tumour of pancreas artses from

(c) Bile pigments which of the following cells? (Karnataka 2009)

(d) Cholesterol (a) a cells (b) b cells
(c) Delta cells (d) VIPoma
intestine: ibd, polyp, tumours 67. Skin lesions are seen in (Karnataka 2006)
(a) Ulcerative colitis (b) Crohns disease
58. Most important prognostic factor for colorectal (c) Both (a) and (b) (d) None of the above
carcinoma is (AIIMS May 2011)
(a) Site of lesion
68. Polyps in Peutz-Jeghers syndrome are
(a) Adenomatous polyps (Karnataka 2004, 2008)
(b) Tumour size and characteristics
(b) Hyperplastic polyps
(c) Age of patient
(c) Hamartomatous polyps
(d) Lymph node status
(d) Pseudopolyps
59. Which of the following is NOT true about FAP? 69. All are malignant in nature except (UP 2000)
(a) AR inheritance (AIIMS May 2011) (a) Juvenile polyp (b) Familial polyp
(b) Screening done by sigmoidoscopy (c) Carcinoid tumor (d) Villous adenoma
(c) Polyps develop in early adulthood
(d) Epidermal cysts and osteomas may occur 70. All are true about Crohns disease except
(a) Rectal involvement is common
(UP 2001)
60. In Peutz-Jeghers syndrome, polyps are mainly seen in (b) Granuloma formation
(a) Rectum (AIIMS May 2010) (c) Erythema nodosum
(b) Colon (d) Fistula formation
(c) Esophagus
(d) Jejunum 71. Most common tumor of appendix is (UP 2005)
(a) Carcinoid tumor
61. Which of the following is not true about FAP? (b) Pseudomyxoma-peritonitis
(AIIMS May 2010, May 2011) (c) Adenocarcinoma
(a) Autosomal recessive inheritance (d) Mucocele
(b) Screening done by sigmoidoscopy
(c) Polyps develop in early adulthood 72. Skip lesions are seen in (UP 2005)
(d) Epidermal cysts and osteomas may occur (a) Ulcerative colitis
(b) Crohns disease
62. Colon carcinoma is associated with all except: (c) Carcinoid syndrome
(a) Rb (AI 2009) (d) Whipples disease
(b) Mismatch repair genes
(c) APC 73. Fistula is most common in (UP 2007)
(d) b-catenin (a) Crohns disease
63. In ulcerative colitis, which of the following is seen? (c) Infective enterocolitis
(a) Cryptitis (AIIMS May 2008) (d) Celiac sprue
(b) Crypt loss
(c) Crypt branching 74. Most common site of carcinoid tumor is (RJ 2000)
(d) Proliferating mucosa (a) Stomach (b) Jejunum
(c) Distal ileum (d) Appendix
64. Which of the following would be the best morphological 75. Most common site of carcinoma pancreas is (RJ 2000)
feature to distinguish ulcerative colitis from Crohns
disease? (AIIMS May 2004) (a) Head (b) Body
(a) Diffuse distribution of pseudopolyps (c) Tail (d) Equal incidence at all sites
(b) Mucosal edema 76. Carcinoid tumor produces all except (RJ 2003)
(c) Crypt abscesses (a) Flushing (b) Diarrhea
(d) Lymphoid aggregates in the mucosa (c) Bronchodilation (d) Raynauds phenomenon
506
77. Which organ is always involved in ulcerative colitis? (a) CMV infection
(a) Jejunum (RJ 2005) (b) Pseudomembranous colitis
(b) Ileum (c) Ulcerative colitis
(c) Rectosigmoid (d) Whipple disease
(d) Duodenum
86. A 50-year-old man Bhupi presents to his doctor with
78. Two identical specimen of the intestine obtained diarrhea, flushing and wheezing. Physical examination
following colectomy shows on examination hemorrhagic is significant for a grade II/VI diastolic murmur located
cobblestone appearance; one of them however, shows at the right sternal border at the 4th intercostal space.
longitudinal grooving. It is likely to be a specimen of: Which of the following substances is most likely to be

(a) Ulcerative colitis (Kolkata 2002) elevated in this patients urine?

(b) Ischemic colitis
(a) 5-HIAA (b) HVA

(c) Multiple polyposis
(c) Phenylalanine (d) Selegiline

(d) Crohns disease
87. Biopsy of a small, rounded rectal polyp demonstrates
79. Carcinoma of colon is associated with all except: glands and sawtooth crypts composed of a proliferation
(a) High fat diet (Kolkata 2005)
of goblet and columnar epithelial cells. No atypia
(b) High fiber diet
is seen. This polyp is best classified as which of the
(c) Streptococcus bovis infection
following?

(a) Hyperplastic polyp
80. Backwash ileitis is seen in: (Bihar 2006)
(b) Peutz-Jeghers polyp
(a) Crohns disease
(c) Tubular adenoma
(d) Tubulovillous adenoma
(c) Colonic carcinoma
(d) Ileal polyp Most Recent Questions
81. Granulomatous inflammation is found in: (Bihar 2006) 87.1. Toxic megacolon is seen in:
(a) Crohns disease (b) Ulcerative colitis
(a) Chronic nonspecific ulcerative colitis
(c) Amoebiasis (d) Giardiasis
(b) Crohns disease
82. Continuous involvement of colonic mucosa is seen in: (c) Colonic diverticulosis
(a) Ulcerative colitis (Bihar 2006) (d) Hamartomatous polyp
(b) Crohns disease
8 7.2. Which of the following is inheritance of Gardner
(c) Carcinoma colon
syndrome?
(d) Colonic polyp
(a) Autosomal recessive
83. All are true about carcinoid syndrome except: (b) Autosomal dominant
(a) Wheezing (Jharkhand 2006) (c) X linked dominant
(b) Pulmonary stenosis (d) X linked recessive
(c) Flushing 8 7.3. Osteomas, adenomatous polyps of intestine and
(d) Splenomegaly periampullary carcinomas are seen in which oif the
84. A 24 year old male Anil B. with a 4-year history of following conditions?
abdominal pain, periodic diarrhea, low-grade fever,
(a) Cowden syndrome
and easy fatigability is found to have an enteroenteric
(b) Peutz Jegers syndrome
fistula on contrast radiography. Colonoscopy shows
(c) FAP
cobblestone mucosa that has linear ulcerations
(d) Gardener syndrome
with skip areas of normal bowel wall. Which of 87.4. True about ulcerative colitis, all except:
the following is the most likely explanation of fistula (a) Rectum involved
formation in this patient? (b) Pseudopolyps

(a) Intramural granulomas (c) Pancolitis

(b) Transmural inflammation (d) Noncaseating granuloma

(c) Marked lymphoid reaction
87.5. Which of the following is the most common location of

(d) Skip lesions of the intestinal wall
carcinoid tumour?
85. A 51 year young man Firdaus had been receiving (a) Pancreas
antibiotics for severe folliculits. He develops fever, (b) Lung
toxicity, and severe diarrhoea. Which of the following (c) Gastrointestinal tract
is the most likely diagnosis? (d) Gonads
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87.6. Carcinoid tumour develops from:

87.13. Following statements regarding ulcerative colitis is:
(a) Hematopioetic cells
(a) Smoking does not have a protective effect
(b) Kulschitsky cells
(b) Smoking has a protective effect
(c) Neuroglial cells
(c) No relation with smoking
(d) Chromaffin cell
(d) Smoking causing relapses
8 7.7. Pseudopolyps are seen in:
87.14. Zollinger Ellison syndrome is not caused by tumors
(a) Crohns disease (b) Ulcerative colitis from:
(c) Juvenile polyposis (d) Tuberculosis
(a) Pancreas
8 7.8. The highest malignant potential is seen in:
(b) Ovary
(a) Crohns disease
(c) Colon
(d) Duodenum
(c) Familial polyposis
87.15. Crohn disease is associated with:
(d) Infantile polyp
(a) NOD2/CARD15 gene
8 7.9. Commonest malignant small intestinal tumor
(b) P53 gene
(a) Adenocarcinoma
(c) Philadelphia chromosome
(b) Lymphosarcoma
(d) BRCA1 gene
(c) Leiomyosarcoma
87.16. A highly sensitive and specific marker for detecting
(d) Carcinoid tumor intestinal inflammation in ulcerative colitis is:
87.10. Most common site of carcinoma pancreas is
(a) CRP
(a) Head (b) Body
(b) Fecal lactoferrin
(c) Tail (d) None
(c) Fecal calprotectin

(d) Leukocytosis
87.11. Which of the following is a special stain for rhabdo
87.17. The minimum number of polyps necessary for a
myosarcoma?
(a) Cytokeratin diagnosis of Familial Adenomatous Polyposis (FAP) is:
(b) Synaptophysin
(a) 05
(c) Desmin
(b) 10
(d) Myeloperoxidase
(c) 50
87.12. Which of the following type of anemia would be

(d) 100
associated with carcinoma of the colon?

87.18. Antibody suggestive of diagnosis of ulcerative colitis?
(a) Megaloblastic anemia
(a) p-ANCA
(b) Iron deficiency anemia
(b) c-ANCA
(c) Aplastic anemia
(c) A.M.A
(d) Hemolytic anemia
(d) A.N.A
508
E xplanations
1. Ans. (b) Intestinal metaplasia (Ref: Robbins 8th/770, 9/e 757)
Direct quote from Robbins . Barrett esophagus is a complication of chronic GERD that is characterized by intestinal
metaplasia within the esophageal squamous mucosa.
2. Ans. (a) Mediastinal fibrosis (Ref: Robbins 7th/607, 8th/773, 9/e p758-759)
E xternal beam irradiation but not mediastinal fibrosis is a risk factor for esophageal cancer.
H PV DNA is found frequently in esophageal squmaous cell carcinoma in high incidence regions..Robbins 7th/807
C austic ingestion, achalasia, bulimia, tylosis (an inherited autosomal dominant trait), Plummer-Vinson syndrome,
external-beam radiation, and esophageal diverticula all have known associations with squamous cell cancer......
...Sabiston textbook of surgery 18th edn
3. Ans. (c) Reflux disease (Ref: Robbins 8th/769, 9/e p755)
Robbins clearly states that Reflux of gastric contents into the lower esophagus is the most important cause of esophagitis.
4. Ans. (a) Edge of the ulcer (Ref: Robbins 8th/768)
Herpes viruses typically cause punched-out ulcers; the nuclear inclusions of herpes virus are found in a narrow rim of
degenerating epithelial cells at the margin of the ulcer.
CMV causes linear ulceration of the esophageal mucosa; the histologic findings of CMV-associated change with both
intranuclear and cytoplasmic inclusions are found in capillary endothelium and stromal cells in the base of the ulcer.
For diagnosis, the biopsy should be taken from edge of ulcer in HSV and base of ulcer in CMV.

So, friends both a and b options are correct. But as we have to choose only one, we will go for option (a) because Herpes
simplex is the most common virus causing esophagitis.
5. Ans. (b) Adenovirus (Ref: Robbins 8th/768, 9/e p754, Harrison 17th/1853)
Viruses that can cause esophagitis are: HSV-1, HSV-2, Varicella zoster virus, Cytomegalovirus and HIV For diagnosis, the
biopsy should be taken from edge of ulcer in HSV and base of ulcer in CMV.
Findings in biopsy of edge of ulcer in HSV are:
Ballooning degeneration
Ground glass changes in nuclei
Cowdry type A intranuclear inclusion bodies.
6. Ans. (a) Squamous to columnar metaplasia (Ref: Robbins 7th/804, 9/e p757)
7. Ans. (c) Gastroesophageal reflux (Ref: Robbins 9/e p757, 8th/770-1; 7th/804-805, 808-809)
8. Ans. (c) Megaloblastic anemia (Ref: Robbins 9/e p753, 8th/662; 7th/776)
9. Ans. (d) It is a known precursor of adenocarcinoma of the esopohagus. (Ref: Robbins 9/e p758, 8th/769-772)
Barrett esophagus is columnar metaplasia of the esophageal squamous epithelium (squamousto-columnar). The colum-
nar epithelium is often of the intestinal type with goblet cells. Barrett esophagus is a complication of long-standing gas-
troesophageal reflux disease and is a precursor of esophageal adenocarcinoma. The most common location is in the distal
(lower) third of the esophagus.
10. Ans. (b) Gastroesophageal junction incompetence (Ref: Robbins 9/e p755, 8th/769)
Gastrointestinal reflux disease (GERD) is a common condition manifesting as heartburn and regurgitation. However, some
patients can have silent GERD, which means they may have symptoms like dysphagia, nocturnal cough, and sore throat
even though they dont feel heartburn.
Gastroesophageal junction incompetence is the primary pathophysiologic mechanism responsible for GERD. This incompetence is
most commonly caused by transient lower esophageal sphincter relaxations and a hypotensive lower esophageal sphincter (LES).
Acidic gastric contents reflux back into the esophagus and irritate the esophageal mucosaleading to an inflammatory reaction and
epithelial repair.
Basal zone hyperplasia, elongation of lamina propria papillae, and inflammatory cells (eosinophils, neutrophils and
lymphocytes) are characteristic histologic findings.
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(Choice A) Pill-induced esophagitis is commonly seen with tetracycline antibiotics, potassium chloride, and bisphos-
phates. Metformin and enalapril do not cause esophagitis.
(Choices C) Candida albicans is the most common cause of infectious esophagitis. White plaques on the erythematous
mucosa are seen on endoscopy. Light microscopy shows Pseudo hyphae and budding spores embedded in necrotic debris.
Candida is the most common cause of oropharyngeal dysphagia odynophagia in HIV and immunocompromised patients.
(Choice D) Absent esophageal peristaltic movements is seen in achalasia and scleroderma.
11. Ans. (b) Zenkers diverticulum (Ref: Robbins 8th/767, 9/e p753)
This is the classic presentation of Zenkers diverticulum, which is a false diverticulum formed by herniation of the mu-
cosa at a point of weakness at the junction of the pharynx and esophagus in the posterior hypopharyngeal wall. It is also
associated with halitosis, and if the diverticulum fills completely with food, it can cause dysphagia or obstruction of the
esophagus.
Mallory-Weiss tears (option A) are mucosal tears at the gastroesophageal junction secondary to repeated, forceful vomiting. They
are often seen in alcoholics.
Schatzki rings (option C) are mucosal rings found in the distal esophagus at the squamocolumnar junction.
In contrast to a Zenkers diverticulum, the usually asymptomatic traction diverticula (option D) are true diverticula involving all of the
layers of the esophagus. They are typically caused by adherence of the esophagus to a scarred mediastinal structure.
12. Ans. (a) Achalasia (Ref: Robbins 8th/768, 9/e p753)

13. Ans. (d) Buccal mucosa (Ref: Robbins 8th/811, 9/e p721-732)
14. Ans. (a) Achalasia Read explanation below (Ref: Robbins 9/e p753)
Achalasia is an acquired insidiously developing esophageal motility disorder due to the loss of inhibitory enteric neurons of the
esophageal body and lower esophageal sphincter. The primary complaint with diffuse esophageal spasm (choice B) is mid-sternal
pain that can be misdiagnosed as cardiac pain. The pain is caused by prolonged contraction of the entire esophageal body.
A manometric study may show poor peristalsis in the smooth muscle portion of the esophageal body, but lower esophageal
sphincter function is unaffected.

The primary complaint with incompetent lower esophageal sphincter (choice C) is heart burn and regurgitation due to
gastroesophageal reflux. A manometric study would show lower-than-normal resting tone in the lower esophageal sphincter, or a
sphincter that relaxes inappropriately.
Since the patients symptoms do not occur until 2-3 seconds after a swallow suggests that oropharyngeal dysphagia (choice D) is
not the diagnosis. The presence of cough, hoarseness, or nasal regurgitation commonly occurs with this disorder. Oropharyngeal
dysphagia is often due to neurological or muscle disorders like stroke, amyotrophic lateral sclerosis, muscular dystrophy, or
myasthenia gravis.
14.1. Ans. (b) Lateral margin

Oral Cancer: Diagnosis, Management, and Rehabilitation pg 100 mentions that 60-70% arise from the lateral sur-
face of the middle third of the tongue.
14.2. Ans (c) Zenker diverticulum (Ref: Robbins 9/e p 758-9)
15. Ans. (b) CD 117 (Ref Robbins 8th/789-790, 9/e p776)
Direct quote Robbins The most useful diagnostic marker for GIDT is c-kit (also known as CD117 ).
Q Q
16. Ans. (b) Stomach Cancer (Ref: Robbins 8th/786, 9/e p776)
17. Ans. (a) CD117 (Ref: Robbins 8th/789-790, 7th 826-827, Harrison 17th/573)
The most useful diagnostic marker is c-kit (CD117) detectable in 95% of the patients. Other markers like CD34 and vimen-
tin can also be expressed by some tumor cells. CD34 is also present on pluripotent hematopoetic stem cell.
18. Ans. (a) CD117 (Ref: Robbins 8th/790, 9/e p776)
19. Ans. (c) Intestinal metaplasia see text for details (Ref: Harrison 17th/572)
20. Ans. (d) Fundus (Sleisenger & Fordtrans text book of Gastroinstestinal disease 7th/813)
Pernicious anemia is associated with autoimmune atrophic gastritis affecting the fundic glands. Intestinal metaplasia
(premalignant for gastric carcinoma), is characteristically seen in this area of atrophic gastritis. Atrophic glands with ex-
tensive intestinal metaplasia are most characteristically confined to the fundus in patients with pernicious anemia.
21. Ans. (a) Gastric carcinoma (Ref: Robbins 8th/786)
510
Metastasis in gastric cancer

Liver (first organ to be affected)
Ovary (where it is known as Krukenbergs tumor)
Periumbilical lymph nodes (Sister Mary Joseph nodule)
Peritoneal cul-de-sac (Blumers shelf palpable on rectal or vaginal examination)
Left supraclavicular lymph node (Virchows lymph node Q).
22. Ans. (c) Interstitial cells of cajal (Ref: Robbins 7th/826, 9/e p775)
23. Ans. (d) Atrophic gastritis > (b) Postgastrectomy (Ref: Sternbergs diagnostic surgical pathology, Volume 2, page 1451,
LWW, Biopsy interpretation of the gastrointestinal tract mucosa by EA Montgomery, Lippincott William Wilkins; 120,
multiple journals)
Sternberg.. Multifocal atrophic gastritis with intestinal metaplasia is present commonly in postgastrectomy stomach. It is not clear
whether it is pre-existing (for which surgery was done) or develops after gastrectomy.
Biopsy interpretation of the gastrointestinal tract mucosa some authors have associated gastric xanthoma with atrophic gastritis.
Digestive Diseases and Sciences, Vol. 31,1986,page 925-8 mentions It says xanthomatosis is characterized by collections
of lipid-laden macrophages, or foam cells , plaques or nodules in many tissues, most commonly the skin. Involvement can
occur in all regions of the gastrointestinal tract, but is most common in the stomach. It is more common in patients with
gastritis, gastric ulcer, and with duodeno-gastric reflux after gastric surgery and mucosal damage has been postulated
to play an important role in its pathogenesis. There is no documented relationship between degree of hyperlipidemia or
hypercholesterolemia and presence of gastric xanthomatosis. Rather, it is associated with atrophic gastritis.
Turkish Journal of gastroenterology.. Lipid islands are found in the stomach only when there are pathological changes
such as chronic gastritis, intestinal metaplasia, atrophic gastritis, gastric ulcer,and changes caused by bile reflux or partial
gastrectomy.
Clinical importance of knowing about gastric xanthoma
Atypical xanthoma cells can be easily confused with signet-ring adenocarcinoma cell. However, xanthoma cells are
negative with periodic acid-Schiff (PAS) stain but show a positive reaction with Oil red 0 and weakly positive reaction with Masson

trichrome. (RefActa Cytol. 2006 Jan-Feb;50(1):74-9).
Signet-ring adenocarcinoma cells showed a strongly positive reaction with PAS stain, cytokeratin and mucicarmine.
24. Ans. (d) Gastric adenoma (Ref: Robbins 7th/817, 823, 826, 9/e p770)
H. pylori is also associated with peptic ulcer disease, gastric cancer and gastric mucosa associated lymphoma (called MALToma
or mucosa associated lymphoid tissue tumor)
Gastric adenoma are polypoid lesions of the stomach found in the antrum most commonly.
25. Ans. (b) Mucosa and submucosa (Ref: Robbins 7th/824, 825; fig/17-25, 9/e p771-772)
GASTRIC CARCINOMA
Classification On the basis of
Depth of invasion Macroscopic pattern Histologic subtype
(a) Early-involving mucosa and submucosa 1. Exophytic (a) Intestinal type
(b) Advanced-extending into muscularis propria and beyond 2. Flat or depressed (b) Diffuse type
3. Excavated
26. Ans. (b) Parietal cell (Ref: Robbins 8th/657; 7th/641, 9/e p765)
27. Ans. (c) Signet ring cell adenocarcinoma (Ref: Robbins 8th/772)
The description is indicative of the presence of leather bottle appearance (linitis plastica) of diffuse gastric carcinoma.
Microscopic examination reveals that in this cancer, diffuse infiltration of the stomach wall by gastric type mucus cells is
present. The tumor cells have a signet ring appearance because the cytoplasmic mucin pushes the nucleus to one side.
Early gastric carcinoma is confined to the mucosa and submucosa.

Gastrointestinal stromal tumors tend to be bulky masses.
In chronic atrophic gastritis, there is no significant scarring or shrinkage but rugal folds are lost.
Info
In the comparison of the whole GIT, granulomas are rarest in the stomach.
28. Ans. (a) Acute gastritis (Ref: Robbins 8th/773, 9/e p763)
Acute gastritis, characterized by patches of erythematous mucosa, sometimes with petechiae and ulceration, can be seen
as a complication of a variety of other conditions (alcohol use, aspirin and other NSAIDs use, smoking, shock, steroid use,
and uremia), which usually have in common disruption of the mucosal barrier of the stomach.
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Chronic antral (type B) gastritis (option B) is associated with Helicobacter pylori.

Lymphocytic gastritis (option C) is thought to be a gastric manifestation of celiac sprue.
Hypertrophic gastritis (Menetriers disease; option D) is an idiopathic condition characterized by markedly enlarged mucosal
folds.
29. Ans. (d) Increased production of macrocytic red blood cells (Ref: Robbins 8th/778-779, 9/e p765)
Autoimmune destruction of parietal cells would lead to decreased secretion of gastric acid and intrinsic factor followed by
poor absorption of dietary vitamin B12 and then pernicious anemia. It is characterized by increased production of macro-
cytes (megaloblasts) by the bone marrow.
The luminal bacteria (option A) would most likely exhibit increased (not decreased) growth due to sterilizing action of the
acid.
A decrease in acid secretion leads to increased secretion of gastrin by antral G cells because low gastric pH (less than 3)
inhibits gastrin secretion via paracrine release of somatostatin from cells in the gastric mucosa that can sense the acidity.
With decreased parietal cells, the pH of the gastric lumen would rise and remove this inhibitory component.
Because less acid would be delivered to the duodenum with parietal cell destruction, less secretin would be released into
the blood.
30. Ans. (c) Esophagus (Read explanation below)
Striated (skeletal) muscle not under voluntary control is an unusual feature of the upper third of the esophagus. The mid-
dle third of the esophagus contains roughly half striated and half smooth muscle; the lower third contains only smooth
muscle. All the other structures listed in the answer choices contain smooth muscle.
31. Ans. (d) Positive staining for mucin by light microscopy (Ref: Robbins 8th/785)
3 1.1. Ans. (d) Stomach (Ref: Robbins 8/e p789-90, 9/e p776)
NEET Key points about Gastrointestinal stromal tumor GIST
Arise from pacemakers of the GIT known as interstitial cells of CajalQ.
GIST is the most common mesenchymal tumorQof the abdomen

The most common location of the GIST is the stomachQ
This is associated with patients having neurofibromatosis-1Q.
Microscopically the tumor may show either epithelioid cells, spindle cells or mixed (both the epithelioid cells and spindle
cells).
The most useful diagnostic marker is c-kit (CD117)Qdetectable in 95% of the patients.
It is best diagnosed withCT scan with PET scanQ(preferable) or CT scan.
Treatmentis done with surgical resection (localized tumors) and non-excisable tumors are managed with tyrosine kinase
inhibitors called imatinib mesylateQor sunitinib.
3 1.2. Ans. (b) High propensity of malignant change (Ref: Robbins 8/e p789-90, 9/e p775-776)
High-yield Imaging: Gastrointestinal p213
Direct quote from High yield.. 90% of stomach GISTs are found to be benign. Do revise all features of GIST from earlier
question.
3 1.3. Ans. (a) Gastric ulcer (Ref: Bailey 25/e p1055, Robbin 9/e p767)
Chronic duodenal ulcers are not associated with malignancy but, in contrast, gastric ulcers are.
It is fundamental that any gastric ulcer should be regarded as being malignant, no matter how classically it resembles
a benign gastric ulcer.
Stomal ulcers occur after a gastroenterostomy or a gastrectomy of the Billroth II type. The ulcer is usually found on the
jejunal side of the stoma.
31.4. Ans (d) Interstitial cells of Cajal (Ref: Robbins 9/e p 775)
31.5. Ans (c) Gastroduodenal artery (Ref: Robbins 9/e p767; Bailey 25/e p1064)
31.6. Ans (d) Superficial spreading (Ref: Robbins 9/e p772-3)
32. Ans. (c) Macrophages with PAS (+) material inside the lamina propria (Ref: Harrison 18th/2474, Robbins 9/e p792)
Hallmark of Whipples disease had been presence of PAS positive macrophages containing the characteristic small bacilli.
Just revise friends that the presence of T. Whipplei outside of macrophages is more important indicator of active disease than
is their presence inside the macrophages.
512
33. Ans. (a) HLA DQ2 (Ref: Harrisons 17th/2051, Robbins 9/e p782)
Celiac sprue is associated with HLA DQ2. For other diseases associated with HLA; refer to the table in the chapter of
Immunity (chap-6)
34. Ans. (b) T-lymphocyte (Ref: Mucosal Immunology Elsevier, 3rd/565)
Direct quote.. IEL are a distinctive population of T cells dispersed among the luminal epithelial cells. Particularly in the
small intestine, there is a predominance of CD 8+T cells.
Increase in IEL is defined as > 40 lymphocytes per 100 enterocytes.
35. Ans. (a) Whipples Disease (Ref: Robbins 7th/884 9/e p792, Harrison 17th/1884)
The hallmark of Whipples disease is a small intestinal mucosa laden with distended macrophages in the lamia propria.
The macrophages contain periodic acid Schiff (PAS) positive granules and small rod shaped bacilli)
36. Ans. (b) Increased in thickness of mucosa (Ref: Robbins 7th/843, 9/e p783, Harrisons 17th/1881)
Characteristic histological features seen on duodenal/jejunal biopsy in celiac sprue are:
1. Absence or reduced height of villi, resulting in flat appearance.
2. Crypt cell hyperplasia compensate for villous atrophy and mucosal thickness remain same
3. Cuboidal appearance and nucleus that are no longer basally oriented and increased intraepithelial lymphocytes.
4. Increased lymphocytes and plasma cells in lamina propria.
These features are characteristic of celiac sprue but not diagnostic because similar features can be seen in:
1. Tropical sprue, 2. Eosinophilic enteritis, 3. Milk-protein intolerance in children
So, for establishing the diagnosis of celiac sprue, the characteristic histological picture on small intestinal biopsy
should also revert back to normal on gluten free diet. Gluten free diet also reverses the symptoms as well as sero-
logical markers (anti-endomysial antibodies).
37. Ans. (b) Megaloblastic (Ref: Harsh Mohan 6th/569-571, Harrison 17th/649)
In intestinal tuberculosis the ileocecal junction is the commonest site of involvement. Ileum is the physiological site for
absorption of vitamin B12. Also, TB is mentioned to be a cause of folic acid deficiency which is therefore going to result in
megaloblastic anemia.
38. Ans. (c) Maize (Ref: Robbins 8th/796, 9/e p782)
It is a disease characterized by increased sensitivity to a protein called gliadin present in the grains like wheat; oat,
barley and rye resulting in a T-cell mediated chronic inflammatory reaction in the small intestine and impaired ab-
sorption. It is associated with HLA-DQ2 or HLA-DQ8.
39. Ans. (c) Lungs (Ref: Robbins 9/e p792, 8th/804, Harrison 17th/1884)
The organs in which these foamy macrophages can be seen are Liver, Small intestine, Lymph nodes, Heart, Eyes, CNS and
synovial membranes of joints.
40. Ans. (c) Distended macrophages with PAS positive granules in lamina propria (Ref: Robbins 9/e p792, 8th/795, 803)
It is feature of Whipples disease.
41. Ans. (c) Perforation is common (Ref: Robbins 9/e p795, 8th/806; 7th/839)
42. Ans. (b) Tropical sprue (Ref: Robbins 9/e p784, 8th/796, 7th/844)
43. Ans. (b) Tuberculosis (Ref: Robbins 8th/798, 9/e p376)
44. Ans. (a) Canker sores (Ref: Robbins 9/e p728, 8th/742, 7th/776)
45. Ans. (b) Stricture formation (Ref: Robbins 9/e p789, 8th/801-802)
46. Ans. (a) Appendix (Ref: Robbins 9/e p816, 8th/828; 7 th/871-872,1097)
47. Ans. (b) Multiple ulcer and transverse (Ref: Robbins 8th/801, 9/e p789)
48. Ans. (c) Atrophy of the villi with blunting and flatterning (Ref: Robbins 8th/796-7, 9/e p782-783)
The description of a malabsorption disorder that responded to dietary treatment is suggestive of celiac disease (glu-
ten sensitivity). The microscopic features are mucosal flattening, diffuse and severe villous atrophy and chronic in-
flammation of the lamina propria. Intraepithelial lymphocytes are also increased.
Lymphatic obstruction and foamy macrophages the lamina propria containing PAS-positive granules occurs in
Whipple disease.
Noncaseating granulomas are present in the intestinal wall in Crohns disease.
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49. Ans. (b) Stomach (Ref: Robbins 9/e p762, 8th/775-6)

The presentation of the patient is suggestive of stress ulcers called as Curling ulcers when they occur in patients with burn
injuries. These small shallow ulcers never penetrate the muscular is propria, but may can bleed profusely. Esophageal varices
occur in patients with portal hypertension usually associated with cirrhosis.
Duodenal ulcer are typically peptic ulcers in individuals with Helicobacter pylori infection.
Ileal ulcerations and colonic ulcerations can either be idiopathic or inflammatory bowel disease or infections.
50. Ans. (c) Duodenal peptic ulcer (Ref: Robbins 8th/780-1, 9/e p767, Bailey and Love 25th/1055-6, Harsh Mohan 6th/553)
Peptic ulcer of the duodenum is not a precursor lesion to carcinoma. This is in contrast to gastric peptic ulcer disease which
are premalignant in nature (though rarely).
Familial multiple polyposis has almost 100% chance of progression to a malignancy.
Colorectal villous adenomas may also undergo malignant change. The same holds true of inflammatory bowel disease
(ulcerative colitis has higher of progression to a malignancy than Crohns disease).
Duodenal and Gastric peptic ulcer
Features Duodenal ulcer Gastric ulcer
Site 1st part of duodenum Along lesser curvature
Incidence More common Less common
Age 25 50 yrs, M>F Beyond 6th decade, M>F
Etiology Almost all patients have H. pylori infection Less stronger association
Acid level High Usually normal; if hypergastrinemia
Pain after food intake Relieved Aggravated
Clinical features Night pain and melena more common No night pain, hematemesis more common
No vomiting/no weight loss Vomiting common/weight loss is present
Complications No malignant change Malignant change present (though rarely)
51. Ans. (d) Antigliadin antibody (Ref: Robbins 9/e p783, 8th/795)
The features in the stem of the question suggest likely diagnosis of celiac disease. These patients have anti-transglutaminase,
anti-gliadin and anti-endomysial (most useful) antibodies. Women are affected more than men. Celiac disease results
from gluten sensitivity. Exposure to the gliadin protein in wheat, oats, barley, and rye (but not rice) results in intestinal
inflammation. Gliadin sensitivity causes epithelial cells to produce IL 15 which activates CD8+ T cells. These T cells
damage the enterocyte. Dermatitis herpetiformis, and enteropathy associated T-cell lymphomas may be seen in some
individuals.
Anticentromeric antibody is most specific for limited scleroderma (CREST syndrome).
Anti- DNA topoisomerase I antibody is most specific for diffuse scleroderma in which GIT may be affected and malabsorption
may be present.
Antimitochondrial antibody is more specific for primary biliary cirrhosis.
52. Ans. (d) Ulcerative colitis (Ref: Robbins 8th/811, 9/e p800)
Sclerosing cholangitis is an extraintestinal manifestation of inflammatory bowel disease, more commonly associated with
ulcerative colitis and less often with, Crohn disease. Explaining other options,
Pancreatitis has no association with sclerosing cholangitis. It may cause bilary tract lithiasis.
Diverticulosis may be complicated by diverticulitis, but the liver is not involved.
Celiac disease may be associated with dermatitis herpetiformis, but not with liver disease. Peptic ulcer disease does not lead to
hepatic complications.
53. Ans. (b) Eat more frequent, smaller meals that are high in fat
Read explanation below
The postgastrectomy symptoms in the given question is called the dumping syndrome. Since all or part of the stomach is
removed, an ingested meal will be delivered to the small intestine more quickly than normal. The large increase in tonicity
in the small intestine causes an osmotic fluid shift from the extracellular fluid (plasma) into the lumen of the gut. The
increased distention of the small intestine increases motility through reflex mechanisms and causes diarrhea. The blood
volume contraction and concomitant release of vasoactive substances such as bradykinin and/or vasoactive intestinal
peptide can create hypotension and reflex tachycardia.
These patients should be instructed to eat more frequent, smaller meals to reduce the osmotic and/or carbohydrate load that is delivered
to the small intestine. Furthermore, since fats are the slowest to be absorbed, a diet that is higher in fat will also reduce the problem of
rapid absorption.
54. Ans. (c) Crohns disease (Ref: Robbins 8th/811, 9/e p799-800)
514
55. Ans. (c) Proximal small bowel (Ref: Robbins 8th/795-796, 9/e p782-783)
The patient has celiac disease, which is apparently an acquired hypersensitivity to the gluten (such as gliadin) in wheat.
Unlike tropical sprue (which may be related to enterotoxigenic E. coli infection), which involves the entire small bowel,
celiac sprue is usually limited to the proximal small bowel.
56. Ans. (d) Ulcerative colitis (Ref: Robbins 8th/811, 9/e p800)
The most frequent GIT disorder which can be associated with sacroiliitis (related to HLA-B27) or lower limb arthritis
is the chronic inflammatory bowel diseases, ulcerative colitis and Crohns disease. Other GI diseases associated with
arthropathy include bypass surgery, Whipples disease, Behcets syndrome, and celiac disease.
Amebic colitis (choice A) is caused by ingestion of infectious cysts (typically from Entamoeba histolytica). Cecal amebiasis
can resemble acute appendicitis.
Diverticulosis (choice C) is usually a disease of older adults. It is often asymptomatic unless inflammation supervenes.
57. Ans. (a) High fiber diet (Ref Robbins 8th/822-3, 9/e p811)
The dietary factors predisposing to a higher incidence of cancer are
Excess dietary caloric intake relative to requirements,
A low content of unabsorbable vegetable fiber,
A corresponding high content of refined carbohydrates,
Intake of red meat, and
Decreased intake of protective micronutrients.
Concept
Reduced fiber content leads to decreased stool bulk, increased fecal transit time in the bowel, and an altered bacterial flora
of the intestine. Potentially toxic oxidative byproducts of carbohydrate degradation by bacteria are therefore present in higher
concentrations in the stools and are held in contact with the colonic mucosa for longer periods of time.
High fat intake (red meat) enhances the synthesis of cholesterol and bile acids by the liver, which may be converted into potential
carcinogens by intestinal bacteria.
Refined diets also contain less of vitamins A, C, and E, which may act as oxygen-radical scavengers.
NSAIDs like aspirin are protective in colon cancer because they inhibit the COX-2 enzyme which is responsible for the proliferation
of the colonic mucosa. The COX-2 expression is upregulated by TLR4 which recognizes lipopolyaccharides and is over-expressed
in adenoma and carcinoma.
57.1. Ans. (a) sigmoid colon (Ref: Robbins 8/e p814-5, 9/e p803, Bailey 25/e p1160)
The condition is found in the sigmoid colon in 90% of cases.
Interestingly in South-east Asia, right-sided diverticular disease is twice as common as the left.
Q
The main morbidity of the disease is due to sepsis . Q
5 7.2. Ans. (c) Ileum (Ref: Robbins 8/e p372)

Although any portion of the gastrointestinal tract may be affected, the terminal ileum and the cecum are the sites most
commonly involved Harrison 18 th
5 7.3. Ans. (c) Cecum (Ref: Robbins 9/e p795, 8/e p806, 7/e p839)
Amoebiasis is seen most frequently in the cecum and ascending colon.Robbins
57.4. Ans. (c) Celiac disease (Ref: Robbins 9/e p783, 8/e p795-796, 7/e p843)
The most sensitive tests are the presence of IgA antibodies to tissue transglutaminase or IgA or IgG antibodies to
deamidated gliadin.
Anti-endomysial antibodies are highly specific but less sensitive than other antibodies.
5 7.5. Ans. (c) Klinefelter syndrome (Robbins 8/e p795, 9/e p782-783)
Direct line There is also an association of celiac disease with other immune diseases including type 1 diabetes, thy-
roiditis, and Sjgren syndrome, as well as ataxia, autism, depression, some forms of epilepsy, IgA nephropathy, Down
syndrome and Turner syndrome
5 7.6. Ans. (a) Zinc (Ref: Robbins 8/e p804)
Paneth cells contain zinc along with lysozyme. They are involved in gut defence.
5 7.7. Ans. (c) Horizontal ulcers (Ref: Bailey 25/e p1174)
Typhoid ulcer
Perforation of a typhoid ulcer usually occurs during the third week and is occasionally the first sign of the disease.
Q
The ulcer is parallel to the long axis of the gut and

Q
Is usually situated in the lower ileum . Q
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5 7.8. Ans. (c) 3rd (Ref: Bailey 25/e p1174)

Perforation of a typhoid ulcer usually occurs during the third week Q
and is occasionally the first sign of the disease.
5 7.9. Ans. (c) Appendicitis (Ref: Bailey 25/e p1132)
Causes of raised serum amylase level other than acute pancreatitis Q
Upper gastrointestinal tract perforation Q
Mesenteric infarction Q
Torsion of an intra-abdominal viscus

Retroperitoneal haematoma
Ectopic pregnancy
Macroamylasaemia
Renal failure
Salivary gland inflammation
57.10. Ans. (d) Oral lichen planus (Ref: Bailey 25/e p735)
Conditions associated with malignant transformation
High-risk lesions Medium-risk lesions Low-risk/equivocal-risk lesions
*Erythroplakia *Oral submucous fibrosis *Oral lichen planus
*Speckled erythroplakia *Syphilitic glossitis *Discoid lupus erythematosus
*Chronic hyperplastic candidiasis *Sideropenic dysphagia *Discoid keratosis congenita
In the Indian subcontinent oral submucous fibrosis is very common. This condition is characterized by limited open-
ing of mouth and burning sensation on eating of spicy food.

57.11. Ans. (d) Blood culture.remember the acronym BASU for blood, antibody, stool and urine.
57.12. Ans (b) Pancreatitis
Purtschers retinopathy is manifested by a sudden and severe loss of vision in a patient with acute pancreatitis. It is caused
by occlusion of the posterior retinal artery with aggregated granulocytes. There are cotton-wool spots and hemorrhages
confined to an area limited by the optic disc and macula.

57.13. Ans (a) Oxalate (Ref: Robbins 9/e p876)
There are two general classes of gallstones: cholesterol stones, containing more than 50% of crystalline cholesterol mono-
hydrate, and pigment stones composed predominantly of bilirubin calcium salts.
58. Ans. (d) Lymph node status (Ref: Robbins 8th/825, 9/e p813)
Direct quote Robbins .. the two most important prognostic factors are depth of invasion and the presence or absence of
lymph node metastasis.
59. Ans. (a) Autosomal recessive inheritance (Ref Robbins 8th/820-821, 9/e p809)
Prophylactic colectomy does not decrease risk for cancer due to adenomas at other sites specially ampulla of Vater and
stomach.
60. Ans. (d) Jejunum (Ref: Robbins 8th/817, 9/e p806)
The polyps of Peutz-Jeghers syndrome are most common in the small intestine, although they may occur in the stomach
and colon, and, with much lower frequency, in the bladder and lungs.
61. Ans. (a) Autosomal recessive inheritance (Ref: Robbins 8th/820-821, , 9/e p809)
Familial polyposis syndrome (FAP) is an autosomal dominant disorder. It is caused by mutation in the adenomatous
Q
polyposis coli or APC gene on chromosome 5q21. Atleast 100 polyps are necessary for a diagnosis of FAP.
Option c..Robbins clearly writes that colorectal carcinoma develop in 100% of untreated FAP patients often before age 30.
As a result, prophylactic colectomy is the standard therapy in patients with APC mutations.
62. Ans. (a) RB (Ref: Robbins 8th/823-824, 9/e p811)
Two distinct genetic pathways are described in adenocarcinoma of colon:
Adenoma-carcinoma sequence: It accounts for 80% of sporadic colon cancers. Mutation of APC gene occurs early or is inherited.
Whenever second allele of APC is mutated or inactivated, b-catenin accumulates [APC protein degrades b-catenin]. Betacatenin
translocates to nucleus and activates genes like myc and cyclin D1.
Additional mutations occuring later are:
Kras
SMAD-2 and SMAD-4
p53
516
Microsatellite instability pathway: Mutations in DNA mismatch repair genes (MSH2 and MLH1) results in expansion of microsatellites.
This microsatellite instability may result in decreased functioning of TGF- b type II and bax proteins. Mutations in BRAF and epigenetic
silencing of genes by hypermethylation may also occur. Kras and p53 are not typically mutated.
Some people were of the opinion that Rb was not the option but the option in the exam was K-RAS. In such a situation, we
can understand that the answer would be none.
63. Ans. (a) Cryptitis (Ref: Robbins 7th/849-850; 9/e 800, Harrison 17th/1888)
The pathology in ulcerative colitis typically involves distortion of crypt architecture, inflammation of crypts (cryptitis),
frank crypt abscess, and hemorrhage or inflammatory cells in the lamina propria.
The mnemonic for important features is Ulcerative COLITIS (described in text).
64. Ans. (a) Diffuse distribution of pseudopolyps (Ref: Harrison 17th/2077, Robbins 8th/807-13, 9/e p800)
Pseudopolyps (inflammatory polyps) can be seen in both Crohns disease and ulcerative colitis.
Even Mucosal edema, crypt abscess and mucosal lymphoid aggregates are features common to both the types of
inflammatory bowel disease.
However, diffuse distribution of these polyps is observed only in ulcerative colitis because in Crohns disease, there
is presence of skip lesions in which there is presence of normal area adjacent to diseased segments of the intestine. So,
patchy distribution of polyps is observed in Crohns disease.
65. Ans. (d) Rectum spared in 50% patients with large bowel involvement. (Ref: Robbins 8th/810-2, 9/e p799, Harrison
17th/1888)
66. Ans. (b) B cells (Ref: Robbins 7th/1205)
67. Ans. (c) Both a and b (Ref: Robbins 7th/849-851, 9/e p800)
Please dont confuse skin lesions with skip lesions, the latter are seen only in Crohn disease.
68. Ans. (c) Hamartomatous polyp (Ref: Robbins 7th/858, 9/e p806)
Peutz-Jeghers polyps are hamartomatous polyps that involve mucosal epithelium, lamina propria and muscularis
mucosa. Peutz-Jeghers polyps are located usually in small intestine most commonly in jejunum.
When they occur in multiple numbers, condition is called Peutz-Jeghers syndrome. It is rare autosomal dominant
syndrome characterized by multiple hamartomatous polyps scattered throughout GIT, along with mucosal and
cutaneous melanotic pigmentation along lips, face, genitalia and palms
Genetic basis of Peutz-Jeghers syndrome is mutation in gene STKII (LKB1) located on chromosome 19 which encodes
protein with serine/threonine kinase activity.
69. Ans. (a) Juvenile polyp (Ref: Robbins 9/e p805, 8th/817; 7th/857)
70. Ans. (a) Rectal involvement is common (Ref: Robbins 9/e p799, 8th/810-811; 7th/851)
71. Ans. (a) Carcinoid tumor (Ref: Robbins 9/e p816, 8th/828, 7th/871)
72. Ans. (b) Crohns disease (Ref: Robbins 9/e p799, 8th/810; 7th/851)
73. Ans. (a) Crohns disease (Ref: Robbins 9/e p800, 8th/810-811, 7th/849)
74. Ans. (c) Distal ileum (Ref: Robbins 9/e p774, 8th/788, 7th/866-867)
75. Ans. (a) Head (Ref: Robbins 9/e p893, 8th/900-903, 7th/950)
76. Ans. (c) Bronchodilation (Ref: Robbins 9/e p774, 8th/321-322, 7th/868)
77. Ans. (c) Rectosigmoid (Ref: Robbins 9/e p800, 8th/812, 7th/849)
78. Ans. (d) Crohns disease (Ref: Robbins 9/e 799, 8th/810-811, 7th/847-848)
79. Ans. (b) High fiber diet (Ref: Robbins 8th/811, 7th/864)
80. Ans. (b) Ulcerative colitis (Ref: Robbins 9/e 800, 8th/810-811; 7th/848 )
81. Ans. (a) Crohns disease (Ref: Robbins 9/e p799, 8th/810-811; 7th/848)
82. Ans. (a) Ulcerative colitis (Ref: Robbins 9/e p800, 8th/811-812; 7th/849)
83. Ans. (d) Splenomegaly (Ref: Robbins 9/e p774, 8th/789; 7th/868)
84. Ans. (b) Transmural inflammation (Ref: Robbins 9/e p799-800, 8th/810)
The typical presentation of Crohns disease is abdominal pain and diarrhea in a 20-30 year old patient. Weight loss,
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fatigability, low grade fever, and aphthous ulcers of the oral mucosa are also common.
Transmural inflammation explains the two most common complications of Crohns disease: strictures, and fistulas.
Chronic inflammation causes edema and fibrosis leading to narrowing of the intestinal lumen (strictures). Necrosis of the
intestinal wall causes ulcer formation. Ulcers can penetrate the entire thickness of the affected intestinal wall, leading to
the formation of a fistula.
Please contrast with ulcerative colitis in which only the mucosa and submucosa are inflammed, so, strictures and fistulas are not
common.
(Choices a and d) Intramural granulomas and skip lesions are commonly found in Crohns disease. They do not,
however, predispose to fistula formation.
(Choice c) A chronic inflammatory infiltration that consists predominantly of monocytes and lymphocytes is charac-
teristic of Crohns disease. However, it is not the composition of the inflammatory infiltrate, rather the fistulas depth
that is responsible for fistula formation.
85. Ans. (b) Pseudomembranous colitis (Ref: Robbins 9/e p791, 8th/803)
Severe diarrhoea, fever, and toxicity following broad-spectrum antibiotic therapy is likely due to pseudomembranous
colitis. This is associated with overgrowth of Clostridium difficile, a commensal microorganism indigenous to the
bowel. The clostridia remain intraluminal, but secrete an enterotoxin that is responsible for the clinical and pathologic
manifestations of the disorder.
IIIrd generation cephalosporinsQ are the most notorious antibiotics causing pseudomembranous colitis.
86. Ans. (a) 5-HIAA (Ref: Robbins 9/e p774, 8th/788-789)

5-HIAA is a metabolite of serotonin, a major secretory product of carcinoid tumors. The signs and symptoms of carcinoid
syndrome include diarrhea, flushing, and wheezing. The cardiac abnormalities are commonly concentrated in the right
heart because carcinoid secretory products are degraded or detoxified in the lung.
The correct answer is D
87. Ans. (a) Hyperplastic polyp (Ref: Robbins 9/e p804, 8th/819)
This is a hyperplastic polyp; these polyps comprise 90% of all colonic polyps and have no malignant potential.
Peutz-Jeghers polyps (choice b) also have no malignant potential, but tend to be larger and have a complex branching
pattern.
Tubular adenomas and tubulovillous adenomas, (choices c and d) are all true neoplastic polyps containing dysplastic
epithelium; the malignant potential of these polyps increases with size and the percentage of the polyp which has a villous
configuration.
8 7.1. Ans. (a) Chronic nonspecific ulcerative colitis (Ref: Robbins 9/e p800, 8/e p812)
In ulcerative colitis, inflammation and inflammatory mediators can damage the muscularis propria and disturb neuro-
muscular function leading to colonic dilation and toxic megacolon, which carries a significant risk of perforation
8 7.2. Ans. (b) Autosomal dominant (Ref: Robbins 9/e p809, 8/e p820)
Familial Adenomatous Polyposis is caused by the mutation of adenomatous polyposis coli (APC) gene present on the long
arm of chromosome 5 (5q21). It is inherited as an autosomal dominant disorder.
Q
Subtypes of FAP
Classic FAP syndrome
The patient has a large number of adenomatous polyps and retinal pigment epithelial hypertrophy. There should be a minimum of
100 polypsQ to make a diagnosis of this syndrome. Most of the adenomatous polyps are tubular polyps.
Attenuated FAP syndrome
The patient has a lower number of adenomatous polyps (around 30) which are located in proximal colon.
Gardener syndrome Q
Intestinal polyps + epidermal cysts + fibromatosis + osteomas (of the mandible, long bones and skull).
Turcot syndrome Q
Adenomatous colon polyposis + CNS tumors (medulloblastoma in 2/3rd and gliomas in 1/3rd patients).
8 7.3. Ans. (d) Gardener syndrome (Ref: Robbins 9/e p809, 8/e p816)
Explained in the earlier question
8 7.4. Ans. (d) Noncaseating granuloma (Ref: Robbins 9/e p799, 8/e p810-2)
Noncaseating granuloma is a feature of Crohn disease and not ulcerative colitis.
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Key points about ulcerative colitis

Ulcerative Ulcers in mucosa and submucosa
C - Continuous retrograde involvement (No skip lesions)
O - Originates in the rectum
L - Lead pipe appearance
I - Increased chances of cancer (More than that in Crohns disease)
T - Toxic megacolon (Due to involvement of transverse colon)
I - Increased growth from the mucosa (Pseudopolyps)
S - Symptoms are severe (As compared to Crohns disease)
8 7.5. Ans. (c) Gastrointestinal tract (Ref: Robbins 9/e p774, 8/e p788 , Harrison 18/e p)
Direct quote from Harrison.. The GI tract is the most common site for these tumors, accounting for 64%, with the
respiratory tract a distant second at 28%.
8 7.6. Ans. (b) Kulschitsky cells (Ref: Robbins 9/e p774, 8/e p787)
Carcinoid tumour arises from the neuroendocrine cells called Kulschitsky cells. These cells are also called as
Enterochromaffin (EC) cellsand are present in gastrointestinal tract and the respiratory tract.
8 7.7. Ans. (b) Ulcerative colitis (Ref: Robbins 9/e p800, 8/e p811, 7/e p849)
Though pseudopolyps may be seen in both Crohn disease and ulcerative colitis, it is more common in ulcerative colitis.
87.8. Ans. (c) Familial polyposis (Ref: Robbins 9/e p809, 8/e p820-821, 7/e p862)
Direct line.. Colorectal cancer develops in 100% of untreated FAP patients often before the age of 30.
8 7.9. Ans. (a) Adenocarcinoma
Small intestinal adenocarcinomas and carcinoids have roughly equal incidence, followed in order by lymphomas
Q
and sarcomas. However, other texts mention that adenocarcinomas are common. So, its he answer of consensus here.
Most common benign small intestinal tumor is adenoma . It is located most commonly near Ampulla of Vater .
Q Q
8 7.10. Ans. (a) Head (Ref: Robbins 9/e p893)
Carcinoma of the pancreas
More than 85% of pancreatic cancers are ductal adenocarcinomas Q.
Ductal adenocarcinomas arise most commonly in the head of the glandQ.
Painless jaundice Q secondary to obstruction of the distal bile duct is the most common symptom.
The jaundice may be associated with nausea and epigastric discomfort.
On examination, there may be evidence of jaundice, weight loss, a palpable liver and a palpable gall bladderQ
If there is a genuine suspicion of a tumour in the head of the pancreas, the preferred test is a contrast- enhanced CT scanQ
The standard resection for a tumour of the pancreatic head or the ampulla is a pylorus-preserving pancreatoduodenectomy.Q
This is considered better than the earlier performed Whipple procedure.

87.11. Ans. (b) Juvenile polyp (Ref: Robbin 8/e p 816-7)

Juvenile polyps are focal malformations of the mucosal epithelium and lamina propria.

The vast majority of juvenile polyps occur in children less than 5 yearsQ of age.

The majority of juvenile polyps are located in the rectumQ and most present with rectal bleedingQ.

87.12. Ans (b) Iron deficiency anemia (Ref: Robbins 9/e p 813)
The underlying cause of iron deficiency anemia in an older man or postmenopausal woman is GI cancer until proven
otherwise.

87.13. Ans. (b) Smoking has a protective effect (Ref: Robbins 9/e p 800)
87.14. Ans (c) Colon (Ref: Robbins 9/e p 769; Harrison 18/e p 2455-6)
Zollinger-Ellison syndrome is caused by gastrin-secreting tumors. These gastrinomas are most commonly found in
the small intestine or pancreas.
The extrapancreatic sites of these tumors are duodenum (most common extrapancreatic site), stomach, bones, ovaries,
heart, liver, and lymph nodes.
Also revise!
Gastrinoma triangle (confluence of the cystic and common bile ducts superiorly, junction of the second and
third portions of the duodenum inferiorly, and junction of the neck and body of the pancreas medially).
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87.15. Ans (a) NOD2/CARD15 gene (Ref: Robbins 9/e p 797)

One of genes most strongly associated with Crohn disease is NOD2 (nucleotide oligomerization binding domain 2),
which encodes an intracellular protein that binds to bacterial peptidoglycans and activates signaling events, including the
NF-B pathway.
87.16. Ans (b) Fecal lactoferrin (Ref: Harrison 18/e)
In ulcerative colitis, active disease can be associated with a rise in acute-phase reactants C-reactive protein (CRP), platelet
count, erythrocyte sedimentation rate (ESR), and a decrease in hemoglobin.
Direct line Fecal lactoferrin is a highly sensitive and specific marker for detecting intestinal inflammation.

OtherFecal calprotectin levels correlate well with histologic inflammation, predict relapses, and detect pouchitis.
options:
Leukocytosis may be present but is not a specific indicator of disease activity.
Fecal lactoferrin is a marker of fecal leukocytes and is more sensitive and is available in latex agglutination and enzyme-
linked immunosorbent assay formats.

87.17. Ans (d) 100 (Ref: Robbins 9/e p809)
At least 100 polyps are necessary for a diagnosis of classic FAP, but as many as several thousand may be present.
87.18.Ans. (a) p-ANCA (Ref: Robbins 9/e p860)
p-ANCA is also called now by the name of anti myeloperoxidase (MPO-ANCA). It is directed against a lysosomal granule
constituent and is seen in the following conditions:
Ulcerative colitis
Churg-Strauss syndrome
Primary sclerosing cholangitis
Microscopic polyangiitis
Focal necrotising and crescentic glomerulonephritis
Rheumatoid arthritis

(Gastrointestinal Tract)
Allgrove (triple A) syndrome, an autosomal recessive disorder characterized by achalasia, alacrima, and
adrenocorticotrophic hormone-resistant adrenal insufficiency.
The most common cause of gastroesophageal reflux is transient lower esophageal sphincter relaxation.
Reflux of gastric contents into the lower esophagus is the most frequent cause of esophagitis.
The malabsorptive diarrhea of Whipple disease is due to impaired lymphatic transport.
Gastritis is a mucosal inflammatory process. When neutrophils are present, the lesion is referred to as acute gastritis.
When inflammatory cells are rare or absent, it is termed as gastropathy.
The most common cause of chronic gastritis is infection with the bacillus H. pylori.
Autoimmune gastritis is the most common cause of diffuse atrophic gastritis. It is the most common form of
chronic gastritis in patients without H. pylori infection.
Carney triad, a nonhereditary syndrome of unknown etiology is seen primarily in young females and includes
gastric GIST, paraganglioma, and pulmonary chondroma.
Carney-Stratakis syndrome (different from Carney triad) is caused by loss of succinate dehydrogenase complex
(SDH) function. It increases the risk of GIST and paraganglioma
Celiac disease is associated with a higher incidence of other autoimmune diseases like including type 1 diabetes,
thyroiditis, and Sjgren syndrome, IgA nephropathy, and neurologic disorders, such as ataxia, autism, depression,
epilepsy, Down syndrome, and Turner syndrome.
Individuals with celiac disease have a higher than normal rate of malignancy. The most common celiac disease-
associated cancer is enteropathy-associated T-cell lymphoma. The patients also have increased risk of small
intestinal adenocarcinoma.
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CHAPTER 13 Liver
The adult liver is an important
organ of the body weighing
around 1.5 kg and supplied
by portal vein (60% of blood
flow) and hepatic artery (40%
of blood flow). It is responsible
for plasma protein synthesis
and metabolism of endogenous
waste products and xenobiotics.
The functional unit of the liver

is a hexagonal lobule having
hepatic vein at its centre and
portal tract (composed of hepatic
artery, portal vein and bile duct)
at its periphery.
The hepatic sinusoids are lined

by fenestrated and discontinu-
ous endothelial cells. There is
presence of Kupffer cells and
stellate cells in the extra sinu-
soidal space (called space of
Disse).
The stellate cells or Ito cells are

required for vitamin A metabo-
Jaundice is characterized by hyperbilirubinemia and yellowing of the skin and sclera (due to
lism and get transformed into
elastin fibers). collagen producing myofibro-
Indirect hyperbilirubinemia is called when unconjugated bilirubin is 85% or more of the blasts during hepatic inflamma-
total bilirubin whereas direct hyperbilirubinemia corresponds to conjugated bilirubin more tion.
than 15% of total.
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Causes of Jaundice
Pre Hepatic Cause Hepatic Cause Post Hepatic Cause

Bilirubin production leading Due to defect in hepatocyte Due to impaired excretion of conjugat-
to unconjugated hyperbiliru- leading to defective conjuga- ed bilirubin as a result of obstruction
binemia tion or decreased excretion of e.g. stone, cancer of pancreas and
e.g. hemolytic anemia. conjugated bilirubin. bile duct etc.
Causes of Hyperbilirubinemia
Unconjugated Conjugated
Physiological jaundice of newborn Biliary tract obstruction
Hemolytic anemia Biliary tract disease like primary biliary cirrhosis
Diffuse hepatocellular disease and primary sclerosing cholangitis
Criggler Najjar syndrome Dubin Johnson syndrome
Gilbert syndrome Rotor syndrome
Unconjugated Hyperbilirubinemia
Physiological jaundice Criggler Najjar Syndrome Gilbert Syndrome

Due to immaturity of the liver Due to decreased UGT Decreased bilirubin
Increased changes activity glucuronidation
with prematurity and Type I Absence of UGT Jaundice associated
Type II Criggler Najjar Syn- erythroblastosis fetalisQ. enzyme; 100% fatal with stress like illness,
drome is treated with pheno- May result in kernicterus Type II Reduced UGT fasting or exerciseQ.
barbitone. (unconjugated bilirubin crosses activity.
BBB causing brain damageQ)
Liver
Gilbert and Criggler Najjar:

Glucuronide Conjugation Not
present
Dubin Johnson and Rotor:
Defect in Removing conju-
gated bilirubin
CIRRHOSIS
It is the end stage liver disease characterized by disruption of the liver architecture by
fibrotic bands that divide the liver into nodules of regenerating liver parenchyma. It can be
Most common cause of micronodular ( if nodule is <3mm) or macronodular (>3 mm) or mixed.
cirrhosis is alcoholic liver
disease. Cau e ss
Non-alcoholic fatty liver dis- Alcoholic liver disease (most common cause ) Q
ease is the most common cause Viral hepatitis

of cryptogenic cirrhosis. Biliary tract disease
Hemochromatosis
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Liver
Cryptogenic/idiopathic (non alcoholic fatty liver disease is its commonest cause)

Wilson disease
a-1-antitrypsin deficiency
The fibrosis is produced by

the hepatic stellate cell or Ito
cell and there is deposition of
primarily type I and type III
collagen in the lobule.
Non-Cirrhotic Portal Fibrosis (NCPF)/Idiopathic Portal Hypertension (IPH)
Liver
It is a condition characterized by portal hypertension and moderate portal fibrosis without
cirrhosis. Though the exact etiology is unknown, it has been associated with the following:
Infections: sepsis, diarrhea in children, bacterial infections
Immunological mechanisms: associated with HLA DR-3
Chemical exposure: arsenic, vinyl chloride, copper sulfate, hypervitaminosis A, drugs
(steroid)
Histopathological Features
Intimal fibroelastosis of medium sized portal veins (Obliterative portovenopathy of
liver): characteristic finding. Other findings include: portal fibrosis (intra portal but not
bridging fibrosis), portal vein sclerosis, portal tract edema and lymphocytic infilteration,
pseudolobulation, and atrophy of liver parenchyma with no regenerative capacity.
i r ii h
F gu e expla n ng t e pat hogenesis of NCPF
Sites of resistance to portal
blood flow in NCPF
Presinusoidal: caused by
thickening/obstruction of medium
to small brnches of portal veins
Perisinusoidal: collagenisation
of Space of Disse
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i ic f r s
Cl n al eatu e
Most common cause of Presentation in the 3 -4 decade of life
rd th
Portal hypertension Low socio economic strata

Adults: Cirrhosis followed by Slight sex preponderance M>F (this may vary however depending on geographical
NCPF areas)
Children: Extra hepatic portal GI bleeding (commonest symptom), massive splenomegaly with normal liver
vein obstruction (EHPVO). function tests.
Clinical significance of NCPF

Massive splenomegaly and emergence of new aberrant blood vessels is most commonly
associated with NCPF out of all causes of portal hypertension.
NET U E
I F C IO S DISORD RS OF IV R L E
Hepatitis
Acute Hepatitis
1. Swelling of the hepatocytes called Ballooning.
2. Presence of apoptotic hepatocytes giving rise to Councilman bodies. Apoptosis of a
single hepatocyte is called spotty necrosis.
3. Disruption of lobular architecture of the liver.
4. Necrosis connecting portal to portal, portal to central, central to central regions of
adjacent lobules is called bridging necrosis
5. Infiltration of portal tract with inflammatory cells.
6. Spilling of inflammatory cells in the adjacent parenchyma causing necrosis of
adjacent cells (Interface hepatitis or piecemeal necrosis).
hronic Hepatitis
Liver
C
Older classification of chronic hepatitic
Chronic persistant Hepatitis Chronic active hepatitis Chronic lobular hepatitis

Inflammation limited to portal Inflammation involving both Inflammation limited to
tracts parenchyma and portal tracts the lobules
Lobular structure of liver is Associated with piecemeal
preserved necrosis and bridging
necrosis
Lobular structure not preserved.
Latest classification of hepatitis is based on
1. Cause (Viral hepatitis, autoimmune hepatitis, drug associated hepatitis etc.)
2. Histological activity or grade
Grading is based on necrosis and inflammation which include assessment of the
following factors:
Periportal necrosis including piecemeal necrosis and bridging necrosis
Portal inflammation
Intralobular necrosis
Fibrosis
3. Degree of progression or stage
Staging is done based on the degree of fibrosis
Absent Mild Moderate Severe Cirrhosis
0 1 (Fibrosis confined to portal 2 (Portal and peri- 3 (Bridging 4 (Cirrhosis)
tracts with portal expansion) portal fibrosis) fibrosis)
524
Liver
1. Hepatitis A virus (Infectious Hepatitis)

It is a benign and self-limiting disease.

Incubation period of HAV is 2-6 weeks.

It does not cause chronic hepatitis or carrier state in hepatitis.

HAV is an unenveloped, single stranded RNA virus belonging to Picornavirus
family.

Feco-oral route is the predominant route of spread.

HAV is present in stools 2-3 weeks before and 1 week after onset of jaundice.

IgM antibody appearing in blood with onset of symptoms is a marker of acute
infection whereas IgG antibody provides life long immunity.
2. Hepatitis B virus (Serum Hepatitis)

It can cause acute hepatitis, non-progressive chronic hepatitis, progressive
chronic hepatitis leading to cirrhosis, fulminant hepatitis, carrier state and
hepatocellular carcinoma.

Incubation Period of HBV is 30-180 days.

HBV is present in all physiologic and pathologic body fluids, except in stools
(unlike HAV).
Mode of Infection
Blood products, needle sticks etc. (30%)
Sexual transmission
Vertical transmission is responsible for development of carrier state
The virus is a double stranded DNA belonging to Hepadnaviridae family.
It is a spherical, double layered Dane particle 42 mm in size.
Genome
The genome of the virus has several genes coding for different proteins or enzymes. These
include:
Liver
S gene C gene P gene X gene
Codes for Codes for 2 nucle- Codes for DNA Codes for HBx proteinQ
envelope pro- ocapsid proteins: polymerase hav- required for viral replica-
tein, HBs AgQ HBc Ag:Q Intracellu- ing reverse tran- tion and transcriptional
(surface anti- lar nucleocapsid core scriptase activi- activator of viral and host
gen) antigen tyQ genes.
HBe Ag:Q Nucleocap- Particularly important in
sid protein with a core the development of hepa-
and precore region. tocellular carcinomaQ.
The precore region directs the release of HBe Ag towards secretion in the blood.
Uncommonly, mutated strains called precore mutants of HBV emerge that do
not produce HBe Ag but are replication competent and express HBc Ag. In these
patients, the HBe Ag may be undetectable despite the presence of HBV viral load. A
mutation in the core promoter region can also lead to an HBeAg negative phenotype.
Clinically both these conditions are characterized by the presence of elevated liver
enzymes and active viral multiplication is indicated only by the high levels of DNA
polymerase.
Phase of Infections
There is an initial proliferative phase in which the viral DNA is present in an episomal form
leading to the formation of complete virion with associated antigens. This is followed by
expression of viral antigens with MHC class I molecules resulting in CD8+ T cells activation
and destruction of infected hepatocytes. There is presence of an integrative phase in which the
viral DNA is incorporated into host DNA. This usually occurs in hepatocytes not destroyed
by immune response.
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Sequential Appearance of Hepatitis B Markers and Significance

Carrier state is defined by
the presence of HBs Ag in the
serum for 6 months or longer
HBs Ag Present in acute diseaseQ
after initial detection. Continued presence indicates chronic disease or carrier state
HBe Ag Seen with active viral replication and denotes high infectivityQ
HBV DNA
DNA polymerase
HBc Ag never appears in the
blood.
Antibody detectable shortly before onset of symptoms
Marker of window periodQ

IgM anti HBc
IgM anti HBc is indicator of recent disease whereas IgG anti HBc is
Concept seen with chronic infection or prior infection
An important mutation seen

in HBV is escape mutants Anti HBe Ab Detected after HBe Ag disappears and denotes low infectivityQ
due to amino acid substitution
causing a conformational change
in HBsAg resulting in loss of IgG anti HBs Appears after disappearance of HBs Ag
neutralizing activity by anti- Provides protection against Hepatitis B and indicates immunityQ
HBs. It is seen in association with
active and passive immunization
Seen in prior infection and in vaccinated personsQ
and in liver transplant patients.

In both these conditions, there is
Nutshell of Hepatitis B Serology
increased concentration of anti HBs Ag IgM anti HBc IgG anti HBc IgG anti HBs
HBs leading to mutation in the
virus so that it can escape from Acute HBV infection + +
the protective effect of anti-HBs. Window period +
Chronic infection + +/- +
Prior infection + +
Immunization +
Liver
Most useful indicator of prior In addition: Remember that the presence of HBe Ag denotes high infectivity and its
infection with HBV is Anti HBc absence denotes low infectivity.
Ag
Immunology concept
Immunization for HBV is based on the fact that anti HBs Ab is protective in nature. So, vaccination with
non- infectious HBs Ag still retaining its immunogenic potential is done.
Microscopically, HBs Ag
is responsible for ground 3. Hepatitis C virus (Transfusion Associated Hepatitis)
glass hepatocytes whereas
HCV is a single stranded RNA virus belonging to Flaviviridae family.
HBc Ag gives sanded nuclei
Incubation Period is 2-26 weeks.
appearance.
Acute HCV infection is generally undetectable clinically whereas chronic
disease occurs in majority of infected individuals.

Spread of the virus is through inoculation and blood transfusion (more
frequently) and less commonly through sexual and vertical transmission.
Focal macrovesicular fatty
Acute illness is usually asymptomatic/mild.
changes indicates HCV infec-
tion

Initially, there is IgM anti-HCV followed by the presence of IgG anti-HCV
antibodies.
Panlobular micro and mac-
rovesicular steatosis indicates

Chronic infection is associated with episodic elevations in serum transaminases
with intervening normal period associated with persistence of HCV RNA in the
Alcohol as the etiology
blood.
Bile duct damage and lymphoid
aggregates in portal tract are in- Note: Antibody against HCV is IgG anti-HCV which does not provide effective immunity because the
dicative of chronic HCV infec- virus demonstrates genomic instability and antigenic variability.
tion.
4. Hepatitis D virus (Delta Agent)

It is a single stranded RNA virus.

Replication is defective and can cause infection only when encapsulated by HBs
Ag.
526
Liver
So, it can cause infection in 2 conditions:

- Acute co-infection: In which there is simultaneous exposure to both HBV
and HDV. However, HBV must establish first. This is associated with
90% chances of recovery and only rare chances of development of chronic
hepatitis.

- Super infection: In which chronic carriers of HBV get infected with HDV.
This is associated with majority developing chronic hepatitis.
The serology shows the presence of IgM Anti HDV which is the most reliable marker
of recent infection.
5. Hepatitis E virus
It is a single stranded RNA unenveloped enterically transmitted virus accounting for
more than 50% of cases of acute hepatitis in India.
Incubation period is 2-8 weeks. HEV is associated with high
It causes sporadic infection in young to middle aged adults (rare in children). mortality in pregnancy.
The disease is self limiting (not associated with chronic disease).

The serology shows the HEV RNA and presence of virions in stool and the liver even
before onset of clinical illness.
IgM anti-HEV IgG anti HEV followed by is seen in 2-4 weeks.
6. Hepatitis G virus
It is a single stranded RNA virus transmitted by the parenteral route i.e. by the
contaminated blood or blood products and possibly by the sexual route. In up to
75% of infections, HGV is cleared from the plasma and the infection becomes chronic
in the remaining 25%. The site of HGV replication is mononuclear cells, so, it does
not cause any rise in serum amino transferases and is non pathogenic. It co-infects
patients with HIV and the dual infection is protective against HIV disease.
Clinicopathologic Syndromes
Liver
1. Acute asymptomatic infection with recovery:
This is identified incidentally with the help of elevated serum transaminases or the
presence of antiviral antibodies
2. Acute viral hepatitis: It has got 4 phases:
Incubation period
Peak infectivity during last days of incubation period and early days of acute symptoms.
Symptomatic pre-icteric phase
Nonspecific, constitutional symptoms, malaise, general fatigability, nausea, and loss of
appetite.
Symptomatic icteric phase
Caused mainly by conjugated hyperbilirubinemia, dark urine and light stools
Convalescence
Recovery due to T cell activity against infected hepatocytes.
3. Chronic viral hepatitis: Symptomatic, biochemical or serologic evidence of continuing

or relapsing disease for > 6 months with histologic documentation of inflammation
and necrosis. Chronic hepatitis constitutes a Carrier State. Healthy carriers are
individuals having the virus without adverse effects. Vertical transmission with
HBV produces carrier in 90-95% cases. The most common symptom is fatigue; less
common symptoms are malaise, loss of appetite, and occasionally mild jaundice.
4. Fulminat hepatitis: Progression of hepatic insufficiency from onset of symptoms
to hepatic encephalopathy within 2-3 weeks, is called fulminant hepatic failure. The
progression in upto 3 months is called subfulminant failure.
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ALCOHOLIC LIVER DISEASE

Alcoholic liver disease
Hepatic steatosis Alcoholic hepatitis Alcoholic cirrhosis

Also called fatty liver
Having hepatocyte swelling Irreversible form of
Characterized by the and necrosis (ballooning alcoholic liver disease
presence of small degeneration)
Initially, liver is
(microvesicular) or
Neutrophilic infilitration in lobule enlarged and later
large (macrovesicular)
Perivenular and periportal there is presence of
lipid droplets inside the fibrosis (due to ito cell in space micronodules and
hepatocytes of sisse) macronodules
Initial centrilobular
Some hepatocytes show the Later, the whole liver
involvement followed by presence of eosinophilic, has tough, pale scar
entire lobule involved cytokeratin filaments called tissue (Laennec
Reversible if there is Mallory Hyaline bodies. Cirrhosis).
abstinence from alcohol.
Conditions where Mallory Hyaline
bodies are seen (Mnemonic: Non Alcoholic Fatty Liver Disease (NAFLD)
New Indian WATCH)

New - Non-alcoholic fatty liver It is a condition that resembles alcohol-induced liver disease but occurs in patients who are not
disease (NAFLD) heavy drinkers. Men and women are equally affected.

Indian - Indian childhood Association
cirrhosis
W - Wilsons disease Strong association with obesityQ, dyslipidemiaQ, hyperinsulinemiaQ and insulin resistanceQ.
A - a1- AT deficiency; Spectrum of disease
T
Alcoholic Liver Disease
- Tumor of liver
NAFLD includes simple hepatic steatosis, steatosis with non specific inflammation and non-
alcoholic steatohepatitis (NASH). Some patients may develop cirrhosis. Patients are largely
(Hepatocellular asymptomatic, with abnormalities only in biochemical laboratory tests.
carcinoma)
C - Chronic cholestatic Clinical Significance
Liver
H
conditions
- Hepatic or Primary
NAFL is now the most common cause of cryptogenic cirrhosisQ. It also contributes to the
progression of other liver diseases like hepatitis C viral infection.
Biliary cirrhosis (it is
not seen in Secondary Diagnosis
biliary cirrhosis) NAFL is a diagnosis of exclusion (excessive alcohol intake has to be excluded).
Liver biopsyQ is the most important diagnostic tool for NASH. It is also associated with AST/ALT
ratio less than 1 (in alcoholic steatohepattis the same ratio is >2.0).
Clinically
The patients are asymptomatic with elevated enzyme levels. Cardiovascular diseaseQ is a
frequent cause of death.
NODULAR HYPERPLASIAS
These are represented by two conditions: Focal nodular hyperplasia and Nodular
regenerative hyperplasia.
Focal nodular hyperplasia
Presents as a spontaneous mass lesion

Most frequently in young to middle-aged adults
Female preponderance
Associated with long term use of anabolic hormones or contraceptives
Typically, there is a central grey-white, depressed stellate scar from which fibrous septa radiate
to the periphery. The central scar contains large vessels, usually arterial, that typically exhibit
fibromuscular hyperplasia with eccentric or concentric narrowing of the lumen.
528
Liver
Nodular regenerative hyperplasia
Associated with the development of portal hypertension and its clinical manifestations.
Occurs in conditions affecting intra hepatic blood flow like rheumatoid arthritis (most commonly),
Felty syndrome, myeloproliferative disorders, hyperviscosity syndromes, solid organ (particularly
renal and liver) transplantation, bone marrow transplantation, HIV infection (Robbins), vasculitic
conditions and drugs (anabolic steroids and cytotoxics).
Characteristically, there is absence of fibrosis in this condition.
Hepatic umors T
Hepatic tumors
Benign Malignant
Cavernous hemangioma Hepatoblastoma
Most common benign lesion of liver Most common liver tumor of young children
Liver cell adenoma (hepatic adenoma) Activation of Wnt/b catein signaling pathway
Seen in young females causes carcinogenesis
Associated with oral contraceptive Angiosarcoma
intake Associated with previous exposure to
Microscopically, the cells have clear arsenic vinyl chloride or thorotrast
cytoplasm and the portal tracts are Hepatocellular carcinoma
absent. Cholangiocarcinoma
HEPATOCELLULAR CARCINOMA (HCC)

Heppar 1 or hepatocyte
It is the most common primary malignant tumor of the liver. It usually affects old patients with a paraffin 1 is specific for
M:F ratio of 3:1. hepatocyte mitochondria and is
considered the most specific
Risk factors for development of HCC and sensitive marker of normal

Liver
Chronic Hepatitis (Hepatitis B, Hepatitis C) and neoplastic hepatocytes. It

Alcoholism has been used in diagnosing

Aflatoxins (due to Aspergillus flavus infection of peanuts, grains) hepatocellular carcinomas.

Tyrosinemia

Hereditary hemochromatosis
Pathogenesis: HBV has the presence of HBX protein which causes activation of host cell
proto-oncogenes and disruption of cell cycle control. Aflatoxins cause mutations in proto-
oncogenes or p53 (tumor suppressor gene). The staining for Glypican-3
Clinical features include malaise, upper abdominal pain, weight loss and fatigue. is used to distinguish early
Laboratory investigations show elevation of serum a-fetoprotein (AFP). AFP elevation can hepatocellular carcinoma from
a dysplastic nodule. Other tests
also be seen in yolk sac tumors, cirrhosis, massive liver necrosis, chronic hepatitis, normal cannot be used because the
pregnancy, fetal distress or death, fetal neural tube defects (anencephaly and spina bifida). levels of serum -fetoprotein are
Histologically, HCC can present as a unifocal mass, multifocal mass or diffuse inconclusive in this condition.
infiltrative cancer involving the entire liver. All the three variants have a strong tendency for
vascular invasion and intrahepatic metastasis. These can involve portal vein or inferior vena
cava extending upto right side of the heart. There is presence of Mallory Hyaline bodies
(eosinophilic intracytoplasmic inclusions of keratin filaments). The tumor marker of fibrolamel-
lar variant of hepatocellular car-
Distinguishing features of Fibrolamellar cancer (from hepatocellular cancer) cinoma is Neurotensin.
Seen in young adults (20-40 years).
Equal incidence in males and females, [In India, however, females > males]
No association with HBV or cirrhosis risk factors.
Has better prognosis.
The marker of choice for differ-
No elevation of serum AFP levels.
entiating between hepatocellular
Microscopic examination shows well differentiated cells separated by dense collagen bands. cancer and its fibrolamellar vari-
Fibrolamellar variant usually affects left lobe of the liver more commonly. ant is AFP.
It spreads by lymphatic route.
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Metastasis from HCC takes place to:

Contiguous spread through hepatic vessels Satellite nodules
1.
Lungs
2.
Perihilar, peri-pancreatic and para-aortic lymph nodes.
3.
CHOLANGIOCARCINOMA
Klatskin tumors are located
at junction of right and Cholangiocarcinoma (CC)
left hepatic ducts. They are
the commonest sub type of CC typically refers to mucin-producing adenocarcinomas that arise from the bile ducts.
cholangiocarcinoma. Classification
Extrahepatic- 90%
Perihilar-60%
Distal bile duct 20 to 30%
Intra-hepatic 10%.
Risk factors (Mnemonic: All have alphabet C)
Primary sclerosing Cholangitis
Liver flukes like Clonorchis sinensis and Opisthorchis viverrini
Cause of chronic biliary inflammation and injury (Choledocholithiasis)
Contrat material: thorotrast
All risk factors of cholangio-

Chronic alcoholic liver disease
Congenital fibropolycystic diease (Choledochal cysts, Carolis disease)
carcinoma start with alphabet
C) Genetic predisposition
There is over expression of IL-6 and K-RAS and reduced expression of p53.
Clinical features
Painless jaundice, often with pruritus or weight loss, and acholic stools.
Microscopically
Liver
It is an adenocarcinoma associated with dense collagenous stroma (desmoplastic reaction). The

differentiated bile duct epithelial cells do not produce bile, so, this cancer is rarely bile stained.
Diagnosis
Percutaneous biopsy for peripheral liver lesions.
Endoscopic retrograde cholangiopancreatography (ERCP) for central lesions.
Tumor markers
Tumors stain positively for cytokeratin 7, 8, and 19 and negatively for cytokeratin 20.
CEA, CA 19-9, and CA-125 are non specific and are useful for following response to therapy.
Metastasis
Spread of the cancer takes place to lungs, vertebrae, adrenals, brain and regional lymph nodes.
M ETASTATIC TUMORS
Secondary liver cancers are more common than primary liver cancers. The common primary
sites include breast, colon and lung. The metastatic nodules have central necrosis and
umbilication.
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Liver

bilirubin metabolism, hyperbilirubinemias Total serum bilirubin of 2.0 mg/dL
Direct bilirubin of 1.4 mg/dL
1. Which of the following condition is associated with SGOT 58 U/L
unconjugated hyperbilirubinemia? (DPG 2011) SGPT 52U/L
(a) Dubin-Johnson syndrome Alkaline phosphate is 300U/L
(b) Rotor syndrome Total protein is 7.2 g/dL with serum albumin of 3.5
(c) Gilbert syndrome g/dL
(d) Gall stones Total cholesterol of 350 mg/dL.
2. A patient with unconjugated bilirubinemia has Which of the following serologic test findings is most
increased excretion of urobilinogen in his urine. This likely to be positive in this patient?
can be seen in all of the following conditions, except: (a) Anti-parietal cell antibody
(a) G6 PD deficiency (AI 2010) (b) Antimitochondrial antibody
(b) Hemolytic anemia (c) Anti-centromere antibody
(c) Hereditary spherocytosis (d) Anti ribonucleoprotein antibody
(d) Biliary cirrhosis
3. In post-hepatic jaundice, the concentration of Most Recent Questions
conjugated bilirubin in the blood is higher than that of
unconjugated bilirubin because: (AIIMS Nov 2002) 7.1. Primary biliary cirrhosis is positive for:
(a) There is an increased rate of destruction of red blood (a) p-ANCA
cells (b) Anti nuclear antibody
(b) The unconjugated bilirubin is trapped by the bile (c) Anti-microsomal antibody
stone produced in the bile duct. (d) Anti-mitochondrial antibody
Liver
(c) The conjugation process of bilirubin in liver remains 7.2. Which of the following is not a function of liver:
operative without any interference. (a) Production of vitamin K
(d) The UDP glucuronyl transferase activity is increased
(b) Production of albumin
manifold in obstructive jaundice
(c) Detoxification of ammonia
4. Function of hepatic stellate cells is/are: (d) Metabolism of drugs
(a) Formation of sinusoids (PGI June 2001)
(b) Vitamin A storage
(c) Increases blood perfusion
cirrhosis, ncpf
(d) Phagocytosis
5. Which of the following diseases is not a cause of 8. Ahe30noticed years old man Surajmal visits his physician because
the development of yellowish skin during
indirect hyperbilirubinemia? (Delhi PG 2009) last 5 days. His physical examination has absence of
(a) Rotors syndrome abdominal pain or tenderness. His blood reports are as
(b) Criggler Najjar syndrome
follows: Haemoglobin 11.5 g/dL, MCV 94m3, platelet
(c) Gilbert syndrome
count 1,80,000/mm3, WBC count 6930/mm3, albumin
(d) Hereditary spherocytosis
3.7g/dL, total protein 5.6 g/dL, total bilirubin 8.2 mg/
6. In unconjugated hyperbilirubinemia, the fraction of dL, direct bilirubin, 0.5 mg/dL, AST, 45 U/L, ALT 32
unconjugated bilirubin to total bilirubin exceeds U/L, and alkaline phosphatase, 340U/L. What of the
(a) 0.65 (UP 2002) following is the most likely diagnosis?
(b) 0.50 (a) Cholelithiasis
(c) 0.35 (b) HAV infection
(d) 0.80 (c) Micronodular cirrhosis
7. A 40 years old woman Hema Thapar presents with (d) Hemolytic anemia
generalized pruritus for last 4 months which is not
relieved by various lotions available in the market. On 9. Which one of the following is not a feature of liver
physical examination is unremarkable but her blood histology in Non cirrhotic portal fibrosis?
sample is sent to the laboratory. Her reports are as (AI 05, DPG 10)
follows: (a) Fibrosis in and around the portal tracts
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(b) Thrombosis of the medium and small portal vein Most Recent Questions
branches

(c) Non specific inflammatory cell infiltrates in the 15.1. Nutmeg liver is seen in which of the following
portal tracts conditions?

(d) Bridging fibrosis
(a) Right sided heart failure

10. Nutmeg liver is seen in (Karnataka 2005)

(b) Left sided heart failure

(a) Portal cirrhosis

(c) Increased pulmonary pressure

(b) Biliary cirrhosis

(d) Decreased pulmonary pressure

(c) Chronic venous congestion of liver
15.2. Nutmeg liver is seen in:

(d) Fatty liver
(a) Right sided heart failure

11. Commonest site of varices in portal hypertension is

(b) Left sided heart failure

(a) Esophagus (UP 2000)

(c) Increased pulmonary pressure

(b) Anal canal

(d) Decreased pulmonary pressure

(c) Periumbilical
15.3. Micronodular cirrhosis is seen in all except:

(d) Liver
(a) Alcoholic cirrhosis

12. In cirrhosis of liver collagen is laid down by

(b) Viral hepatitis

(a) Hepatocytes (AP 2005)

(c) Budd-Chiari syndrome

(b) Hepatic stellate cells

(d) Indian childhood cirrhosis

(c) Biliary epithelial cells

(d) Kupffer cells h i is
epat t
13. An old alcoholic Chivas R Signature presents to the 16. A 20 yr old man with HBs Ag +ve, HbeAg ve with
medical emergency of GS Hospital with confusion
SGOT and SGPT raised 5 times the normal value. The
and lethargy. The medical specialist on duty, Dr.
Thamim carried out the physical examination in which HBV DNA copies are 1,00,000/ml. Which is the likely
Mr Signature was visibly jaundiced with ascites. His diagnosis? (AI 2010)
blood sample was taken and sent to the laboratory. The
(a) Wild type HBV
(b) Surface mutant HBV
investigations reveled increased prothrombin time and
(c) PreCore mutant HBV (d) Inactive HBV carrier
prolonged activated partial thromboplastin time, as 17. Which one of the following diseases characteristically
Liver
well as significantly increased serum ammonia levels. causes fatty change in liver? (AI 2005)
With the known finding of significantly increased (a) Hepatitis B virus infection
serum ammonia, which of the following physical (b) Wilsons disease
findings may be expected in this patient? (c) Hepatitis C infection

(a) Capillary telangiectasias (d) Chronic alcoholism

(b) Asterixis
18. Councilman bodies are seen in: (AIIMS Nov 2007)

(c) Caput medusae
(a) Wilson disease (b) Alcoholic hepatitis

(d) Gynecomastia
(c) Acute viral hepatitis (d) Auto immune hepatitis
14. A 50-year-old chronic alcoholic with jaundice and
ascites secondary to known cirrhosis becomes 19. In Chronic Viral Hepatitis (AIIMS May 2004)
disoriented and confused. Asterixis (flapping tremor) (a) Hepatitis A virus infection is a common cause in
can be demonstrated. Which of the following is not children
associated with the development of ascites? (b) Morphological classification into Chronic Active

(a) Hypoalbuminemia Hepatitis and Chronic Persistent Hepatitis are

(b) Increased hepatic lymph formation important

(c) Increased portal venous pressure
(c) Fatty change is pathognomic of Hepatitis C virus

(d) Portal-systemic venous shunting infection
15. A 42-year-old woman Kiran with polycythemia
(d) Grading refers to the extent of necrosis and
vera develops progressive severe ascites and tender inflammation
hepatomegaly over a period of several months. Liver
function tests are near normal. Which of the following
20. The liver biopsy in acute hepatitis due to hepatitis B
virus is likely to show all of the following, except
tests would be most likely to establish the probable
diagnosis? (AIIMS May 2004)

(a) Endoscopic retrograde cholangiopancreatography (a) Ballooning change of hepatocytes

(b) Hepatic venography (b) Ground glass hepatocytes

(c) Serum alpha fetoprotein (c) Focal or spotty necrosis

(d) Serum iron (d) Acidophil bodies
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Liver
21. All are correctly matched except: (PGI June 2006) 31. Indicator of active multiplication of hepatitis B virus
(a) Hepatitis B - Ground glass hepatocytes is: (Bihar 2004)
(b) Reyes syndrome - Ground glass hepatocytes (a) HBs Ag
(c) Alcohol - Mallory bodies (b) HBc Ag
(d) Wilson disease - Mallory bodies (c) Hbe Ag
(e) Acute hepatitis - councilman bodies (d) Anti-HBs Ab
22. Centrilobular necrosis of liver occurs in 32. Chronic carrier stage is not found in (RJ 2003)
(a) Phosphorus (UP 2000) (a) Hepatitis B Virus
(b) Phenol (b) Hepatitis C Virus
(c) Arsenic (c) Both a and b
(d) Mercury (d) Hepatitis A Virus
23. Most common Pathological change seen in acute viral 33. A 30 year old woman Aishwarya goes to her gynecologist
hepatitis is (UP 2002) Dr. Harmeet for a pre-pregnancy examination. Routine
(a) Ballooning degeneration prenatal laboratory testing demonstrates normal
(b) Neutrophilic infiltration hematological profile with controlled sugar as well
negative TORCH infections. She normal liver function
(c) Piece meal necrosis
tests with the following profile: HBsAg negative, anti-
(d) Periportal fatty change
HBcAg (-), anti- HBeAg (-), HBV DNA polymerase (-)
24. Steatosis is NOT seen in (UP 2004) but anti- HBsAg is positive. Which of the following
(a) Hepatitis-B infection likely represents the status of the patient?
(b) Hepatitis-C infection
(a) Hepatitis B carrier
(c) Alcoholic person
(b) Recently infected with hepatitis B
(d) Protein malnutrition
(c) Immunized against hepatitis B
25. Piece meal necrosis is seen in (RJ 2001)

(d) Infected with hepatitis B and highly transmissible
(a) Alcoholic hepatitis 34. In a pioneering clinical study at Spartans Institute,
(b) Toxic hepatitis patients having infection with infectious hepatitis, (as
(c) Chronic active hepatitis in hepatitis A, B, C, D, E, F, and G) are being followed
(d) Malignancy for 40 months. During that time the subjects are required
to undergo regular investigations like prothrombin
26. In pregnancy, which viral infection has maximum
Liver
time, serum AST, ALT, alkaline phosphatase, total
mortality? (RJ 2003) bilirubin, and ammonia. Every 6months, a liver biopsy
(a) Hepatitis A Virus is performed microscopically examined. Which of
(b) Hepatitis B Virus the following is the best predictor of development of
(c) Hepatitis C Virus chronic disease progressing to cirrhosis?
(d) Hepatitis E Virus.
(a) Presence of inflammatory cell in the sinusoids on a
27. Hepatitis B virus is not associated with (RJ 2004) liver biopsy specimen
(a) Fulminant hepatitis
(b) Degree to which hepatic transaminase enzymes are
(b) Chronic active hepatitis elevated.

(c) Length of time that hepatic enzymes remain elevated
(d) Cholangiocarcinoma

(d) Specific form of hepatitis virus responsible of the in-
fection
28. Piece meal necrosis is pathognomic of (RJ 2006)
35. An eminent hepatobiliary expert Dr. Sarin conducts a
(a) Alcoholic Liver disease
study in hepatitis B patients for which the patients are
(b) Chronic active hepatitis
followed for almost a decade. Their detailed history
(c) Toxic hepatitis regarding the mode of transmission of HBV is taken.
(d) Wilson disease A battery of tests including periodic serologic testing
29. Hepatitis E is transmitted by (AP 2004) for HBs Ag, anti HBs and anti-HBc, and serum levels
(a) Blood of bilirubin, SOT, SGPT, alkaline phosphatase, and
(b) Feco-oral prothrombin time is conducted. Dr. Sarin finds that a
(c) Venereal particular group of patients happen to be chronic carriers
(d) All of the above of HBV. This finding is most likely to be associated
with which of the following modes of transmission of
30. Incubation period of hepatitis B is (Bihar 2004) HBV?
(a) 6 weeks to 6 months
(a) Blood transfusion
(b) 6 days to 6 weeks
(b) Heterosexual transmission
(c) 6 months to 6 years
(c) Vertical transmission during childbirth
(d) More than 6 years
(d) Needle stick injury
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36. A 34-year-old man Bholu presents to his physician 43. Mallorys hyaline is seen in: (Delhi PG 2009 RP)
with loss of appetite, nausea and vomiting, and fatigue. (a) Hepatitis C infection
Laboratory examination confirms the diagnosis of (b) Amoebic liver abscess
hepatitis B, and the man becomes icteric 2 weeks later. (c) Indian childhood cirrhosis
This patient may also be particularly vulnerable to the (d) Autoimmune hepatitis
development of which of the following disorders?
(a) Berry aneurysm
44. Mallory hyaline body is seen in all except:
(a) Indian childhood cirrhosis (Delhi PG-2007)
(b) Coronary artery aneurysm (b) Alcoholism
(c) Polyarteritis nodosa (c) Secondary biliary cirrhosis
(d) Giant cell arteritis (d) a-1 antitrypsin deficiency
37. After passing his physical exam, a young army recruit 45. Mallory bodies are composed of:
gives urine and blood samples for further testing. (a) Fat droplets (Karnataka 2009)
Serum analysis yields elevated ALT, HBsAg, Anti-HBc, (b) Mitochondria
HBeAg, and bilirubin. All other values are normal. (c) Lysosomal enzymes
Which of the following is the hepatitis B status of this (d) Intermediate filaments
recruit?
(a) Asymptomatic carrier
46. Alcoholic hyaline seen in alcoholic liver disease is
composed of (UP 2007)
(b) Chronic active carrier
(a) Lipofuschin
(c) Fulminant hepatitis B
(b) Eosinophilic intracytoplasmic inclusions
(d) Recovered from acute self-limited HBV (c) Basophilic intracytoplasmic inclusions
(d) Hemazoin
alcoholic liver disease, nodular hyperplasia
47. In Alcoholic liver disease, which of the following
pigments is deposited in the hepatocytes?
38. In a chronic alcoholic all the following may be seen in (a) Hemosiderin (UP 2008)
the liver except (AI 2002) (b) Hemoglobin
(a) Fatty degeneration (c) Lipofuschin
(b) Chronic hepatitis (d) Melanin
(c) Granuloma formation
(d) Cholestatic hepatitis
48. Mallory bodies are seen is (RJ 2006)
(a) Viral hepatitis
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39. Nodular regenerative changes in liver most commonly (b) Toxic hepatitis
occur in: (AIIMS May 2009) (c) Alcoholic hepatitis
(a) Drugs induced hepatitis (d) All
(b) Alcoholic hepatitis 49. Mallory bodies are seen in all except (AP 2004)
(c) Hepatitis B (a) Alcoholic cirrhosis
(d) Autoimmune hepatitis (b) Biliary cirrhosis
40. Mallory hyaline is seen in: (PGI Dec 2000) (c) Cardiac cirrhosis
(a) Alcoholic liver disease (d) Wilson disease
(b) Hepatocellular carcinoma 50. A 46-year-old man, Sushil who has a long history of
(c) Wilsons disease excessive drinking presents with signs of alcoholic
(d) I.C.C. (Indian childhood cirrhosis) hepatitis. Microscopic examination of a biopsy of this
(e) Biliary cirrhosis patients liver reveals irregular eosinophilic hyaline
inclusions within the cytoplasm of the hepatocytes.
41. All of the following are true except? These eosinophilic inclusions are composed of which
(DPG &AIIMS Nov 10) of the following substances?
(a) LKM 1 Autoimmune hepatitis (a) Immunoglobulin
(b) LKM 2 Drug induced (b) Excess plasma proteins
(c) LKM 1 Chronic hepatitis C (c) Prekeratin intermediate filaments
(d) LKM 2 Chronic hepatitis D (d) Basement membrane material
42. A chronic alcoholic has an elevated serum alpha (e) Lipofuscin
fetoprotein levels. Which of the following neoplasms is
most likely seen? (Delhi PG 09 RP) Most Recent Questions
(a) Prostatic adenocarcinoma
5 0.1. Mallory bodies contain:
(a) Vimentin (b) Cytokeratin
(c) Keratin (d) Collagen
(d) Glioblastoma multiforme
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Liver
50.2. Which of the following is not associated with Mallory dl, TLC is 7,000/mm3, ESR is 12mm/hr. Her kidney and
hyaline bodies? liver function tests are also normal. She undergoes a
(a) Alcoholic liver disease radiological scanning too. Dr. Sethi, the radiologist
(b) Primary biliary cirrhosis describes her findings to be normal except a mass in
(c) Secondary biliary cirrhosis the right lobe of the liver. A biopsy is taken which
(d) Indian childhood cirrhosis confirms the diagnosis of a liver adenoma. Which of the
following is likely to be associated with this lesion?
5 0.3. Which of the following may not cause microvesicular
(a) Polycythemia vera
steatosis?
(a) Alcoholic fatty liver

(b) Hepatitis B
(b) Tetracycline toxicity

(c) Oral contraceptives
(c) Acute fatty liver of pregnancy

(d) Polyvinyl chloride
(d) Reyes syndrome Most Recent Questions

5 0.4. The following are true attributes of hepatitis B infection
except: 56.1. Thorium induced tumor:
(a) Infants develop chronic infections (a) Angiosarcoma of liver
(b) HBc Ag in serum is indicative of active infection (b) Renal cell carcinoma
(c) Can cause hepatocellular cancer (c) Lymphoma
(d) Interferons are used for treatment (d) Astrocytoma
5 6.2. Commonest benign tumor of liver is:
hepatic tumours (a) Hamartoma
(b) Hemangioma
51. Which of the following most significantly increases the (c) Adenoma
risk of hepatocellular cancer? (d) Nodular focal hyperplasia
(a) Hep A (AIIMS May 2012)
(b) Hep B BILIARY TRAC T DISORDER
(c) CMV
(d) EBV 57. Most common site of Cholangiocarcinoma is?
52. True about Fibrolamellar carcinoma of Liver is all, (a) Distal biliary tree (AIIMS Nov 2008)
(b) Hilum
Liver
(a) Females do not increased incidence than males (c) Intrahepatic biliary duct
(b) Has good prognosis (d) Multifocal
(c) Not associated with liver cirrhosis 58. Cholangiocarcinoma of liver is caused by
(d) Serum AFP levels are usually > 1000 mg/litre (a) Hepatitis B infection (UP 2008)
53. Which of the following is not correct about fibrolamellar (b) Cirrhosis of liver
variant of hepatocellular carcinoma? (c) Antitrypsin deficiency
(Delhi PG 2009 RP) (d) Clonorchis sinensis infection
(a) Occurs in young males and females 59. Most common bile duct tumor is (RJ 2000)
(b) Hepatitis B virus is an important risk factor (a) Adenocarcinoma
(c) Often has a better prognosis (b) Squamous cell cancer
(d) Is a hard scirrhous tumor (c) Transitional cell carcinoma
54. Most common primary malignant tumour of liver in (d) All
adult is (UP 2002) 60. A 50-year-old male film actor Sallu Kahn looses
(a) Squamous cell carcinoma weight rapidly for one of his forthcoming films. He
(b) Hepatoblastoma experiences occasional abdominal discomfort few days
(c) Hepatocellular carcinoma after that and guided by his physician, he undergoes a
(d) Hepatoma radiological scan (HIDA scan) is shown to have slow
55. Which is not correct about hepatocellular carcinoma? and incomplete gallbladder emptying in response to
(a) More in females (Jharkhand 2004) cholecystokinin stimulation. This patient is likely to
(b) Rise of AFP noted develop which of the following?
(c) Has stronger propensity to invade vascular channels.
(a) Black pigment stones
(d) Chronic HBV has high rate of hepatocellular carci-
(b) Brown pigment stones
noma
(c) Biliary sludge
56. A young woman Ms Shaano who is otherwise normal
(d) Phospholipid stones
goes for an annual examination in a nursing home. 61. A middle aged woman comes to the emergency
Her blood investigations reveal hemoglobin is 15 gm/ room complaining of severe, right-sided abdominal
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pain, fever, and chills for the past several hours. She 64. Liver granulomas may be associated with all of the
has a history of gallstones and her family doctor following except (AI 2002)
recommended a cholecystectomy after a similar episode (a) Candida
several months ago. Upon examination, she has a (b) Halothane
temperature of 102.7F (39.3C), is tender in the right (c) Sarcoidosis
upper quadrant, and is visibly jaundiced. Her white (d) Hepatic metastasis
blood count is 18,000/mm3. In which of the following
locations is a gallstone most likely lodged in this
65. Histological finding in Reyes syndrome is
(a) Budding and branching of mitochondria
patient?
(b) Swelling of endoplasmic reticulum

(a) Common bile duct
(c) Para-nuclear micro-dense deposits

(b) Cystic duct
(d) Glycogen depletion

(c) Fundus of gallbladder

(d) Proximal duodenum 66. Finding on histopathological examination of liver in
case of malaria is (AIIMS May 2007)
Most Recent Questions (a) Microabscess formation
(b) Kupffers cell hyperplasia with macrophage infiltra-
61.1. Which is risk factor for cholangiocarcinoma: tion around periportal area laden with pigments.
(a) Obesity (c) Non caseating granuloma
(b) Primary sclerosing cholangitis (d) Non specific finding of neutrophilic infiltration
(c) Salmonella carrier state 67. Pigmentation in the liver is caused by all except
(d) HBV infection (a) Lipofuscin (PGI Dec 01)
6 1.2. Klatskin tumor is: (b) Pseudomelanin
(a) Nodular type of cholangiocarcinoma (c) Wilsons disease
(b) Fibrolamellar hepatocellular carcinoma (d) Malarial pigment
(c) Gall bladder carcinoma (e) Bile pigment
(d) Hepatocellular carcinoma 68. True statements about a-l antitrypsin deficiency is
6 1.3. All of the following are risk factors for carcinoma gall (a) Autosomal dominant disease (PGI June 2003)
bladder, except: (b) Emphysema
(a) Typhoid carriers (c) Fibrosis of portal tract
(d) Diastase resistant positive hepatocytes
(b) Adenomatous gall bladder polyps
Liver
(e) Orcein positive granules

(c) Choledochal cysts
(d) Oral contraceptives 69. KayserFleischer ring is seen in (UP 2007)
(a) Wilsons disease
6 1.4. Focal diffuse gall bladder wall thickening with comet
(b) a 1 antitrypsin deficiency
tail reverberation artifacts on USG are seen in:
(c) Hemochromatosis
(a) Adenomyomatosis of gall bladder
(d) Primary biliary cirrhosis
(b) Carcinoma gall bladder
(c) Adenomatous Polyps 70. All are true about Wilsons disease except
(d) Xanthogranulomatous gall bladder (a) Liver Cu (RJ 2000,2004,2006)
(b) Urine Cu
61.5. Onion skin fibrosis of the common bile duct is: (c) Ceruloplasmin
(a) Primary biliary cirrhosis (d) Serum Cu
(b) Primary sclerosing cholangitis
(c) Extrahepatic biliary fibrosis 71. -1 antitrypsin deficiency causes (AP 2000)
(d) Congenital hepatic fibrosis (a) Congenital cystic fibrosis
(b) Neonatal hepatitis
(c) Pulmonary fibrosis
mISCELLANEOUS (d) All of the above
62. True about hemochromatosis is: (AI 2009) 72. Centrilobular necrosis is seen in (Kolkata 2005)
(a) Complete penetrance (a) CCl
4
(b) White phosphorus
(c) Phlebotomy leads to cure (c) Yellow fever
(d) More common in females (d) Eclampsia
63. All are seen in hemochromatosis except: 73. A retired man Pradyuman R complains of vague
(a) Hypogonadism (AI 2008) abdominal pain since last 6 months. One fine day,
(b) Arthropathy he experienced acute chest pain with dyspnea. He
(c) Bronze diabetes was rushed to the emergency of Gangaram Hospital
(d) Desferrioxamine is the treatment of choice where his chest and abdomen CT scans demonstrate a
536
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pulmonary embolus. The radiologist Dr. Sandeep Goel 73.2. Bronze diabetes is seen in:
also notices a 7.5 cm mass in the body of the pancreas. (a) Wilsons disease
His blood investigations reveal elevated levels of CEA (b) Sarcoidosis
and CA 19-9. Which of the following genetic mutations (c) Lead intoxication
is likely to be associated with this pancreatic mass? (d) Hemochromatosis

(a) BRCA -2
7 3.3. Copper is mainly transported by:

(b) K-RAS
(a) Albumin

(c) PRSS1
(b) Haptoglobin

(d) SPINK1
(c) Ceruloplasmin
Most Recent Questions (d) Globulin
7 3.4. Gene of Wilsons disease is:
73.1. Liver in hemochromatosis is stained by which of the (a) ATP 7A
following stain? (b) ATP 7B
(a) Perls iron stain (b) Alcian blue (c) ADP 7A
(c) Congo Red (d) Masson trichome (d) ADP 7B
Liver
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E xplanations
1. Ans. (c) Gilbert syndrome (Ref: Harrison 17th/1929, 9/e p854)
2. Ans. (d) Biliary cirrhosis (Ref: Robbins 8th/868, 9/e p853-854)
Biliary cirrhosis is characterized by conjugated hyperbilirubinemia. Rest all the mentioned options cause unconjugated
hyperbilirubinemia.
3. Ans. (c) The conjugation process of bilirubin in liver remains operative without any interference (Ref: Harrison
17th/262-3, Ganong 22nd/503, 9/e p853)
Post hepatic jaundice is due to impaired excretion of conjugated bilirubin as a result of obstruction. However, the process
of conjugation is not interfered with.
4. Ans. (b) Vitamin A storage: (Ref: Robbins 7th/878, 9/e p436)
The hepatic stellate cells (also called Ito cells) are of mesenchymal origin, found in space of Disse. The stellate cells play a role in
the storage and metabolism of vitamin A and are transformed into collagen producing myofibroblasts when there is inflammation and
cause fibrosis of liver.
5. Ans. (a) Rotors syndrome (Ref: Robbins 9/e p854, 8th/841, Harrison 17th/26)
6. Ans. (d) 0.80 (Ref: Robbins 9/e p853, Harrison 17th/262)
Indirect hyperbilirubinemia is called when unconjugated bilirubin is 85% or more of the total bilirubin whereas direct
hyperbilirubinemia corresponds to conjugated bilirubin more than 15% of total.
7. Ans. (b) Anti mitochondrial antibody (Ref: Robbins 8th/867, 9th/858)
The findings in the stem of the question are suggestive of clinical condition of primary biliary cirrhosis. It is seen in middle
aged women in which the jaundice may progress due to progressive intrahepatic destruction. In these patients, there is
Liver
presence of anti mitochondrial antibodies.

Other options
Anti parietal antibodies are seen in pernicious anemia.
Anti-centromere antibody is seen in systemic sclerosis.
Anti-ribonucleoprotein antibody is seen in different connective tissue disorders.
The following disorders present with insidious onset of features of obstructive jaundice like pruritus, jaundice, malaise
dark urine, light stools and hepatosplenomegaly.
Features of the Bile Duct Disorders
Primary Biliary Cirrhosis Secondary Biliary Cirrhosis Primary Sclerosing Cholangitis
Cause Possibly autoimmune Biliary atresia, gallstones, stricture, Autoimmune; usually associated
cancer of pancreatic head with inflammatory bowel disease
Sex predilection Female to male: 6:1 None Female to male: 1:2
Distribution Intrahepatic bile duct obstruction Extrahepatic bile duct obstruction Extra + intra hepatic duct affected
Lab. findings Same as secondary biliary conjugated bilirubin, serum Same as secondary biliary cirrhosis
cirrhosis with elevated serum IgM alkaline phosphatase with with hypergammaglobulinemia
antimitochondrial antibody increased cholesterol (IgM), atypical p-ANCA (+)
Histological findings Dense lymphocytic infiltrate in Bile stasis in bile ducts, bile ductules Periductal portal tract fibrosis (onion
portal tracts with granulomatous proliferation with surrounding skin fibrosis), segmental stenosis of
destruction of bile ducts neutrophils, portal tract edema extra and intrahepatic bile ducts
An important feature is Atypical p-ANCA (+) is seen with primary sclerosing cholangitis but that this antibody is directed against a
nuclear envelope protein and not myeloperoxidase seen with typical p-ANCA antibodies.
7.1. Ans. (b) Anti-mitochondrial antibody (Ref: Robbins 8/e p867, 9/e p858)
Friends, please do not get confused between options b and d.
Antimicrosomal antibodies are autoantibodies, directed against the microsomes (in particular peroxidase) of the
thyroid cells leading tothyroiditis, tissue damage, and disruption of thyroid function. It is associated with autoimmune
conditions like Hashimotos thyroiditis and Graves disease.
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Liver
Anti-mitochondrial antibody is seen in primary biliary cirrhosis.

Key points for primary biliary cirrhosis
Non-suppurative, inflammatory destruction of medium-sized intrahepaticQ bile ducts.
Female to male ratio 6 : 1
Serum alkaline phosphatase and cholesterol are almost always elevatedQ, even at onset; hyperbilirubinemia is a late
development and usually signifies incipient hepatic decompensation.
Antimitochondrial antibodiesQ are present in 90% to 95% of patients.
Associated with increased risk to develop hepatocellular carcinomasQ.
The major cause of death is liver failureQ,
7.2. Ans. (a) Production of vitamin K (Ref: Robbins 9/e p 822)
Vitamin K is produced by the bacteria of gut and is used by liver for gamma carboxylation of factor 2/7/9/10.
Liver produces albumin which falls in liver cirrhosis producing ascites/edema
Ammonia is combined with carbon dioxide to produce urea which in turn is excreted by the liver.
The cytochrome p450 is responsible for metabolism of drugs.
8. Ans. (d) Hemolytic anemia (Ref: Robbins 8th/840-1, 9/e p853)
The patient has unconjugated hyperbilirubinemia which can result in the given options from hemolytic anemia. Option
(a), Cholelithiasis results in conjugated hyperbilirubinemia.
Option (c) and (d), hepatitis and micronodular cirrhosis can present with both unconjugated and conjugated hyperbiliru-
binemia though conjugated bilirubin predominates.
9. Ans. (d) Bridging fibrosis (Ref: Tropical Hepato-Gastroenterology by Tandon Elsevier 1st/391, Histopathology of the
liver in non-cirrhotic portal hypertension of unknown etiology Histopathology 1996;28:195204 by Nakanuma Y et al.,
Non-cirrhotic portalfibrosis: current concept and management by Sarin SK, Kapoor D in J Gastroenterol Hepatol 2002;
17:526-534)
The Following is a Figure explaining the pathogenesis of NCPF along with Histologically findings in NCPF
Portal fibrosis (intra portal but not bridging fibrosis)

Portal vein sclerosis

Subcapsular scarring

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Pseudolobulation

Portal tract edema and lymphocytic infilteration

Intimal fibroelastosis of medium sized portal veins;
obliterative portal venopathy (characteristic lesion)

Sclerosis and obliteration of portal vein radicals

Atrophy of liver parenchyma with no regenerative
capacity

Collagen deposition in the space of Disse
So, the answer is clear from the above mentioned features given collectively in all the references mentioned above.
Bridging fibrosis is not seen in NCPF.
10. Ans. (c) Chronic venous congestion of liver (Ref: Robbins 7th/122-3, 9/e p864)
Congestion is a passive process resulting from impaired outflow from a tissue. In long standing or chronic venous con-
gestion, the stasis results in chronic hypoxia resulting in parenchymal cell death. The central part of hepatic lobule is red
brown and slightly depressed (due to loss of cells) and is accentuated against surrounding zone of uncongested tan liver.
This is called nutmeg liver. Microscopically, there is presence of hemosiderin laden macrophages.
In severe cases (as with heart failure); there may be presence of hepatic fibrosis which is called cardiac cirrhosis.
11. Ans. (a) Esophagus (Ref: Robbins 9/e p830,8th/839; 7th/885, 7th/885)
12. Ans. (b) Hepatic stellate cells (Ref: Robbins 9/e p822, 8th/837; 7th/883)
13. Ans. (b) Asterixis (Ref: Robbins 8th/836, 9/e p826)
Asterixis is a flapping tremor of the hands associated with hepatic encephalopathy. Failure of the liver to detoxify me-
tabolites absorbed from the gastrointestinal tract results in accumulation of nitrogenous wastes that are neurotoxic.
Disturbed mental status is also attributed to production of false neurotransmitters, increased CNS sensitivity to
GABA, reduced activity of urea cycle enzymes due to zinc deficiency and swelling of astrocytes. Ref 2013 (CMDT).
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Caput medusa results from dilation of the periumbilical venous collaterals as a result of portal hypertension and
opening of portal-caval anastomoses. Other findings like palmar erythema, capillary telangiectasias, and gynecomas-
tia results from the inability of the liver to metabolize estrogen leading to hyperestrinism.
14. Ans. (d) Portal-systemic venous shunting (Ref: Robbins 8th/839, 9/e p830, Harrison 18th/2600)
Portal-systemic venous shunting leads to encephalopathy in end-stage cirrhosis. It is also contributing to other features like
esophageal varices, rectal haemorrhoids, and distention of periumbilical venous collaterals. Other factors like hypoalbu-
minemia, increased hepatic lymph formation and increased portal venous pressure mentioned as the options contribute to
the development of ascites, but not to encephalopathy.
15. Ans. (b) Hepatic venography (Ref: Robbins 8th/872-873, 9/e p863-864)
The clinical presentation is most consistent with Budd-Chiari syndrome (hepatic vein obstruction), which may occur as
a complication of thrombogenic and myeloproliferative disorders including polycythemia vera. The presentation in the
question is the most common. Hepatic venography is the best technique of those listed to demonstrate the occlusion of
the hepatic venous system.
Endoscopic retrograde cholangiopancreatography (choice A) is most useful in demonstrating lesions of the biliary tree.
Serum alpha fetoprotein (choice C) is a marker for hepatocellular carcinoma.
Serum iron studies (choice D) are useful when considering hemochromatosis as a cause of cirrhosis.
15.1. Ans. (a) Right sided heart failure (Ref: Robbins 8/e p872, 9/e p864)
Right-sided cardiac decompensation leads to passive congestion of the liver. In long standing or chronic venous congestion,
the central part of hepatic lobule is red brown and slightly depressed (due to loss of cells) and is accentuated against
surrounding zone of uncongested tan liver. This is called nutmeg liver.
In severe cases this is called as cardiac sclerosis or cardiac cirrhosis.
1 5.2. Ans. (a) Right sided heart failure explained earlier (Ref: Robbins 9/e p864)
1 5.3. Ans. (b) Viral hepatitis (Ref: Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases: Volume 2 Springer
publications p952)
Common causes ofmicronodular cirrhosis (nodules <3mm in diameter) Alcohol, Metabolic, Hemachromatosis, Wil-
sons Disease, Indian childhood cirrhosis, chronic venous outflow tract obstruction, bile duct obstruction
Common causes ofmacronodular cirrhosis (nodules >3mm in diameter) Viruses, Toxins, Poisoning
Budd-Chiari syndrome is characterized by the obstruction of two or more major hepatic veins produce liver enlargement,
Liver
pain, and ascites. So, it is a cause of hepatic venous outflow obstruction.

16. Ans. (c) preCore mutant HBV (Ref: Robbins 8th/846, Harrison 17th/1935-6)
The precore region directs the release of HBeAg towards secretion in the blood. Uncommonly, mutated strains called
precore mutants of HBV emerge that do not produce HBeAg but are replication competent and express HBcAg. In these
patients, the HBeAg may be undetectable despite the presence of HBV viral load. Another mutation in the core promoter
region can also lead to an HBeAg negative phenotype. Clinically both these conditions are characterized by the presence
of elevated liver enzymes and active viral multiplication is indicated only by the high levels of DNA polymerase.
Additional info
Another important mutation seen in HBV is escape mutants due to amino acid substitution causing a conformational change in HBs
Ag resulting in loss of neutralizing activity by anti-HBs. It is seen in association with active and passive immunization and in liver
transplant patients. In both these conditions, there is increased concentration of anti HBs leading to mutation in the virus so that it can
escape from the protective effect of anti-HBs.
17. Ans. (d) Chronic alcoholism (Ref: Robbins 7th/903-4, 9/e p 842, Harrisons 17th/1982)
Alcoholic liver disease (ALD) is the most common cause of fatty liver. So, Fatty liver is characteristically seen in chronic
alcoholism. However, now many other causes of fatty liver have also been elucidated known as Non-Alcoholic fatty liver
disease (NAFLD) or Non-alcoholic steatohepatitis (NASH). These are explained in the chapter review.
Sternberg 4th mentions although fatty change has been reported as a common feature of hepatits C, the degree of fatty changes
is usually minimal and absence is not unusual.
18. Ans. (c) Acute viral hepatitis (Ref: Robbins 7th/899, 9/e p823; Harrison 17th/1929)
Councilman bodies are feature of acute hepatitis. These are associated with the cellular phenomers of opposit.
19. Ans. (d) Grading refers to the extent of necrosis and inflammation (Ref: Harrison 17th/1955), Sternbergs diagnostic
surgical pathology 4th/1682
The new classification system of hepatitis is based on its etiology, grade or stage. Grading refers to the assessment of
necroinflammatory activity whereas the staging refers to degree of progression.
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Concept
Regarding option c, Sternberg writes clearly although fatty change has been reported as a common feature of hepatits C, the degree
of fatty changes is usually minimal and absence is not unusual. Fatty change due to virus is most likely associated with genotype 3.
Biopsy in hepatitis B and C is done for purpose of staging and grading and not for diagnosis.
20. Ans. (b) Ground glass hepatocytes (Ref: Harrison 17th/1727; Robbins 7th/899, 8th/851, 9/e p837)
Ground glass hepatocytes are large hepatocytes containing surface antigen. Their cytoplasm is ground glass in appear-
ance. These cells are a feature of chronic hepatitis and not acute hepatitis.
21. Ans. (b) Reyes syndromeground glass appearance of hepatocytes. (Ref: Robbins 7th 898, 9/e p841, H Mohan 6th-602)
In acute hepatitis B, hepatocytes show ground glass appearance.
In Reyes syndrome, hepatocytes show microvesicular fatty change.
Mallory bodies are seen in alcoholic hepatitis, primary biliary cirrhosis, non-alcoholic fatty liver disease, Wilsons
disease, chronic cholestatic jaundice and hepatocellular carcinoma.
22. Ans. (b) Phenol (Ref: Robbins 7th/903)
23. Ans. (a) Ballooning degeneration (Ref: Robbins 9/e p838, 8th/851; 7th/897-9)
24. Ans. (a) Hepatitis-B infection (Ref: Robbins 9/e p841-842, 8th/846; 7th/907-8)
25. Ans. (c) Chronic active hepatitis (Ref: Robbins 8th/852-3, 7th/899)
26. Ans. (d) Hepatitis E Virus (Ref: Robbins 9/e p835, 8th/849, 7th/897)
27. Ans. (d) Cholangiocarcinoma (Ref: Robbins 9/e p833, 841-842, 8th/845-7, 7th/926)
28. Ans. (b) Chronic active hepatitis (Ref: Robbins 8th/851-2, 7th/899)
29. Ans. (b) Feco-oral (Ref: Robbins 9/e p835, 8th/849, 7th/896)
30. Ans. (a) 6 weeks to 6 months (Ref: Robbins 9/e p831-832, 8th/845; 7th/891)
31. Ans. (c) HBeAg (Ref: Robbins 9/e p832, 8th/846; 7th/893)
32. Ans. (d) Hepatitis A Virus (Ref: Robbins 9/e p831, 8th/844, 7th/891)
Liver
33. Ans. (c) Immunized against hepatitis B (Ref: Robbins 9/e 832-833, 8th/846, Harrison 18th/2550)
Ms Aishwarya is positive only for the antibody to the hepatitis B antigen. This is suggestive of her being vaccinated for
hepatitis B virus (HBV). The vaccine consists of recombinantly produced HBV surface antigen (HBsAg) alone and the
antibodies to this protein provide immunity.
HBsAg would be seen in the serum within the first 3-4 months after initial infection. Antibodies to the core protein (anit-
HBcAg) appear during acute illness and between the disappearance of HBsAg and the appearance of anti-HBsAg, the
window period. Anti-HBeAg appears during the window period as well. HBeAg and HBV DNA polymerase are the
indices of infectivity.
Nutshell of Hepatitis B Serology
HBs Ag IgM anti HBc IgG anti HBc IgG anti HBs
Acute HBV infection + +
Window period +
Chronic infection + +/- +
Prior infection + +
Immunization +
Also know: The presence of HBe Ag denotes high infectivity and its absence denotes low infectivity.
34. Ans. (d) Specific form of hepatitis virus responsible of the infection (Ref: Robbins 9th/836)
The best predictor for viral disease progressing to chronic liver disease and even cirrhosis is decided by the causative agent
of the viral hepatitis. On comparing all viruses, hepatitis C is the commonest cause of chronic viral hepatitis.
Other viruses like hepatitis A, hepatitis E and hepatitis G never progress to chronic hepatitis. The histologic changes,
degree and duration of transaminase elevation dont influence the progression to chronic hepatitis.
35. Ans. (c) Vertical transmission during childbirth (Ref: Robbins 8th/845, 9/e p832)
Hepatitis B infection is not commonly transmitted through blood transfusion now (due to mandatory screening of blood
and its products), heterosexual transmission and needle stick injury (much more chances in comparison to HIV and HCV).
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Important concept
In adults, the viral hepatitis develops because they are immunocompetent, so, HBV induced T cells induce apoptosis of infected
liver cells.
Vertical transmission during childbirth is responsible for HBV chronic carrier stage. This is attributed to the fact that unlike the adults,
the immune responses in the neonatal period are not fully developed thereby preventing the development of hepatitis.
Clinical significance of high carrier rate is increased risk of development of hepatocellular cancer.
36. Ans. (c) Polyarteritis nodosa (Ref: Robbins 8th/514, 9/e p509)
Thirty percent of patients with polyarteritis nodosa have hepatitis B antigenemia. Polyarteritis is a systemic necrotizing
vasculitis that can be difficult to diagnose, since the vascular involvement is typically widely scattered, and the specific
symptoms depend on the specific vessels (small- to medium-sized arteries) involved. Patients typically present with low-
grade fever, weakness, and weight loss. Abdominal pain, hematuria, renal failure, hypertension, and leukocytosis may
occur. The disease is frequently fatal if untreated.
37. Ans. (b) Chronic active carrier (Ref: Robbins 8th/846, 9/e 837)
The presence of elevated ALT, HBsAg, anti-HBc, HBeAg, and bilirubin all point to active hepatitis B.
An asymptomatic carrier (choice A) does not have elevated ALT and bilirubin.
The absence of findings on physical examination rules out fulminant hepatitis B (choice C).
Recovery from acute self-limited HBV (choice D) is associated with the presence of anti-HBs and the decrease in
HBsAg and HBeAg.
38. Ans. (c) Granuloma formation (Ref: Robbins 7th/94 - 905, 9/e 842 Harrison - 17th/1970)
Spectrum of alcoholic liver disease includes:
Fatty Liver (Hepatic steatosis)
Alcoholic hepatitis - Hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration,
spotty necrosis, polymorphonuclear infiltrate and fibrosis in the perivenular and perisinusoidal space of Disse. Mal-
lory bodies may also be present.
Alcoholic Cirrhosis
Granuloma is not seen in alcoholic liver disease.

Liver
39. Ans. (a) Drugs induced hepatitis (Ref: Robbins 8th/876, Diseases of the liver and biliary system by Sheila Sherlock, Sheila
Sherlock (Dame.), James S. Dooley Blackwell Science 11th/530)
Nodular regenerative hyperplasia: summary from Robbins and Sherlock
Associated with the development of portal hypertension and its
clinical manifestations.
Occurs in conditions affecting intra hepatic blood flow like

rheumatoid arthritis (most commonly), Felty syndrome,
myeloproliferative disorders, hyperviscosity syndromes, solid
organ (particularly renal and liver) transplantation, bone marrow
transplantation, HIV infection (Robbins), vasculitic conditions
and drugs (anabolic steroids and cytotoxics).
Characteristically, there is absence of fibrosis in this condition.
40. Ans. (a) Alcoholic liver disease; (b) Hepatocellular carcinoma; (c) Wilsons disease; (d) ICC (Indian childhood cirrho-
sis); (e) Biliary cirrhosis (Ref: Robbins 7th/905, 9/e p843)
Mallory bodies- scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins,
visible as eosinophilic cytoplasmic inclusions in degenerating hepatocytes.
41. Ans. d) LKM 2- Chronic hepatitis D (Ref: Harrison 17th/1956, 1968 CMDT/595-600, Robbin 839-840)
LKM stand for liver kidney microsomal antibodies
Type of LKM antibody Associated conditions
Anti LKM 1 antibodies Chronic hepatitis C, Autoimmune hepatitis type 2
Anti LKM 2 antibodies Drug induced hepatitis
Anti LKM 3 antibodies Chronic hepatitis D, type 2 autoimmune hepatitis (rarely)
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Liver
42. Ans. (c) Hepatocellular carcinoma (Ref: Robbins 8th/879-880, 9/e p873)
Elevated levels of serum -fetoprotein are found in 50 to 75% of patients with HCC.
False-positive results are encountered with yolk-sac tumors and many non-neoplastic conditions, including cirrhosis, mas-
sive liver necrosis, chronic hepatitis, normal pregnancy, fetal distress or death, and fetal neural tube defects such as anen-
cephaly and spina bifida.
Concept
The staining for Glypican-3 is used to distinguish early hepatocellular carcinoma from a dysplastic nodule. Other tests cannot be used

because the levels of serum -fetoprotein are inconclusive in this condition.
43. Ans. (c) Indian childhood cirrhosis (Ref: Harsh Mohan 6th/621-622)
44. Ans. (c) Secondary biliary cirrhosis (Ref: Robbin 7th/904, 9/e p843)
45. Ans. (d) Intermediate filaments (Ref: Robbins 7th/905, 9/e p843)
Scattered hepatocytes accumulate tangled skeins of cytokeratin intermediate filaments and other proteins, visible as eosin-
ophilic cytoplasmic inclusions in degenerating hepatocytes called as Mallory bodies. These inclusions are a characteristic
but not specific feature of alcoholic liver disease.
46. Ans. (b) Eosinophilic intracytoplasmic inclusions (Ref: Robbins 8th/858; 7th/612, 9/e p843)
47. Ans. (a) Hemosiderin (Ref: Robbins 8th/857; 7th/905)
48. Ans. (c) Alcoholic hepatitis (Ref: Robbins 9/e p843, 8th/858, 7th/905)
49. Ans. (c) Cardiac cirrhosis (Ref: Robbins 9/e p843, 8th/858; 7th/905,911)
50. Ans. (c) Prekeratin intermediate filaments; (Ref: Robbins 7th/34, 37- 41, 423, 905 9/e p843)
Hyaline is a nonspecific term that is used to describe any material, inside or outside the cell, that stains a red homo-
geneous color with the routine H&E stain.
Alcoholic hyaline inclusions (Mallory bodies) are irregular eosinophilic hyaline inclusions that are found within the
cytoplasm of hepatocytes. These are composed of pre-keratin intermediate filaments. They are a nonspecific finding
and can be found in patients with several diseases other than alcoholic hepatitis, such as Wilsons disease, and in
patients who have undergone bypass operations for morbid obesity.
Other options
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Immunoglobulins may form intracytoplasmic or extracellular oval hyaline bodies called Russell bodies.
Excess plasma proteins may form hyaline droplets in proximal renal tubular epithelial cells or hyaline membranes in the alveoli of
the lungs.
The hyaline found in the walls of arterioles of kidneys in patients with benign nephrosclerosis is composed of basement membranes
and precipitated plasma proteins.
5 0.1. Ans. (b) Cytokeratin (Ref: Robbins 8/e p858, 9/e p843)
Mallory bodies are visible as eosinophilic cytoplasmic clumps in hepatocytes. They are composed of tangled skeins of
cytokeratin intermediate filaments such as cytokeratin 8 and 18, in complex with other proteins such as ubiquitin.
Q
5 0.2. Ans. (c) Secondary biliary cirrhosis (Ref: Robbins 9/e 843, 8/e 858, 7/e p905)
Mallory Hyaline bodies are seen in conditions memorized by Mnemonic: New Indian WATCH.
5 0.3. Ans. (a) Alcoholic fatty liver (Ref: Robbins 9/e p830, 841, 8/e p857-8, Schiffs Diseases of the Liver)
Steatosis is considered to be microvesiuclar when multiple small cytoplasmic vacuoles tend to leave the nucleus centrally
placed. In contrast, macrovesicular steatosis has a single large fat vacuole which displaces the nucleus to the periphery.
Causes of Microvasicular steatosis
Reye syndrome, acute fatty liver of pregnancy, drugs (tetracycline, valproate, aspirin, nucleoside analogs of anti HIV drugs)
Causes of Macrovasicular steatosis
Malnutrition, diabetes, obesity, malabsorption, steroid therapy, some metabolic diseases
Alcohol intake can be associated with both microvesicular (initially) and macrovesicular steatosis (later on continued
drinking).
50.4. Ans (b) HBc Ag in serum is indicative of active infection (Ref: Robbins 9/e p833)
HBe Ag and not HBc Ag in serum is indicative of active infection.
Persistence of HBeAg is an important indicator of continued viral replication, infectivity, and probable progression
to chronic hepatitis.
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51. Ans. (b) Hep B (Ref: Robbins 8th/878-9, 9/e p870)

Risk factors for development of hepatocellular cancer (HCC)
Chronic Hepatitis (Hepatitis B, Hepatitis C)
Alcoholism
Aflatoxins (due to Aspergillus flavus infection of peanuts, grains)
Tyrosinemia
Hereditary hemochromatosis
52. Ans. (d) Serum AFP levels are usually greater than 1000mg/liter (Ref: Robbins 7th/925, 9/e p873)
As discussed in text fibrolammelar cancer is not associated with elevated AFP levels.
53. Ans. (b) Hepatitis B is an important risk factor (Ref: Robbins 8th/879, 9/e p873)
54. Ans. (c) Hepatocellular carcinoma (Ref: Robbins 8th/878; 7th/922-4, 9/e p869)
55. Ans. (a) More in females (Ref: Robbins 9/e p873, 8th/878; 7th/925)
56. Ans. (c) Oral contraceptives (Ref: Robbins 8th/877, 9/e p868)
Liver adenomas are benign liver tumors commonly associated with oral contraceptive use in young women (usually 3-4 th
decade of life). They may resemble hepatocellular carcinoma. If they are subscapular, they can rupture, causing intra-
abdominal haemorrhage leading to acute abdominal pain.
Hepatitis B may lead to hepatocellular carcinoma.
Polycythemia vera is associated with thrombosis of the hepatic veins.
Polyvinyl chloride, thorotrast (a contrast material) and arsenic are the risk factors for development of angiosarcoma
of the liver. Immunohistochemical staining of these tumor cells is positive for the CD 31 cell marker.
5 6.1. Ans. (a) Angiosarcoma of liver (Ref: Robbins 8/e p877, 9/e p875)
Angiosarcoma of the liver is a highly aggressive tumor which is associated with exposure to:
Vinyl chloride ,
Q
Arsenic , or
Q
Thorotrast ,
Q
Thorotrast is a suspension containing particles of the radioactive compound thorium dioxide. It emits alpha particles due
Liver
to which it has been found to be extremely carcinogenic.

5 6.2. Ans. (b) Hemangioma (Ref: Robbins 9/e p867, 8/e p876, 7/e p922)
Cavernous hemangiomas are the most common benign liver tumours.
57. Ans. (b) Hilum (Ref: Robbins 9/e 874, 8th/880, Harrison 17th/585)
The commonest location of the cholangiocarcinoma is at the hilum. Klatskin tumors are located at the junction of the right
and the left hepatic ducts.
58. Ans. (d) Clonorchis sinensis infection (Ref: Robbins 9/e p874, 8th/880; 7th/671)
59. Ans. (a) Adenocarcinoma (Ref: Robbins 9/e p874, 8th/888, 7th/926-927)
60. Ans. (c) Biliary sludge (Ref: Robbins 9/e p876, 8th/882-4. Harrison 18th/2617-9)
The demonstration of slow or incomplete gallbladder emptying in response to cholecystokinin stimulation is called gall-
bladder hypomotility. This is usually associated with risk factors like pregnancy, rapid weight loss prolonged use of total
parenteral nutrition or octreotide, and high spinal cord injuries.
Gallbladder hypomotility frequently results in the formation of biliary sludge, which results from bile precipitation. Bil-
iary sludge typically contains cholesterol monohydrate crystals, calcium bilirubinate, and mucus and is a known precursor
to stone formation. Complications such as acute cholecystitis occur in up to 20% of patients with biliary sludge.
(Choice b) Brown pigment stones are most likely to arise in cases of biliary tract infection.
(Choice a) Black pigment stones are most likely to arise in cases of intravascular hemolysis.
(Choice d) Gallstones do not typically contain phospholipid as a primary ingredient.
Concept
Gallbladder hypomotility often results in bile precipitation and the formation of biliary sludge.
61. Ans. (a) Common bile duct (Ref: Robbins 9/e p877, 8th/887)
The patient is probably suffering from choledocholithiasis, a condition in which a gallstone becomes lodged in the com-
mon bile duct.
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Liver
She is displaying Charcots triad (fever, jaundice, and right upper quadrant pain), which is indicative of cholangitis
(infection of the biliary tree proximal to an obstruction such as a gallstone or malignancy).
The important point in this case is the fact that the patient is jaundiced, eliminating all options other than a stone in the
common bile duct. Stones within the cystic duct (option B) or gallbladder (option C) or small intestine (options D) do not
cause jaundice.
61.1. Ans. (b) Primary sclerosing cholangitis (Ref: Robbins 8/e p880)
Risk factors (Mnemonic: All have alphabet C)
Primary sclerosing Cholangitis
Liver flukes like Clonorchis sinensis and Opisthorchis viverrini
Cause of chronic biliary inflammation and injury (Choledocholithiasis)
Contrat material: thorotrast
Chronic alcoholic liver disease
Congenital fibropolycystic diease (Choledochal cysts, Carolis disease)
6 1.2. Ans. (a) Nodular type of cholangiocarcinoma (Ref: Robbins 9/e p874, 8/e p880)
According to their localization, cholangiocarcinomas (CCAs) are classified into intrahepatic and extrahepatic forms.
Eighty to 90% of the tumors are extrahepatic . Q
The extrahepatic forms include perihilar tumors known as Klatskin tumors , which are located at the junction of the
Q
right and left hepatic ducts forming the common hepatic duct, and distal bile duct tumors.
Q
Most extrahepatic CCAs appear as firm, gray nodules within the bile duct wall
Q
Klatskin tumors generally have slower growth than other CCAs, show prominent fibrosis, and infrequently involve
distal metastases.
6 1.3. Ans. (d) Oral contraceptives (Ref: Robbins 9/e p879, 8/e p888, Cancer Nursing: Principles and Practice 7/e p1317)
Risk factors of gall bladder cancer
Gallstones: most important risk factor associated with gallbladder carcinoma.
Gholedochal cyst
Carcinogens and chemicals including nitrosamines, rubber and textile industries
Rubber plant workers
Obesity
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Estrogen
T yphoid carrier
P orcelain gall bladder (calcification of the gallbladder wall)
G all bladder polyps
Anomalous pancreatobiliary duct junction
Also know
Only 0.5% of patients with gallstones develop gallbladder cancer after twenty or more years
In Asia, where pyogenic and parasitic diseases of the biliary tree are common, the coexistence of gallstones in gall-
bladder cancer is much lower.
6 1.4. Ans. (a) Adenomyomatosis of gallbladder (Ref: Learning Ultrasound Imaging p9, Harrison 17/e 1998)
Focal diffuse gall bladder wall thickening with comet tail reverberation artifacts on USG is a diagnostic finding of Adeno-
myomatosis of gall bladder.
61.5. Ans. (b) Primary sclerosing cholangitis (Ref: Robbins 9/e p860)
62. Ans. (b) Autosomal recessive (Ref: Robbins 9/e p847-849, 8th/861, Harrison 18th/3166)
Hemochromatosis is characterized by excessive accumulation of iron in the body.
It is an autosomal recessive disorder most commonly caused by mutations in HFE gene located at 6p21.3.
It is more common in males characterized by the triad of
*Micronodular cirrhosis *Diabetes mellitus and *Skin pigmentation
Most of the cells of the body have increased amounts of hemosiderin in them but skin pigmentation is primarily due to increased
intracellular melanin.
Inflammation is characteristically absent
Deposition of hemosiderin in the joint synovial lining can result in acute synovitis and pseudogout.
Derangement of the hypothalamo-pituitary axis results in hypogonadism (loss of libido and impotence in male and amenorrhea in
the female).
Treatment is removal of excessive iron and it is accomplished by weekly or twice weekly phlebotomy.
Chelating agents like desferrioxamine are indicated only when anemia or hypoproteinemia is severe enough to preclude phlebotomy.
Cardiac failure and hepatocellular carcinoma are the most common causes of death.
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63. Ans. (d) Desferrioxamine is the treatment of choice (Ref: Harrison 18th/3166; Robbins 7th/615-7, 9/e p849)
Desferrioxamine is the drug of choice.
The treatment of choice is phlebotomy at regular intervals.
64. Ans. (d) Hepatic Metastasis (Ref: Harrisons 17th/1983; Oxford Texbook of Pathology by McGeel 1312t, Robbins 9/e p841)
Causes of Hepatic Granulomas
Systemic disease Infections Drugs
Sarcoidosis - Tuberculosis Sulfonamides
Hodgkins and Non-Hodgkins - MAC, Leprosy Isoniazid
lymphoma - Brucellosis Allopurinol
Primary biliary cirrhosis - EBV, CMV, Chicken pox Methyldopa
Berylliosis - Histoplasmosis, Candidiasis Quinidine
Crohns disease - Schistosomiasis Phenylbutazone
Wegeners granulomatosis - Q fever Halothane

Idiopathic - Syphilis
65. Ans. (d) Glycogen depletion (Ref: OP Ghai 6th/524; 7th/543, CPDT 18th/662-3)
Reyes Syndrome/Jamshedpur Fever

Described as a diffuse fatty infiltration of the liver, kidney and cerebral edema with diffuse mitochondrial injury.

An acute self-limiting metabolic insult resulting in generalized mitochondrial dysfunction due to inhibition of fatty acid -oxidation
due to:

Salicylates

Inborn error of coenzyme A dehydrogenase

Varicella or Influenza B viral infections

Contamination of food with aflatoxin

Usually observed from 2 month - 15 years of age.
Clinical features

Child presents with vomiting, anorexia, listlessness followed by altered sensorium, irregular breathing, seizures and coma.

Hepatomegaly is present in 50% cases. Jaundice and focal neurological signs are absent.
Liver
Diagnosis

Liver biopsy shows fatty change and glycogen depletion but no NECROSIS of liver cells.

Liver is showing fatty change, so these lipids can be stained with Oil Red O.
66. Ans. (b) Kupffers cell hyperplasia with macrophage infiltration around periportal area laden with pigments
(Ref: Robbins 7th/402, 9/e p391-392)
In severe infections with Plasmodium falciparum, the vital organs are packed with erythrocytes containing mature
form of the parasite. There is abundant intra and extraerythrocytic pigment and organs such as liver, spleen and
placenta may be grey black in color.
Liver and spleen in severe malaria
Liver
Liver is generally enlarged and may be black from malarial pigment.
There is congestion of the centrilobular capillaries with sinusoidal dilatation and Kupffer cell hyperplasia
The Kupffer cells are heavily laden with malarial pigment, parasites and cellular debris.
Sequestration of parasitized erythrocytes is associated with variable cloudy swelling of the hepatocytes and perivenous ischemic
change and sometimes centrizonal necrosis.
Hepatic glycogen is often present despite hypoglycemia.
Spleen
The spleen is often dark or black from malarial pigment enlarged, soft and friable.
It is full of erythrocytes containing mature and immature parasites.
There is evidence of reticular hyperplasia and architectural reorganization.
The soft and acutely enlarged spleen of acute lethal infections contrasts with the hard fibrous enlargement associated with
repeated malaria.
Also know
Durcks granuloma is pathognomic of malignant cerebral malaria.
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Liver
67. Ans. None (Ref: Harsh Mohan 6th/628; Robbins 39, 910, 914)
Pigmentation in liver is caused by:

1. Lipofuscin: It is an insoluble pigment known as lipochrome and wear and tear pigment. It is seen in cells undergoing low,
regressive changes and is particularly prominent in liver and heart of ageing patient or patients with severe malnutrition and
cancer cachexia.

2. Pseudomelanin: After death, a dark greenish or blackish discoloration of the surface of the abdominal viscera results from the
action of sulfated hydrogen upon the iron of disintegrated hemoglobin. Liver is also pigmented.
3. Wilsons disease: Copper is usually deposited in periportal hepatocytes in the form of reddish granules in cytoplasm or reddish
cytoplasmic coloration stained by rubeanic acid or rhodamine stain for copper or orcein stain for copper associated protein.
Copper also gets deposited in chronic obstructive cholestasis.

4. Malarial pigment: Liver colour varies from dark chocolate red to slate-grey even black depending upon the stage of congestion.

5. In biliary cirrhosis liver is enlarged and greenish-yellow in colour due to cholestasis. So liver is pigmented due to bile.
68. Ans. (b) Emphysema; (c) Fibrosis of portal tact; (d) Diastase resistance positive hepatocytes (Ref: Robbins 7th/911-2, 9/e
p850-851)
This is an autosomal recessive disease characterized by deficiency of -antitrypsin (important protease inhibitor).
1
There is portal tract fibrosis in neonatal hepatitis. About 10% - 20% of newborn with -antitrypsin deficiency
Q
1
develop neonatal hepatitis and cholestasis.
Hepatocellular carcinoma develops in 2-3 % a - antitrypsin deficiency in adults.
1
The treatment and cure, for severe hepatic disease is orthotopic liver transplantation.
Most important treatment for pulmonary disease is to avoid cigarette smoking because it accelerates the development
of emphysema.
69. Ans. (a) Wilsons disease (Ref: Robbins 9/e p850, 8th/864, 7th/911)
70. Ans. (c) Ceruloplasmin (Ref: Robbins 8th/863-4, 9/e p849-850, Harrison 17th/1492)
71. Ans. (b) Neonatal hepatitis (Ref: Robbins 9/e p851, 8th/865-6; 7th/492,719)
72. Ans. (a) CCl (Ref: Robbins 8th/872, 7th/882)
4
73. Ans. (b) K-RAS (Ref: Robbins 8th/900-2, 9/e p892)
Liver
Presence of pulmonary thromboembolism with a pancreatic mass in an old man suggests a diagnosis of pancreatic cancer
with Trosseau syndrome. This is also supported with elevated serum levels of tumor markers like CEA and CA 19-9.
The K-RAS gene (chromosome 12p ) is the most frequently altered oncogene in pancreatic cancer. This oncogene is
Q
activated by point mutation in 80% to 90% of pancreatic cancers.

Other options
BRCA 2 mutation may be associated with some pancreatic cancers but usually there is a history of other cancers like breast cancer,
prostate cancer (in males) and breast and ovarian cancers (in females).
PRSS1 mutation is also associated with pancreatic cancer but this is usually a cancer starting early in life secondary hereditary
pancreatitis.
SPINK1 is only associated with hereditary pancreatitis but not pancreatic cancer.
73.1. Ans. (a) Perls iron stain (Ref: Robbins 8/e p862, 9/e p849)
In the liver, iron becomes evident as golden yellow hemosiderin granules in the cytoplasm of periportal hepatocytes
which stain blue with Prussian blue stain. The last mentioned stain is also called as Perls iron stain.
7 3.2. Ans. (d) Hemochromatosis (Ref: Robbins 8/e p862, 9/e p849)
In hemochromatosis, there is iron deposited in different tissues in the form of hemosiderin. This deposition along with
increased epidermal melanin production leads to a characteristic slate-gray color to the skin. The development of diabetes
in these patients is therefore termed as bronze diabetes.
73.3. Ans. (c) Ceruloplasmin (Ref: Robbins 8/e p863, 9/e p849-850)
Wilson disease is an autosomal recessive disorder caused by mutation of the ATP7B gene , resulting in impaired copper
Q
excretion into bile and a failure to incorporate copper into ceruloplasminQ.

73.4. Ans. (b) ATP 7B.. see above explanation..(Ref: Robbins 8/e p863, 9/e p849)
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Golden Points / Updated information from 9th edition of robbins

(Liver)
The receptor for HAV is HAVcr-1, a 451amino acid class I integral-membrane mucin-like glycoprotein.
Liver failure (Robbins 9th/825)

The most severe clinical consequence of liver disease is liver failure. It may be the result of sudden and massive hepatic
destruction, acute liver failure, or, more often, chronic liver failure, which follows upon years or decades of insidious, progressive
liver injury.
In some cases, individuals with chronic liver disease develop acute on- chronic liver failure, in which an unrelated acute injury
supervenes on a well-compensated late-stage chronic disease or the chronic disease itself has a flare of activity that leads directly
to liver failure.
Acute liver failure is defined as an acute liver illness associated with encephalopathy and coagulopathy that occurs within 26
weeks of the initial liver injury in the absence of pre-existing liver disease. It is most commonly caused by hepatitis B/C in Asia
and by intake of paracetamol in USA.
The liver is small and shrunken.
Clinical features include nausea, vomiting, and jaundice, followed by life threatening encephalopathy, and coagulation
defects. The serum liver transaminases are markedly elevated. Other manifestations of acute liver failure include progressively
increasing jaundice and icterus, hepatic encephalopathy (alterations in the nervous system including disturbances in consciousness,
confusion and stupor, to deep coma), coagulopathy (increased bleeding tendency), portal hypertension, ascites, and hepatorenal
syndrome (a form of renal failure occurring in liver failure patients with no intrinsic morphologic or functional causes for kidney
dysfunction).
Mnemonic for causes of acute liver failure (Robbins 9th/830)
A: Acetaminophen, hepatitis A, autoimmune hepatitis

B: Hepatitis B
C: Hepatitis C, Cryptogenic
D: Drugs/toxins, hepatitis D
Liver

E: Hepatitis E, Esoteric causes (Wilson disease, Budd-Chiari)
F: Fatty change of the microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)
Chronic liver failure and cirrhosis

Liver failure in chronic liver disease is most often associated with cirrhosis, a condition marked by the diffuse transformation
of the entire liver into regenerative parenchymal nodules surrounded by fibrous bands and variable degrees of vascular (often
portosystemic) shunting.
The leading causes of chronic liver failure worldwide include chronic hepatitis B, chronic hepatitis C, nonalcoholic fatty liver
disease, and alcoholic liver disease.
The Child-Pugh classification of cirrhosis distinguishes between class A (well compensated), B (partially decompensated),
and C (decompensated), which correlate with different morphologic features histologically. This classification helps to monitor the
decline of patients on the path to chronic liver failure.
Portopulmonary hypertension
Portopulmonary hypertension refers to pulmonary arterial hypertension arising in liver disease and portal hypertension. It is
caused by excessive pulmonary vasoconstriction and vascular remodeling. The most common clinical manifestations are
dyspnea on exertion and clubbing of the fingers.
P L
recursor esions of HCC... Robbins 9th /871-2
Several cellular and nodular precursor lesions apart from hepatocellular adenoma have been identified.
1. Cellular dysplasias
These changes serve as markers in biopsy specimens to indicate patients requiring more aggressive cancer surveillance.

a. Large cell change: it is a marker of increased risk of HCC in the liver as a whole, but in hepatitis B they may also be directly
premalignant.
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Liver
It has scattered hepatocytes that are larger than normal hepatocytes and with large and often multiple pleomorphic
nuclei with the nuclear-cytoplasmic ratio being normal.

b. Small cell change: it is thought to be directly premalignant.
This has hepatocytes have high nuclear: cytoplasmic ratio and mild nuclear hyperchromasia and/or pleomorphism.
2. Dysplastic nodules
These are usually detected in cirrhosis, either radiologically or in resected specimens and have a different appearance (in size or
vascular supply or appearance) from the surrounding cirrhotic nodules. They can be of the following types:
I.
Low-grade dysplastic nodules: their presence indicates a higher risk for HCC in the liver as a whole. These nodules are
devoid of cytologic or architectural atypia and are clonal.

II. High-grade dysplastic nodules: these are probably the most important primary pathway for emergence of HCC in viral
hepatitis and alcoholic liver disease. These nodules have cytologic (e.g., small cell change) or architectural features
(occasional pseudoglands, trabecular thickening) suggestive of, but still insufficient for diagnosis of overt HCC.
Precursor Lesions of Hepatocellular and Cholangiocarcinoma
Hepatocellular Cancer Cholangiocarcinoma
Intraductal
Low Grade High Grade Mucinous Papillary
Hepatocellular Small Cell Large Cell Dysplastic Dysplastic Cystic Biliary
Adenoma Change Change Nodule Nodule BiIIN-3 Neoplasm Neoplasia
Focality in liver Single or Diffuse Diffuse Single or Single or Diffuse or Single Focal or
multiple multiple multiple multifocal diffuse
(adenomatosis)
Premalignant Yes yes In some Uncertain* Yes Yes Yes Yes
HBV*
Association Rare Common Comon Usual Usual Sometimes No No
with cirrhosis
Commonly NAFLD, Sex HBV, HCV, HBV, HCV, HBV, HCV, HBV, HCV, PSC, None None
Liver
associated hormone Alcohol, Alcohol, Alcohol, Alcohol, Hepatolithiasis
diseases exposures NAFLD, NAFLD, NAFLD, NAFLD, Liver flukes
Glycogen A1AT, A1AT, HH A1AT, HH A1AT, HH,
storage HH, PBC PBC PBC PBC
diseases
Occurrence Occasional No No No No Yes Yes Yes
without
identified
predisposing
condition
Need for depending Yes Yes Yes Yes Yes No Yes
surveillance on presence of
cancer predisposing
screening condition
*While these are not certain to be directly premalignant, they are always at least an indication of increased risk for malignancy in the liver
as a whole.
BillN-3, Bliary intraepithelial neoplasia, high grade; NAFLD, nonalcoholic fatty liver disease; HBV, hepatitis B virus; hepatitis C virus; A1AT,
1
-antitrypsin deficiency; HH, hereditary hemochromatosis PBC, primary biliary cirrhosis, PSC, primary sclerosis cholangitis.
Precursor Lesions of Cholangiocarcinoma Robbins 9th/874

Premalignant lesions for cholangiocarcinoma are also known, the most important of which are biliary intraepithelial neoplasias
(low to high grade, BilIN-1, -2, or -3).
BilIN-3, the highest grade lesion, incurs the highest risk of malignant transformation.
Rarer are mucinous cystic neoplasms and intraductal papillary biliary neoplasia.
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CHAPTER 14
MALE GENITAL TRACT
Genital System and Breast
Hypospadias
Penis Urethral opening located on
ventral (inferior) surface of the
Congenital malformations affecting the penis are abnormal locations of urethral penis.
openings and phimosis. These abnormal locations may produce obstruction of urinary
Results from failure of urethral
tract infection or infertility.
folds to close.
Phimosis occurs when the orifice of the prepuce (foreskin) is too small to permit
normal retraction. It may be due to abnormal development or more commonly due
to inflammatory scarring. It interferes with cleanliness and favors the development
of secondary infections and possibly carcinoma.
Epispadias
Paraphimosis is inability to roll back the prepuce after forcible retraction over glans Urethral opening located on
penis. It is extremely painful and may cause obstruction of urinary tract (cause of ventral (inferior) surface of the
acute urinary retention) or blood flow (may lead to necrosis of penis). penis.
Balanoposthitis is a non-specific infection of glans and prepuce. It is mostly caused
Results from faulty position of
by Candida, anerobic bacteria and Gardernella.
genital tubercle.
Tumors of penis may be benign [condyloma acuminata] or malignant [carcinoma in-situ
and invasive carcinoma]. It is associated with exstrophy
of urinary bladder and undes
Condyloma acuminatum is a benign tumor caused by human papilloma virus (HPV), most cended testes.
commonly type 6 and sometimes type 11. Koilocytosis is a characteristic of infection with HPV.
It is seen in condyloma as well as carcinoma.

Carcinoma in-situ refers to epithelial lesions in which cytological changes of
malignancy are confined to epithelium, with no evidence of local invasion or
Koilocytosis is clear vacuoliza-
metastasis. These are considered as pre-cancerous lesions. In about 80% of cases, tion of superficial, prickle cell lay-
these lesions are associated with HPV-16. Bowen disease, Erythroplasia of Queyrat ers of epithelial cells associated
(a variant of Bowens disease) and Bowenoid papulosis are examples of carcinoma with HPV infection.
in-situ. Bowen disease may transform into invasive squamous cell carcinoma in 10%
patients and is associated with occurrence of visceral cancers in about one thirds
of patients. In contrast, bowenoid papulosis never develops into invasive carcinoma and
many times, it spontaneously regresses.
Squamous cell carcinoma is associated with cigarette smoking and infection with Squamous cell carcinomas
HPV-16 (more commonly) and HPV-18. Mostly, squamous cell carcinoma invades risk is reduced by circumcision;
tissue as finger like projections (papillary) of atypical squamous epithelial cells. therefore it is rare in Jews and
These show varying degree of differentiation. A variant of squamous cell carcinoma Muslims.
is verrucous carcinoma [also known as Giant condyloma or Buschke-Lowenstein
tumor] which invades the underlying tissue along a broad front (in contrast,
papillary carcinoma invades as finger like projections).
Buschke-Lowenstein tumor is
TESTIS AND EPIDIDYMIS a well differentiated variant of
squamous cell carcinoma.
Cryptorchidism (undescended testes) is found in 1% of 1-year-old boys and is
mostly unilateral (Right > Left). Testicular descent has two phases; transabdominal
and inguino-scrotal. Transabdominal phase is controlled by Mullerian-inhibiting
substance whereas inguino-scrotal phase is androgen dependent (mediated by Increased risk of malignancy
androgen induced release of CGRP from genitofemoral nerve). Grossly, testis is (most commonly seminoma)
occurs with undescended testes
small, brown and atrophic. Microscopically, tubules are atrophic with thickened
(more for abdominal than for
basement membranes. Leydig cells are spared and appear to be prominent. inguinal).
Occasionally, proliferation of Sertoli cells may also be seen. Smaller but definite
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Review of Pathology
risk of malignancy is present for contra-lateral, correctly placed testis. Persistently

Concept undescended testes require orchiopexy (placement in scrotal sac) preferably before
The risk of malignancy is NOT 2 years before histological deterioration sets in. Orchiopexy does not guarantee
REDUCED by orchiopexy. fertility.
Note: Cryptorchidism is associated with trisomy 13 and genitourinary malformations like hy-
Superficial inguinal pouch is pospadias or in-utero exposure of DES.
the most common site of ectopic
Ectopic testes is the deviation of testes from normal path of descent. Gubernaculum
testis.
testis has five tails (namely scrotal, pubic, perineal, inguinal and femoral).
Normally scrotal tail is strongest, so testes descend to scrotum. If other accessory
tails become strong, testis may drain toward that tail. Difference of ectopic testis
from undescended testis is that former is fully developed and hence has normal
Gonorrhea and tuberculosis

almost invariably arise in epidi
spermatogenesis whereas latter lacks spermatogenesis.
dymis whereas syphilis affects Scrotal swelling may occur due to inflammation, abnormality of blood vessels, cysts
the testis first. or tumors of testes or epididymis.
Non-specific inflammations in a sexually active young patient (< 35 years) is mostly
caused by Chlamydia trachomatis and Neisseria gonorrhea whereas most common
culprit in men older than 35 years are E. coli and pseudomonas.
Twisting of spermatic cord resulting in cut-off of the venous drainage and arterial
Prehan sign: Manually lifting of supply to testis may result in TORSION. Neonatal torsion lacks any associated
scrotal sac causes:
pain in torsion:
anatomical defect whereas adult torsion results from a bilateral anatomical defect in
pain in orchitis. which testes have increased mobility [bell-clapper abnormality]. If untwisted within
6 hours, testes may remain viable. To prevent subsequent torsion, contralateral
normal testis is fixed to scrotum [orchiopexy].
Note: Doppler flow studies and testicular scintigraphy are useful if testicular torsion is ex-
Concept pected clinically.
Transillumination is helpful in
differentiation of cysts (which Benign scrotal cysts may form from abnormalities of tunica vaginalis. Processus

transilluminate) and tumors vaginalis is an outpouching of the peritoneum that enters into the scrotum. When
(which do not). testis reaches the scrotum, proximal portion of processus vaginalis obliterates
Inguino-scrotal ultrasound is whereas distal portion persists and forms tunica vaginalis. Cysts involving tunica
used to confirm the diagnosis. vaginalis can be hydrocele [contain clear fluid], hematocele [results from hemorrhage
into a hydrocele], chylocele [accumulation of lymph in tunica due to elephantiasis)
or spermatocele (cystic enlargement of efferent ducts or rete testis with numerous
Sertoli cell only syndrome:
spermatocytes present]. Varicocele results from dilatation of testicular veins in
Absence of germ cells pampiniform plexus. It is associated with oligospermia (< 20 million spermatozoa/
Results in infertility due to ml of semen) and is most common cause of infertility. Left side is affected more
absence of spermatogenesis. commonly.
Sertoli cell only syndrome also known as Del-Castillos syndrome is a condition in
which seminiferous tubules are lined by only Sertoli cells.
Seminomas are the most com

mon type of germ cell tumors
(50%).
Yolk sac tumor is the commo

nest testicular tumor in infants
and children up to 3 years of
age.
Seminoma is commonest testi

cular tumor in young adults.
Lymphoma is commonest testi

cular tumor in elderly.
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Testicular Germ Cell Tumors

Most of these arise from intra tubular germ cell neoplasia (ITGCN) except spermatocytic Testicular Germ Cell Tumors
seminoma and teratoma. Most of these arise from intra
tubular germ cell neoplasia
(ITGCN) except spermatocytic
Predisposing factors for germ cell tumors are: seminoma and teratoma.
Cryptorchidism [abdominal > inguinal]

Testicular dysgenesis [feminization and Klinefelter]
Siblings of affected person (have tenfold higher risk)
Isochromosome of short arm of chromosome 12, i (12p) is seen in all germ cell tumors [both
testicular as well as ovarian]
Seminomas almost never occur
Clinically germ cell tumors of testes can be divided into seminoma and non-seminomatous in infants.
germ cell tumors (NSGCT).
S eminomatous germ cell tumors

Seminomas are characterized by large cells with distinct cell membranes and clear Counterpart of seminoma in
cytoplasm, large central nucleus with prominent one or two nucleoli. Cytoplasm contains ovary is dysgerminoma.
glycogen. Classical seminomas do not contain alpha fetoprotein (AFP). Human
chorionic gonadotropin (hCG) is present in 15% of seminomas that contain
syncytiotrophoblasts. Spermatocytic seminoma is a distinctive tumor characterized
by being found in old age and having excellent prognosis [do not metastasize].
Histologically, it is characterized by maturation of tumor cells, some of which
resemble secondary spermatocytes. Spermatocytic seminoma is seen only in testis.

There is no ovarian counterpart.
Pure choriocarcinoma is most
No - n seminomatous germ cell tumors aggressive testicular tumor.
These may be embryonal carcinoma, yolk sac tumors, choriocarcinoma or teratoma.

Choriocarcinomas have a mixture of malignant cytotrophoblasts and syncytio
trophoblasts. These are most aggressive variants. Malignant teratomas have tissue
derived from all three germ layers with scattered immature neural elements. In
children, differentiated mature teratomas are considered benign whereas in post- Yolk sac tumor are charac
pubertal males, all teratomas are regarded as malignant. terized by elevated AFP and
Embryonal cell carcinomas present as sheets of undifferentiated cells. Focal choriocarcinoma by elevated
glandular differentiation may be present. Elevated AFP and hCG is seen in this hCG. AFP is never elevated in
seminoma.
tumor.
Yolk sac tumor or infantile embryonal carcinoma or endodermal sinus tumor are
the most common testicular tumor in infants and children up to 3 years of age. These have
very good prognosis. Half of tumors show Schiller-Duval bodies or glomeruloid
structures [structures resembling endodermal sinuses]. Presence of AFP is highly
Concept
characteristic of yolk sac tumors. Biopsy of testicular neoplasm is
Seminoma NSGCT
associated with risk of tumor spill-
1. Radiosensitive Radio resistant

age, therefore radical orchiec
tomy should be done on pre-
2. Localized to testes for long duration (70% Early dissemination (60% present in sumption of malignancy.
present in stage 1) stage II & III)
3. Metastasis first to lymph nodes Early hematogenous metastasis
4. Tunica albuginea spared Tunica breached mostly Extragonadal site of germ cell
tumors include mediastinum
(commonest), retroperitoneum
Important points about germ cell tumors and pineal gland.
Painless enlargement of testis is a characteristic feature.

Lymphatic spread is common to all testicular tumors. Retroperitoneal nodes are first involved. Rod shaped crystalloids of
Hematogenous spread is primarily to lungs. Reinke are seen in about 25%
of Leydig cell tumors.
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Non-Germinal Tumors
Leydig cell tumors are derived from stroma and Sertoli cell tumors from sex cords.
Sertoli cell tumors are also known as Androblastoma. Both these tumors are benign.
Gonadoblastoma contains a mixture of germ cells and gonadal stromal elements.
Lymphomas are most common testicular neoplasms in men over the age of 60 years. The prognosis
is extremely poor. These are most common cause of bilateral testicular tumors.
O
PR STATE
In a normal adult prostate weighs about 20g. It is divided into peripheral, central, transitional
zones and the region of anterior fibromuscular stroma. Prostate is a combined tubuloalveolar
organ. Characteristically, the glands are lined by two layer of cells, basal layer of cuboidal cells
covered by a layer of columnar secretory cells. Three important conditions of prostate are
inflammations, hyperplasia and tumors.
Inflammation of prostate (prostatitis)

It is characterized by finding at least 15 leukocytes per high power field in prostatic secretions.
Acute prostatitis present with sudden onset of fever, chills and dysuria. It is mostly
caused by E. coli
Chronic bacterial prostatitis is associated with recurrent UTI.
Chronic abacterial prostatitis is associated with infections with Chlamydia or
Ureaplasma.
Granulomatous prostatitis is mostly caused by intravesical administration of BCG
(used for treatment of superficial bladder carcinoma).

BPH mostly originates from tran
sitional zone of prostate whereas Malacoplakia is a granulomatous disease with defective intracellular lysosomal digestion of bacteria.
carcinoma mostly arises from It is mostly caused by E. coli. Sharply demarcated spherical structures with concentric owl eye (known
peripheral zone. as Michaelis-Guttmann bodies) are seen histologically.
Nodular hyperplasia
Concept It is also known as benign prostatic hyperplasia (BPH). Clinical symptoms are urinary frequency,
BHP is NOT a pre-malignant nocturia, difficulty in starting or stopping urination, dribbling and dysuria. Histologically,

condition. nodules are composed of hyperplastic stromal cells and hyperplastic glands. Glands consist
of two layer of cells; cuboidal and columnar [in carcinoma single layers of cells are present
5-a-reductase inhibitors (e.g.
finasteride) and a1A receptor in glands] with intervening stroma. Histological signs of malignancy are absent. Development

antagonists (e.g. tamsulosin) of BHP is associated with advanced age and high testosterone levels. Di-hydrotestosterone
can be used for treatment of (DHT) is produced from testosterone with the help of an enzyme, 5a-reductase type 2. DHT
BPH. is the main substance responsible for prostatic growth. In addition to mechanical effects of
enlarged prostate, clinical symptoms are also due to smooth muscle mediated contraction of
prostate by a1A receptors.
Most of the prostatic carcinomas
are acinar adenocarcinoma and Note: In some cases, nodular enlargement may project up into the floor of urethra as a hemispherical

arise in peripheral zone, classi mass, which is termed as median lobe hypertrophy.
cally in a posterior location.
Tumors
Adenocarcinoma of prostate is most common form of cancer in men. Advancing age, race (more
in American blacks, least in Asians), dietary factors (increases with more fat consumption,
Concept decreases with lycopene, vitamin A, vitamin E, selenium and soy products), androgens and
Feature that differentiate benign genetic factors are implicated in pathogenesis of prostate cancer. Genetic factors include germ
and malignant prostate gland line mutations of BRCA2 tumor suppressor gene, chromosomal re-arrangements that juxtapose ERG or
is that benign glands contain
ETV1 next to androgen regulated TMPRSS2 promoter and epigenetic alterations like hypermethylation
basal cells [two layered; basal
cells and columnar cells] that are of glutathione 5-transferase (GSTP1) gene causing down regulation of GSTP1 expression. Local
absent in cancer [single layered extension most commonly involves seminal vesicles and later base of bladder; Fascia of
cells]. Denonvilliers prevents the backward extension of the tumor. Hematogenous spread
occur chiefly to bones (osteoblastic secondaries) most commonly to lumbar spine. Lymphatic
554
spread occurs initially to obturator nodes. Histologically, most lesions are adenocarcinomas
characterized by small glands that appear back to back without intervening stroma or
that appear to be infiltrating beyond the normal prostate lobules.
Most prostate cancers arise peripherally, away from urethra; therefore urinary symptoms occur
late. Osteoblastic secondaries in bone are virtually diagnostic of prostate cancer.
Gleason score is used for

Grading of prostate cancer Grading of prostate cancer.
Grade 1 is well differentiated and Grade 5 shows no glandular differentiation. Grade 2, 3 and
4 are in-between. Most tumors contain more than one pattern, so primary grade is assigned to
dominant pattern and secondary grade to sub-dominant pattern. Combined Gleason score is
Minimum Gleason score is 2
derived by addition of these two grades. Tumors with only one pattern are assumed to have (1 + 1) and is most differentiated
both primary and secondary grade as same. Thus Gleason score for these is double the grade. whereas maximum score is 10
Score of 2-4 are considered well-differentiated, 5-6 as moderately differentiated, 7 moderate (5 + 5), least differentiated.
to poorly differentiated and 8-10 high grade cancers. Grading is of particular importance in
prostatic cancer, as it is the best marker, along with stage, for predicting prognosis.
Major role of transrectal ultrasonography (TRUS) in prostate cancer is in guiding the placement of
needle biopsies to thoroughly sample the gland. Transperineal or transrectal biopsy is required for
diagnosis.
Prostate specific antigen (PSA): 20-40% patients with prostate cancer have PSA value of 4 PSA is organ specific but not
ng/ml or less and so, four different refinements in PSA value can be utilized. cancer specific because it may
be elevated in BHP, prostatitis,
a. PSA density: It is the ratio of serum PSA value and volume of prostate. It reflects PSA infarct, ejaculation etc. apart
produced per gram of prostate tissue. Upper normal limit is 0.15.

from prostatic cancer.
b. Age specific reference range
Age Upper normal value

40-49 years 2.5 ng/ml
c. PSA velocity: It is rate of change of PSA with time. At least 3 PSA measurements
PSA velocity of 0.75 ng/ml/
should be taken over a period of 1.5 to 2 years. year best distinguishes between
d. Percentage of free PSA: It is calculated as cancer and benign lesions.
Free PSA/Total PSA 100
It is more valuable, when total PSA is in gray zone of 4 to 10 ng/ml. Free PSA less than 10%
indicates high risk of carcinoma whereas value > 25% indicates lower risk.
FEMALE GENITAL TRACT
Embryology Mesonephric ducts in males:

develop into the vas deferens,
The paired genital ducts consist of the mesonephric (Wolffian) duct, which extends from the
epididymis, and seminal vesi
mesonephros to the cloaca, and the paramesonephric (Mullerian) duct, which runs parallel cles.
and lateral to the Wolffian duct. Mesonephric ducts in fema
The mesonephric ducts in males, if stimulated by testosterone (secreted by the les: Gartner duct cysts in the
Leydig cells), develop into the vas deferens, epididymis, and seminal vesicles. In contrast, vagina.
because normal females do not secrete testosterone, the Wolffian ducts regress and
form vestigial structures. They may, however, form mesonephric cysts in the cervix
or vulva, or they may form Gartner duct cysts in the vagina. The cranial group of
mesonephric tubules (the epoophoron) remains as vestigial structures in the broad
ligament above the ovary, while the caudal group of mesonephric tubules (the
paroophoron) forms vestigial structures in the broad ligament beside the ovary.
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The paramesonephric ducts in the female form the fallopian tubes, the uterus, the
Paramesonephric ducts in uppermost vaginal wall, and the hydatid of Morgagni. The lower portion of the vagina
the female: form the fallopian and the vestibule develop from the urogenital sinus. Males secrete Mullerian-
tubes, the uterus, the uppermost inhibiting factor (MIF) from the Sertoli cells of the testes, which causes regression
vaginal wall, and the hydatid of
of the Mullerian ducts. This results in the formation of the vestigial appendix testis.
Morgagni.
Several abnormalities result from abnormal embryonic development of the
Mullerian ducts.

Uterine agenesis may result from abnormal development or fusion of these
paired paramesonephric ducts. Developmental failure of the inferior portions
of the Mullerian ducts results in a double uterus, while failure of the superior
portions to fuse (incomplete fusion) may form a bicornuate uterus.

Retarded growth of one of the paramesonephric ducts along with incomplete
fusion to the other paramesonephric ducts results in the formation of a
bicornuate uterus with a rudimentary horn.
GENITAL CYSTS
Obstruction of the ducts of any of the glands found within the female genitalia may cause the
formation of a genital cyst.
Bartholins cyst: The paired Bartholins glands, which are analogous to the bulbourethral glands
of the male, are located in the lateral wall of the vestibule. If these are obstructed, a cyst may form
that is usually lined with transitional epithelium.
Gartners duct cysts: These are derived from Wolffian (mesonephric) duct remnants and are
located in the lateral walls of the vagina.
Chocolate cysts: These refer

Mesonephric cysts: Cysts derived from the same Wolffian duct may also be found on the lateral
to cystic areas of endometriosis
that include hemorrhages and aspect of the vulva and are called mesonephric cysts.
blood clots. Nabothian cysts: Obstruction of the ducts of the mucous glands in the endocervix may result in
small mucous (Nabothian) cysts.
Epithelial inclusion cysts: Cysts may also be found within the skin of the vulva. These cysts,
which contain white, cheesy material, are called keratinous (epithelial inclusion) cysts. Clinically
they are referred to as sebaceous cysts, which is a misnomer.
Follicular cysts: These are benign cysts of the ovary.
O U
DISEASES F V LVA
1. Leukoplakia
Several pathologic conditions are associated with the formation of white plaques on the
The male counterpart of lichen vulva, which are clinically referred to as leukoplakia.
sclerosis, called balanitis xero Lichen sclerosis is seen histologically as atrophy of the epidermis with underlying
tica obliterans, is found on the
penis. dermal fibrosis.
The four cardinal histologic features are:
Atrophy (thinning) of the epidermis, with disappearance of the rete pegs

Hydropic degeneration of the basal cells
Replacement of the underlying dermis by dense collagenous fibrous tissue
A monoclonal bandlike lymphocytic infiltrate
Loss of pigment in the epidermis (vitiligo) can also produce leukoplakia.

Inflammatory skin diseases, squamous hyperplasia and vulvar intraepithelial
neoplasia can also present with leukoplakia.
2. Benign Tumors
a. Papillary Hidradenoma
Hidradenomas consist of tubular ducts lined by a single or double layer of
nonciliated columnar cells, with a layer of flattened myoepithelial cells underlying
556
the epithelium. These myoepithelial elements are characteristic of sweat glands and
sweat gland tumors. It is identical in appearance to intraductal papillomas of the
breast.

b. Condyloma Acuminatum
Condylomata acuminata are sexually transmitted, benign tumors that have a Koilocytotic atypia (nuclear
distinctly verrucous gross appearance. Condylomata are caused by HPV, principally
atypia and perinuclear vacuo
types 6 and 11. It is not considered to be precancerous lesions. lization) caused by HPV is con
sidered a viral cytopathic effect.
3. Premalignant and Malignant Neoplasms
i. Squamous cell carcinoma
It may be associated with high-risk HPV or with squamous cell hyperplasia and lichen Most (85%) of the malignant
sclerosus. tumors of vulva are squamous
Rare variants of squamous cell carcinoma include verrucous carcinomas, which are cell carcinomas.
fungating tumors resembling condyloma acuminatum, and basal cell carcinomas,
which are identical to their counterparts on the skin. Neither tumor is associated
with papillomaviruses.
ii. Pagets disease Concept

It manifests grossly as pruritic, red, crusted, sharply demarcated map-like areas. Pagets disease of the vulva

Histologically, it reveals single anaplastic tumor cells infiltrating the epidermis. (extramammary Pagets disease)
is similar to Pagets disease of
These cells are characterized by having clear spaces (halos) between them
the nipple except that 100% of
and the adjacent epithelial cells. These malignant cells stain positively with PAS cases of Pagets disease of the
or mucicarmine stains. nipple are associated with an

iii. Malignant melanoma underlying ductal carcinoma of
Malignant melanoma of the vulva may resemble Pagets disease, however, these the breast, while vulvar lesions

malignant cells stain positively with a melanin stain or S100 immunoperoxidase are most commonly confined
to the skin.
stain.
DISEASES F VAGINAO
1. Adenocarcinoma
The tumors are most often located on the anterior wall of the vagina, usually in the
upper third. Clear cell adenocarcinomas
These are often composed of vacuolated, glycogen-containing cells, hence the term are seen in young women
clear cell carcinoma. These cancers can also arise in the cervix. whose mothers had been
A probable precursor of the tumor is vaginal adenosis, a condition in which

treated with diethylstilbestrol
(DES) during pregnancy
glandular columnar epithelium of Mllerian type either appears beneath the
squamous epithelium or replaces it.
2. Embryonal rhabdomyosarcoma or sarcoma botryoides

It is an uncommon vaginal tumor most frequently found in infants and in children
younger than 5 years of age.
The tumor consists predominantly of malignant embryonal rhabdomyoblasts and is
Sarcoma botryoides or Em
bryonal rhabdomyosarcoma
thus a type of rhabdomyosarcoma.
These tumors have the appearance and consistency of grapelike clusters (hence the Tumor cells have tennis racket
appearance.
designation botryoides, meaning grapelike).
DISEASES F CERVIXO
1. Cervicitis
Acute cervicitis is characterized by acute inflammatory cells, erosion, and reactive
or reparative epithelial change.
Chronic cervicitis includes inflammation, usually mononuclear, with lymphocytes,
macrophages, and plasma cells.
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HSV is most strongly associated with epithelial ulcers (often with intranuclear
inclusions in epithelial cells) and a lymphocytic infiltrate, and C. trachomatis with
Risk factors for cervical neoplasia
lymphoid germinal centers and a prominent plasmacytic infiltrate. Epithelial
Early age at first intercourse spongiosis is associated with T. vaginalis infection.
Multiple sexual partners
Increased parity 2. Intraepithelial and Invasive Squamous Neoplasia
A male partner with multiple
previous sexual partners a. Cervical Intraepithelial Neoplasia (CIN)
Presence of a cancer-asso CIN can be divided into three grades; CIN I, CIN II and CIN III
ciated HPV
Exposure to oral contracep-
tives and nicotine CIN I: These lesions are on the extreme low end of the spectrum and are often indistinguishable
Genital infections (chlamydia) histologically from condylomata acuminata . These have a low rate of progression to cancer.
Persistent detection of a high CIN II: These consist of the appearance of atypical cells in the lower layers of the squamous
viral load of high-risk HPV. epithelium but nonetheless with persistent (but abnormal) differentiation toward the prickle and
Certain HLA and viral subtypes keratinizing cell layers.
CIN III: As the lesion evolves, there is progressive loss of differentiation accompanied by greater
atypia in more layers of the epithelium, until it is totally replaced by immature atypical cells,
exhibiting no surface differentiation (CIN III).

b. Squamous Cell Carcinoma
Invasive cervical carcinoma manifests in three somewhat distinctive patterns:
fungating (or exophytic), ulcerating, and infiltrative cancers. The most common
variant is the fungating tumor, which produces an obviously neoplastic mass
that projects above the surrounding mucosa.
About 95% of squamous car
cinomas are composed of rela On histologic examination, a small subset of tumors (less than 5%) are poorly
tively large cells, either kera differentiated small cell squamous or, more rarely, small cell undifferentiated
tinizing (well-differentiated) or carcinomas (neuroendocrine or oat cell carcinomas). The latter closely resemble
nonkeratinizing (moderately oat cell carcinomas of the lung and have an unusually poor prognosis owing

differentiated) patterns. to early spread by lymphatics and systemic spread. These tumors are also
frequently associated with a specific high-risk HPV, type 18.
Clear cell adenocarcinomas of the cervix in DES-exposed women are similar to those occurring in the
vagina.
OU U
DISEASES F TER S
1. Endometeritis
The endometrium and myometrium are relatively resistant to infections. Therefore,
inflammation of the endometrium (endometritis) is rare.
Acute endometritis is usually caused by bacterial infection following delivery or
miscarriage and is characterized by the presence of neutrophils in non-menstrual
Presence of benign endometrial endometrium.
glands surrounded by endo The histologic diagnosis of chronic endometritis depends on finding plasma cells
metrial stroma within the within the endometrium. All it takes is one plasma cell to make the diagnosis.
myometrium (conventionally Chronic endometritis may be seen in patients with intrauterine devices (IUDs),
atleast 2.5 mm below the endo pelvic inflammatory disease (PID), retained products of conception (postpartum),
myometrial junction), is called
adenomyosis. or tuberculosis.
Ectopic endometrial tissue 2. Endometriosis and Adenomyosis

outside of the uterus is called
Adenomyosis is thought to result from the abnormal down growth of the
endometriosis
endometrium into the myometrium. Symptoms produced by adenomyosis include
menorrhagia, colicky dysmenorrhea, dyspareunia, and pelvic pain.
Endometriosis is thought to possibly arise from metaplasia of celomic epithelium into
Cysts containing blood clots in endometrial tissue or implantation of normal fragments of menstrual endometrium
endometriosis are called as
chocolate cysts.
either via the fallopian tubes or via the blood vessels. Histologically, it reveals
endometrial glands, stroma, and hemosiderin pigment (from the cyclic bleeding).
558
Repeated cyclic bleeding in patients with endometriosis can lead to the formation of
cysts (3-5 cm diameter) that contain areas of new and old hemorrhages.
Sites of endometriosis include the ovary, uterine ligaments (associated with
dyspareunia), the rectovaginal pouch (associated with pain on defecation and low
back pain), the fallopian tubes (associated with peritubular adhesions, infertility,
and ectopic pregnancies), the urinary bladder (associated with hematuria), the GI Most common site of endo
tract (associated with pain, adhesions, bleeding and obstruction), and the vagina metriois is ovary.
(associated with bleeding).
3. Menstrual abnormalities
With normal menstruation about 30 to 40 ml of blood is lost. Amount greater than 80 ml lost
on a continued basis are considered to be abnormal.
Postmenopausal bleeding occurs
Menorrhagia refers to excessive bleeding at the time of menstruation, either in the number of
more than 1 year after the
days or the amount of blood. A submucosal leiomyoma could produce menorrhagia.
normal cessation of menses at
Metrorrhagia refers to bleeding that occurs at irregular intervals.
menopause.
Menometrorrhagia refers to excessive bleeding that occurs at irregular intervals. Causes of
metro or menometrorrhagia include cervical polyps, cervical carcinoma, endometrial carcinoma,
or exogenous estrogens.
Oligomenorrhea refers to infrequent bleeding that occurs at intervals greater than 35 days.
Causes include polycystic ovarian syndrome and too low a total body weight. Dysmenorrhea refers to pain-
Polymenorrhea refers to frequent, regular menses that are less than 22 days apart. It is ful menses. It is associated with
commonly associated with anovulatory cycles, which can occur at menarche.
increased levels of prostaglan-
din F in the menstrual fluid.
4. Dysfunctional uterine bleeding (D B) U

DUB is defined as abnormal uterine bleeding that is due to a functional abnormality rather
than an organic lesion of the uterus.
The three main categories of DUB are: DUB: Abnormal uterine blee
Anovulatory cycles (the most common form), ding due to a functional abno
rmality; NO organic lesion of
Inadequate luteal phase the uterus.
Irregular shedding.
Anovulatory cycles consist of persistence of the Graffian follicle without ovulation. This
results in continous and excess estrogen production without the normal postovulatory rise in
progesterone levels. With no progesterone production, no secretory endometrium is formed.
Instead, biopsies reveal proliferative endometrium with mild hyperplasia. The mucosa
Avovulatory cycles charac
teristically occur at menarche
becomes too thick and is sloughed off, resulting in the abnormal bleeding. and menopause; are also asso
ciated with polycystic ovary
If there is ovulation but the functioning of the corpus luteum is inadequate, then the levels of pro-
gesterone are decreased, resulting in asynchrony between the chronologic dates and the histologic

(Stein-Leventhal) syndrome.
appearance of the secretory endometrium. This is referred to as an inadequate luteal phase (luteal
phase defect).
The luteal phase defect is an important cause of infertility. Biopsies are usually performed
several days after the predicted time of ovulation. If the histologic dating of the endometrium
lags 4 or more days behind the chronologic date predicted by menstrual history, the diagnosis
of luteal phase defect can be made. Clinically, these patients exhibit low serum progesterone,
FSH, and LH levels.
Prolonged functioning of the corpus luteum (persistent luteal phase with continued
progesterone production) results in prolonged heavy bleeding at the time of menses.
Histologically, there is a combination of secretory glands mixed with proliferative glands
(irregular shedding). Clinically, these patients have regular periods, but the menstrual
bleeding is excessive and prolonged (lasting 10 to 14 days).
5. Endometrial hyperplasia (Endometrial Intraepithelial Neoplasia)
It is related to excess estrogens and is important clinically because of its relation to the
development of endometrial adenocarcinoma. The types of endometrial hyperplasia include
simple hyperplasia and complex hyperplasias.
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Note: The shift in gland morphology from benign to precancerous is often highlighted by a loss of
PTEN gene expression.
6. Endometrial carcinoma
Endometrial cancer risk factors Endometrial carcinomas that are associated with hyperplasia tend either to be well-
(Mnemonic: ENDOMETrial) differentiated, mimicking normal endometrial glands (endometrioid) in histologic
appearance, or to display altered differentiation (mucinous, tubal, squamous
E Elderly differentiation).
N Nulliparity
Endometrial cancer not associated with pre-existing hyperplasia are generally more
D Diabetes
O Obesity poorly differentiated, including tumors that resemble subtypes of ovarian carcinomas
M Menstrual irregularity (papillary serous carcinomas). Overall, these tumors have a poorer prognosis than
E Estrogen therapy estrogen-related cancers do. In contrast to endometrioid tumors, serous subtypes
T Tension (hypertension) infrequently display microsatellite instability and are linked to mutation of p53.
Histologically most of the endometrial carcinomas are adenocarcinomas.

If there are areas of squamous differentiation within these tumors, they are called adenoacanthomas.
If there are areas of malignant squamous differentiation, they are called adenosquamous
carcinomas.
7. Tumors of the Endometrium with Stromal Differentiation

a. Carcinosarcomas or malignant mixed Mllerian tumors
Carcinosarcomas consist of endometrial adenocarcinomas in which malignant
stromal differentiation takes place. The stroma tends to differentiate into a variety
of malignant mesodermal components, including muscle, cartilage, and even
osteoid. On histology, the tumors consist of adenocarcinoma mixed with the stromal
(sarcoma) elements Sarcomatous components may mimic extrauterine tissues (i.e.,
striated muscle cells, cartilage, adipose tissue, and bone).
b. Adenosarcomas
It consists of malignant appearing stroma, which coexists with benign but abnormally
shaped endometrial glands.
c. Stromal Tumors
The endometrial stroma occasionally gives rise to neoplasms that may resemble
normal stromal cells. Stromal neoplasms may be benign stromal nodules or
endometrial stromal sarcomas.
8. Tumors of Myometrium
Fibroids (Leiomyoma) of the uterus arise in the myometrium, submucosally,
subserosally, and mid-wall, both singly and several at a time. They are benign
smooth-muscle tumors that are sharply circumscribed, firm, gray-white, and
whorled on cut section.
Concept Their malignant counterpart, leiomyosarcoma of the uterus, is quite rare in the de
Mitoses are the most important novo state and arises even more rarely from an antecedent leiomyoma.
criteria in assessing malignancy
in smooth-muscle tumors of the
uterus. OO
DISEASES F VARIES
1. Stein-Leventhal syndrome/Polycystic ovarian disease (PC D) O

The symptoms of patients with this syndrome are related to increased androgen
production, which causes hirsutism, and decreased ovarian follicle maturation, which
PCOD patients typically have can lead to amenorrhea.
excess androgens (andros The cause of this syndrome is thought to be the abnormal secretion of gonadotropins
tenedione), increased estrogen
by the pituitary. Increased secretion of LH stimulates the thecal cells to secrete
levels, increased LH levels,

increased GnRH levels, and excess amounts of androgens, which are converted to estrone by the peripheral
aromatization of androgens by the adrenal gland. Excess estrogens in turn increase
decreased FSH levels (with a
high LH/FSH ratio). the levels of gonadotropin-releasing hormone (GnRH) but decrease the levels of
560
FSH. The GnRH increases the levels of LH, which then stimulate the thecal cells of
the ovary to secrete more androgens, and the hormonal cycle begins again.
The ovaries in these patients are enlarged and show thick capsules, hyperplastic ovarian stroma, and
numerous follicular cysts, which are lined by a hyperplastic theca interna. Because these patients Concept
do not ovulate, there is a markedly decreased number of corpora lutea, which, in turn, results in de- PCOD is associated with in-
creased progesterone levels. creased risk of developing en-

dometrial hyperplasia and en-
O
2. varian tumors dometrial carcinoma because of
the excess estrogen production.
Ovarian neoplasms may be divided into four main categories; epithelial tumors, sex cord-
stromal tumors, Germ cell tumors and metastases.
Mnemonic:
WHO classification of ovarian tumors
1. Surface Epithelial Tumors 2. Germ Cell Tumors

My Mucinous Doctor Dysgerminoma
Servant Serous Examined Endodermal Sinus tumor
Began Brenner The Teratoma
Experiencing Endometrioid Ovaries Ovarian choriocarcinoma
Cancer Clear
3. Sex cord Stromal Tumors 4. Metastatic
She Sertoli-Leydig Killed: Krukenberg

Felt Fibroma-thecoma
Grim Granulosa theca
A. Surface Epithelial Tumors

These are derived from the surface celomic epithelium, which embryonically gives rise to
the Mullerian epithelium. Therefore, these ovarian epithelial tumors may recapitulate the
histology of organs derived from the Mullerian epithelium.
a. Serous ovarian tumors
These are composed to ciliated columnar serous epithelial cells, which are similar to
the lining cells of the fallopian tubes.

They commonly involve the surface of ovary.
Surface epithelial tumors are

Bilaterality is common, occurring in 20% of benign cystadenomas, 30% of the most common tumors of
borderline tumors, and approximately 66% of cystadenocarcinomas. ovary.

Concentric calcifications (psammoma bodies) characterize serous tumors,
although they are not specific for neoplasia when they are found alone.
b. Mucinous ovarian tumors
Benign mucinous tumors are characterized by a lining of tall columnar epithelial Serous cystadenocarcinomas
cells with apical mucin and the absence of cilia, akin to benign cervical or intestinal account for approximately 40%
epithelia. In gross appearance, the mucinous tumors differ from the serous variety in of all cancers of the ovary and
several ways: are the most common mali
gnant ovarian tumors.
They are characterized by more cysts of variable size and a rarity of surface involvement.
They are less frequently bilateral.
Mucinous tumors tend to produce larger cystic masses, and some have been recorded
with weights of more than 25 kg.
Serous tumors are also the
One group of typically benign or borderline mucinous tumors arises in most common bilateral tumors
of the ovaries.
endometriosis and is termed Mllerian mucinous cystadenoma, resembling
endometrial or cervical epithelium. These tumors are uncommonly malignant.
The second, more common group includes tumors exhibiting abundant gland-
like or papillary growth with nuclear atypia and stratification and is strikingly
similar to tubular adenomas or villous adenomas of the intestine. These tumors
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are presumed precursors to most cystadenocarcinomas. Cystadenocarcinomas

contain more solid growth with conspicuous epithelial cell atypia and
stratification, loss of gland architecture, and necrosis, and are similar to colonic
cancer in appearance.

Pseudomyxoma peritonei refers to the formation of multiple mucinous masses
within the peritoneum. This condition results from the spread of mucinous
tumors, either from metastasis or rupture of an ovarian mucinous cyst.
c. Endometrioid ovarian tumors
These are composed of nonciliated columnar cells, which are similar to the epithelial
cells of the endocervical glands.
Most cases of Pseudomyxoma d. Clear cell carcinoma of the ovary
peritonei result from spread of It is similar histologically to clear cell carcinoma of the kidney, or more accurately,
a mucinous tumor located in the
the clear cell variant of endometrial adenocarcinoma or the glycogen-rich cells
appendix (mucocele).
associated with pregnancy.
e. Brenner tumor
It is similar to the transitional lining of the renal pelvis or bladder. This ovarian tumor is
associated with benign mucinous cystadenomas of the ovary. Most Brenner tumors
are benign, but borderline (proliferative Brenner tumor) and malignant counterparts
have been reported.
f. Cystadenofibromas
These are variants in which there is more pronounced proliferation of the fibrous
stroma that underlies the columnar lining epithelium. They may be composed of
mucinous, serous, endometrioid, and transitional (Brenner tumors) epithelium.
B. Sex-Cord Stromal Tumors

Examples of ovarian stromal tumors include thecomas, fibromas, granulosa cell tumors, and
Sertoli-Leydig cell tumors.
Thecomas are composed of spindle-shaped cells with vacuolated cytoplasm. They are
vacuolated because of steroid hormone (estrogen) production, which can be stained with
an Oil Red O stain.
Meigs syndrome = ovarian fib
roma + ascites + hydrothorax. Fibromas are also composed of spindle-shaped cells, but they do not produce steroid

(usually right sided). hormones and are Oil Red O-negative.
Granulosa cell tumor: These are the most common type of ovarian tumor that
Concept is composed of cells that stain positively with inhibin. Histologically, the cells may
form Call-Exner bodies, which are gland-like structures formed by the tumor cells
Granulosa cell tumor: Stain

positively with inhibin; Call- aligning themselves around a central space that is filled with acidophilic material.
The tumor cells may secrete estrogens and cause precocious sexual development in
Exner bodies are present.
girls or increase the risk for endometrial hyperplasia and carcinoma in women. Less
Sertoli-Leydig tumors: May
stain positively with inhibin, but commonly granulosa cell tumors can secrete androgens and produce masculinization.
Call-Exner bodies are not Sertoli-Leydig tumors (Androblastomas): These also may secrete androgens and
present. produce virilization in women. The tumor cells may stain positively with inhibin, but
Call-Exner bodies are not present. Granulosa cell tumors vary in their clinical behavior,
but they are considered to be potentially malignant.

Reinke crystalloids is a typical Hilus cell tumors (Pure Leydig cell tumor): The ovarian hilum normally contains
cytoplasmic structure charac clusters of polygonal cells arranged around vessels (hilar cells). Hilus cell tumors are
teristic of Leydig cells is usually rare tumors derived from these cells and are mostly unilateral. These are characterized
present. histologically by large lipid-laden cells with distinct borders. Typically, patients with
hilus cell tumors present with evidence of masculinization, hirsutism, voice changes,
and clitoral enlargement. True hilus cell tumors are almost always benign.
Small cell carcinoma of the ovary is the another tumor of possible stromal origin.
These malignant tumors occur predominantly in young women and may be
associated with hypercalcemia.
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C. Germ Cell Tumors Concept

Most consistent lab finding in
Hilus cell tumors is an elevated
17-ketosteroid excretion level
unresponsive to cortisone sup-
pression.
a. Teratomas: These are divided into three categories: mature (benign), immature
(malignant), monodermal or highly specialized.
Mature (Benign) Teratomas:

Cystic teratomas are usually found in young women during the active repro
ductive years.


Characteristically, they are unilocular cysts containing hair and cheesy sebaceous
material. Most benign teratomas are
Within the wall, it is common to find tooth structures and areas of calcification. cystic and are known as der
moid cysts; they arise from

On histologic examination, the cyst wall is composed of stratified squamous the ectodermal differentiation of
totipotential cells.
epithelium with underlying sebaceous glands, hair shafts, and other skin
adnexal structures.

In most cases, structures from other germ layers can be identified, such as
cartilage, bone, thyroid tissue, and other organoid formations. The karyotype of all benign ova

About 1% of the dermoids undergo malignant transformation of any one of the rian teratomas is 46, XX.
component elements (e.g., thyroid carcinoma, melanoma, but most commonly,
squamous cell carcinoma).

These tumors arise from an ovum after the first meiotic division.
Monodermal or Specialized Teratomas:

The most common of the specialized teratoma are struma ovarii and carcinoid.
They are always unilateral.
Struma ovarii is composed entirely of mature thyroid tissue. Interestingly, these
thyroidal neoplasms may hyperfunction, causing hyperthyroidism.
The ovarian carcinoid presumably arises from intestinal epithelium in a

teratoma and may result in carcinoid syndrome. Primary ovarian carcinoid can
be distinguished from metastatic intestinal carcinoid, the latter virtually always
bilateral.

Even more rare is the strumal carcinoid, a combination of struma ovarii and
carcinoid in the same ovary.
Immature Malignant Teratomas:

These are rare tumors that differ from benign teratomas in that the component
tissue resembles that observed in the fetus or embryo rather than in the adult.

The tumor is found chiefly in prepubertal adolescents and young women, the
mean age being 18 years.

On microscopic examination, there are varying amounts of immature tissue
differentiating toward cartilage, glands, bone, muscle, nerve, and others.
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b. Dysgerminoma

It is the ovarian counterpart of the seminoma of the testis.

Similar to the seminoma, it is composed of large vesicular cells having a clear
All dysgerminomas are malig
cytoplasm, well-defined cell boundaries, and centrally placed regular nuclei.
Most of these tumors have no endocrine function. A few produce elevated levels
nant.
of chorionic gonadotropin and may have syncytiotrophoblastic giant cells on
These neoplasms are extremely histologic examination.
radiosensitive.
These are usually unilateral (80% to 90%) and solid.

On histologic examination, the dysgerminoma cells are dispersed in sheets or
cords separated by scant fibrous stroma. As in the seminoma, the fibrous stroma
is infiltrated with mature lymphocytes and occasional granulomas.
Characteristic histologic fea
c. Endodermal Sinus (Yolk Sac) Tumor
ture of yolk sac tumor is a
glomerulus-like structure com It is the second most common malignant tumor of germ cell origin.
posed of a central blood vessel It is thought to be derived from differentiation of malignant germ cells toward
enveloped by germ cells within extraembryonic yolk sac structure.
a space lined by germ cells Similar to the yolk sac, the tumor is rich in -fetoprotein and 1-antitrypsin.
(Schiller-Duval body).
d. Choriocarcinoma
More commonly of placental origin, the choriocarcinoma, similar to the
endodermal sinus tumor, is an example of extraembryonic differentiation of
malignant germ cells.

Most ovarian choriocarcinomas exist in combination with other germ cell
tumors, and pure choriocarcinomas are extremely rare.
Concept
Like all choriocarcinomas, they elaborate high levels of chorionic gonadotropins
In contrast to choriocarcinomas that are sometimes helpful in establishing the diagnosis or detecting recurrences.
arising in placental tissue, those e. Other Germ Cell Tumors

arising in the ovary are generally
These include embryonal carcinoma (another highly malignant tumor of
unresponsive to chemotherapy primitive embryonal elements, histologically similar to tumors arising in the
and are often fatal. testes), polyembryoma (a malignant tumor containing so-called embryoid
bodies) and mixed germ cell tumors (containing various combinations of
dysgerminoma, teratoma, endodermal sinus tumor, and choriocarcinoma).
Gonadoblastoma is an uncommon tumor thought to be composed of germ cells and sex
cord-stroma derivatives. It occurs in individuals with abnormal sexual development and in
gonads of indeterminate nature. Eighty per cent of patients are phenotypic females, and 20%
are phenotypic males with undescended testicles and female internal secondary organs. On
microscopic examination, the tumor consists of nests of a mixture of germ cells and sex cord
derivatives resembling immature Sertoli and granulosa cells. A coexistent dysgerminoma
occurs in 50% of the cases. The prognosis is excellent.
D. Metastatic tumors of ovary

The most common metastatic tumors of the ovary are probably derived from
tumors of Mullerian origin: the uterus, fallopian tube, contralateral ovary, or pelvic
peritoneum.
The most common extramullerian primaries are the breast and gastrointestinal tract,
including colon, stomach, biliary tract, and pancreas.
Also included in this group are the rare cases of pseudomyxoma peritonei, derived
from appendiceal tumors.
Krukenberg tumors are often
Krukenberg tumor classically refers to a metastatic ovarian malignancy whose
found in both ovaries. primary site arose in the gastrointestinal tract or breast. Microscopically, they are
characterized by appearance of mucin-secreting signet-ring cells in the tissue of
the ovary; when the primary tumor is discovered, the same signet-ring cells are
typically found. Carcinomas of colon, appendix, and breast (mainly invasive lobular
Stomach is the primary site in carcinoma) are the next most common primary sites. Rare cases of Krukenberg
most of the cases of Krukenberg tumor originating from carcinomas of the gallbladder, biliary tract, pancreas, small
tumor. intestine, ampulla of Vater, cervix, and urinary bladder/urachus have been reported
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O
SEC NDARY AMEN RRHEA O Concept
Secondary amenorrhea refers to absent menses for 3 months in a woman who had previously Pregnancy can be diagnosed
had menses. Causes of secondary amenorrhea include pregnancy (the most common cause), by obtaining a clinical history
hypothalamic/pituitary abnormalities, ovarian disorders, and end organ (uterine) disease. along with a pregnancy test that
determines serum or urine beta-
The remainder of the disorders causing secondary amenorrhea can be differentiated by
human chorionic gonadotropin
examining gonadotropin (FSH and LH) levels along with the results of a progesterone (beta-hCG) levels.
challenge test.
Withdrawal bleeding following progesterone administration indicates that the
endometrial mucosa had been primed with estrogen, which, in turn, indicates that
the hypothalamus/pituitary axis and ovaries are normal.
Hypothalamic/pituitary disorders, which are characterized by decreased FSH
and LH levels, include functional gonadotropin deficiencies, such as can be seen
in patients with a weight loss syndrome. In these patients, markedly decreased
body weight (> 15% below ideal weight) causes decreased secretion of GnRH
from the hypothalamus. Decreased gonadotropin levels decrease estrogen levels,
which results in amenorrhea and an increased risk for osteoporosis. Because of the
decreased estrogen levels, progesterone challenge does not result in withdrawal
bleeding.
Ovarian conditions, such as surgical removal of the ovaries, would most likely
produce elevated gonadotropin levels due to the lack of negative feedback from
estrogen and progesterone. Because of the decreased estrogen levels, a progesterone
challenge would not result in withdrawal bleeding.
Uterine (end organ) disorders are characterized by normal FSH and LH levels. An Ashermans syndrome is a
example is Ashermans syndrome. (Describe alongside) A patient with Ashermans clinical condition caused by

syndrome would have no response to progesterone.
numerous aggressive dilatation
and curettage of the endo
metrium for menorrhagia lea
O O O
GESTATI NAL TR PH BLASTIC DISEASES ding to removal of the stratum
basalis. It is also associated with
The diseases in this category include; benign hydatidiform mole (partial and complete), absence of the glandular epithe
invasive mole, placental site trophoblastic tumor and choriocarcinoma. lium.
1. Hydatidiform mole: Both partial and complete, are composed of avascular, grape-like
structures that do not invade the myometrium. .
Differentiating features between partial and complete mole
In complete (classic) moles, all the chorionic villi are abnormal and fetal parts are not found. In
partial moles, only some of the villi are abnormal and fetal parts may be seen.
Complete moles have a 46, XX diploid pattern and arise from the paternal chromosomes of a
Concept
single sperm by a process called androgenesis. In contrast, partial moles have a triploid or a It is important to differentiate
tetraploid karyotype and arise from the fertilization of a single egg by two sperm. between partial and complete
Another way to differentiate these two disorders is to use immunostaining for p57, which is a gene mole these two disorders be-
cause about 2% of complete
that is paternally imprinted (inactivated). Because the complete mole arises only from paternal
chromosomes, immunostaining for p57 will be negative. moles may develop into chrio
carcinoma, but partial moles are
2. Invasive moles: This is defined as a mole that penetrates and may even perforate rarely followed by malignancy
the uterine wall. There is invasion of the myometrium by hydropic chorionic villi,
accompanied by proliferation of both cytotrophoblast and syncytiotrophoblast.
Hydropic villi may embolize to distant sites, such as lungs and brain, but do not
grow in these organs as true metastases.

3. Placental site trophoblastic tumor: In contrast to syncytial cytotrophoblast, which is
present on the chorionic villi, intermediate trophoblast is found in the implantation
site and placental membranes. Intermediate trophoblasts may give rise to placental
site trophoblastic tumors (PSTTs). PSTTs comprise less than 2% of gestational
trophoblastic neoplasms and present as neoplastic polygonal cells infiltrating the
endomyometrium. PSTTs may be preceded by a normal pregnancy (one-half),
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spontaneous abortion (one-sixth), or hydatidiform mole (one-fifth). Distinction of

PSTTs from normal exaggerated placental implantation site trophoblast may be
difficult and can be achieved by using biomarkers (Mel-Cam and Ki-67) that detect
increased proliferation in the trophoblastic cells.
4. Gestational choriocarcinomas: These are composed of malignant proliferations of
both cytotrophoblasts and syncytiotrophoblasts without the formation of villi, can
arise from either normal or abnormal pregnancies: 50% arise in hydatidiform moles,
25% in cases of previous abortion, 22% in normal pregnancies, and the rest in ectopic
pregnancies or teratomas. Both hydatidiform moles and choriocarcinomas have
high levels of human chorionic gonadotropin (hCG); the levels are extremely high in
choriocarcinoma unless considerable tumor necrosis is present.
BREAST
Pain (mastalgia or mastodynia) is the most common breast symptom.

Discrete palpable masses are the second most common breast symptom. A breast mass usually
does not become palpable until it is about 2 cm in diameter. Approximately 50% of carcinomas
arise in the upper outer quadrant, 10% in each of the remaining quadrants, and about 20% in
the central or subareolar region.
Nipple discharge is a less common presenting symptom but is of concern when it is spontaneous
and unilateral. Bloody or serous discharges are most commonly associated with benign
lesions but, rarely, can be due to a malignancy. The most common etiologies for discharge
are a solitary large duct papilloma, cysts, or carcinoma.
The principal mammographic signs of breast carcinoma are densities and calcifications:
Densities. Most neoplasms grow as solid masses and are radiologically denser than the
intermingled connective and adipose tissue of the normal breast. Mammography can detect
DCIS is the most common masses before they become palpable. The most common lesions that are detected as densities

malignancy associated with are invasive carcinomas, fibroadenomas, and cysts. Ductal carcinoma in situ (DCIS, or carcinoma
calcifications limited to the ductal system) rarely presents as a density.
Calcifications. Calcifications are associated with secretory material, necrotic debris, and hyalinized
stroma. Calcifications associated with malignancy are commonly small, irregular, numerous, and
clustered or linear and branching.
INFLAMMATI NS O
Acute Mastitis
Acute mastitis occuring during
lactation is usually caused by Almost all cases of acute mastitis occur during lactation usually caused by Staphylococcus
Staphylococcus aureus. aureus.
Periductal Mastitis/Zuska disease

This condition is also known by the names of recurrent subareolar abscess or squamous metaplasia of
More than 90% of patients lactiferous ducts. Both women, as well as men, present with a painful erythematous subareolar mass.
with periductal mastitis are The main histologic feature is keratinizing squamous epithelium extending to an abnormal depth into
smokers. the orifices of the nipple ducts.
Mammary Duct Ectasia

This disorder tends to occur in the fifth or sixth decade of life, usually in multiparous women,
and, unlike periductal mastitis, is not associated with cigarette smoking.
Patients present with a poorly defined palpable periareolar mass, sometimes with skin
retraction, often accompanied by thick, white nipple secretions. This lesion is characterized
chiefly by dilation of ducts, inspissation of breast secretions, and a marked periductal and
interstitial chronic granulomatous inflammatory reaction.
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Fat Necrosis
Fat necrosis can present as a painless palpable mass, skin thickening or retraction, a
mammographic density, or mammographic calcifications.
BENIGN EPITHELIAL LESI NS O

Nonproliferative Breast Changes (Fibrocystic Changes)
Three principal patterns of morphologic change:

1. Cyst formation, often with apocrine metaplasia;
2. Fibrosis; and
3. Adenosis
Cysts: Small cysts form by the dilation and unfolding of lobules. When cystic lobules coalesce,
larger cysts are formed. Unopened cysts are brown to blue (blue-dome cysts) owing to the Concept
contained semitranslucent, turbid fluid. Cysts are lined either by a flattened atrophic epithelium
or by cells altered by apocrine metaplasia. Metaplastic cells have an abundant granular, Milk of calcium is a term
radiologists use to describe
eosinophilic cytoplasm, with round nuclei, resembling the apocrine epithelium of sweat glands. calcifications in large cysts that
Fibrosis: Cysts frequently rupture, with release of secretory material into the adjacent stroma. look as if they are lining the
The resulting chronic inflammation and fibrous scarring contribute to the palpable firmness bottom of a rounded cyst on
of the breast. mammography.
Adenosis: Adenosis is defined as an increase in the number of acini per lobule.
The acini are often enlarged (blunt duct adenosis) and are not distorted as is seen in sclerosing
adenosis.
Proliferative Breast Disease without Atypia

This group of disorders is characterized by proliferation of ductal epithelium and/or stroma
without cellular abnormalities suggestive of malignancy. The following entities are included
in this category: (1) moderate or florid epithelial hyperplasia, (2) sclerosing adenosis,
(3) complex sclerosing lesions, (4) papillomas, and (5) fibroadenoma with complex features.
Epithelial Hyperplasia
In the normal breast, only myoepithelial cells and a single layer of luminal cells are present above
the basement membrane. Epithelial hyperplasia is defined by the presence of more than two cell
layers.
Sclerosing Adenosis
The number of acini per terminal duct is increased to at least twice the number found in uninvolved
lobules. The normal lobular arrangement is maintained. The acini are compressed and distorted in
the central portions of the lesion but characteristically dilated at the periphery. Myoepithelial cells
are usually prominent.
Complex Sclerosing Lesion (Radial Scar)
Radial scars are stellate lesions characterized by a central nidus of entrapped glands in a
hyalinized stroma.
Papillomas
Papillomas are composed of multiple branching fibrovascular cores, each having a connective
tissue axis lined by luminal and myoepithelial cells. Growth occurs within a dilated duct.
Small duct papillomas have been shown to be a component of proliferative breast disease and
increase the risk of subsequent carcinoma.
Proliferative Breast Disease with Atypia

Proliferative disease with atypia includes atypical ductal hyperplasia (ADH) and atypical lobular
hyperplasia (ALH). Concept
ADH is recognized by its histologic resemblance to ductal carcinoma in situ, including a Atypical hyperplasia is a cellular
monomorphic cell population, regular cell placement, and round lumina. However, the lesions are proliferation resembling ductal
characteristically limited in extent, and the cells are not completely monomorphic in type or they carcinoma in situ (DCIS) or
lobular carcinoma in situ (LCIS)
fail to completely fill ductal spaces.
but lacking sufficient qualitative
ALH refers to a proliferation of cells identical to those of LCIS (described later), but the cells do
or quantitative features for a
not fill or distend more than 50% of the acini within a lobule.
diagnosis of carcinoma in situ.
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Non-proliferative changes do not increase the risk of cancer. Proliferative disease is associated
with a mild increase in risk. Proliferative disease with atypia (ADH and ALH) confers a
moderate increase in risk.
O O
CARCIN MA F THE BREAST
Carcinoma is the most common malignancy of the breast, and breast cancer is the most common non-
Breast cancer is the most skin malignancy in women.
common malignancy in women
in India O O
PR GN STIC FACT RS O
Major
Invasive carcinoma has worse prognosis than in-situ carcinoma
Distant metastasis indicates bad prognosis.
Axillary lymph node involvement is associated with worse prognosis.
Axillary lymph node status is Tumor Size: Less than 1 cm good prognosis, more than 2 cm bad prognosis.
the most important prognostic Local invasion into skeletal muscle carries poor prognosis.
factor for invasive carcinoma Inflammatory carcinoma has poor prognosis.
in the absence of distant
metastases. Minor
Histological type: Invasive ductal carcinoma (no special type; NST) carries poor prognosis.
Special types have good prognosis except medullary.
Nottingham histological score (Scarff-Bloom-Richardson grade): Grade 1 good prognosis,
grade 3 poor
Estrogen and Progesterone receptor positivity indicates good response to anti-estrogen
Triple assessment in breast
therapy.
cancer = clinical examination+
radiological examination
HER2/neu overexpression: Poor prognosis
Lymphovascular invasion: poor prognosis
(mammography)+FNAC.
High proliferative rate indicates worse prognosis
Aneuploidy indicates bad prognosis
The major risk factors for the development of breast cancer are hormonal and genetic (family
history). Breast carcinomas can, therefore, be divided into sporadic cases, possibly related to
hormonal exposure, and hereditary cases, associated with family history or germ-line mutations.
Hereditary Breast Cancer

Mutated BRCA1 also markedly increases the risk of developing ovarian carcinoma, which
is as high as 20 to 40%. BRCA2 confers a smaller risk for ovarian carcinoma (10 to 20%) but
is associated more frequently with male breast cancer. BRCA1 and BRCA2 carriers are also
susceptible to other cancers, such as colon, prostate, and pancreas, but to a lesser extent. BRCA1-
associated breast cancers are commonly poorly differentiated, have medullary features and
In comparison to BRCA1, do not express hormone receptors or HER2/neu (so called, triple negative phenotype). Their
BRCA2 is associated more
gene profile signature is similar to basal-like breast cancers. These are frequently associated
frequently with male breast
cancer. with loss of inactive X-chromosome and reduplication of active X, resulting in absence of
Barr body. BRCA2 are also poorly differentiated but are more commonly estrogen receptor
positive.
Sporadic Breast Cancer

The major risk factors for sporadic breast cancer are related to hormone exposure: gender, age at
menarche and menopause, reproductive history, breast-feeding, and exogenous estrogens.
The majority of these cancers occur in postmenopausal women and overexpress estrogen
receptors (ER).
O O
CLASSIFICATI N F BREAST CARCIN MA O
Almost all breast malignancies are adenocarcinomas, all other types (i.e., squamous cell carci
nomas, phyllodes tumors, sarcomas, and lymphomas) making up fewer than 5% of the total.
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Carcinomas are divided into in situ carcinomas and invasive carcinomas.

Noninvasive carcinomas (carinoma in situ) may be located within the ducts (intraductal
carcinoma) or within the lobules (lobular carcinoma in situ). There are several variants of
intraductal carcinoma, including comedocarcinoma, cribriform carcinoma, and intraductal
papillary carcinoma. Comedocarcinoma grows as a solid intraductal sheet of cells with a
central area of necrosis, that commonly undergoes calcification. It is frequently associated
with the erb B2/neu oncogene and a poor prognosis. Cribriform carcinoma is characterized
by round, ductlike structures within the solid intraductal sheet of epithelial cells, while
intraductal papillary carcinoma has a predominant papillary pattern.
Infiltration of the nipple by large cells with clear cytoplasm is diagnostic of Pagets
disease. These cells are usually found both singly and in small clusters in the epidermis. Concept
Pagets disease is always associated with (in fact, it begins with) an underlying intraductal Paget cells may resemble the
carcinoma that extends to infiltrate the skin of nipple and areola. Paget cells may resemble cells of superficial spreading
the cells of superficial spreading melanoma, but they are PAS-positive and diastase-resistant melanoma, but they are PAS-
positive and diastase-resistant
(mucopolysaccharide-or mucin-positive), unlike melanoma cells.
(mucopolysaccharide-or mucin-
positive), unlike melanoma cells.
INVASIVE (INFILTRATING) CARCIN MA O
Invasive breast carcinoma is divided into two main types:
No- special type carcinoma [Intraductal]
Intraductal carcinoma is most

Special carcinoma common carcinoma of breast
Lobular and carries poor prognosis.
Cribriform
Colloid

Medullary
Special type carcinomas carry
Papillary good prognosis but inflammatory
Metaplastic carcinoma has poor prognosis.
Invasive carcinomas of no special type include the majority of carcinomas (70 to 80%) that
cannot be classified as any other subtype.
Invasive Carcinoma, No Special Type (NST; Invasive Ductal Carcinoma)

On gross examination, most carcinomas are firm to hard and have an irregular border.
Within the center of the carcinoma, there are small pinpoint foci or streaks of chalky white
elastotic stroma and occasionally small foci of calcification. There is a characteristic grating
sound (similar to cutting a water chestnut) when cut or scraped. Five major patterns of gene
expression in the NST group are noted:
Luminal A (40-55%): ER positive and HER2/neu negative. These are generally slow growing and
respond to hormonal treatments.
Luminal B (15-20%): Triple positive cancers i.e. ER, PR and HER2/neu positive. These are of
higher grade and more likely to have lymph node metastasis.
Normal breast-like (6-10%): Well-differentiated ER positive and HER2/neu negative.
Basal-like (13-25%): Triple negative cancers i.e. ER, PR and HER2/neu negative. Express
markers of typical myoepithelial cells (e.g. basal keratins, P-cadherin, p63 or laminin), progenitor
cells or putative stem cells (cytokeratin 5 and 6). Members of this group include medullary
carcinoma, metaplastic carcinoma (e.g. spindle cell carcinoma or matrix producing carcinoma)
and carcinomas with a central fibrotic focus. Many cancers in women with BRCA-1 mutations are
of this type.
HER2 positive (7-12%): ER negative but overexpress HER2/neu. In more than 90%, it is due to
amplification of the segment of DNA on chromosome 17q21.
Lobular Carcinoma
Lobular carcinoma (invasive)
Lobular carcinoma (invasive) of breast is one of the very few carcinomas which are seen of breast occurs bilaterally.
bilaterally. Histologic hallmark is the presence of dyscohesive infiltrating tumor cells, often
arranged in single file or in loose clusters or sheets. Tubule formation is absent. Signet ring
cells containing intracytoplasmic mucin droplets are common. It metastasizes frequently
to peritoneum, retroperitoneum, leptomeninges, GIT and ovaries. The incidence of this
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carcinoma is increasing among postmenopausal females presumably because of increasing

Concept use of HRT.
Both lobular carcinoma of breast
and signet ring carcinoma of GIT Medullary Carcinoma
are characterized by the loss of
E-cadherin. The tumor has a soft, fleshy consistency (medulla is Latin for marrow) and is well-
circumscribed. The carcinoma is characterized by
Solid, syncytium-like sheets (occupying more than 75% of the tumor) of large cells with vesicular,
pleomorphic nuclei, containing prominent nucleoli
Frequent mitotic figures
A moderate to marked lymphoplasmacytic infiltrate surrounding and within the tumor
A pushing (non-infiltrative) border.
Medullary carcinomas have slightly better prognosis than do NST carcinomas, despite
the almost universal presence of poor prognostic factors. These show overexpression of
E-cadherin and basal like gene expression.
Mucinous (Colloid) Carcinoma

The tumor cells are seen as clusters and small islands of cells within large lakes of mucin that
push into the adjacent stroma.
Tubular Carcinoma
These tumors consist exclusively of well-formed tubules. However, a myoepithelial cell layer
is absent, and tumor cells are in direct contact with stroma.
Invasive Papillary Carcinoma

Invasive carcinomas with a papillary architecture are rare and represent 1% or fewer of all
invasive cancers. Papillary architecture is more commonly seen in DCIS.
Metaplastic Carcinoma
Metaplastic carcinoma includes a wide variety of rare types of breast cancer (<1% of all
cases), including conventional adenocarcinomas with a chondroid stroma, squamous cell
carcinomas, and carcinomas with a prominent spindle cell component that might be difficult
to distinguish from sarcomas. Some of these carcinomas express genes in common with
myoepithelial cells and likely to arise from this cell type.
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male genital tract 9. Gleasons classification is used for: (UP 2008)
(a) Carcinoma breast
1. Alpha fetoprotein is Not raised in which testicular (b) Carcinoma prostate
tumors? (AI 2010) (c) Carcinoma pancreas
(a) Choriocarcinoma (d) Carcinoma rectum
(b) Teratocarcinoma 10. Which of the following is not a malignant tumor of
(c) Yolk sac tumor germ cell origin? (AP 2002)
(d) Embryonal cell carcinoma (a) Mature teratoma
2. Which one of the following is not used as a tumor mar (b) Choriocarcinoma
ker in testicular tumors? (AI 2005) (DNB 2007) (c) Dysgerminoma
(a) AFP (b) LDH (Kolkata 2008) (d) Embryonal carcinoma
(c) hCG (d) CEA 11. Metastasis is least common with: (AP 2007)
3. All of the following statements about Gleason grading (a) Embryonal cell carcinoma
system are true except: (AIIMS Nov 2008) (b) Endodermal sinus tumor
(a) Score range from 1 to 10 (c) Teratocarcinoma
(b) High score is associated with bad prognosis (d) Spermatocytic seminoma

(c)
(d)
Helps in grading of tumor
Helps decide treatment modality
12. A 25-year-old man, Ramesh presents with a testicular mass
and is found to have high serum levels of -fetoprotein
4. Infertility is a common feature in Sertoli cell only (AFP). Microscopic examination of a biopsy from this
rome because:
synd (AIIMS May 2003) mass reveals sheets of undifferentiated cells along with
(a) Too many Sertoli cells inhibit spermatogenesis via focal primitive glandular differentiation. The tumor
inhibin cells have large and hyperchromatic nuclei. Further
(b) Proper blood testis barrier is not established workup fails to reveal the presence of any metastatic
(c) There is no germ cell in this condition disease as the tumor is confined within the testis. Based
(d) Sufficient numbers of spermatozoa are not produced on all of these findings, which of the following best
characterizes this tumor?
5. Predisposing factors for germ cell tumor are: Tumor Aggressiveness Grade Stage
(a) Cryptorchidism (PGI Dec 2002) (a) Benign Low Low
(b) Testicular feminizing syndrome (b) Benign Low High
(c) Klinefelters syndrome (c) Malignant Low Low
(d) Smoking (d) Malignant High Low
(e) Right side more common than left side. (e) Malignant High High
6. In the testis intratubular germ cell neoplasia is seen in 13. In which of the following respects do a seminoma
all, except: (Delhi 2009 RP) involving the testis and a dysgerminoma involving the
(a) Seminomas ovary differ most significantly?
(b) Spermatocytic seminoma (a) Most common age of presentation
(c) Yolk sac tumor of testis (b) Number of mitoses
(d) Embryonal carcinoma (c) Potential to contain foci of more aggressive tumors
7. Condyloma are mostly caused by HPV types: (d) Ultrastructural appearance
(a) 11 and 13 (Delhi PG-2006) 14. A 10-year-old child develops a testicular mass and
(b) 6 and 11 undergoes orchiectomy. On cut section, the mass shows
(c) 6 and 13 a variety of appearances and colors. Histologically,
(d) 30 and 33 many different tissues are seen, including cartilage,
8. Which one of the following is not used as a tumor mar
thyroid, and neural tissue. A small focus of clear-
ker in testicular tumors? (DNB- 2007) cut squamous cell carcinoma is seen. Which of the
(a) AFP (b) LDH following is the most appropriate classification for this
(c) HCG (d) CEA tumor?
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(a) Dermoid cyst 19. An ovarian neoplasm in a 14-year old girl is most likely
(b) Teratoma with malignant transformation to be: (Delhi 2009)
(c) Immature teratoma (a) Germ cell tumor
(d) Solid mature teratoma (b) Epithelial tumor
(c) Sertoli-Leydig cell tumor
Most Recent Questions (d) Granulosa cell tumor
14.1. Which one of the following is not used as a tumor 20. The incidence of
approximately:
bilaterality in a dermoid cyst is
(Delhi 2009)
marker in testicular tumors?
(a) AFP (a) 10% (b) 30%
(b) LDH (c) 50% (d) 70%
(c) HCG 21. The risk of sarcoma developing in a fibroid uterus is
(d) CEA approximately: (Delhi 2009)

14.2. Benign hyperplasia of prostate first develops in: (a) < 1%
(c) 30%
(b) 10%
(d) 50%
(a) Central zone
(b) Peripharal zone
(c) Periurethral transition zone
22. Uterine leiomyoma is least likely to undergo:
(a) Malignant change (Delhi PG-2005)
(d) Any of the above (b) Hyaline change
14.3. The commonest site for extragonadal germ cell tumour (c)
(d)
Calcification
Red degeneration
is:
(a)
(b)
Pineal gland
Mediastinum
23. Carcino-sarcoma occurs in: (UP 2003)
(a) Uterus (b) Liver
(c) Retroperitoneum (c) Breast (d) Lungs
(d) Sacrococyygeal region
24. Schiller Duval bodies are seen in: (UP 2005, 2007)
(a) Teratoma
female genital tract (b) Seminoma
(c) Yolk-Sac tumor
15. The cytogenicity of solid tumors is not easily assessed (d) Choriocarcinoma
especially in carcinoma cervix because
(a) Metaphase is distinct (AIIMS Nov 2010) 25. Call-Exner bodies are seen in: (UP 2007)
(b) Due to contamination with infectious agents (a) Mature teratoma
(c) High mitotic rate (b) Endodermal sinus tumor
(d) Deficient tissue sample (c) Granulosa cell tumor
(d) Sertoli Leydig cell tumor
16. With regard to the malignant behavior of
leiomyosarcoma, the most important criterion is: 26. Hormone produced by endodermal sinus tumor is
(a) Blood vessel penetration by tumor cells (AI 2006) (a) AFP (RJ 2002)
(b) Tumor cells in lymphatic channels (b) Alpha1 antitrypsin
(c) Lymphocyte infiltration (c) Both
(d) The number of mitoses per high power field (d) hCG
17. All are true about polycystic ovarian disease except: 27. Choriocarcinoma is characterized by all except:
(a) Persistently elevated LH (AIIMS Nov 2008) (a) Primarily trophoblastic tumor (AP 2004)
(b) Increased LH/FSH ratio (b) It can occur following hydatidiform mole
(c) Increased DHEAS (c) Villi present
(d) Increased prolactin (d) It can metastasize to lungs
18. Sections from a solid-cystic unilateral ovarian tumor in 28. Call-Exner bodies are characteristic feature of (AP 2005)
a 30-year old female show a tumor composed of diffuse (a) Granulosa theca cell tumor
sheets of small cells with doubtful nuclear grooving (b) Brenner tumor
and scanty cytoplasm. No Call-Exner bodies are seen. (c) Dysgerminoma
The ideal immunohistochemistry panel would include:
(d) Endodermal sinus tumor
(AIIMS May 2006)
(a) Vimentin, epithelial membrane antigen, inhibin, CD99 29. Tennis Racquet cells are seen in: (AP 2007)
(b) Desmin, S-100 protein, smooth muscle antigen, (a) Rhabdomyoma
cytokeratin (b) Rhabdomyosarcoma
(c) Chromogranin, CD45, CD99, CD20 (c) Histiocytoma
(d) CD3, Chromogranin, CD 45, Synaptophysin (d) Eosinophilic granuloma
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30. A 30-year-old woman Shagun visits her gynecologist for (a) Apocrine DCIS
a surgery. After laparotomy, a mass is removed which (b) Neuroendocrine DCIS
on microscopic examination demonstrates a cystic (c) Will-differentiated DCIS
cavity filled with hair and keratin debris, and the wall (d) Comedo DCIS
contains skin, adnexal tissue, thyroid tissue, and neural
tissue. All of the tissues are similar to those normally
35. BRCA 1 gene is located on: (AIIMS Nov 2008)
(a) Chromosome 13 (b) Chromosome 11
found, and no malignant changes are seen. Which of the (c) Chromosome 17 (d) Chromosome 22
following is the most likely diagnosis?
(a) Immature teratoma 36. Increased susceptibility to breast cancer is likely to be
associated with a mutation in the following gene:
(b) Leiomyoma
(a) p53 (b) BRCA-1 (AIIMS Nov 2004)
(c) Leiomyosarcoma
(c) Retinoblastoma (Rb) (d) H-Ras
(d) Mature teratoma
31. Bilateral ovarian masses are identified on pelvic exami 37. Ainfemale patient presented with a firm mass of 2 2 cms
the upper outer quadrant of the breast. She gives a
nation of a 40-year-old woman for which she undergoes family history of ovarian carcinoma. The investigation
total abdominal hysterectomy. Pathologic examination that needs to be done to assess for mutations is:
demonstrates papillary carcinoma producing serous (a) p53 (b) BRCA-2 (AIIMS May 2002)
fluid. Which of the following tumor markers would be (c) Her 2/Neu gene (d) C-myc gene
most useful in monitoring for recurrence?
(a) Alpha-fetoprotein 38. Bilateral breast carcinoma is: (PGI June 2002)
(a) Scirrhous carcinoma (b) Medullary carcinoma
(b) Bombesin
(c) Lobular carcinoma (d) Ductal carcinoma
(c) CA-125
(e) Pagets carcinoma
(d) PSA
32. A patient with chronic pelvic pain undergoes a hyste 39. Rare histological variants of carcinoma breast with
better prognosis include all except: (Delhi 2009)
rectomy. The resected uterus is filled with nodules (a) Colloid carcinoma

composed of benign smooth muscle cells. Which of the (b) Medullary carcinoma
following terms best describes these nodules? (c) Inflammatory carcinoma
(a) Angiosarcoma (b) Leiomyoma (d) Tubular carcinoma
(c) Leiomyosarcoma (d) Rhabdomyoma
40. Tumor marker useful in the diagnosis of the cancer of
the breast is: (Karnataka 2005)
(a) CEA (b) AFP

32.1. An adenofibroma of the ovary in which the epithelial (c) CA-125 (d) CA-15-3
component consists of the nests of transitional cells is 41. Histologic hallmark of Pagets disease of nipple is:
called: (a) Caseous necrosis (Karnataka 2004)
(a) Thecoma (b) Infiltration of the epidermis by malignant cells
(b) Brenner tumour (c) Atypical lobular hyperplasia
(c) Serous cystadenoma (d) Desmoplasia
(d) Granulose cell tumor
42. BRCA-1 gene lies on chromosome: (DNB- 2008)

32.2. Endodermal sinus tumor is characterized by: (a) 17 (b) 18
(a) Call Exner body (c) 20 (d) 21
(b) Psammoma body
43. Commonest carcinoma of the breast with multifocal
(c) Schiller duval body
(d) Homer wright body
origin is: (UP 2001)
(a) Scirrhous carcinoma (b) Adenocystic carcinoma
(c) Lobular carcinoma (d) Ductal carcinoma
breast tissue 44. Which of the following breast tumors is bilateral?
(a) Colloid carcinoma (UP 2003)
33. Lesions affecting the teminal duct lobulat unit (TDLU) (b) Invasive ductal carcinoma
in breast are all except (DPG 2011) (c) Invasive lobular carcinoma
(a) Nipple adenoma (d) Medullary carcinoma
(b) Blunt duct adenosis
(c) Intraductal papilloma
45. Indian file pattern is seen in histopathological exami
nation of: (RJ 2006)
(d) Fibroadenoma
(a) Infiltrating duct carcinoma
34. The type of mammary ductal carcinoma in situ (DCIS) (b) Fibroadenoma
most likely to result in a palpable abnormality in the (c) Fibro carcinoma
breast is: (AI 2006) (d) Lobular carcinoma
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46. Fleshy, soft lymphatic infiltration of skin in breast C onceptual QUESTIONS

cancer appears as: (TN 1996) (AP 2001)
(a) Puckering (b) Peau d orange
(c) Cancer encurasse (d) All of the above 1-3. Will have two statements, assertion and reason. Read
both of them carefully and answer according to these
Most Recent Questions options.
(a) Both assertion and reason are true and reason is cor-
46.1. BRCA-1 gene lies on chromosome: rect explanation of assertion.
(a) 17 (b) 18 (b) Both assertion and reason are true and reason is not
(c) 20 (d) 21 the correct explanation of assertion.
46.2. A 54-year-old female Shanti presents for an annual (c) Assertion is true and reason is false.
(d) Both assertion and reason are false.
exam. Her right breast is swollen, red, and tender. The
physician palpates a firm area in the breast and suspects 1. Assertion: Stromal cells are responsible for androgen
inflammatory breast cancer. Which of the following dependent prostatic growth
best describes the histological changes observed in this Reason: Stromal cells have 5 reductase activity which
disorder? produces testosterone in prostate.
(a) Acute inflammation in breast carcinoma 2. Assertion: Struma ovarii is mature teratoma
(b) Chronic inflammation in breast carcinoma
(c) Dermal lymphatic invasion by cancer cells
Reason: It is responsible for production of the
gonadotropins
(d) Epidermal invasion by cancer cells 3. Assertion: Seminoma is germ cell tumor with good

46.3. Pagets disease of the nipple is: prognosis.
(a) Infection (b) Dermatisis Reason: The tumor cells rarely have areas of necrosis
(c) Neoplasia (d) Hypopigmentation and hemorrhage
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E xplanations
1. Ans. (a) Choriocarcinoma (Ref: Robbins 9/e p978, 8th/327, 989-991, 7th/339)
AFP is a marker of hepatocellular cancer and non-seminomatous germ cell tumors of testes.
Non-seminomatous germ cell tumors may be embryonal carcinoma, yolk sac tumors, choriocarcinoma or teratoma.
Embryonal cell carcinomas and Yolk sac tumor have elevated AFP levels.
Dorlands dictionary 27th edition writes that Teratocarcinoma refers to a germ cell tumor that is a mixture of teratoma
with embryonal carcinoma, or with choriocarcinoma, or with both. So, it may be having elevated levels of AFP.
Choriocarcinomas have elevated levels of HCG which can be readily demonstrated in the cytoplasm of
syncytiotrophoblastic cells.
2. Ans. (d) CEA (Ref: Robbins 7th/1045, 9/e p979, Harrison 17th/602)
Biological markers of germ cell testicular tumors include AFP, hCG, placental alkaline phosphatase, placental
lactogen and LDH. AFP, hCG and LDH are widely used clinically and have proved to be valuable in the diagnosis
and management of testicular cancer.
CEA is an onco-fetal antigen and may be used as a tumor marker in adenocarcinoma of colon, pancreas, lung, breast
and ovary. It is however not used as marker for Germ cell tumors.
About 70% patients with non-seminomatous germ cell tumors (NSGCT) show increased concentration of AFP or
hCG. Latter may also be elevated in 10% of seminomas. But AFP is never increased in seminoma.
The presence of increased AFP level in a patient whose tumor shows only seminoma indicates that an occult NSGCT component

exists.
LDH levels are not as specific as AFP or hCG but are increased in 50-60% patient with NSGCT and up to 80% patients
with advanced seminoma.
AFP, hCG and LDH levels should be determined before and after orchiectomy. Reappearance of these markers or
failure to decline according to predicted half life is an indication of persistent or recurrent tumor.
3. Ans. (a) Score range from 1 to 10 (Ref: Schwartz 8th/1216, Robbins 9/e 987)
A Gleason score is given to prostate cancer based upon its microscopic appearance. Cancers with a higher Gleason
score are more aggressive and have a worse prognosis. Most tumors contain more than 1 pattern.
The pathologist assigns a grade to the most common tumor, and a second grade to the next most common tumor. The
two grades are added together to get a Gleason score. For example, if the most common tumor was grade 3, and the
next most common tumor was grade 4, the Gleason score would be 3 + 4 = 7.
The Gleason grade ranges from 1 to 5, with 5 having the worst prognosis. The Gleason score ranges from 2 to 10, with
10 having the worst prognosis.
It should be noted that for Gleason score 7, a Gleason 4+3 is a more aggressive cancer than a Gleason 3+4. Also, there
is not really any difference between the aggressiveness of a Gleason score 9 or 10 tumour.
Gleason scores are associated with the following features:
Grade 1: The cancerous prostate closely resembles normal prostate tissue. The glands are small, well-formed,
and closely packed
Grade 2: The tissue still has well-formed glands, but they are larger and have more tissue between them.
Grade 3: The tissue still has recognizable glands, but the cells are darker. At high magnification, some of these
cells have left the glands and are beginning to invade the surrounding tissue.
Grade 4: The tissue has few recognizable glands. Many cells are invading the surrounding tissue.
Grade 5: The tissue does not have recognizable glands. There are often just sheets of cells throughout the surrounding tissue
The Gleason score is used to help evaluate the prognosis of men with prostate cancer. Together with other parameters,
the Gleason score is incorporated into a strategy of prostate cancer staging which predicts prognosis and helps guide
therapy.
4. Ans. (c) There is no germ cells in this condition (Ref: Anderson 10th 2177)
Sertoli cell only syndrome also called as Germ cell aplasia has small seminiferous tubules. In this condition seminiferous
tubules are smaller than normal and are lined by a single layer of Sertoli cells and no germ cells. Without germ cell, sper-
matogenesis does not take place resulting in infertility.
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5. Ans. (a) Cryptorchidism ; (b) Testicular feminising syndrome; (c) Klinefelter syndrome; (e) Rt. side has more common
flow than Lt. side (Ref: Robbins 7th/1041, 9/e p975, Harrison 16th/550)
The predisposing factors of germ cell tumors of testes are:
Cryptorchidism
Testicular feminization syndrome
Klinefelter syndrome
Excess 12P copy number either in the term of i(l2P) or increased 12P an aberrantly banded marker chromosome.
Prior germ cell tumor
Strong family history of germ cell tumor
In most large testicular tumour approximately 10% associated with cryptorchidism.
Abdominal cryptorchid testes are at higher risk than inguinal cryptorchid testes.
Klinefelters syndrome is associated with mediastinal GCT.
An isochromosome of short arm of chromosome 12[i(l2P)] is pathognomic of GCT in all histological types.
Blacks have very low incidence of germ cell neoplasms.
Seminoma is most common GCT.
6. Ans. (b) Spermatocytic seminoma (Ref: Robbins 8th/988, 9/e p975,)
Most testicular germ cell tumors originate from intratubular germ cell neoplasia (ITGCN).
ITGCN is seen adjacent to all germ cell tumors in adults except for spermatocytic seminoma and epidermoid and dermoid cysts. With
rare exceptions, it is also not seen in pediatric tumors (teratomas, yolk sac tumors Robbins 7th edition page 1096)
So, obviously friends, if we have to choose between options b and c, we would prefer option b as the answer. ITCGN is
seen with a high frequency in the following conditions:
Cryptorchidism
Prior germ cell tumors
Strong family history of germ cell tumor
Androgen insensitivity syndrome
Gonadal dysgenesis syndrome.

Untreated ITGCN progresses to invasive germ cell tumor in approximately 50% of cases over 5 years of follow-up.
7. Ans. (b) 6 and 11 (Ref: Robbins 7th/1035, 9/e p970)
Condyloma are most commonly caused by HPV types 6 and 11.
Condyloma acuminatum is a benign tumor caused by human papilloma virus (HPV).
It is related to the common wart (verruca vulgaris) and may occur on any moist mucocutaneous surface of the exter-
nal genitalia in either sex.
Also, HPV and associated diseases are sexually transmitted.
On the penis, these lesions occur most often about the coronal sulcus and inner surface of the prepuce.
They consist of single or multiple sessile or pedunculated, red papillary excrescences that vary from 1 mm to several
mm in diameter.
Histologically a branching, villous, papillary connective tissue stroma is covered by a thickened hyperplastic
Epithelium that may have considerable superficial hyperkeratosis and thickening of the underlying epidermis (acan-
thosis).
The normal orderly maturation of the epithelial cells is preserved.
Clear vacuolization of the prickle cells (Koilocytosis), characteristic of HPV infection, is noted in these lesions.
The basement membrane is intact, and there is no evidence of invasion of the underlying stroma.
Condyloma acuminata tend to recur but do not evolve into invasive cancers.
8. Ans. (d) CEA (Ref: Robbins 8th/327, 9/e p979)
9. Ans. (b) Carcinoma prostate(Ref: Robbins 8th/999-1000, 9/e p987)
10. Ans. (a) Mature teratoma (Mature teratoma is a benign tumour) (Ref: Robbins 9/e p979, 8th/1047; 7th/1093,1096)
11. Ans. (b) Endodermal sinus tumor (Ref: Robbins 8th/1049, 9/e p977)
12. Ans. (d) (Ref: Robbins 7th/335, 1043, 9/e p977, Chandrasoma/307-308)
An embryonal carcinoma is testicular malignancy that secretes alpha-fetoprotein (a-AFP) and is composed of undif-
ferentiated cells along with primitive glandular differentiation. Once the diagnosis of malignancy is established,
prognosis for the patient is estimated through the process of grading and staging.
It is important to understand the difference between these two terms. First of all, note that these terms are applied
only to malignant neoplasms. Basically, grading is done histologically, while staging is done clinically.
Lower grades, such as grades I and II, are more differentiated, less aggressive and have a better prognosis, while
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higher grades, such as grades III and IV, are less differentiated, more aggressive and have a worse prognosis. Tumors
composed of malignant cells that appear primitive or undifferentiated are classified as high grade tumors.
In contrast to grading, the staging of cancers is based on the size of the primary lesion, the presence of lymph node
metastases, and the presence of blood-borne metastases. Two main staging systems are Union International Centre le
Cancer (UICC) and American Joint Committee (AJC), UICC classification is called the TNM classification. AJC stag-
ing system generally divides cancers into stages 0 through IV. Lower stage tumors are smaller, localized, and have a
better prognosis, while higher stage tumors are larger, widespread, and have worse prognosis.
13. Ans. (a) Most common age of presentation (Ref: Robbins 8th/988, 1049, 9/e p976, 1030)
Seminomas and dysgerminomas are very similar tumors but differ in two significant respects: the most common
age of presentation in men is in the fourth decade, while in women, it is in the third decade. Also, seminomas are
relatively common in men (30% of testicular germ cell tumors), while dysgerminomas are rare in women (1% of
ovarian tumors).
Both of these tumors are composed of sheets of uniform polyhedral cells with intervening fibrous septa of connective
tissue, lymphocytes, and multinucleated giant cells. The number of mitoses (choice B) per high-power field and
ultrastructural appearance (choice D) do not differ greatly between the two tumors.
These tumors in pure form are very radiosensitive but can be much more aggressive (choice C) if foci of other germ
cell tumors (notably embryonal carcinoma, choriocarcinoma, and yolk sac tumors) are present.
14. Ans. (b) Teratoma with malignant transformation (Ref: Robbins 8th/991, 9/e p978)
This is teratoma with malignant transformation. The possibility of malignant transformation is the reason why ma-
ture teratomas with very well differentiated tissues should be completely excised. Malignant transformation is more
common in teratomas in adults than in children or babies.
Dermoid cyst (choice A) is a cystic form of mature teratoma, usually found in the ovaries.

Immature teratoma (choice C), while clinically malignant, shows embryonal tissues and often displays no clear-cut
cytological evidence of malignancy.
Solid mature teratoma (choice D) without the added descriptor with malignant transformation is by definition a
benign tumor. Careful extensive sampling is required to exclude minute foci of cancerous transformation.

14.1. Ans. (d) CEA (Ref: Robbins 8/e 327, 9/e p979)
Carcino embryonic antigen is increased in cancers of the pancreas and colon.

14.2. Ans. (c) Periurethral transition zone (Ref: Robbins 9/e p982)
14.3. Ans. (b) Mediastinum (Ref: Robbins 9/e p475; Harsh Mohan 6/e p703)
15. Ans. (b) Due to contamination with infectious agents (Ref: Enzinger and Weiss Soft Tissue Tumors, 5th/73, Wintrobes
Hematology, 12th/50-60)
Cytogenetics is the study of chromosome structure which can be done with techniques like karyotyping or molecular
techniques (FISH, spectral karyotyping/multicolor FISH, comparative genomic hybridization). These techniques
needs metaphase (more commonly) but can be applied to interphase also. Cytogenetics is easy if the metaphase is
distinct. So, culture is often done in solid tumors to get the cells in metaphase.
Cytogenetics is also easier if mitotic rate is high.
The problems with cytogenetics are:
Unpredictable growth of the neoplastic cells in tissue culture
Overgrowth of neoplastic cells by reactive non-neoplastic cells
Contamination of tumor cultures by bacteria or fungi
Predominance of nonviable tumor (necrotic sample)
Deficient tissue sampling like sampling from nonrepresentative areas or the necrotic areas will impair the results in most
of the solid tumors but the commonest problem with cancer of the cervix is the high contamination rate. So, option B is
better than option D.
16. Ans. (d) The number of mitoses per high power field (Ref: Robbins 7th/1090, 9/e p1021)
The most important criterion for distinction of leiomyosarcoma from leiomyoma (malignant transformation) is the
number of mitoses present.
Ten high power fields (hpf) are examined. If > 10 mitoses are seen, it signifies malignancy. If cellular atypia is also
present, > 5 mitoses are enough to make a diagnosis of leiomyosarcoma.
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17. Ans. (d) Increased Prolactin (Ref: Shaw 13th/353, 9/e p1022)
The diagnosis of polycystic ovarian syndrome (PCOS) is straightforward using the Rotterdam criteria, even when the
syndrome is associated with a wide range of symptoms.
Standard diagnostic assessments
History-taking, specifically for menstrual pattern, obesity, hirsutism, and the absence of breast discharge. A clinical
prediction rule found that these four questions can diagnose PCOS with a sensitivity of 77.1% (95% CI 62.7-88.0%)
and a specificity of 93.8% (95% CI 82.8-98.7%).
Gynecologic ultrasonography, specifically looking for small ovarian follicles. These are believed to be the result of
disturbed ovarian function with failed ovulation, reflected by the infrequent or absent menstruation that is typical of
the condition. In normal menstrual cycle, one egg is released from a dominant follicle - essentially a cyst that bursts
to release the egg. After ovulation the follicle remnant is transformed into a progesterone producing corpus luteum,
which shrinks and disappears after approximately 12-14 days. In PCOS, there is a so called follicular arrest, i.e.
several follicles develop to a size of 5-7 mm, but not further. No single follicle reach the preovulatory size (16 mm
or more). According to the Rotterdam criteria, 12 or more small follicles should be seen in an ovary on ultrasound
examination. The follicles may be oriented in the periphery, giving the appearance of a string of pearls. The numerous
follicles contribute to the increased size of the ovaries, that is, 1.5 to 3 times larger than normal.
Laparoscopic examination may reveal a thickened, smooth, pearl-white outer surface of the ovary.
Serum (blood) levels of androgens (male hormones), including androstenedione, testosterone and dehydroepian-
drosterone sulfate may be elevated: free testosterone is more sensitive than total. Free testosterone is reflected as the
ratio of testosterone to sex hormone-binding globulin (SHBG).
Some other blood tests are suggestive but not diagnostic. The ratio of LH (Luteinizing hormone) to FSH (Follicle
stimulating hormone) is greater than 1:1, as tested on Day 3 of the menstrual cycle. The pattern is not very specific and
was present in less than 50% in one study. There are often low levels of sex hormone binding globulin, particularly
among obese women.
18. Ans. (a) Vimentin, epithelial membrane antigen, inhibin, CD99 (Ref. Sternberg Pathology/2581, 2583, 2543, 2579, 2652
Ackermans Pathology/1694, 1675, 1681, 687)
The specimen in the given question is most likely to be of granulosa cell tumor of ovary:
The features pointing toward this diagnosis are:
Unilateral tumor Solid and cystic areas
Small cells arranged in sheets Nuclear grooving
Scant cytoplasm
The only point against this diagnosis is absence of Call-Exner bodies, but note that these structures if found are diagnostic
of Granulosa cell tumors but these are not prerequisite for diagnosis.
Vimentin, ema, inhibin and CD99 all are the markers of granulosa cell tumors.
19. Ans. (A) Germ cell tumor (Ref: Robbins 8th/1047-1049, 9/e p1029, Harrison 17th/606, 604)
Epithelial tumors of ovary usually occur in old age
Germ cell tumors of ovary generally occur in younger women. About 75% of these occur in women <30 years old
Stromal tumors (like Sertoli Leydig tumors and granulosa cell tumors) occur in all ages.
Granulosa- theca cell tumors are mostly seen in postmenopausal women. - Robbins/1050
Sertoli-Leydig cell tumors occur in women of all ages, although the peak incidence is in second and third decade
-Robbins/1051
Thus, we are left with two options: Germ cell tumors and Sertoli Leydig cell tumors. But, if we see the frequency of tumors;
germ cell tumors have 15-20% whereas all sex-cord stromal tumors (Sertoli Leydig is one of them) together constitute only
5-10% of ovarian neoplasms
Thus, a 14-year-old girl is most likely to have germ cell tumor.
Important Points About Ovarian Neoplasms
These may develop from epithelial cells (like serous, mucinous, Brenner tumor etc), germ cells (like granulose cell tumor,
Sertoli-Leydig cell tumors etc).
Most common ovarian neoplasms are epithelial tumors
Most common malignant ovarian neoplasms are epithelial tumors.
Two types of autosomal dominant familial cancers have been identified:

Breast/ovarian cancer syndrome: Due to mutations in BRCA1 or BRCA2 genes.

Lynch type II syndrome: Results due to mutations in mismatch repair genes. This is associated with Non-polyposis
colorectal cancer, endometrial and ovarian cancer.
CA-125 is marker of epithelial ovarian cancers
Dysgerminoma is ovarian counterpart of seminoma and is highly sensitive to radiation therapy
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20. Ans. (a) 10% (Ref: Robbins 8th/1047, 9/e p1029)

Germ cell tumors constitutes 15-20% of all ovarian tumors
Most are benign cystic teratoma, also known as dermoid cyst.
Benign teratomas are bilateral in 0-15% of cases --- Robbins 1047
21. Ans. (a) < 1% (Ref: Robbins 8th/1037, 9/e p1020)
Fibroid is the term used for uterine leiomyoma. Malignant transformation (leiomyosarcoma) within a leiomyoma is ex-
tremely rare -- Robbins/1037
Fibroids are most common tumor in women
They have characteristic whorled pattern of smooth muscle bundles on cut section as well as histologically
Differences between leiomyoma and leiomyosarcoma is mainly based on number of mitoses
If >10 mitoses per high power field are present or > 5 mitoses with nuclear atypia are present, it indicates malignancy
22. Ans. (a) Malignant change (Ref: Shaws 13th/341, Robbins 9/e p1020)
Secondary changes (degenerations) in uterine leiomyoma:
Atrophy: It can be:
After menopause
After delivery
Tumour becomes firmer and more fibrotic. It is due to diminished blood supply.
Calcareous degeneration: Phosphates and carbonates of lime are deposited in the periphery along the course of the
vessels.
Womb-stones in graveyard: In old patients with long-standing myomas.
Red (Carneous) degeneration: It is more common during pregnancy. The myoma becomes tense and tender and
causes severe abdominal pain with constitutional upset and fever. The tumour itself assumes a peculiar purple-red
color and develops a fishy odour.
Although the patient is febrile with moderate leucocytosis and raised ESR, the condition is an aseptic one.

It needs to be differentiated from
- Appendicitis
- Twisted ovarian cyst
- Pyelitis
- Accidental hemorrhage
Sarcomatous change: It is extremely rare. Incidence is no more than 0.5% of all myomas.

Intramural and submucous tumors have a higher potential than sub-serous.

It is rare for malignant change to develop in a women under the age of 40.

It is highly malignant and spreads through blood.
Other complications:

Torsion

Inversion

Capsular hemorrhage

Infection

Associated endometrial carcinoma
23. Ans. (a) Uterus (Ref: Robbins 9/e p1018, 8th/1035; 7th/1088)
24. Ans. (c) Yolk-Sac tumour (Ref: Robbins 8th/1049, 9/e p1031)
25. Ans. (c) Granulosa cell tumour(Ref: Robbins 8th/1050, 9/e p1032)
26. Ans. (c) Both (Ref: Robbins 8th/1049, 9/e p1031)
27. Ans. (c) Villi present (Ref: Robbins 7th/1113, 9/e p1041)
28. Ans. (a) Granulosa theca cell tumor (Ref: Robbins 9/e p1032, 8th/1050; 7th/1102)
29. Ans. (b) Rhabdomyosarcoma (Ref: Robbins 9/e p1001, 8th/1017)
30. Ans. (d) Mature teratoma (Ref: Robbins 9/e p1029, 8th/1047-1048)
The lesion is a mature teratoma. Teratomas located in the ovary and containing a hair and keratin filled cyst are sometimes
called dermoid cysts. They contain cells of a variety of types, often including skin, skin adnexal structures (hair follicles,
sweat glands, sebaceous glands), connective tissues, neural tissue, muscle, and thyroid tissue. If immature tissues such as
primitive neuroepithelial cells or developing skeletal muscle cells are seen, the lesion is considered potentially malignant
and classified as an immature teratoma (option A).
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31. Ans. (c) CA-125 (Ref: Robbins 9/e p1029, 8th/327)

The tumors are serous papillary cystadenocarcinomas of the ovaries. These tumors express CA-125 and are apparently
derived from the surface epithelium of the ovaries.
Bombesin (choice B) is a marker for neuroblastoma, small cell carcinoma, gastric carcinoma, and pancreatic carcinoma.
32. Ans. (b) Leiomyoma (Ref: Robbins 8th/327, 9/e p1020)
32.1. Ans. (b) Brenner tumour (Ref: Robbins 9/e p1028)
Transitional cell tumors contain neoplastic epithelial cells resembling urothelium and are usually benign. They
comprise roughly 10% of ovarian epithelial tumors and are also referred to as Brenner tumors
32.2. Ans. (c) Schiller duval body (Ref: Robbins 9/e p977)
33. Ans. (c) Intraductal papilloma (Ref: Pathology and Genetics of tumours of breast and female genital organs/81, Robbin 9/e p1044)
Successive branching of the large ducts eventually leads to the terminal duct lobular unit (TDLU).
All breast cancers whether ductal or lobular originate from terminal duct lobular unit (TDLU).
Most of the benign breast diseases also originate from TDLU except intraductal papilloma, 90% of which occurs in
large ducts in the central portion of breast.
34. Ans. (d) Comedo DCIS (Ref: Robbins 7th/1139, 9/e p1057)
DCIS most frequently presents as mammographic calcifications. Less typically DCIS may present as a vaguely
palpable mass. This is most likely with Comedocarcinomas.
Most of the breast malignancies are adenocarcinomas. These can be divided into insitu carcinomas and invasive
carcinomas.
Carcinoma in situ refers to a neoplastic population of cells limited to ducts and lobules by the basement membrane.
It does not invade into lymphatics and blood vessels and cannot metastasize.
Invasive carcinoma (synonymous with infiltrating carcinoma) has invaded beyond the basement membrane into
stroma. Here, the cells might also invade into the vasculature and thereby reach regional lymph nodes and distant
sites. Even the smallest invasive breast carcinomas have some capacity to metastasize.
All carcinomas are thought to arise from the terminal duct lobular unit, and the terms ductal and lobular do not
imply a site or cell type of origin.
O
CARCIN MA IN SIT U
Ductal Carcinoma in Situ (DCIS; Intraductal Carcinoma)
DCIS most frequently presents as mammographic calcifications. DCIS consists of a malignant population of cells
limited to ducts and lobules by the basement membrane. The myoepithelial cells are preserved, although they may be
diminished in number. DCIS is a clonal proliferation and usually involves only a single ductal system. The majority
of cases of DCIS cannot be detected by either palpation or visual inspection of the involved tissue.
Occasional cases of comedocarcinoma are associated with sufficient periductal fibrosis to produce a thickening of
the tissue, and punctate areas of necrosis (comedone-like) can be seen grossly.
DCIS can be divided into
Comedocarcinoma: It is characterized by solid sheets of pleomorphic cells with high-grade nuclei and central
necrosis. The necrotic cell membranes commonly calcify and are detected on mammography as clusters or linear and
branching microcalcifications. Periductal concentric fibrosis and chronic inflammation are common, and extensive
lesions are sometimes palpable as an area of vague nodularity. Microinvasion (defined by foci of tumor cells less than
0.1 cm in diameter invading the stroma) is most commonly seen in association with comedocarcinoma.
Non-comedo DCIS consists of a monomorphic population of cells with nuclear grades ranging from low to high.
These may be cribriform (cookie cutter-like intraepithelial spaces), Solid (completely fills the involved spaces),
Papillary (grows into spaces and lines fibrovascular cores typically lacking the normal myoepithelial cell layer) and
Micropapillary (bulbous protrusions without a fibrovascular core).
Pagets disease of the nipple is a rare manifestation of breast cancer and presents as a unilateral erythematous eruption
with a scale crust. Pruritus is common, and the lesion might be mistaken for eczema. Malignant cells, referred to as
Paget cells, extend from DCIS within the ductal system into nipple skin without crossing the basement membrane.
The Paget cells are easily detected by nipple biopsy or cytological preparations of the exudate. The carcinomas are
usually poorly differentiated and overexpress HER2/neu.
Lobular Carcinoma in Situ (LCIS)
LCIS is not associated with calcifications and is bilateral in 20-40% of women compared to 10-20% of cases of DCIS. LCIS
is more common in young women.
Cells of LCIS and invasive lobular carcinoma are identical in appearance, and both lack expression of
E-cadherin. The loss of expression correlates with the histologic appearance of lobular carcinomas as single detached cells.
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Older studies indicated that both breasts were at equal risk of developing invasive carcinoma, but a recent report
suggests that the ipsilateral breast may be at greater risk in women with lobular neoplasia.
The abnormal cells consist of small cells that have oval or round nuclei with small nucleoli that do not adhere to one
another. Signet-ring cells containing mucin are present commonly. LCIS almost always expresses estrogen and
progesterone receptors, and overexpression of HER2/neu is not observed.
35. Ans. (c) Chromosome 17 (Ref: Harrison 17th/563, Robbin 9/e p1054)
Tumor-suppressor gene, BRCA-1, has been identified at the chromosomal locus 17q21; this gene encodes a zinc finger
protein, and the product therefore may function as a transcription factor. The gene appears to be involved in gene
repair. Women who inherit a mutated allele of this gene from either parent have at least a 6080% lifetime chance of
developing breast cancer and about a 33% chance of developing ovarian cancer. The risk is higher among women
born after 1940, presumably due to promotional effects of hormonal factors. Men who carry a mutant allele of the
gene have an increased incidence of prostate cancer and breast cancer.
BRCA-2, which has been localized to chromosome 13q12, is also associated with an increased incidence of breast
cancer in men and women.
36. Ans. (a) p53 (Ref: Robbins 7th/286, 300, 302, 8th/290-291, 9/e p1054, Harrison 16th/516, 517; 17th/563)
Breast cancer can be either familial (associated with germline mutation) or sporadic (associated with somatic mutation).
The familial breast cancer is caused due to mutation in the following 4 genes:
p53 tumor suppressor gene (called Li Fraumeni syndrome having multiple malignancies like breast cancer, osteo-
genic sarcoma etc.)
PTEN gene: Gene on chromosome 10q associated with epithelial cancers of breast, endometrium and thyroid.
BRCA1 gene: Located on 17q: females having mutant gene have increased incidence of breast and ovarian cancer
whereas males having mutant gene have high incidence of breast and prostate cancer.
BRCA2 gene: Located on chromosome 13q is associated with increased incidence of breast cancer in men and women.
Sporadic breast cancer is associated with mutation in p53 gene (p53 defect is present in 40% of human breast cancer as an

acquired defect) and PTEN gene.
Since, incidence of sporadic cancer is much more than familial cancer, so the most important gene mutation increasing susceptibility
to breast cancer should be answered as p53.
37. Ans. (b) BRCA2 (Ref: Harrison 17th/604, 9/e p1054)
In women with hereditary breast/ovarian cancer, there can be two susceptibility loci:
BRCA1 located on chromosome 17q12-21, and
BRCA2 located on 13q12-13.
Both these are tumor-suppressor genes which produce nuclear proteins that interact with RAD 51 affecting genomic integ-
rity.
The cumulative risk of ovarian cancer with critical mutations of BRCA1 or - BRCA2 is 25%. Men in such families have an
increased risk of prostate cancer.
38. Ans. (c) Lobular Ca (Ref: Robbins 7th/1144/1141, 9/e p1065)
Lobular carcinoma (invasive) of breast is one of the very few carcinomas which are seen bilaterally.
Lobular carcinoma in situ in 20-40% cases is bilateral.
Histologic hallmark is pattern of single infiltrating tumor cells often only one cell in width or in loose clusters or
sheets.
Signet ring cells common.
Metastasize frequently to peritoneum, retroperitoneum, leptomeninges, GIT and ovaries.
The incidence of this carcinoma is increasing among postmenopausal females presumably because of increasing use
of HRT.
39. Ans. (c) Inflammatory carcinoma (Ref: Robbins 8th/1083)
40. Ans. (d) CA 15-3 (Ref: Robbins 7th/339, 9/e p337, Anderson pathology 144-152)
41. Ans. (b) Infiltration of the epidermis by malignant cells (Ref: Robbins 7th/1140, 9/e p1057)
42. Ans. (a) 17 (Ref: Robbins 8th/275-276, 9/e p1054)
43. Ans. (d) Ductal carcinoma (Ref: Robbins 8th/1080,1083, 9/e p1057)
44. Ans. (c) Invasive lobular carcinoma (Ref: Robbins 8th/1082; 7th/1142, 9/e p1059)
45. Ans. (d) Lobular carcinoma (Ref: Harsh Mohan 6th/762-763)
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46. Ans. (b) Peau d orange (Ref: Robbins 9/e p1067, 8th/1083; 7th/122,1140,1142)
4 6.1. Ans. (a) 17 (Ref: Robbins 8/e p275-276, 9/e p1054)
BRCA 1 gene: chromosome 17
BRCA2 gene: chromosome 13
46.2. Ans. (c) Dermal lymphatic invasion by cancer cells (Ref: Robbins 8th/1089, 9/e p1067)
Inflammatory breast cancer is a pattern of invasive breast cancer in which the neoplastic cells infiltrate widely through
the breast tissue. The cancer involves dermal lymphatics and therefore has a high incidence of systemic metastasis
and a poor prognosis. If the lymphatics become blocked, then the area of skin may develop lymphedema and peau
dorange, or orange peel appearance. The overlying skin in inflammatory breast cancer is usually swollen, red, and
tender.
Acute inflammation (option A) is associated with secondary infection or abscess whereas chronic inflammation in breast
cancer (option B) is a non-specific finding. In medullary breast cancer, a type of invasive ductal carcinoma, there are a
large number of lymphocytes around the tumor and a desmoplastic reaction is often absent in the surrounding tissue.
Epidermal invasion by cancer cells (option D) is a poor prognostic indicator. Intraepidermal malignant cells are called
Paget cells. Pagets disease of the nipple is a type of ductal carcinoma that arises in large ducts and spreads intraepi-
dermally to the skin of the nipple and areola. There is usually an underlying ductal carcinoma.

46.3. Ans. (c) Neoplasia (Ref: Robbins 9/e p1057)
Paget disease of the nipple is a rare manifestation of breast cancer (1% to 4% of cases) that presents as a unilateral erythe-
matous eruption with a scale crust. Pruritus is common, and the lesion may be mistaken for eczema.
EXPLANATIONS TO C onceptual QUESTIONS

Explanations(1-3): While solving assertion reason type of questions, we can use a particular method.
1. First of all, read both assertion (A) and reason (R) carefully and independently analyse whether they are true or false.
2. If A is false, the answere will directly be (d) i.e. both A and R are false. You can note that all other options (i.e. a, b or c)
consider A to be true.
3. If A is true, answer can be (a), (b) or (c), Now look at R. If R is false, answer will be (c)
a
4. If both A and R are ture, then we have to know whether R is correctly explaining [answer is (a)] or it is not the
explanation of assertion [answer is (b)]
1. Ans. (c) Assertion is true and reason is false. (Ref: Robbins 8th/995, 9/e p983)
Stromal cells are responsible for androgen dependent prostatic growth. The main hormone responsible for androgen
dependent prostatic growth is dihydrotestosterone (and not testosterone) because stromal cells have type 2 5 reductase
enzyme which converts testosterone into dihydrotestosterone. DHT is more potent than testosterone because it binds more
strongly to the androgen receptor.
FGF-7Q (fibroblast growth factor-7) is the most important factor mediating paracrine regulation of androgen dependent growth.
Type 1 Q 5 reductase enzyme is minimally present in prostate and is mainly located mainly in liver and skinQ.

Struma ovarii is mature teratoma which is composed of functioning thyroid tissue. It is therefore responsible for
production of the thyroid hormones (and not gonadotropins).
3. Ans. (b) Both assertion and reason are true and reason is not the correct explanation of assertion. (Ref: Robbins 8th/988-9, 9/e p976)
Seminoma is a germ cell tumor with a good prognosis because it is an extremely radiosensitive and chemosensitive tumor.
These tumors histologically have necrosis and hemorrhage only rarely.
Features Seminoma Non seminoma
Localization Localized to testes for long time Metastasize early
Stage 70% patients present in stage I 60% in stage II and III
Metastasis Mainly lymph node: hematogenous Hematogenous spread more frequent
spread later
Necrosis and hemorrhage Rare Common
Radiation sensitivity Radiosensitive Radio-resistant
General behavior Less aggressive More aggressive
Prognosis Good Bad
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CHAPTER 15
CEREBRAL HERNIATION
Central Nervous System
The cranial cavity is separated into compartments by infoldings of the dura. The two cerebral The most common herniations
hemispheres are separated by the falx, and the anterior and posterior fossae by the tentorium. are Transtentorial herniation.
Herniation refers to displacement of brain tissue into a compartment that it normally does not
occupy. These are of three main types: transtentorial, transfalcine (subfalcine) and tonsillar
(foraminal).
Transtentorial Herniation
Uncal transtentorial herniation:
compression of IIIrd cranial
The most common herniations are from the supratentorial to the infratentorial compartments
nerve; eye deviated down and
through the tentorial opening, hence transtentorial. These may be divided into temporal out; mydriasis.
(Uncal) or central herniations.
Uncal transtentorial herniation refers to impaction of the anterior medial temporal gyrus (the
uncus) into the tentorial opening just anterior to and adjacent to the midbrain. The displaced brain
tissue compresses the third nerve and results in mydriasis and ophthalmoplegia (pupil point
down and out) of the ipsilateral pupil.
Central transtentorial herniation denotes a symmetric downward movement of the thalamic
medial structures through the tentorial opening with compression of the upper midbrain. Miotic
pupils and drowsiness are the heralding signs.
Transfalcine Herniations
Concept
These are caused by herniation of the medial aspect of the cerebral hemisphere (cingulate
gyrus) under the falx, which may compress the anterior cerebral artery. Tonsillar herniation may also
occur if a lumbar puncture is
performed in a patient with
Tonsillar Herniation increased intracranial pressure.
Therefore, before performing
Masses in the cerebellum may cause tonsillar herniation, in which the cerebellar tonsils
a lumbar puncture, the patient
are herniated into the foramen magnum. This may compress the medulla and respiratory should be checked for the
centers, causing death. presence of papilledema.
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DEVELOPMENTAL ABNORMALITIES OF THE BRAIN
Developmental abnormalities of the brain include the Arnold-Chiari malformation, the

Dandy-Walker malformation, and the Phakomatoses, which include tuberous sclerosis,
Dandy Dilated 4th ventricle
Walker Water on the brain neurofibromatosis, von Hippel-Lindau disease, and Sturge-Weber syndrome.
Dandy-Walker malformation has severe hypoplasia or absence of the cerebellar
(hydrocephalus)

Syndrome Small or absent vermis vermis. There is cystic distention of the roof of the fourth ventricle, hydrocephalus,
and possibly agenesis of the corpus callosum.
Arnold-Chiari malformation consists of herniation of the cerebellum and fourth ventricle into
the foramen magnum, flattening of the base of the skull, and spina bifida with meningomyelocele.
Newborns with this disorder are at risk of developing hydrocephalus within the first few days of
delivery secondary to stenosis of the cerebral aqueduct.
Triad of tuberous sclerosis:
Seizures+mental retardation+
Tuberous sclerosis may show characteristic firm, white nodules (tubers) in the
congenital white spots or macules
(leukoderma). cortex and subependymal nodules of gliosis protruding into the ventricles (candle
drippings) Facial angiofibromas (adenoma sebaceum) may also occur.
von Hippel-Lindau disease shows multiple benign and malignant neoplasms
including hemangioblastomas of the retina, cerebellum, and medulla oblongata;
angiomas of the kidney and liver; and renal cell carcinomas.
The most common location of Sturge-Weber syndrome is a non-familial congenital disorder, display angiomas
a syrinx is the cervical region of the brain, leptomeninges, and ipsilateral face, which are called port-wine stains
and so, the loss of pain and (nevus flammeus).
temperature sensation affects
Syringomyelia: Bilateral loss of pain and temperature sensations in both arms is most
both arms.
likely to be caused by syringomyelia, which is a chronic myelopathy that results from
formation of a cavity (syrinx) involving the central gray matter of the spinal cord.
This is the location where pain fibers cross to join the contralateral spinothalamic
The diagnosis of syringomyelia tract. Interruption of the lateral spinothalamic tracts results in segmental sensory
is best made with MRI of the dissociation with loss of pain and temperature sense, but preservation of the sense
cervical spine. of touch and pressure or vibration, usually over the neck, shoulders, and arms. Other
features of syringomyelia include wasting of the small intrinsic hand muscles (claw
hand) and thoracic scoliosis. The cause of syringomyelia is unknown, although
one type is associated with a Chiari malformation with obstruction at the foramen
magnum.
Concept
NEURAL TUBE DEFECTS
Neural tube defects are
associated with increased These are caused by defective closure of the neural tube. These defects may occur anywhere
maternal serum levels of along the extent of the neural tube and are classified as either caudal or cranial defects. Failure
a-fetoprotein (AFP), which
of development of the cranial end of the neural tube results in anencephaly, while failure of
is a glycoprotein synthesized
by the yolk sac and the fetal development of the caudal end of the neural tube results in spina bifida.
liver. Increased serum levels
Anencephaly, which is not compatible with life, is characterized by the absence of
are also associated with yolk the forebrain. Instead, there is a mass of disorganized glial tissue with vessels in
sac tumors of the testes and this area called a cerebrovasculosa. Ultrasound examination will reveal an abnormal
liver cell carcinomas (note that shape to the head of the fetus with an absence of the skull.
decreased AFP is associated
with Down syndrome). Spina bifida can be spina bifida occulta which results due to failure of closure of vertebral arches
posteriorly. It is a mild disorder with normal meninges and spinal cord. If meninges also herniate
out, it is known as meningocele whereas protruding out of both meninges as well as spinal cord
Maternal folate level must be is called meningomyelocele.
fr
adequate be o e pregancy to
Neural tube defects are associated with maternal obesity and decreased folate
decrease the risk of neural tube
defects. during pregnancy (folate supplementation in diet decreases the incidence of these
development defects).
CEREBRAL HEMORRHAGE
It can be epidural, subarachnoid, subdural and intraparenchymal.

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Epidural hemorrhage: It results from hemorrhages into the potential space between
the dura and the bone of the skull. These hemorrhages result from severe trauma The artery involved in epidural
that typically causes a skull fracture. The hemorrhage results from rupture of one of hemorrhage is usually the
the meningeal arteries, as these arteries supply the dura and run between the dura middle meningeal artery,
and the skull. Since the bleeding is of arterial origin (high pressure), it is rapid and which is a branch of the maxillary
artery, as the skull fracture is
the symptoms are rapid in onset, although the patient may be normal for several
usually in the temporal area.
hours (lucid interval). Bleeding causes increased intracranial pressure and can lead
to tentorial herniation and death.
Subarachnoid hemorrhage: It is much less common than hypertensive intracerebral hemorrhage.

It most often results from the rupture of a berry aneurysm. These aneurysms are Saccular Excluding trauma, Berry aneu-
aneurysms that result from congenital defects in the media of arteries. They are typically located rysm is the commonest cause of
subarachnoid hemorrhage.
at the bifurcations of arteries. They are not the result of atherosclerosis. Instead, berry aneurysms
are called congenital, although the aneurysm itself is not present at birth. The chance of rupture
of berry aneurysms increases with age (rupture is rare in childhood). Rupture causes marked
bleeding into the subarachnoid space and produces severe headaches, typically described as the
worst headache ever. Additional symptoms include vomiting, pain and stiffness of the neck (due
to meningeal irritation caused by the blood), and papilledema. Death may follow rapidly.
Berry aneurysms are most
commonly found in the circle
of Willis, typically either at
Subdural Hemorrhage: The space beneath the inner surface of the dura mater and the junction of the anterior
the outer arachnoid layer of the leptomeninges is also a potential space. communicating artery with
the anterior cerebral artery or
at the junction of the middle
CEREBRAL ISCHEMIA cerebral artery and the posterior
communicating artery.
Decreased brain perfusion may be generalized (global) or localized.

Global ischemia results from generalized decreased blood flow, such as with shock,
cardiac arrest, or hypoxic episodes (e.g. near drowning or carbon monoxide poisoning).

The gross changes produced by global hypoxia include watershed (border zone)
infarcts, which typically occur at the border of areas supplied by the anterior Subdural hemorrhage most
and middle cerebral arteries, and laminar necrosis, which is related to the short, commonly occurs due to rupture
penetrating vessels originating from pial arteries. of bridging veins.
The microscopic changes produced by global hypoxia are grouped into three
categories. The earliest histologic changes, occurring in the first 24 h, include the
formation of red neurons (acute neuronal injury), characterized by eosinophilia of
the cytoplasm of the neurons, and followed in time by pyknosis and karyorrhexis.
Subacute changes occur at 24 h to 2 weeks. These include tissue necrosis, vascular The Purkinje cells of the
proliferation, and reactive gliosis. cerebellum and the pyramidal
neurons of Sommers sector
in the hippocampus are
INTRACRANIAL ANEURYSMS particularly sensitive to ischemic
damage.
B
Charcot- ouchard aneurysms: It results from weakening of the wall of cerebral artery by
lipohyalinosis (deposition of lipids and hyaline material) caused by hypertension. Hypertensive
hemorrhage shows a predilection for the distribution of the lenticulostriate arteries (branch of
middle cerebral artery) with small (lacunar) hemorrhages, or large hemorrhages obliterating the
corpus striatum, including the putamen and internal capsule. Hypertensive hemorrhages also
commonly occur in cerebellum and pons and are often fatal.
Berry aneurysms (small saccular aneurysms) are the result of congenital defects in the media of
blood vessels and are located at the bifurcations of arteries.
Atherosclerotic aneurysms are fusiform (spindle-shaped) aneurysms usually located in the
major cerebral vessels. They rarely rupture, but may become thrombosed.
Mycotic (septic) aneurysms result from septic emboli, most commonly from subacute bacterial
endocarditis.
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CNS INFECTIONS
Meningoencephalitis caused by HIV (human immunodeficiency virus) is characterized by

microglial nodules within the brain that are composed of mononuclear cells, microglia, and
scattered multinucleated giant cells.
Herpes simplex virus produces characteristic Cowdry type A intranuclear inclusions in neurons
and glial cells.
Rabies form characteristic inclusions within neurons called Negri bodies. Rabies, caused by a
single-stranded RNA rhabdovirus, is transmitted by the bite of a rabid animal, usually a dog, and
travels to the brain via peripheral nerves. Symptoms caused by destruction of neurons in the
brainstem include irritability, difficulty in swallowing and spasms of the throat (these two resulting
in hydrophobia), seizures, and delirium. The illness is almost uniformly fatal.
Enlarged cells (cytomegaly) with intranuclear and intracytoplasmic inclusions are seen with
cytomegalovirus infection.
Progressive multifocal leukoencephalopathy (PML): It is a demyelinating disease

The pathognomonic feature of
of the central nervous system that results from infection of oligodendrocytes by the
PML is the oligodendrocytes
in areas of demyelination, JC polyomavirus. Signs and symptoms of PML are varied but include dementia and
which have a ground-glass ataxia along with abnormal vision and speech. PML occurs as a terminal complication in
appearance of their nuclei due to immunosuppressed individuals, especially individuals with AIDS.
infection with the viral particles. Neurosyphilis: Neurosyphilis, a tertiary stage of syphilis, includes syphilitic meningitis,
paretic neurosyphilis, and tabes dorsalis.

Syphilitic meningitis is characterized by perivascular infiltrates of lymphocytes and
O
D RSALIS plasma cells that cause obliterative endarteritis and meningeal fibrosis.
Tabes dorsalis is the result of degeneration of the posterior columns of the spinal cord.
D Dorsal column degeneration
OO
rthopedic pain (Charcot This is caused by compression atrophy of the posterior spinal sensory nerves, which
joints) produces impaired joint position sensation, ataxia, loss of pain sensation (leading
R Reflexes decreased (deep to joint damage, i.e. Charcot joints), and Argyll Robertson pupils (pupils that react to
tendon)
accommodation but not to light).
S Shooting pain
A Argyll-Robertson pupils
Prion diseases: The spongiform encephalopathies include Creutzfeldt-Jakob disease (CJD), Gerst-
L Locomotor ataxia
mann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia, and kuru. Microscopically, there
I Impaired proprioception
is characteristic spongiform change in the gray matter (cluster of grapes vacuolation) without inflam-
S Syphilis
mation.
All of the spongiform encephalopathies are associated with abnormal forms of a prion
protein (PrP). Disease results from alternate folding of the normal a-helix (called PrPc) to
an abnormal b-pleated sheet form (called PrPsc). This conformational change can occur
spontaneously at a very slow rate. Once formed, however, PrPsc can combine with PrPc
to much more quickly form many more PrPsc particles, which can crystallize and form
plaques. PrPc can also form PrPsc at much higher rates if mutations are present in PrPc, which
can result from mutations in the gene that codes for PrPc called PRNP. Mutations in this
gene have been identified in patients with the familial forms of CJD, GSS, and fatal familial
insomnia.
Note: SOD1 mutations are seen with amyotrophic lateral sclerosis (ALS), FGFR3 mutations
with achondroplasia, UBE3A mutations with Angelmans syndrome, and PTEN mutations with
endometrial and prostate cancers.
CSF Findings in CNS Infections
Parameters Normal values B
acterial Tuberculous Viral Meningitis
Meningitis Meningitis
Pressure 50-180 mm water Raised Raised Raised
Gross appearance Clear and colorless Turbid Clear (may clot) Clear
Protein 20 50 mg/dL High Very High Slightly high
Glucose 40-70 mg/dL Very low Low Normal
Chloride 116 122 g/dL Low Very low Normal
Cells < 5/microlitre Neutrophils Pleocytosis Lymphocytosis
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Meningitis [inflammation of the arachnoid and the cerebrospinal fluid (CSF)] may be
classified as acute pyogenic, aseptic, or chronic. The etiology and CSF findings vary in these
three groups.

The CSF in acute pyogenic meningitis, which is usually caused by bacteria, is grossly In bacterial meningitis,
cloudy (not bloody, which is suggestive of a subarachnoid hemorrhage) and displays majority of organisms originate
increased pressure, increased neurophils, increased protein, and decreased glucose. in nasopharynx whereas

With chronic meningitis, such as that caused by Mycobacterium tuberculosis, the CSF Viral meningitis is most often
is clear grossly, with only a slight increase in leukocytes (either mononuclear cells transmitted by fecal-oral route.
or a mixed infiltrate), a markedly increased protein level, increased pressure, and
moderately decreased or normal amounts of sugar.
Brain abscesses and subdural empyemas, which are parameningeal infections
rather than direct meningeal infections, cause increased CSF pressure (more marked
with abscess because of mass effect) along with increased inflammatory cells
(lymphocytes and polymorphonuclear cells) and increased protein but a normal
glucose level. The CSF is clear.

Encephalitis, also not a direct infection of the meninges, results in clear CSF, increased Meningitis
CSF protein (viral, bacterial, fungal)
pressure, increased protein, normal glucose, and possibly increased lymphocytes.
CSF glucose (bacterial, fungal)
DEMYELINATING DISORDERS
Multiple Sclerosis
Multiple sclerosis is the
In primary CNS demyelination there is loss of myelin sheaths with relative preservation of most common demyelinating
axons. Primary demyelination is seen predominately in multiple sclerosis, in the perivenous disease.

encephalomyelopathies, and in progressive multifocal leukoencephalopathy (PML).
Multiple sclerosis (MS), a disease of unknown etiology, causes disseminated but focal
plaques of primary demyelination anywhere in the CNS, but often in the white matter near
the angles of the lateral ventricles. It primarily affects young adults between 20 and 40 years
of age, with the onset of symptoms such as abnormalities of vision, tremors, paresthesias,
and incoordination. The course is typically remitting and relapsing. Early findings include
weakness of the lower extremities and visual abnormalities with retrobulbar pain.
Apart from the Charcot triad, another pathognomonic feature in MS is internuclear ophthalmoplegia
(INO), also known as the MLF syndrome, which results from demyelination of the medial longitudinal The classic (Charcot) triad
fasciculus. It results in medial rectus palsy in attempted lateral gaze and monocular nystagmus in in patients with MS consists of
abducting eye with convergence. scanning speech, intension
tremor, and Nystagmus (mnemonic
Examination of the CSF in patients with MS reveals increased T lymphocytes, increased is SIN).
protein, and normal glucose. Protein electrophoresis of the CSF reveals oligoclonal bands
(individual monoclonal spikes), although this latter finding is not specific for MS.
Neuromyelitis Optica (also known as Devic disease)
It is characterized by the development of synchronous bilateral optic neuritis and spinal cord
demyelination.
DEGENERATIVE DISORDERS
The degenerative diseases of the CNS are diseases that affect the gray matter and are
characterized by the progressive loss of neurons in specific areas of the brain.
Alzheimers Disease
Alzheimers disease (AD) is the most common cause of dementia in elderly (followed by
vascular multi-infact dementia and diffuse Lewy body disease). AD often begins insidiously
with impairment of memory and progresses to dementia. Histologically, AD is characterized
by numerous neurofibrillary tangles and senile plaques with a central core of amyloid alpha-
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protein. Both tangles and plaques are found to a lesser extent in other conditions, for example,
neurofibrillary tangles in Down syndrome. Silver stains demonstrate tangles and plaques and
AD: density of NF tangles and
senile (neuritic) plaques in the
Congo red shows amyloid deposition in plaques and vascular walls (amyloid angiopathy).
brain. In AD there are also numerous Hirano bodies, and granulovacuolar degeneration is found
in more than 10% of the neurons of the hippocampus. Grossly, brain atrophy (narrowed gyri
NF tangles: hyperphosphoryl- and widened sulci) is predominant in the frontal and superior temporal lobes.
ated tau protein in neuron.
The etiology of AD is not well understood, but it is clear that there are multiple etiologic
pathways to this disease state. Alzheimers disease has been linked to abnormalities
involving four specific genes. Cleavage of the beta-amyloid precursor protein (beta-APP)
by alpha-secretase precludes beta-A formation; but cleavage of beta-APP by beta-secretase
Age is the main risk factor for AD
(BACE-1) or gamma-secretase produces fragments that tend to aggregate into the pathogenic
amyloid fibrils. Beta-amyloid deposition is necessary but not sufficient for the development
of Alzheimers disease. Early-onset familial Alzheimers is also related to mutations in
Concept presenilins. The presenilin 1 (PS1) gene is located on chromosome 14, while the presenilin 2
The gene for beta-amyloid (A-
(PS2) gene is located on chromosome 1.
beta) is located on chromosome
21 and so, the high incidence Parkinsons Disease
of Alzheimers disease is seen
in individuals with trisomy 21 It is characterized by a mask-like facial expression, coarse tremors, slowness of voluntary
(Down Syndrome). movements, and muscular rigidity, there is degeneration and loss of pigmented cells in the
substantia nigra, resulting in a decrease in dopamine synthesis. The decreased synthesis of
dopamine by neurons originating in the substantia nigra leads to decreased amounts and
functioning of dopamine in the striatum. This results in decreased dopamine inhibition and
Idiopathic Parkinsons disease a relative increase in acetylcholine function, which is excitatory in the straitum. The effect
is the most common cause of of this excitation, however, is to increase the functioning of GABA neurons, which are
parkinsonism. inhibitory. The result, therefore, is increased inhibition or decreased movement. The severity
of the motor syndrome correlates with the degree of dopamine deficiency.
Lewy Body Disorders

Lewy bodies (eosinophilic in-
Lewy bodies are intracytoplasmic eosinophilic inclusions that are composed of fine filaments,
tracytoplasmic inclusions) are
found in the surviving neurons of which are densely packed in the core but loose at their rim. These filaments are composed of
the substantia nigra in PD. neurofilament antigens, parkin, and ubiquitin, but the major component of the Lewy body
is alpha-synuclein. The histologic presence of Lewy bodies can be seen in several disorders
(Lewy body disorders) that differ in the location where the Lewy bodies are found.
In classic Parkinsons disease, Lewy bodies are found in the nigrostriatal system (producing
extrapyramidal movement disorder).
Concept In Lewy body dementia, Lewy bodies are found in the cerebral cortex (producing dementia; this
is the third most common cause of dementia).

Unlike Parkinsons disease, how-
In Shy-Dragger syndrome, Lewy bodies are found in sympathetic neurons in the spinal cord
ever, no mutations in the gene
(causing autonomic dysfunction, including orthostatic hypotension, impotence, abnormal sweat
that codes for alpha-synuclein
and salivary gland secretion, and pupillary abnormalities).
have been found with the Shy-
Drager syndrome.
Huntingtons Disease: (HD)
It is characterized by choreiform movements and progressive dementia that appear after the
age of 30. It is an autosomal dominant disorder that results from an abnormal gene (showing
CAG repeats) on chromosome-4. Choreiform movements and progressive dementia appear
after the age of 30. There is degeneration of GABA neurons in the striatum, which leads to
decreased function (decreased inhibition) and increased movement.
HD involves the extrapyramidal
system and atrophy of the Note: Huntingtons disease is one of four diseases that are characterized by long repeating sequenc-
caudate nuclei and putamen. es of three nucleotides (the other diseases being fragile X syndrome, myotonic dystrophy, and spinal
and bulbar muscular atrophy).
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Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs disease, is a degenerative The triad of atrophic weakness
disorder of motor neurons, principally the anterior horn cells of the spinal cord, the motor of hands and forearms, slight
nuclei of the brainstem, and the upper motor neurons of the cerebral cortex. Clinically, spasticity of the legs, and gen-
eralized hyperreflexiain the
this disease is a combination of lower motor neuron (LMN) disease with weakness and absence of sensory changes
fasciculations and upper motor neuron (UMN) disease with spasticity and hyperreflexia. suggests the diagnosis of ALS.
Early symptoms include weakness and cramping and then muscle atrophy and fasciculations.
Reflexes are hyperactive in upper and lower extremities, and a positive extensor plantar Riluzole (NMDA antagonist)
and baclofen are used for the
(Babinski) reflex develops because of the loss of upper motor neurons. The clinical course is
treatment of ALS.
rapid, and death may result from respiratory complications.
TUMORS
CNS tumors can be gliomas, neuronal tumors, poorly differentiated neoplasms, meningiomas
and metastatic tumors. Metastatic tumors are most

1. Gliomas: These are most common group of primary brain tumors. These include common intracranial tumors.
astrocytoma, oligodendroglioma and ependymoma.

a. Astrocytoma

It is the most common primary brain tumors in adults and range from low grade
to very high grade (glioblastoma multiforme). These grades of astrocytomas
include:
Grade I The least aggressive and histologically difficult to differentiate from Astrocytoma is the most com-
reactive astrocytosis. mon primary brain tumors in
Grade II Some plemorphism microscopically. adults
Grade III Anaplastic astrocytoma, characterized histologically by increased

pleomorphism and prominent mitoses.
Grade IV Glioblastoma multiforme. A highly malignant tumor characterized
Glioblastoma multiforme: high
histologically by endothelial proliferation and serpentine areas of necrosis
grade astrocytoma with worst
surrounded by peripheral palisading of tumor cells. It frequently crosses the prognosis.
midline (butterfly tumor).
Progression of low grade astrocytoma to a higher grade (secondary glioblastoma
multiforme) is associated with several genetic abnormalities, such as disruption
of the p16/CDKNZA gene or overexpression of PDGF-A and its receptor.

b. Oligodendroglioma
These most commonly involve the cerebrum (hemispheres) in adults, are slow-
growing tumors that have a high recurrence rate. Some oligodendrogliomas
do proliferate in a rapid and aggressive fashion and may be associated with a
malignant astrocytoma component. Histologically, oligodendrogliomas consist
of sheets of cells with clear halos (fried-egg appearance) and various amounts
of calcification (which can be seen on x-ray). Cytogenetic abnormalities have
therapeutic significance for this type of tumor, as only tumors with deletion
involving 19q or 1p respond to chemotherapy.
E
MC Site of pendymoma

c. Ependymoma In children: typically near fourth
These most often arise next to the ependyma-lined ventricular system, including ventricle whereas
central canal of spinal cord. Spinal cord ependymoma frequently occur in setting In adults: spinal cord.
of neurofibromatosis type 2.
2. Neuronal tumors
The most common CNS tumor containing mature appearing neurons (ganglion cells)
is ganglioglioma. These are most commonly found in temporal lobe and frequently
contain ganglion cells with binucleated forms.
3. Poorly differentiated neoplasms
Most common among these is medulloblastoma. Others include atypical tetroid/
rhabdoid tumor.

a. Medulloblastoma
Primitive neuroectodermal tumors (PNETs) are a type of malignant embryonal
tumor that can be found at sites within or outside of the central nervous system.
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An example of a PNET located outside of the CNS is Ewings sarcoma of bone.

Medulloblastoma is the most PNETs of the CNS can be divided into supratentorial tumors (sPNET) and
common tumor located in the infratentorial tumors (iPNET). The latter are also called as medulloblastoma and
posterior fossa of a child. they usually arise in the midline of the cerebellum (the vermis) but in adults,
where the incidence is much less than in children, they are more apt to arise in
the cerebellar hemispheres in a lateral position. In about one-third of cases, these
show rosette formation centered by neurofibrillary material. Medulloblastomas
grow by local invasive growth and may block cerebrospinal fluid circulation
(CSF block) via compression of the fourth ventricle.
4. Meningioma
Meningioma contain calcified A tumor that is attached to the dura is most likely to be a meningioma. This type
bodies called psammoma bodies. of tumor arises from the arachnoid villi of the brain or spinal cord. Although they
usually occur during middle or later life, a small number occur in persons 20 to 40
years of age. They commonly arise along the venous sinuses (parasagittal, sphenoid
wings, and olfactory groove).
Note: Both oligodendroglioma and craniopharyngioma show calcification fairly frequently, oligoden-
droglioma is often located in the frontal lobe, whereas craniopharyngioma occurs around the third
ventricle and demonstrates suprasellar calcification.
Metastatic tumors
5.
Lung cancer is the most These are most common intracranial tumors. Five most common sites are
common cancer causing meta-
stasis to the brain.
Lung
Breast
Choriocarcinoma has high likeli- Skin (melanoma)
Kidney
hood of metastasizing to brain

whereas prostatic carcinoma
almost never grow in the brain.
GIT.
Note:
Deletion of region 12 on chromosome 22 is the most common cytogenetic abnormality of
meningiomas.
Duplication of the long arm of chromosome 17 is the most common genetic abnormality seen in
medulloblastomas.
CNS Tumors and Age
The location of a tumor and the age of the patient are both very important in the differential
diagnosis of tumors of the central nervous system. Astrocytomas occur predominantly in
the cerebral hemispheres in adult life and old age, in the cerebellum and pons in childhood,
and in the spinal cord in young adult. The pilocytic astrocytoma is a subtype that is the most
common brain tumor in children, and therefore it is also called a juvenile pilocytic astrocytoma.
It is characterized by its location in the cerebellum and better prognosis. Meningiomas, found
within the meninges, have their peak incidence in the fourth and fifth decades. The highly
malignant glioblastoma multiforme is also found primarily in adults. Oligodendrogliomas
also involve the cerebrum in adults. Ependymomas are found most frequently in the fourth
ventricle, while the choroid plexus papilloma, a variant of the ependymoma, is found most
commonly in the lateral ventricles of young boys. The medulloblastoma is a tumor that arises
exclusively in the cerebellum and has its highest incidence toward the end of the first decade.
In children medulloblastomas are located in the midline, while in adults they are found in
more lateral locations.
PERIPHERAL NERVE SHEATH TUMOR
Schwannomas
These are benign tumors that generally appear as extremely cellular spindle cell neoplasms,
sometimes with metaplastic elements of bone, cartilage, and skeletal muscle. Schwannomas
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(neurilemomas) are single, encapsulated tumors of nerve sheaths, usually benign, occurring
on peripheral, spinal, or cranial nerves. The acoustic neuroma is an
Acoustic neuromas typically located at the cerebellopontine angle or in the internal example of a Schwannoma that
acoustic meatus. Initially, when they are small, these tumors produce symptoms by arises from the vestibulococh-
compressing CN VIII and CN VII (facial). CN VIII symptoms include unilateral tinnitus lear nerve (CN VIII).
(ringing in the ear), unilateral hearing loss, and vertigo (dizziness). Involvement of the facial
nerve produces facial weakness and loss of corneal reflex. Histologically, an acoustic neuroma
consists of cellular areas (Antoni A) and loose edematous areas (Antoni B). Verocay bodies
(foci of palisaded nuclei) may be found in the more cellular areas.
Familial Tumor Syndromes
a. Tuberous sclerosis
Tuberous sclerosis is an autosomal dominant syndrome characterized by the clinical
triad of angiofibromas (adenoma sebaceum), seizures, and mental retardation.
Patients develop hamartomas in the central nervous system including tubers, Clinical triad of tuberous sclero-
which are film areas with haphazardly arranged neurons and glia with stout sis is angiofibromas (adenoma
processes. The syndrome is associated with the development of several different sebaceum), seizures, and men-
types of tumors, including subepedymal giant cell tumor, rhabdomyoma of the heart, tal retardation.
and angiomyolipoma of the kidney. Mutations at several loci have been associated
with tuberous sclerosis including the TSC1 locus, which codes for hamartin, and the
TSC2 locus, which codes for tuberin. These two proteins inhibit mTOR, which is the Rhabdomyoma of the heart
mammalian target of rapamycin. mTOR plays a central role in the regulation of cell is highly predicitve of tuberous
growth. sclerosis.

Note: Dysregulation of mTOR activity is associated with several hamartoma syndromes,
including the tuberous sclerosis, von Hippel-Lindau syndrome, Peutz-Jeghers syndrome,
and the PTEN-related hamartoma syndromes.

b. von Hippel-Lindau disease
In this rare autosomal dominant disorder, multiple benign, and malignant
neoplasms occur. These include hemangioblastomas of retina and brain (cerebellum
and medulla oblongata), angiomas of kidney and liver, and renal cell carcinomas
(multiple and bilateral) in 25 to 50% of cases.

c. Neurofibromatosis type 1
Classic neurofibromatosis (NF-1) is an autosomal dominant disorder. It is characterized
by cafe-au-lait skin macules, axillary freckling, multiple neurofibromas, plexiform
neurofibromas, and Lisch nodules (pigmented iris hamartomas). Lisch nodules Hamartomas of the iris are not
are found in 95% of patients after age 6. There is increased risk of developing present in central or acoustic
neurofibromatosis (NF-2), though
meningiomas or even pheochromocytoma. A major complication of NF-1 is the both types of neurofibromatosis
malignant transformation of a neurofibroma to a neurofibrosarcoma. The gene for produce cafe-au-lait macules
the classic form (NF-1) is lcoated on chromosome 17. It encodes for neurofibromin, a and neurofibromas.
protein that regulates the function of p21 oncoprotein.

d. Neurofibromatosis type 2
Central neurofibromatosis (NF-2) is an autosomal-dominant disorder in which
patients develop a range of tumors, most commonly bilateral VIII nerve
schwannomas and multiple meningiomas. Gliomas, typically ependymomas of the
spinal cord, also occur in these patients. Many individuals with NF2 also have non-
neoplastic lesions, which include nodular ingrowth of Schwann cells into the spinal Only the central, or acoustic,
form produces bilateral acoustic
cord (schwannosis), meningioangiomatosis (a proliferation of meningeal cells and neuromas; the classic form
blood vessels that grows into the brain), and glial hamartia (microscopic nodular may produce unilateral acoustic
collections of glial cells at abnormal locations, often in the superficial and deep neuroma.
layers of cerebral cortex). The NF2 gene is located on chromosome 22 and encodes
for merlin.
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developmental defects, cerebral hemorrhage, 7. A 17 year old female presents with a history of fever and
aneurysm headache and now develops altered sensorium. CT scan
shows basal exudates with meningeal enhancement. The
1. Cervical syringomyelia all are seen except CSF is most likely to show (AIIMS Nov 2011)

(a) Burning sensation in hands (AIIMS Nov 2012)
(a) Lymphocytic pleocytosis, low sugar, low protein

(b) Hypertrophy of abductor pollicis brevis
(b) Polymorphonuclear pleocytosis, normal sugar, high

(c) Extensor plantar response is present

protein

(d) Absent biceps reflex. (c) Lymphocytic pleocytosis, low sugar, high protein

(d) Lymphocytic pleocytosis, normal sugar, high protein
2. The best described etiology for Berry aneurysm is

which of the following? (AIIMS May 2011) 8. Inclusion body in oligodendroglia is a feature of which

(a) Degeneration of internal elastic lamina

of the following? (AIIMS Nov 2010)
(b) Degeneration of tunica media

(a) Progressive Multifocal Leucoencephalopathy
(c) Defect in muscular layer

(b) Japanese Encephalitis
(d) Low grade inflammation in the vessel wall

(c) Polio
(d) CJD
3. The defect in Berry aneurysm is (AIIMS May 2010)

(a) Degeneration of internal elastic lamina 9. Which of the following is not a Prion disease?
(DPG 2011)
(b) Degeneration of media

(a) Creutzfeldt- Jakob disease
(b) Fatal familial insomnia

(c) Deposition of mucoid material in media

(d) Low grade inflammation of vessel wall (c) Gerstmann-Straussler-Scheinker syndrome
4. Which of the following would distinguish hydro-

(d) Parkinsons disease
cephalus due to aqueductal stenosis when compared to 10. All of the following diseases show abnormal folding of
that due to Dandy walker malformation?
proteins except: (AIIMS Nov 2008)

(a) Third ventricle size (AIIMS Nov 2002)
(a) Creutzfeldt-Jakob disease
(b) Posterior fossa volume
(b) Prion disease
(c) Lateral ventricular size

(c) Multiple sclerosis
(d) Head circumference

(d) Amyloidosis
11. Prion includes: (AIIMS Nov 2007)
5. Most common site for berry aneurysm is: (UP 2002)
(a) DNA and RNA (b) Only RNA
(a) Basilar artery
(c) Proteins (d) Only DNA
(b) Anterior communicating artery
(c) Posterior communicating artery 12. Pathologic features of brain in AIDS are all, except:

(d) Posterior cerebral artery (a) Perivascular giant cell invasion

(b) Microglial nodules
(AIIMS Nov 2001)

(c) Vasculitis

(d) Temporal lobe infarction
5.1. Middle meningeal vessel damage results in: 13. Febrile response in CNS is mediated by: (PGI Dec 2003)

(a) Subdural hemorrhage
(a) Bacterial toxin (b) IL-l

(b) Extradural hemorrhage
(c) IL-6 (d) Interferon

(c) Subarachnoid hemorrhage
(e) Tumor Necrosis Factor

(d) Intracerebral hemorrhage
14. Cerebral infarction is caused by: (PGI June 01)
cns infections demyelinating disease
(a) Toxoplasma (b) Cryptococcus
,
(c) Aspergillus (d) Mucor
6. Enzymes found in CSF: (AIIMS Nov 2012)

(e) Histoplasma

(a) GGT+ALP 15. Complications of tubercular meningitis are:

(a) Endarteritis (PGI Dec 2000)

(b) ALP+CK-MB

(b) Hydrocephalus

(c) CK+LDH

(c) Deafness

(d) Deaminase and Peroxidase

(d) Venous sinus infarct
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16. The pathogenesis of cerebral malaria includes: 2 0.5. Albumino-cytologic dissociation occurs in cases of:

(a) Cytoadhesion (PGI Dec 2000)
(a) Guillain Barre syndrome

(b) Sequestration of cerebral vessels by RBCs
(b) TB meningitis

(c) Reticulocytopenia
(c) Motor neuron disease

(d) Also caused by P. vivax
(d) Demyelinating disorder

(e) Sporozoites are sequestrated in blood
20.6. Dissociated sensory loss is seen in:
17. Brain infarct is seen in: (PGI Dec 2003)
(a) Syringomyelia

(a) TB
(b) Vitamin B12 deficiency

(b) Cryptococcosis
(c) Transverse myelitis

(c) Aspergillosis
(d) Pellagra

(d) Toxoplasmosis
20.7. Locomotor ataxia, a late manifestation of syphilis due

(e) Rabies
to parenchymatous involvement of the spinal cord is

18. Commonest cause of cerebral infarction is: (DNB- 2000) called:

(a) Arterial thrombosis
(a) General paralysis of insane

(b) Arteritis
(b) Tabes dorsalis

(c) Venous thrombosis
(c) Meningovascular syphilis

(d) Embolism
(d) Syphilitic amyotrophy
19. Albumino-cytologic dissociation occurs in cases of:
(a) Guillain Barre syndrome (DNB- 2004) alzheimer disease, parkinson disease and other
(b) TB meningitis degenerative disease
(c) Motor neuron disease
(d) Demyelinating disorder 21. Disease or infarction of neurological tissue causes it to
20. Most common type of pathological changes seen in be replaced by: (AI 2002)
Rabies are: (UP 2000) (a) Fluid
(b) Neuroglia

(a) Meningitis (b) Cranial arteritis
(c) Ventriculitis (d) Brain stem encephalitis (c) Proliferation of adjacent nerve cells
(d) Blood vessel
Most Recent Questions 22. Nucleus involved in Alzheimers disease is:
20.1. All of the following are seen in thymoma except

(a) Nucleus Basalis of Meynert (Delhi PG-2005)

(b) Superior salivary nucleus
(a) Hypogamma globulinemia

(c) Ventromedial nucleus of thalamus
(b) Hyperalbuminemia

(c) Red cell aplasia


(d) Myasthenia Gravis 23. Damage to nervous tissue is repaired by:
(a) Neuroglia (DNB- 2001,2005)
20.2. Spongiform degeneration of cerebral cortex occurs in (b) Fibroblasts
which of the following? (c) Axons

(a) Subacute sclerosing panencephalitis (d) Microglia

(b) Fatal familial insomnia
24. The following is not a feature of Alzheimers disease:

(c) Creutzfeldt-Jakob disease
(a) Neurofibrillary tangles (DNB- 2007)

(d) Cerebral toxoplasmosis
(b) Senile (neuritic) plaques
20.3. What is the histological appearance of brain in (c) Amyloid angiopathy
Creutzfeldt-Jakob disease? (d) Lewy bodies

(a) Neuronophagia 25. Neurofibrillary tangles are seen in: (UP 2007)

(b) Spongiform change in brain (a) Parkinsonism

(c) Microabscesses (b) Alzheimers disease

(d) Demyelination (c) Multiple sclerosis
20.4. Perivascular lymphocytes and microglial nodules are (d) Perivenous encephalomyelitis
seen in: 26. Dementia in an old man with senile plaques is usually

(a) Multiple sclerosis associated with: (AP 2004)

(b) CMV meningitis (a) Alzheimers disease

(c) Bacterial meningitis (b) Picks disease

(d) HIV encephalitis (c) Parkinsons disease
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Most Recent Questions 30. Which of the following brain tumors does not spread
via CSF? (DPG 2011)
26.1. Most common site for medulloblastoma is:
(a) Germ cell tumors (b) Medulloblastoma

(a) Medulla
(b) Cerebellum
(c) CNS Lymphoma (d) Craniopharyngioma

(c) Cerebrum
(d) Pineal gland
31. A metastatic carcinoma in the brain of an adult, most
26.2. Medulloblastoma most common metastasis is to: often comes from a primary in the:
(AIIMS Nov 2005)
(a) Lung (b) Liver
(a) Stomach
(b) Ovary
(c) Spleen (d) CNS
(c) Oral cavity
(d) Lung
26.3. Rosenthal fibres are seen in which of the following 32. Which of the following is true about Medullo-
tumours? blastoma? (PGI Dec 2005)

(a) Pilocytic astrocytoma (a) Radiosensitive tumor

(b) Glioblastoma (b) Spreads through CSF

(c) Medulloblastoma (c) Surgical treatment not done

(d) Ependymoma (d) Occurs in young age group
26.4. Most common cerebellar tumor in children? 33. Commonest type of intracranial tumor is:
(a) Medulloblastoma (a) Astrocytoma (DNB- 2000, 2004, 2007)
(b) Ependymoma (b) Medulloblastoma
(c) Astrocytoma (c) Meningioma
(d) PNET (d) Neurofibroma
(e) Secondaries
26.5. Commonest type of intracranial tumor is: 34. Most common CNS tumor is: (RJ 2000)
(a) Astrocytoma (b) Medulloblastoma
(c) Meningioma (d) Secondaries (a) Astrocytoma (b) Meduloblastoma
(c) Meningioma (d) Oligodendroma
2 6.6. Which of the following is affected in patients with
35. Glial fibrillary proteins are present in: (RJ 2002, 2006)
Alzheimers disease?
(a) Astrocytoma (b) Meduloblastoma

(a) Parietal and frontal lobe
(c) Ependymoma (d) All
(b) Parietal and temporal lobe
(c) Temporal and occipital lobe 36. Enamel like superstructure is seen in which CNS
(d) Parietal and occipital lobe lesion? (AP 1998, TN 1 (AP 2001)
(a) Craniopharyngioma
2 6.7. Lewy bodies are found in the substantia nigra neurons (b) Pituitary tumour
in (c) Astrocytoma
(a) Alzheimer disease (d) Glioma
(b) Parkinson disease
(c) Huntington disease 37. Pseudorosettes are seen in all except: (AP 2002)
(d) Pick disease (a) Neuroblastoma (b) Retinoblastoma
(c) Medulloblastoma (d) Thecoma
26.8. Tuberous sclerosis is associated with all EXCEPT:
(a) Ash leaf macule 38. Most common intracranial malignancy is:
(b) Shagreen patch (a) Glioblastoma multiforme (Jharkhand 2003)
(c) Schwannoma (b) Ependymoma
(d) Adenoma sebaceum (c) Choroid angioma
(d) Pinealoma
cns tumours 39. Worst prognosis meningioma is: (Jharkhand 2005)

(a) Syncytial (b) Fibroblastic
(c) Anaplastic (d) Atypical
27. Which of the following receptor on neuronal membrane
that induces development of glioma? (AIIMS Nov 2012)
(a) CD45 (b) CD133
(c) CD33 (d) CD24 39.1. Commonest cause of cerebral infarction is:
28. Pituitary adenomas are regarded as macroadenomas (a) Arterial thrombosis
when their size is (AI 2012) (b) Arteritis
(a) > 1 cm (b) > 1.5 cm (c) Venous thrombosis
(c) > 2 cm (d) > 2.5 cm (d) Embolism
29. Which is not a neuronal tumor? (AI 2011) 3 9.2. Damage to nervous tissue is repaired by:
(a) Ependymoma (b) Neuroblastoma (a) Neuroglia (b) Fibroblasts
(c) Gangliocytoma (d) Ganglioglioma (c) Axons (d) Microglia
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39.3. The following is not a feature of Alzheimers disease: 1. Assertion: Berry aneurysm is the commonest cause of

(a) Neurofibrillary tangles subarachnoid hemorrhage

(b) Senile (neuritic) plaques Reason: Rupture of the aneurysm occurs commonly in

(c) Amyloid angiopathy childhood

(d) Lewy bodies

39.4. Which of the following is incorrect about neuro-
2. Assertion: B12 deficiency causes subacute combined
blastoma? degeneration of the spinal cord

(a) Most common abdominal tumor in infants Reason: B12 deficiency causes degeneration of both the

(b) X-ray abdomen shows calcification ascending and descending tracts of the spinal cord

(c) Can show spontaneous regression 3. Assertion: Alzheimers disease is associated with Down

(d) Urine contains 5H.I.A.A
syndrome
aSSERTION AND REASON QUESTIONS Reason: Beta amyloid gene is located on chromosome 21
1-5. Will have two statements, assertion and reason. Read
4. Assertion: Shy-Dragger syndrome is characterized by
autonomic dysfunction
options.
Reason: Lewy bodies are found in nigrostriatal neurons

(a) Both assertion and reason are true and reason is 5. Assertion: Huntingtons disease is characterized by
correct explanation of assertion. chorea and dementia

(b) Both assertion and reason are true and reason is not Reason: Degeneration of GABA neurons in the striatum
the correct explanation of assertion.
leads to decreased function (decreased inhibition) and

(c) Assertion is true and reason is false.
increased movement.

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E xplanations
1. Ans. (b) Hypertrophy of abductor pollicis brevis (Ref: Robbins 8th/1286, 9/e p1258)
Atrophy and not hypertrophy of the abductor pollicis brevis is a feature of syringomyelia.
Syringomyelia
It is a chronic myelopathy that results from formation of a cavity (syrinx) involving the central gray matter of the spinal cord. The
cause of syringomyelia is unknown, although one type is associated with a Chiari malformation with obstruction at the foramen
magnum.
Since the gray matter is the location where pain fibers cross to join the contralateral spinothalamic tract, the interruption of the
lateral spinothalamic tracts results in segmental sensory dissociation with loss of pain and temperature sense, but preservation of
the sense of touch and pressure or vibration, usually over the neck, shoulders, and arms.
The most common location of a syrinx is the cervicothoracic region and therefore, the loss of pain and temperature sensation
affects both arms.
Other features of syringomyelia include wasting of the small intrinsic hand muscles (claw hand) and thoracic scoliosis. This
is accompanied by areflexic weakness in the upper limbs. As the cavity enlarges, spasticity and weakness of the legs, bladder and
bowel dysfunction as well as Horner syndrome appear due to compression of the long tracts.
The diagnosis of syringomyelia is best made with MRI of the spine (cervical region should be examined first)
2. Ans. (b) Degeneration of tunica media (Ref: Robbins 8th/1297-8, 9/e p1270)
Direct quote from Robbins the berry aneurysms develop over time because of an underlying defect in the media of the
vessel.
Concept
It is different from other causes of aneurysm (atherosclerosis, trauma, infections) which cause only cerebral infarction and not
Salient points about Berry aneurysm (saccular aneurysm)

Saccular aneurysm is the most common type of intracranial aneurysm.
Risk factors
Smoking and hypertension are the important risk factors for Berry aneurysm. They are not the result of atherosclerosis (which is
a disease of intima).
Berry aneurysms are called congenital, although the aneurysm itself is not present at birth.
Location
Commonest location is in the circle of Willis, typically at the junction of the anterior communicating artery with the anterior cerebral
arteryQ.
It is also present at the junction of the middle cerebral artery and the posterior communicating artery.
Clinically
It is responsible for a clinically significant subarachnoid hemorrhage. In fact, excluding trauma, berry aneurysm is the commonest
cause of subarachnoid hemorrhage.
The chance of rupture of berry aneurysms increases with age (rupture is rare in childhood). Rupture causes marked bleeding into the
subarachnoid space and produces severe headaches, typically described as the worst headache ever.
3. Ans. (b) Degeneration of media (Ref: Robbins 8th/1297-8, 9/e p1270)
Direct quote from Robbins the berry aneurysms develop over time because of an underlying defect in the media of the
vessel.
Concept
It is different from other causes of aneurysm (atherosclerosis, trauma, infections) which cause only cerebral infarction and not
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4. Ans. (b) Posterior fossa volume (Ref: Robbins illustrated 6th/27691, 9/e p1255)
The basics of CSF production and drainage
CSF production (Occurs by choroid plexus of lateral and IIIrd ventricle)

Foramen of Monro

Third ventricle

Aqueduct of Sylvius

Fourth ventricle

Foramen of Magendie and Lushka

Subarachnoid space (It is absorbed here, by arachnoid villi)
Both Aqueductal stenosis and Dandy Walker syndrome cause non-communicating hydrocephalus but the site of
obstruction is different.
Let us see the causes of hydrocephalus in aqueductal stenosis and Dandy-Walker malformation.
Aqueductal stenosis
In aqueductal stenosis the aqueduct connecting the 3rd and 4th ventricle is stenosed which leads to hydrocephalus with
the dilatation of ventricular system prior to the aqueduct, i.e. lateral ventricles and third ventricle.
Dandy Walker Malformation
In Dandy Walker malformation there is cystic dilatation of the fourth ventricle in the posterior fossa with obstruction
at the formation of Lushka and Magendie.
So the ventricular system in this condition will also be dilated as in aqueductal stenosis but here the posterior fossa is

also enlarged (in contrast to normal posterior fossa size in aqueductal stenosis). i.e.
5. Ans. (b) Anterior communicating artery (Ref: Robbins 9/e p1270, 8th/1297; 7th/1367)
5.1. Ans. (b) Extradural hemorrhage (Ref: Robbins 9th/1261)
6. Ans. (c) CK and LDH (Ref: Chatterjee Shinde 8th/730)
The following enzymes are present in the CSF:
Aspartate transaminase (AST): 5- 12 units/ml. Its value increases in abscess, cerebral hemorrhage and infarction and in primary or
metastatic malignant disease. It may increase in some patients with multiple sclerosis.
Lactate dehydrogenase (LDH): normal value is 5- 40IU/l. Its value increases in abscess, cerebral hemorrhage and infarction and in
metastatic malignant disease.
Increase in LDH4 isoenzyme of CSF is seen in tuberculous meningitis.
Creatine kinase (CK): CK-BB is present in the brain. Its value increases in associated with meningitis, cerebral hemorrhage and
infarction.
>30 units/ml is suggestive of tubercular meningitis and <30 units/ml is suggestive of pyogenic meningitis.
In MI, lDH1 increases but in heart failure, LDH 5 increases because right sided heart failure causing hepatic congestion and
release of LDH5 from them. .Dinesh Puri 3 /122-3
rd
7. Ans. (c) Lymphocytic pleocytosis, low sugar, high protein (Ref: Harrison 18th/3426, Harsh Mohan 6th/appendix)
CT scan shows basal exudates with meningeal enhancement is highly suggestive of tuberculous meningitis. For CSF
changes in CNS infection see text.
8. Ans. (a) Progressive multifocal leukoencephalopathy (PML) (Ref: Robbins 8th/1305, 9/e p1278)
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system that results
from infection of oligodendrocytes by the JC polyomavirus. It occurs almost exclusively in immunocompromised
individuals as in HIV due to reactivation of the virus.
Microscopic examination shows lesions in the white matter which is an area of demyelination, in the center of which
are scattered lipid-laden macrophages and a reduced number of axons. At the edge of the lesion are greatly enlarged
oligodendrocyte nuclei whose chromatin is replaced by glassy amphophilic viral inclusion..Robbins
Significance of microscopic findings in PML
In PML, the virus also infects astrocytes, leading to bizarre giant forms with irregular, hyperchromatic, sometimes multiple nuclei
that can be mistaken for tumor.
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OTHER OPTIONS
In acute cases of Polio, there is mononuclear cell perivascular cuffs and neuronophagia of the anterior horn motor neurons of
the spinal cord.
In CJD, microscopically, there is characteristic spongiform change in the gray matter (cluster of grapes vacuolation) without
inflammation.
9. Ans. (d) Parkinsons Disease (Ref: Harrison 17th/2647, Robbins 8th/1308, 9/e p1281)
Prions disease of humans include:
Iatrogenic Creutzfeldt-Jakob disease
Sporadic Creutzfeldt-Jakob disease
Variant Creutzfeldt-Jakob disease
Fatal Familial Insomnia
Gerstmann-Straussler-Scheinker syndrome
Sporadic Fatal Insomnia
Kuru
10. Ans. (c) Multiple sclerosis (Ref: Harrison 17th/2647; Robbins 9/e p57, 1283-1284)
Disorders caused by misfolding of proteins are
Amyloidosis
Alzheimers disease and other neurodegenerative diseases
Transmissible prion diseases like CJD
Some genetic diseases caused by mutations that lead to misfolding of protein and loss of function, such as certain of
the cystic fibrosis mutations.
Prions are infectious proteins that cause degeneration of the central nervous system (CNS). Prion diseases are disorders
of protein conformation, the most common of which in humans is called Creutzfeldt-Jakob disease (CJD). CJD typically
presents with dementia and myoclonus, is relentlessly progressive, and generally causes death within a year of onset.
Four new concepts have emerged from studies of prions:
Prions are the only known infectious pathogens that are devoid of nucleic acid; all other infectious agents possess genomes
composed of either RNA or DNA that direct the synthesis of their progeny.
Prion diseases may manifest as infectious, genetic, and sporadic disorders; no other group of illnesses with a single etiology
presents with such a wide spectrum of clinical manifestations.
Prion diseases result from the accumulation of PrPSc, the conformation of which differs substantially from that of its precursor, PrPC.
PrPSc can exist in a variety of different conformations, each of which seems to specify a particular disease phenotype. How a specific
conformation of a PrPSc molecule is imparted to PrPC during Prion replication to produce nascent PrPSc with the same conformation
is unknown. Additionally, it is unclear what factors determine where in the CNS a particular PrPSc molecule will be deposited.
11. Ans. (c) i.e. Proteins (Ref: Harrison 17th/2646; 16th/2495, 9/e p1281)
Prions are infectious proteins that cause degeneration of the central nervous system (CNS). Prion diseases are
disorders of protein conformation, the most common of which in humans is called Creutzfeldt-Jakob disease (CJD).

In mammals, prions reproduce by binding to the normal, cellular isoform of the prion protein (PrPC) and stimulating
conversion of PrPC into the disease-causing isoform (PrPSc). PrPC is rich in alpha-helix and has little beta-structure,
while PrPSc has less alpha-helix and a high amount of beta-structure. This alpha-to-beta structural transition in the
prion protein (PrP) is the fundamental event underlying prion diseases.

Prions are the only known infectious pathogens that are devoid of nucleic acid; all other infectious agents possess
genomes composed of either RNA or DNA that direct the synthesis of their progeny.
Prion diseases may be manifest as infectious, genetic, and sporadic disorders
The sporadic form of CJD is the most common prion disorder in humans. Familial CJD (fCJD), Gerstmann-Straussler-
Scheinker (GSS) disease, and fatal familial insomnia (FFI) are all dominantly inherited prion diseases that are caused
by mutations in the PrP gene.

Although infectious prion diseases account for <1% of all cases and infection does not seem to play an important
role in the natural history of these illnesses, the transmissibility of prions is an important biologic feature. Kuru is an
infectious prion disease thought to have resulted from the consumption of brains from dead relatives during ritualistic
cannibalism in New Guinea.

A major feature that distinguishes prions from viruses is the finding that both PrP isoforms are encoded by a chromo-
somal gene. In humans, the PrP gene is designated PRNP and is located on the short arm of chromosome 20.

Accidental transmission of CJD to humans appears to have occurred with corneal transplantation, contaminated
electroencephalogram (EEG) electrode implantation, surgical procedures, implantation of dura mater grafts and from
contaminated human growth hormone preparations.

On light microscopy, the pathologic hallmarks of CJD are spongiform degeneration and astrocytic gliosis. The lack of
an inflammatory response in CJD and other prion diseases is an important pathologic feature of these degenerative
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disorders. Spongiform degeneration is characterized by many 1- to 5-micrometers vacuoles in the neuropil between
nerve cell bodies. Amyloid plaques have been found in ~10% of CJD cases.
In variant CJD, a characteristic feature is the presence of florid plaques. These are composed of a central core of PrP
amyloid, surrounded by vacuoles in a pattern suggesting petals on a flower.
The constellation of dementia, myoclonus, and periodic electrical bursts in an afebrile 60-year-old patient generally
indicates CJD.
12. Ans. (c) Vasculitis (Ref: Anderson10th/2728, Robbins 9/e p1278)
Anderson clearly mentioned that Unlike most other encephalitides, HIV does not seem to infect neurons and perivascu-
litis is conspicuously absent
Characteristic multinuclear Giant Cells of Macrophage origin are seen in white matter of frontal and temporal lobes
particularly in perivascular location
Feature of CNS involvement in AIDS
Diffuse and focal spongiform changes
Vacuolar myelopathy of posterior column of spinal cord
Major cells affected are macrophages and monocytes
Most characteristics finding is chronic inflammatory reaction with widely distributed infiltrates of microglial nodules
13. Correct answer: (a) Bacterial toxin; (b) IL-l; (d) Interferon; (e) Tumor necrosis factor (TNF). (Ref: Robbins 7th/84,
Harrison 16th/106)
Fever is produced in response to substances called pyrogens that act by stimulating prostaglandin synthesis in the vascular
and perivascular cells of hypothalamus.
They can be classified as
Exogenous pyrogensLipopolysaccharides (bacterial toxin) stimulate WBCs to release endogenous pyrogens.
Endogenous pyrogens IL-1 (, ) and TNF-, IL-6, Ciliary neurotropic factor and interferons that increase the
enzyme (cyclooxygenase) that converts arachidonic acid into prostaglandins.
NSAIDs reduce fever by inhibiting cyclooxygenase.

14. Ans. (a) Toxoplasma; (c) Aspergillus; (d) Mucor (Ref: Robbins 7th/1363, 1378)
Arteritis of small and large vessels causes cerebral infarcts.
Causes of cerebral infarction:
Syphilis
Tuberculosis
Infectious vasculitis in setting of immunosuppression
Toxoplasmosis
Aspergillosis
CMV encephalitis
Mucormycosis
15. Ans. (a) Endarteritis; (b) Hydrocephalus (Ref: Robbins 9/e p1274, 7th/1371, OPG 6th/520-22)
Most serious complication of chronic tubercular meningitis
Arachnoid fibrosis Hydrocephalous
Obliterative endarteritis Arterial occlusion and infarction of underlying brain.
Spinal roots may also be affected.
Calcification
Tuberculomas
16. Ans. (a) Cytoadhesin ; (b) Sequestration of cerebral vessels by RBCs (Ref: Harrison 16th/1222, Robbins 9/e p391)
Cerebral malaria is caused by P. falciparum.
Pathophysiology of cerebral malaria
Cytoadhesion: On the surface of infected RBC appears an antigen called PfEMP1 (P. falciparum erythrocyte membrane
protein-I). Due to this antigen infected RBCs adheres in the blood vessels.
Sequestration: It is the key events of falciparum pathology. Brain capillaries especially capillaries of white matter of brain
are plugged with parasitized RBCs which terminally leads to thrombosis. Three receptors for parasitized RBC have been
identified (ICAM - 1, CD36, thrombospondin). These cause focal cerebral damage.
Rosetting occurs in middle of a sexual life cycle. It is seen in cerebral malaria in brain capillaries.
17. Ans. (a) T.B.; (c) Aspergillosis; (d) Toxoplasmosis. (Ref: Robbins 7th/1363, 1378)
18. Ans. (a) Arterial thrombosis (Ref: Robbins 8th/1291-1292, 9/e p1263)
19. Ans. (a) Guillain Barre syndrome (Ref: Harrison 17th/2667, Robbin 9/e p1231)
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20. Ans. (d) Brain stem encephalitis (Ref: Robbins 9/e p1277, 8th/1304-1305; 7th/1375)
2 0.1. Ans. (b) Hyperalbuminemia (Ref: Robbins 8/e p636-7, 9/e p627)
Direct linesIn addition to myasthenia gravis, other associated autoimmune disorders with thymoma include
hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious anemia, dermatomyositis-polymyositis, and Cushing
syndrome.
20.2. Ans. (c) Creutzfeldt-Jakob disease (CJD) (Ref: Robbins 9/e p1282)
In CJD, on microscopic examination, the pathognomonic finding is a spongiform transformation of the cerebral
cortex and, often, deep gray-matter structures (caudate, putamen).
This multifocal process results in the uneven formation of small, apparently empty, microscopic vacuoles of varying
sizes within the neuropil and sometimes in the perikaryon of neurons.
In advanced cases there is severe neuronal loss, reactive gliosis, and sometimes expansion of the vacuolated areas into
cystlike spaces (status spongiosus).
No inflammatory infiltrate is present.
20.3. Ans. (b) Spongiform change in brain.see earlier explanation. (Ref: Robbins 9/e p1282)
20.4. Ans. (d) HIV encephalitis (Ref: Robbins 8/e p1375, 9/e p1278)
HIV encephalitis is best characterized microscopically as a chronic inflammatory reaction with widely distributed
infiltrates of microglial nodules.
The microglial nodules are also found in the vicinity of small blood vessels, which show abnormally prominent
endothelial cells and perivascular foamy or pigment-laden macrophages. These changes occur especially in the
subcortical white matter, diencephalon, and brainstem.
An important component of the microglial nodule is the macrophage-derived multinucleated giant cell.
20.5. Ans. (a) Guillain Barre Syndrome (Ref: Robbins 8/e p1262, 9/e p1231, Harrison 17/e p2667)
In patients with Guillanin Barre syndrome, there is elevation of the CSF protein due to inflammation and altered perme-
ability of the microcirculation within the spinal roots as they traverse the subarachnoid space. Inflammatory cells are
contained within the roots, however, and there is little to no CSF pleocytosis. This is termed as albumin-cytological dis-
sociation.
20.6. Ans. (b) Syringomyelia (Ref: Robbins 9th/1258)
20.7. Ans. (b) Tabes dorsalis (Ref: Robbins 9th/1275)

Tabes dorsalis is the result of damage to the sensory axons in the dorsal roots. This causes impaired joint position
sense and ataxia (locomotor ataxia); loss of pain sensation, leading to skin and joint damage (Charcot joints); other
sensory disturbances like the characteristic lightning pains; and absence of deep tendon reflexes.

Meningovascular neurosyphilis is chronic meningitis involving the base of the brain. It may be associated with
obliterative endarteritis (Heubner arteritis) accompanied by a distinctive perivascular inflammatory reaction.
Cerebral gummas (plasma cell-rich mass lesions) may also be present.

General paresis of the insane is caused by the invasion of the brain by T. pallidum. It manifests as progressive cognitive
impairment associated with mood alterations (including delusions of grandeur) terminating in severe dementia.

Syphilitic amyotrophy presents with painless and progressive weakness.
21. Ans. (b) Neuroglia (Ref: Robbins 7th/1349, 9/e p1252)
Neuroglia (astrocytes) are the principal cells in the central nervous system responsible for reaction to injury repair
and scar formation in the brain. They perform function similar to fibroblasts in the CNS.
Gliosis is the most important histopathological indicator of CNS injury. Astrocytes participate in this process by
undergoing both hypertrophy and hyperplasia.
Neuroglial cells can be ectodermal in origin (e.g. astrocytes and oligodendrocytes) or derived from mesoderm (microglia).

Microglia resemble macrophages and act as scavenger cells whereas oligodendrocytes help in myelin formation
[similar to Schwann cells in PNS]
22. Ans. (a) Nucleus basalis of Meynert (Ref: Harrison 16th/2395, Robbins 9/e p1290)
The brain of Alzheimers disease patients shows severe neuronal loss in the nucleus basalis of Meynert, the major source
of cholinergic input to cerebral cortex.
The major microscopic abnormalities of Alzheimers disease are:
Neurofibrillary tangles, neuropil threads
Senile (Neuritic) plaques
Amyloid angiopathy
Granulovacuolar degeneration
600
A dominant component of the plaque core is A, a peptide of approximately 40-43 amino acid residues derived from
a larger molecule, amyloid precursor protein (APP).
Although neurofibrillary tangles are characteristic of Alzheimers disease, they are not specific to this condition.
Hirano bodies: Found especially in Alzheimers disease, are elongated, glassy, eosinophilic bodies consisting of
paracrystalline arrays of beaded filaments with actin as their major component.
23. Ans. (d) Neuroglia (Ref: Robbins 8th/1282, 9/e p1252)
24. Ans. (d) Lewy bodies (Ref: Robbins 8th/1313-1317, 9/e p1290)
25. Ans. (b) Alzheimers disease (Ref: Robbins 8th/1314)
26. Ans. (a) Alzheimers disease (Ref: Robbins, 9/e p1290, 8th/1113-1117; 7th/1386)
2 6.1. Ans. (b) Cerebellum (Ref: Robbins 8/e p1336, 9/e p1312)
Medulloblastoma
In children, the location is in the midline of the cerebellum, but lateral locations are more often found in adults.
Medulloblastomas are the most common malignant brain tumor of childhood
5% of children have it in association with Gorlin syndrome (the most common of the inherited disorders due to
Q
mutations in the patched-1; PTCH-1 gene.

Histologically, there is presence of Homer-Wright rosettes .Q
Dissemination through the CSF is a common complicationQ, presenting as nodular masses elsewhere in the CNS,
including metastases to the cauda equina that are termed drop metastasesQ.
26.2. Ans. (d) CNS.explained earlier (Ref: Robbins 9/e p1312)
2 6.3. Ans. (a) Pilocytic astrocytoma (Ref: Robbins 8/e p1333, 9/e p1309)
On microscopic examination of pilocytic astrocytoma, the tumor is composed of bipolar cells with long, thin hairlike

processes that are GFAP-positive and form dense fibrillary meshworks; Rosenthal fibers and eosinophilic granular bodies, are
often present.
2 6.4. Ans. (c) Astrocytoma (Ref: Robbins 8/e)
2 6.5. Ans. (d) Secondaries (Ref: Robbins 8/e p1339, 9/e p1315)
Metastatic lesions, mostly carcinomas, account for approximately a quarter to half of intra-cranial tumors in hospital-
ized patients.
The meninges are also a frequent site of involvement by metastatic disease.
2 6.6. Ans. (b) Parietal and temporal lobe (Ref: Robbin 8/e p1314)
Grossly, the brain shows a variable degree of cortical atrophy marked by widening of the cerebral sulci that is most pro-
nounced in the frontal, temporal, and parietal lobes.. (Ref: Robbind 8/e p 1314
Hippocampus and other medial temporal lobe structures are the earliest and most severely affected in Alzheimers disease.

Bradleys Neurology mentions that.. cortical atrophy is most pronounced in the temporal and parietal lobe with the
frontal lobe involvement being later in the disease.
26.7. Ans. (b) Parkinson disease (Ref: Robbins 9th/1294)
26.8. Ans. (c) Schwannoma (Ref: Robbins 9th/1316-7)
Tuberous sclerosis is an autosomal dominant syndrome characterized by the development of hamartomas and be-
nign neoplasms involving the brain and other tissues. Elsewhere in the body, renal angiomyolipomas, retinal glial
hamartomas, pulmonary lymphangioleiomyomatosis and cardiac rhabdomyomas develop over childhood and ado-
lescence. Cysts may be found at various sites, including the liver, kidneys, and pancreas.
Cutaneous lesions include angiofibromas, localized leathery thickenings (shagreen patches), hypopigmented areas
(ash-leaf patches), sebaceous adenomas and subungual fibromas.
27. Ans. (b) CD133 (Ref: Wintrobes 12th/2559)

CD 133 is used as a marker for leukemia and glioblastoma stem cell. It is also used for identifying immature leukemic
stem cell in AML and pro B leukemia.

CD 45 is required for lymphocyte activation. Its deficiency causes Severe Combined Immunodeficiency disease
(SCID).
28. Ans. (a) > 1cm (Ref: Robbins 8th/1100, 9/e p1075)
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Pituitary adenomas are designated as the following:

Microadenomas if they are less than 1 cm in diameter and
Macroadenomas if they exceed 1 cm in diameter
The most common cause of hyperpituitarism is an adenoma arising in the anterior lobe.
29. Ans. (a) Ependymoma (Ref: Robbins 8th/1330, 9/e p1306)
The four major classes of brain tumors are:
1. Gliomas
Astrocytoma

Pleomorphic xanthoastrocytoma

Brainstem glioma

Pilocytic astrocytoma

Fibrillary (diffuse) astrocytomas

Glioblastoma
Oligodendroglioma
Ependymoma
2. Neuronal tumors
Ganglion cell tumors
Gangliocytoma
Ganglioglioma
Dysembryoplastic neuroepithelial tumor
Cerebral neuroblastomas
3. Poorly differentiated neoplasms
4. Meningiomas
30. Ans. (d) Craniopharyngioma (Ref: Robbins 8th/1106, 9/e p1082)

Brain tumors spreading via CSF are

Ependymoma

Medulloblastoma

Choroid plexus carcinoma

Astrocytoma

Germinoma

Pineoblastoma

CNS Lymphoma
31. Ans. (d) Lung (Ref: Robbins 8th/1339, 9/e p1315)
32. Ans. (a) Radiosensitive tumor; (B) Spreads through CSF; (D) Occurs in young age group. (Ref: Robbins 7th/1407;
9/e p1312 Harrison 16th/2455)
Medulloblastoma:
The tumor occurs predominantly in children and exclusively in cerebellum (infratentorial tumor).
Histopathological hallmark is Homer-Wright rosettes.
Dissemination of tumor occurs through CSF.
The tumor is highly malignant.
It is a radiosensitive tumor. Radiotherapy improves the survival in children.
Cranio-spinal irradiation (CSI) reduces the recurrence from CSF dissemination.
33. Ans. (e) Secondaries (Ref: Robbins 8th/1339, 9/e p1315)
34. Ans. (a) Astrocytoma (Ref: Robbins 8th/1330, 9/e p1306)
35. Ans. (a) Astrocytoma (Ref: Robbins 8th/1330, 9/e p1253)
36. Ans. (a) Craniopharyngioma (Ref: Robbins 9/e p1082, 8th/1106; 7th/1129)
37. Ans. (d). Thecoma (Ref: Robbins 8th/1051; 7th/1442)
38. Ans. (a) Glioblastoma multiforme (Ref: Robbins 8th/1330-1331, 9/e p1308)
39. Ans. (c) Anaplastic (Ref: Robbins 9/e p1315, 8th/1339; 7th/1409)
39.1. Ans. (a) Arterial thrombosis (Ref: Robbins 8/e p1291-1292)
The majority of thrombotic occlusions are due to atherosclerosis. The most common sites of primary thrombosis causing
cerebral infarction are the carotid bifurcation, the origin of the middle cerebral artery, and either end of the basilar artery.
Robbins
602
3 9.2. Ans. (d) Neuroglia (Ref: Robbins 8/e p1282, 9/e p1252)
Gliosis is the most important histopathological indicator of CNS injury regardless of its etiology and is characterized by
both hypertrophy and hyperplasia. The chief cell involved in this reaction is an astrocyte. Please remember that the oli-
godendrocytes and the ependyma do not participate in active response to injury.
In contrast, microglia are the fixed macrophage system in the CNS.
3 9.3. Ans. (d) Lewy bodies (Ref: Robbins 8/e p1313-1317, 9/e p1290)
The following are the histopathological features of Alzheimers disease:
Neuritic plaques : diagnostic feature
Neurofibrillary tangles : diagnostic feature
Cerebral amyloid angiopathy (CAA)
Hirano bodies
3 9.4. Ans. (d) Urine contains 5H.I.A.A (Ref: Robbins 9th/478)
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy.
About 90% of neuroblastomas, regardless of location, produce catecholamines, which are an important diagnostic
feature (i.e., elevated blood levels of catecholamines and elevated urine levels of the metabolites vanillylmandelic acid
and homovanillic acid.
Increased urinary 5HIAA is a feature of carcinoid tumour and not neuroblastoma.
EXPLANATIONS TO aSSERTION AND REASON QUESTIONS

Explanations (1-5): While solving assertion reason type of questions, we can use a particular method.
First of all, read both assertion (A) and reason (R) carefully and independently analyse whether they are true or
false.
If A is false, the answer will directly be (d) i.e. both A and R are false. You can note that all other options (i.e. a, b
or c) consider A to be true.

If A is true, answer can be (a), (b) or (c), Now look at R. If R is false, answer will be (c)
a
If both A and R are ture, then we have to know whether R is correctly explaining [answer is (a)] or it is not the
1. Ans. (d) Both assertion and reason are false. (Ref: Robbins 8th/1297, 9/e p1270)
Already explained in text and answer 3.
2. Ans. (a) Both assertion and reason are true and reason is correct explanation of assertion. (Ref: Robbins 8th/1321, 9/e p1304)
Vitamin B deficiency leads to a swelling of myelin layers, producing vacuoles that begin segmentally at the mid-thoracic
12
level of the spinal cord in the early stages. With time, axons in both the ascending tracts of the posterior columns and the
descending pyramidal tracts degenerate. This is called as subacute combined degeneration of the spinal cord.
Concept
Though isolated involvement of descending or ascending tracts may be a feature of many spinal cord diseases, the combined
degeneration of both ascending and descending tracts of the spinal cord is characteristic of vitamin B12 deficiency.
The gene for amyloid precursor protein (APP) is located on chromosome 21. APP gene mutation causes increased
generation of A. Alzheimer disease is associated with trisomy 21. This is related to a gene dosage effect with increased
production of APP and subsequently A.
Other genes linked to early-onset familial Alzheimer disease are:
Chromosomes 14Q and 1Q as these two chromosomes encode highly related intracellular proteins, presenilin-1 (PS1) and presenilin-2
(PS2).
4. Ans. (b) Both assertion and reason are true and reason is not the correct explanation of assertion. (Ref:Robbins 8th/1319-1321)
Shy-Dragger syndrome is characterized by autonomic dysfunction including orthostatic hypotension, impotence, abnor-
mal sweat and salivary gland secretion, and pupillary abnormalities. The Lewy bodies are found in sympathetic neurons
in the spinal cord.
Lewy bodies in the nigrostriatal neurons produce extrapyramidal symptoms and are a feature of classic Parkinsons
disease.
Lewy bodies in the cerebral cortex produce dementia and are a feature of Lewy body dementia.
Concept
Unlike Parkinsons disease, however, no mutations in the gene coding for alpha-synuclein has been found with the Shy-Drager
syndrome.
Huntingtons disease has already been explained in the text. 603
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CHAPTER
PANCREAS
16 Endocrine System
The endocrine pancreas consists of the islets of Langerhans, which contain four major cell
types-b, a, d, and PP (pancreatic polypeptide) cells.
Cell Hormone secreted

b cell Insulin, Amylin Amylin reduces food intake and
weight gain by acting on central
a cell Glucagon
neurons in the hypothalamus.
d cells Somatostatin
PP cells Pancreatic polypeptide (vasoactive intestinal peptide, VIP)
Diabetes Mellitus
Diabetes mellitus is a group of metabolic disorders having the feature of hyperglycemia which results
from either defect in insulin secretion, insulin action, or both. The diagnosis of diabetes is
established by elevation of plasma glucose by any one of three criteria:
A random plasma glucose concentration of 200 mg/dL or higher, with classical signs and symptoms Glysosylated hemoglobin
A fasting glucose concentration of 126 mg/dL or higher on more than one occasion, or A1C (HbA1C) is formed due to
An abnormal oral glucose tolerance test (OGTT), in which the glucose concentration is 200 mg/dL non enzymatic attachment of
or higher 2 hours after a standard carbohydrate load (75 gm of glucose). glucose with globin component
A level of glycated hemoglobin (HbA1c) > 6.5 g/dL (accepted as an additional criteria for the of hemoglobin. It is used for
diagnosis of DM by American Diabetic Association. diagnosis as well as a marker of
glucose control in diabetics.
Apart from over diabetics, the following types of individuals are there:
Its target level during the
Euglycemic individuals: serum fasting glucose values less than 110 mg/dL, or less treatment of DM is <7%.
than 140 mg/dL following an OGTT
Impaired glucose tolerance: serum fasting glucose greater than 110 but less than 126
mg/dL, or OGTT values of greater than 140 but less than 200 mg/dL. It is associated
with increased risk of progressing to diabetes. The most important stimulus
The insulin gene is expressed in the cells of the pancreatic islets. Preproinsulin that triggers insulin synthesis
synthesized in the rough endoplasmic reticulum is delivered to the Golgi apparatus where it and release is glucose itself.
is converted to insulin and a cleavage peptide, C-peptide.
The vast majority of cases of diabetes fall into one of two broad classes:
Type 1 diabetes: it is characterized by an absolute deficiency of insulin secretion caused

Concept
by pancreatic -cell destruction, usually resulting from an autoimmune attack. Since both insulin and
C-peptide are secreted in equal
Type 2 diabetes: it is caused by a relative insulin deficiency due to combination of
amounts equimolar quantities
peripheral resistance to insulin action and an inadequate compensatory response of insulin
after physiologic stimulation,
secretion by the pancreatic cells.
C-peptide levels are used
a marker for endogenous
insulin secretion.
a
P thog enesis of type 1 diabetes mellitus
The following are the risk factors for the development of type 1 DM:

1. Genetic factors: these could affect The presence of islet cell
HLA genes (commonest locus being affected is on chromosome 6p21(HLA D) like antibodies is used as a
HLA DR3/DR4 with DQ8 haplotype predictive marker for type 1
The non HLA genes like that for insulin or polymorphism in CD25 (normally DM. There is characteristically
presence of insulitis in these
regulated the function of T cells)
patients.
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2. Environmental factors: viral infections like coxsackie B, mumps, rubella or

The genetic factors are much cytomegalovirus.
more important in type 2 DM The failure of self tolerance in T cells is the main defect in type 1 DM. The autoreactive Tcells
than in type 1 DM. (TH1 cells and CD8+ cytotoxic T cells) get activated and cause b cell injury resulting in the
reduction of cell mass. Autoantibodies against a variety of b-cell antigens, including insulin,
islet cell autoantigen 512 and glutamic acid decarboxylase are also found in the patients.
The presence of islet
amyloid protein (amylin) is a a
P thog enesis of type 2 diabetes mellitus
characteristic feature of long The disease is characterized by the following metabolic defects:
standing type 2 DM. There is no Insulin resistance: it is defined as resistance to the effects of insulin on glucose
insulitis in type 2 DM (which is
characteristically seen in type 1
uptake, metabolism, or storage. It is a characteristic feature of most individuals with
DM). type 2 diabetes.
-cell dysfunction: inadequate insulin secretion in the presence of insulin resistance
and hyperglycemia
There is no autoimmune basis of type 2 DM. The insulin resistance is being contributed
maximally by the loss of sensitivity in the hepatocytes.
Obesity is the most important

risk factor insulin resistance.
Endocrine System
g
50% of carriers of lucokinase
g
mutations develop estational
*An increase in the number of and size of islets is characteristic of non diabetic infants of diabetic
diabetes mellitus.
mothers.
Patients with lipoatrophic
diabetes have hyperglycemia
with loss of adipose tissue.
Mo og n enic Forms of Diabetes
The monogenic forms of diabetes can be due to the following causes:
Primary defect in -cell function Defect in insulin-insulin receptor signaling
Autosomal-dominant inheritance with Type A insulin resistance (severe insulin resistance
high penetrance + hyperinsulinemia + DM)
Early onset (usually before age 25) Lipoatrophic diabetes (insulin resistance +
Absence of obesity hypertriglyceridemia + DM + acanthosis nigricans
Lack of islet cell autoantibodies + hepatic steatosis)
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Endocrine System
Pathogenesis of Complications of DM
n cal features of DM
Cli i
Endocrine System
Concept
Honeymoon period is the
symptom free interval period
in a patient of DM in which the
individual is asymptomatic. It is
due to the reserve cell mass
in the pancreatic islets
The paradoxical combination

of weight loss and polyphagia
should make the physician
suspicious of DM
Recent information
A family of proteins called sirtuins, identified to be involved in aging are now implicated in diabetes. Sirt-
1 improves glucose tolerance, enhance cell insulin secretion, and increase production of adiponectin.
Acute Complications of DM
1. Type 1 DM
Diabetic ketoacidosis is an important complication seen in type 1 diabetics. It is
usually precipitated by inadequate insulin therapy, intercurrent infection, emotional
stress and excessive alcohol intake.
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The clinical feature of these patients would be nausea, vomiting, respiratory

difficulties, fruity breath odour of acetone, and signs of dehydration (dry skin and
Endocrine System
poor skin turgor) and altered consciousness to coma.

Concept 2. Type 2 DM
Type 2 DM patients dont These patients are usually older (>40 years) and frequently obese. It may present
develop ketoacidosis and its with polyuria and polydipsia but mostly it is diagnosed after routine blood or urine
symptoms (nausea, vomiting, testing. A complication that is seen in these patients is hyperosmolar nonketotic
respiratory difficulties) because
coma due to the severe dehydration resulting from sustained osmotic diuresis in
of elevated portal insulin levels.
The fat sparing effect of patients who do not drink enough water to compensate for urinary losses from
insulin prevents the formation chronic hyperglycemia. It is usually seen in elderly person who are unable to
of ketone bodies by inhibiting the maintain adequate water intake.
fatty acid oxidation in the liver.
r n c complications of DM
Ch o i
The long-standing diabetes may involve:
Both large- and medium-sized muscular arteries (macrovascular disease)
Capillary dysfunction in target organs (microvascular disease): diabetic retinopathy,
nephropathy, and neuropathy.
Metformin is the only oral agent
which reduces macrovascular
M acrovascular disease
events in type 2 DM. It includes increased cardiovascular complications like MI, stroke and gangrene. The hallmark
of diabetic macrovascular disease is accelerated atherosclerosis affecting the aorta and large
and medium-sized arteries. It is having earlier onset and greater severity. Advanced vascular
disease can lead to gangrene of the lower extremities. The LDL cholesterol is kept under
MI is the most common cause of 100mg/dL in these patients usually with statins. The vascular lesion in diabetics is Hyaline
death in diabetics. arteriolosclerosis (amorphous, hyaline thickening of the wall of the arterioles causing
narrowing of the lumen).
Renal atherosclerosis and arteriolosclerosis is due to macrovascular disease in diabetics.
A characteristic feature of renal involvement in diabetics is Hyaline arteriolosclerosis affecting both

the afferent as well as the efferent arterioles.
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Endocrine System
Mi crovascular disease
The most consistent morphologic feature of diabetic microangiopathy is diffuse thickening
of basement membranes. However, the affected vessels (diabetic capillaries) are having
increased permeability to plasma proteins. The microangiopathy is responsible for the
development of diabetic nephropathy, retinopathy, and some forms of neuropathy.
1. Diabetic nephropathy
The most important glomerular lesions are capillary basement membrane thickening;
diffuse increase in mesangial matrix, and nodular glomerulosclerosis (PAS positive
nodules called Kimmelsteil Wilson lesion). These patients also have increased
risk of papillary necrosis. Clinical features include microalbuminuria (urinary Diabetic nephropathy
excretion of 30-300 mg/dayQ of albumin). In uncontrolled diabetes, there is presence
Most characteristic lesion:
of glucosuria resulting in glycogen accumulation in PCT cells (called as Armani Nodular Glomerulosclerosis
Ebstein cells). Patients with microalbuminuria are managed with ACE inhibitors. or Kimmelsteil Wilson lesion
(See diabetic nephropathy for details in the chapter on kidney).
Most common lesion: Diffuse
2. Diabetic retinopathy
The ocular involvement may present as retinopathy, cataract formation, or
Glomerulosclerosis
glaucoma. Retinopathy is the most common pattern and can be of the following
types: nonproliferative (background) retinopathy and proliferative retinopathy.
Nonproliferative retinopathy includes intraretinal or pre-retinal hemorrhages,
retinal exudates, microaneurysms (saccular dilations of retinal choroidal capillaries),
venous dilations, edema, and, most importantly, thickening of the retinal capillaries
(microangiopathy). The retinal exudates can be either soft (microinfarcts) or
hard (deposits of plasma proteins and lipids).
Proliferative retinopathy includes the process of neovascularization and fibrosis.
Peripheral, symmetric neuro-
Macular involvement can cause blindness whereas vitreous hemorrhages can result pathy of the lower extremities
from retinal detachment. It is managed with laser photocoagulation.
Endocrine System
is the commonest pattern in

3. Diabetic Neuropathy diabetic neuropathy.
DM can affect both the central and peripheral nervous systems. The most frequent
pattern of involvement is a peripheral, symmetric neuropathy of the lower extremities
that affects both motor and sensory function. It can also manifest as autonomic Concept
neuropathy (can produce disturbances in bowel and bladder function) and diabetic
Dawn phenomenon is an early
mononeuropathy (can manifest as sudden foot drop, wrist drop, or isolated cranial
morning rise in plasma glucose
nerve palsies). The neurological changes may be due to microangiopathy, increased requiring increased amounts of
permeability of the capillaries supplying the nerves and direct axonal damage due insulin to maintain euglycemia.
to alterations in sorbitol metabolism. The delayed gastric emptying is called diabetic
Somogyi effect is rebound
gastroparesis and is managed with metoclopramide or erythromycin. hyperglycemia in the morning
because of counter-regulatory
Treatment of DM is done with insulin and/or anti-hyperglycemic agents. The latter include
hormone release after an episode
Sulfonylureas; (Glipizide, Glibenclamide), Biguanides (metformin), Meglitinides (Repaglinide),
of hypoglycemia in the middle of
Glucosidase inhibitor (Acarbose) and DPP-4 inhibitors (Vildagliptin).
the night.
INSULINOMA
-cell tumors (insulinomas) are the most common of pancreatic endocrine neoplasms. These
benign tumors may be responsible for the elaboration of sufficient insulin to induce clinically
significant hypoglycemia.
There is a characteristic clinical triad resulting from these pancreatic lesions:
1. Attacks of hypoglycemia occur with blood glucose levels below 50 mg/dl

Insulinomas are the most
2. The attacks consist principally of such central nervous system manifestations as confusion,
stupor, and loss of consciousness common pancreatic endocrine
3. The attacks are precipitated by fasting or exercise and are promptly relieved by feeding or neoplasms; characterized by.the
parenteral administration of glucose. presence of Whipples triad.
Hyperinsulinism may also be caused by diffuse hyperplasia of the islets which is usually
seen in neonates and infants.
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The critical laboratory findings in insulinomas are high circulating levels of insulin and
a high insulin-glucose ratio. Surgical removal of the tumor is usually followed by prompt
Nesidioblastosis is diffuse islet reversal of the hypoglycemia.
hyperplasia and is seen with
maternal diabetes and Beckwith-
Wiedemann syndrome. THYROID GLAND
It is a gland (weighing 15-20 g) responsible for the secretion of the thyroid hormones (T3 and T4)
and calcitonin. Thyroid hormones are required for the development of brain and maintenance

of basal metabolic rate whereas calcitonin is involved in calcium homeostasis. The two types
of disorders associated with this gland are hyperthyroidism and hypothyroidism.
HYPERTHYROIDISM
Graves disease is the commonest It is a state of hyperfunctioning of the thyroid gland characterized by elevated levels of free
cause of thyrotoxicosis
T3 and T4 and associated with increased sympathetic activity. It should be differentiated
from thyrotoxicosis which is a hypermetabolic state due to elevated levels of free T3 and T4
(so, thyrotoxicosis includes hyperthyroidism as well as other causes). The causes for this
condition include
Thyrotoxicosis factitia is Exog-
1. Diffuse toxic hyperplasia (Graves disease) (Accounts for 85% of cases)
enous thyroid hormone induced
2. Toxic multinodular goiter
hyperthyroidism

3. Toxic adenoma

4. Uncommon causes:
Acute or subacute thyroiditis
The cardiac manifestations are Hyperfunctioning thyroid carcinoma
the earliest and most consistent TSH secreting pituitary adenoma
feature of hyperthyroidism. Struma ovarii
Endocrine System
Iatrogenic hyperthyroidism
Thyrotoxicosis factitia
Clinical features: The salient features include tachycardia, palpitations, diaphoresis
Serum TSH is best screening (increased sweating), heat intolerance, tremors, diarrhea and weight loss despite a good
test for thyroid dysfunction.
appetite.
The diagnosis is made using serum TSH. It is the most useful screening test as its level may
be altered in patients with even subclinical hyperthyroidism. In primary hyperthyroidism,
serum TSH is low and free T4 is increased whereas in secondary (due to increased TSH
secretion from the pituitary) and tertiary (due to increased thyrotropin releasing hormone or
TRH secretion from the hypothalamus) hyperthyroidism, serum TSH is high.
HYPOTHYROIDISM
It is caused due to decreased secretion of the thyroid hormones either due to a primary
Autoimmune hypothyroidism is
the commonest cause of hypo-
defect in the thyroid (most commonQ) or a secondary (TSH deficiency) or rarely a tertiary
thyroidism in iodine sufficient (TRH deficiency) cause. This can result in cretinism in children and myxedema (or Gull disease) in
areas of the world. adults. The clinical features of the disease include lethargy, sensitivity to cold, reduced cardiac
output, constipation, myxedema [due to accumulation of glycoaminoglycans, proteoglycans
and water resulting in deep voice, macroglossia (enlarged tongue) and non- pitting edema of
hands and feet] and menorrhagia (increased menstrual blood loss).
The diagnosis is made using serum TSH. It is the most useful screening test. Serum TSH is
elevated in primary hypothyroidism and it is reduced in secondary and tertiary hypothyroidism.
THYROIDITIS
Primary hypothyroidism: It is defined as the inflammation of the thyroid gland which may be associated with illness
serum T4; serum TSH.
and severe thyroid pain (as in infectious thyroiditis or subacute granulomatous thyroiditis)
Secondary hypothyroidism: or can be painless (subacute lymphocytic thyroiditis or Reidel thyroiditis). The important
serum T4; serum TSH. types of thyroiditis include:
610
Endocrine System
Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)

Hashimoto Thyroiditis: Auto-
It is a chronic inflammation with lymphocytic infiltration of the thyroid gland (the latter
immune thyroiditis
responsible for the term struma lymphomatosa). It is more commonly seen in females (F: M
ratio is 10:1) of the age group of 45-65 years. This condition is associated with HLA-DR5, HLA- Most common type of thy-
DR3 and chromosomal defects like Turner and Down syndrome. Increased susceptibility to roiditisQ and the most common
Hashimotos thyroiditis has been associated with polymorphisms of cytotoxic T lymphocyte cause of hypothyroidism in are-
as having sufficient iodine levels.
associated antigen-4 (CTLA4) and protein tyrosine phosphatase-22 (PTPN 22).
Pathogenesis: There is replacement of the thyroid cells with lymphocytic infiltration
and fibrosis. There is presence of antithyroid antibodies (anti-TSH receptor antibodies, anti-
thyroglobulin and anti-thyroid peroxidase antibodies) in the serum of the affected patients.
Morphology: The thyroid gland is diffusely enlarged with intact capsule. There is presence of well Concept
developed germinal centers and extensive infiltration of parenchyma by mononuclear inflammatory
The fibrosis does not extend
cells like lymphocytes and plasma cells. The thyroid follicles are atrophic and lined by epithelial cells
beyond capsule (which is the
having abundant eosinophilic and granular cytoplasm called Hurthle cells.Q main differentiating feature from
Clinical features: It is characterized by the presence of painless enlargement of the thyroid gland Reidel thyroiditis
and a gradual loss of thyroid function (though initially, thyroid follicular disruption may cause transient
hyperthyroidism). The disorder is associated with autoimmune diseases (like SLE, Sjgren syndrome,
myasthenia gravis) and there is increased risk of development of B-cell non-Hodgkin lymphoma.
L T T
Subacute ymphocytic hyroiditis (or Silent/Painless hyroiditis or Postpartum hyroiditis) T Subacute painless lymphocytic
thyroiditis: develops post partum
It is a self limitingQ episode of thyrotoxicosis seen commonly in middle aged females especially and progression to hypothyroidism.
in postpartum period. It is associated with HLA DR-3 and HLA DR-5 and is autoimmune in
There is absence of Hurthle
etiology. Painless and post-partum thyroiditis are variants of Hashimotos thyroiditis. cells and fibrosis (differentiating
Morphology: The thyroid gland has lymphocytic infiltration with hyperplastic germinal feature from Hashimoto thyroiditis).
centers and patchy collapse of thyroid follicles.
Endocrine System
Clinical features are painless enlargement of the thyroid and transient hyperthyroidism
(lasting about 2-8 weeks). Investigations reveal elevated levels of T3 and T4 and reduced TSH.
T G T
Subacute hyroiditis ( ranulomatous hyroiditis or De Quervain hyroiditis) T
It is a disorder seen commonly in females (Female: Male ratio is 3 to 5:1) of the age group
30-50 years. It is more commonly seen in summer, is preceded by a viral infection (caused by Subacute Granulomatous Thy-
roiditis: Most common cause of
coxsackie virus, mumps, measles, adenovirus etc.) and is associated with HLA-B5.
painful thyroid; virus induced;
Pathogenesis: It results due to virus induced host tissue damage or direct viral damage. o
n cervical lymphadenopathy
Morphology: The thyroid gland is diffusely enlarged with intact capsule. There is presence of patchy
changes. In the initial stages, there is active inflammation characterized by disruption of follicles by
neutrophils (forming micro abscess), lymphocytes, histiocytes, plasma cells and multi-nucleated giant
cells which is followed by fibrosis.
Clinical features are pain in neck, sore throat, fever, fatigue, anorexia, myalgia, enlarged thyroid and
the presence of transient hyperthyroidism which usually diminishes in 2-6 weeks. It may be followed
by asymptomatic hypothyroidism but recovery is seen in most of the patients. Almost all patients have
high T3 and T4 and low TSH initially which recovers in 6-8 weeks after the disease completes the
course.
T F T I T
Reidels hyroiditis (or ibrous hyroiditis/ nvasive hyroiditis)
Reidels Thyroiditis: Fibrous
It is an idiopathic rare disorder characterised by the destruction of the thyroid gland by dense
tissue replacement of gland and
fibrosis. Fibrosis of the surrounding structures like trachea and esophagus can also occur. It is surrounding tissue.
more commonly seen in females of middle age and is associated with retroperitoneal and
mediastinal fibrosis.
Triad of Graves Disease =
Graves Disease hyperthyroidism + infiltrative
ophthalmopathy + localized, in-
It is the commonest causeQ of endogenous hyperthyroidism characterized by the triad of
filtrative dermopathy (pretibial
hyperthyroidism due to hyperfunctional diffuse enlargement of gland, infiltrative ophthalmopathy myxedema)
and localized, infiltrative dermopathy (also called as pretibial myxedema). The disorder is more
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common in females of the age group of 20-40 years. It is associated with polymorphisms in
HLA B8, HLA DR3, CTLA4 and PTPN-22.
Thyroid acropachy is digital
swelling and clubbing of fingers Pathogenesis: It is an autoimmune disease most commonly due to formation of
in Graves disease. antibodies to TSH receptors (called TSI or LATS meaning Thyroid Stimulating Immunoglobulin
and Long Acting Thyroid Stimulator respectively). The other antibodies found in this condition
include TGI (Thyroid Growth stimulating Immunoglobulin) and TBII (TSH Binding
Concept Inhibitor Immunoglobulin), the latter sometimes responsible for paradoxical hypothyroidism
seen in some of these patients. The anti-TSH antibodies stimulate the TSH receptor in this
In Graves disease, there is
crowding of cells with papillae condition in contrast to Hashimotos thyroiditis in which the antibodies inhibit the receptor.
formation without fibrovascular Morphology: The thyroid gland is symmetrically enlarged with diffuse hypertrophy
core (presence of the latter is and hyperplasia. The capsule is intact.
the differentiating feature of pap-
illary thyroid cancer). Clinical features as described above include hyperthyroidism, ophthalmopathy (due to increased
volume of extraocular muscle and retro-orbital connective tissue as a result of expression of TSH
receptor by orbital fibroblasts) and localized, infiltrative dermopathy (most commonly in skin overlying
shin). Investigations reveal increased levels of T3 and T4 with reduced TSH levels. There is a diffuse
increase in the uptake of radioactive iodine.
D IFFUSE AND MULTINODULAR GOITER

Goiter is enlargement of the thyroid gland. Both diffuse and multinodular goiter are caused
due to impaired synthesis of thyroid hormones most commonly due to dietary iodine
deficiency. This results in increased secretion of TSH leading to hypertrophy and hyperplasia
of the thyroid gland. The degree of enlargement is proportional to the level and duration of
thyroid hormone deficiency. Usually, the enlargement takes place to maintain a euthyroid
state but may also be associated with hyperthyroid state.
Endocrine System
G G
Diffuse Non-toxic oiter (Colloid oiter or Simple oiter) G
In this condition, the thyroid shows no nodules and there are colloid filled follicles (so, the
other name is colloid goiter). It can be endemic (when >10% of population is affected usually
due to low dietary iodine intake) or sporadic (seen more commonly in females during
In Toxic multinodular goiter: one
puberty; usually due to enzyme defects affecting thyroid hormone synthesis or ingestion
or more nodules becom TSH
independent. of Goitrogens which are substances interfering with thyroid hormone synthesis like calcium,
cabbage, cauliflower, turnip, cassava, etc.)
Exophthalmos and pretibial Histologically, there can be two stages: initial hyperplastic stage having diffuse,
myxedema are n ot seen in
symmetrically enlarged gland with thyroid follicular hyperplasia and later, the stage of colloid
toxic multinodular goiter
involution.
Presence of a hyper functioning

n d ar Goiter (MNG)
Multi o ul
nodule developing in MNG called This is a condition resulting from recurrent episodes of hyperplasia and involution resulting
as Plummer Syndrome. in irregular enlargement of thyroid gland. The differential sensitivity of follicular cells for TSH
results in multinodular goiter. Grossly, there is presence of enlarged multinodular thyroid with
presence of hemorrhage, fibrosis, calcification and cystic change.
Clinical features are due to mass effect (enlarged thyroid causing compression of
Factors risk of neoplasia in ST N esophagus, trachea, etc.) or cosmetic effect.
(MY SR is Cool)
Male patients
Young patients
S OLITARY THYROID NODULE (STN)
Solitary as compared to multiple It is a clinical entity seen more commonly in females. STN is more likely to be neoplastic in the
nodules presence of certain risk factor (mentioned alongside).
Radiation exposure to head and
neck is present
Cold nodule on radioactive scan THYROID ADENOMA
(nodules taking less amount of
radioactive iodine in imaging studies) These are solitary masses of the thyroid tissue composed of follicular epithelium and are
therefore, called as follicular adenomas. They are formed due to chronic overactivation of
612
Endocrine System
cAMP pathway (due to somatic mutation of the TSH receptor or the a subunit of Gs receptor). Concept
They are usually asymptomatic and present as cold nodules on radio imaging scans.
Morphologically, these are solitary, spherical lesions having an intact capsule Usually, (Presence of intact capsule dis-
the cells form uniform appearing follicles containing colloid but they can have the following tinguishes a benign follicular ad-
enoma from follicular carcinoma
subtypes:
because in the latter the capsule

Follicular or simple colloid is not intact).

Microfollicular: Seen in fetal life

Hurthle cell (oxyphil, oncocytic) adenoma: Cells have eosinophilic, granular
cytoplasm

Atypical adenoma: Increased variation in cellular and nuclear morphology

Clear cell follicular adenoma: Cells have clear cytoplasm.
THYROID CARCINOMAS
It is a cancer seen more commonly in females in early and middle adult life. The four
histological types of thyroid cancers are:

1. Papillary cancer

2. Follicular cancer

3. Medullary cancer

4. Anaplastic cancer
F T
Risk actors for hyroid Cancers
N
Papillary cancer: It is associated with mutation in either tyrosine kinase receptors RET or TRK1
(Neurotrophic Tyrosine Kinase Receptor 1) or BRAF oncogene. RET is located on chromosome10
and translocation with chromosome 17 causes formation of a fusion gene ret/PTC (ret/papillary
Endocrine System
thyroid cancer) which is responsible for increased tyrosine kinase activity of cells resulting in
All thyroid cancers arise from fol-
papillary thyroid cancer. This cancer is also seen after exposure to ionizing radiation during first
licular epithelium except medul-
two decades of life.
lary cancer (arises from C cells)
N
Follicular cancer: It is associated with mutation in RAS oncogenes particularly -RAS. A specific
translocation associated with follicular cancer is t(2;3) resulting in PAX8-PPAR1fusion. PPAR is
peroxisome proliferator-activated receptor required for terminal differentiation of the cell whereas
PAX8 is a homeobox gene required for thyroid development.
Medullary cancer: It is the only thyroid cancer to arise from parafollicular C cells. It is
associated with mutation in RET proto-oncogene resulting in constitutional activation of the
receptor.
Remember that ret/PPTC is NOT seen in medullary carcinoma of thyroid.
Anaplastic cancer: It is associated with mutation in the p53 tumor suppressor gene.
S lia ent features of thyroid cancers

Papillary Carcinoma
It is the commonest type of thyroid cancer Q
Seen in 20-40 years old age group

Spread is by lymphatic route Q Papillary Thyroid tumor (6Ps)
Carries excellent prognosis Q
Popular (Most common)
Microscopically there is presence of papillae with fibrovascular stalk, calcified Palpable Lymph nodes (Spreads
structures called Psammoma bodiesQ and cancer cells have diagnostic nuclear by lymphatics)
features like presence of fine chromatin leading to ground glass or Orphan Annie Positive I (131) uptake
eye nucleiQ, intranuclear inclusions (called pseudoinclusions) or intranuclear Positive Prognosis (Excellent
prognosis)
longitudinal grooves. Post radiation in head and neck

The variants include encapsulated variant (good prognosis), follicular variant (poor (cause)
prognosis) and tall cell variant (poorest Prognosis). Psammoma bodies
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Follicular Carcinoma
Follicular carcinoma (4Fs) It is the 2 most common form of thyroid cancer
nd
Seen in women of older age (40-50 yrs.)

Female
Vascular invasion is common (less lymphatic spread) to bone, lung, liver etc.
Faraway metastasis
Favorable prognosis Microscopically, there is presence of cells forming small follicles having colloid with
Flow in blood (vascular invasions NO Psammoma bodies. Uncommonly, cells have abundant , eosinophilic cytoplasm
are common) called as Hurthle cellsQ

Differentiation from follicular adenoma is based on the presence of capsular invasion
preferably and vascular invasion Q (capsular vessel invasion).
M edullary Carcinoma
Arises from parafollicular cells/C cells and secretes calcitonin Q
Medullary carcinoma (3Ms)

Sporadic in 80% of cases
Associated with multiple endocrine neoplasia II (MEN) syndromesQ
MEN association (associated Only thyroid cancer associated with amyloidosisQ
with MEN IIa and MEN IIb) Unilateral in sporadic cases and bilateral and multicentric in familial cases
Median node dissection
Microscopically, there is presence of polygonal, spindle cells in amyloid stroma.
aMyloid (associated with amyloi-
dosis) Familial cancers characteristically show the presence of multicentric C-cell
hyperplasia.
A naplastic Carcinoma
Undifferentiated thyroid cancer
Have the worst prognosis Q
Seen mostly in elderly female patients

50% patients give a history of presence of multinodular goiter Q
Endocrine System
Microscopically, there is presence of highly anaplastic cells which can either be

giant cells, spindle cells, mixed giant and spindle cells or small cells.
Quick revision of frequently asked MCQs from thyroid cancers:
Most common thyroid carcinoma -PapillaryQ

Least common thyroid carcinoma -AnaplasticQ
Least malignant -PapillaryQ
Most malignant -AnaplasticQ
Most common cancer after radiation -PapillaryQ
Cancer developing in Hashimotos thyroiditis -LymphomaQ
Thyroid cancer developing in long standing multinodular goiter -Follicular, Anaplastic (rare)
Type of thyroid cancer in MEN syndrome -MedullaryQ
Thyroid cancer associated with amyloidosis -MedullaryQ
Psammoma bodies seen in -PapillaryQ
Orphan-Annie Eyed Nuclei seen in -PapillaryQ
Thyroid Ca associated with dystrophic calcification -PapillaryQ
Carcinoma derived from C cell of thyroid -MedullaryQ
Carcinoma developing in thyroglossal tract -PapillaryQ
Parathyroid Gland
These are four glands situated near the thyroid gland and are composed of chief cells
(containing PTH granules) and oxyphil cells (containing glycogen).
PTH secretion is responsible for elevating serum calcium level and increasing phosphate
excretion in the urine. Malignancy is the most common cause of clinically apparent hypercalcemia,
The parathyroid gland activity is while primary hyperparathyroidism is the commonest cause of asymptomatic hypercalcemia.
controlled by the concentration Increased calcium levels associated with malignancies can be because of osteolytic metastasis
of free calcium in the body. and secretion of a PTH related peptide (PTHrP).
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Endocrine System
HYPERPARATHYROIDISM
Hyperparathyroidism can be primary (due to autonomous, spontaneous overproduction of
PTH) or secondary. Rarely it can be tertiary.
H
Primary yperparathyroidism; 1 P H TH
It is the most important cause of asymptomatic hypercalcemia and can be due to a parathyroid
adenoma, primary hyperplasia or parathyroid malignancy. Hyperparathyroidism can be
Parathyroid adenoma is the
familial or sporadic. The important molecular defects associated with sporadic hyperparathyroidism
commonest cause of Primary
include HPTH

1. PRAD 1 proto-oncogene on chromosome 11 causes over-expression of cyclin D1 resulting in
proliferation of the parathyroid cells.

2. MEN I suppressor gene on 11 q 13.
The genetic syndromes associated with familial hyperparathyroidism include
Best intial screening test for

1. Multiple endocrine neoplasia I and II (MEN-I and II), the genes for which are located Primary Hyperparathyroidism:
on chromosome 11q and 10 q respectively. intact serum PTH levels.

2. Familial hypocalciuric hypercalcemia (FHH) gene results in reduced sensitivity to
extracellular calcium and is responsible for increased secretion of PTH.
Morphology
Concept
Invasion of surrounding tissue
Adenoma: There is presence of solitary nodule with shrunken glands outside the adenoma. or metastasis is the only
Primary hyperplasia: There is asymmetric involvement of all four glands with the presence of chief reliable criteria for diagnosis of
cells. malignancy.
Parathyroid carcinoma: Involvement of a single gland.
Clinical features: Usually asymptomatic, the only indicator for diagnosis is increased
Endocrine System
serum calcium and PTH. Symptomatic patients may have nephrolithiasis (urinary tract Clinical features of Primary
stones) or nephrocalcinosis (calcification of renal interstitium and tubules), osteoporosis, Hyperparathyroidism; 1 HPTH:
osteitis fibrosa cystica (bone marrow having foci of fibrosis, hemorrhage and cyst formation), Stones, bones, abdominal groans,
metastatic calcification (in blood vessels, stomach and myocardium) and neurological and psychic moans
changes like depression, lethargy, etc.
S econdary Hyperparathyroidism
It is seen in renal failure (most common cause), vitamin D insufficiency, steatorrhea and Renal failure is most common
nutritional deficiency. The hypocalcemia due to any of these causes stimulates the secretion cause of Secondary HPTH
of PTH.
Morphology shows the presence of hyperplastic parathyroid glands.
Clinical features are similar to primary hyperparathyroidism. There is also presence
of calciphylaxis (vascular calcification causing organ ischemia). Investigations reveal reduced
serum calcium and increased PTH levels.
Tertiary Hyperparathyroidism Surgical removal of the para-

Autonomous excessive parathyroid activity even when serum calcium is increased is called as thyroid gland is the commonest
cause of hypoparathyroidism.
tertiary hyperparathyroidism which is usually managed by parathyroidectomy.
HYPOPARATHYROIDISM
It is seen due to surgical removal (commonest causeQ), congenital absence (as in DiGeorge
syndrome; failure of development of 3rd and 4th pharyngeal pouch leading to absence of Concept
thyroid and parathyroid glands) or is idiopathic. Hyperventilation worsens the
symptoms because the alkalosis
Clinical features are due to hypocalcemia and the hallmark is tetany characterised by neuromuscu-
decreases free calcium levels.
lar hyperexcitability, cataract, hypotension, QT prolongation on ECG, tingling in circumoral region and
hands and feet. Investigations demonstrate the presence of Chvostek sign (percussion of facial nerve
over ear causes contraction of facial muscles and upper lip) and Trousseau sign (inflation of blood pres-
sure cuff more than the systolic blood pressure for around 3 minutes causes flexion at metacarpophalan-
geal joint with extension at interphalangeal joint). Diagnosis is made by low serum calcium levels.
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P ITUITARY GLAND
It is a gland weighing 0.5g, present in sella turcica. It has two distinct lobes; anterior lobe and
posterior lobe (stores oxytocin and antidiuretic hormone or vasopressin).
HYPERPITUITARISM
Depending on the size, adenoma It can be caused due to adenoma arising from the anterior lobe (commonest cause), hyperplasia
can be macrodenoma (> 1cm) and carcinoma.The majority of the adenomas are monoclonal in origin or can be associated
or microadenoma (< 1 cm). with MEN I. Histologically; the adenomas are composed of polygonal cells with little reticulin
or connective tissue. The common pituitary tumors include the following:
Prolactinoma: It is the most common pituitary tumor. Small microadenomas secrete
Concept large amount of prolactin responsible for the clinical features of amenorrhea,
galactorrhea and infertility. Since men will obviously not have amenorrhea and females
The absence of reticulin network
and presence of cellular mono- are detected early due to menstrual problems, so, microadenomas are commoner in
morphism differentiates pituitary females.
adenoma from non-neoplastic
anterior pituitary parenchyma. Any mass in suprasellar compartment may disturb the normal inhibitory influence of the hy-
pothalamus on prolactin secretion resulting in hyperprolactinemia. This is called stalk effect.
Growth hormone adenoma: It is the second most common type of pituitary adenoma.
Almost 40% of the patients have persistent GH activity resulting in hypersecretion of
insulin like growth factor I (or IGF-I or somatomedin C) causing gigantism in children
The best initial investigation and acromegaly in adults. Gigantism is characterized by features of tall stature and
is measurement of serum long extremities whereas acromegaly has features of prominent jaw (prognathism),
IGF-I levels (which would be
flat, broad forehead, enlarged hands and feet and enlargement of internal organs like
elevated) and the confirmatory
test is failure to suppresss GH heart, spleen, kidney etc.

Endocrine System
production in response to an oral Other pituitary tumors include corticotroph cell adenoma producing ACTH (causing
load of glucose. Cushing disease), thyrotrope adenoma secreting TSH (causing hyperthyroidism),
gonadotrope adenoma secreting FSH and LH.
HYPOPITUITARISM
It is usually seen when more than 75% of parenchyma is lost. GH and gonadotropins (FSH,
Pituitary adenoma is the com-
monest cause of panhypopitui-
LH) are typically lost early as compared to other hormones. The causes of hypopituitarism
tarism include:
Compression of the normal pituitary tissue by tumors or cysts

Pituitary surgery or radiation exposure
Pituitary apoplexy (acute hemorrhagic infarction of a pre-existing pituitary adenoma)
Ischemic necrosis
Sheehan syndrome is post- Sheehan syndrome (postpartum pituitary necrosis due to obstetric hemorrhage or shock)
partum pituitary necrosis due to Empty sella syndrome.
obstetric hemorrhage or shock
Clinical features depend upon the hormone whose function is lost for example, there
can be growth failure (due to GH deficiency), loss of libido, amenorrhea, infertility (due
to gonadotropin deficiency), hypothyroidism and hypoadrenalism. Loss of melanocyte
stimulating hormone (MSH) may cause pallor of the skin.
Concept O T IOR PITUITARY SYNDROMES

P S ER
In Primary empty sella syn- Diabetes insipidus: It is caused due to deficiency of ADH or vasopressin resulting
drome, the herniation of the in polyuria, polydipsia, hypernatremia and hyperosmolality (due to excessive renal
arachnoid mater and CSF from loss of free water) and dehydration.
the defect in diaphragmatic sella
Syndrome of inappropriate ADH secretion (SIADH): Excessive production of
causes pituitary compression
whereas in secondary empty ADH can cause oliguria, retention of water, hyponatremia and cerebral edema.
sella, surgical removal of adenoma The causes of SIADH include ectopic ADH secretion by small cell lung cancer
results in hypopituitarism (commonest), injury to hypothalamus or pituitary or both by head trauma and drugs
(like vincristine).
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Endocrine System
LOT
ADRENA C R EX
GFR
Adrenal gland is divided into adrenal cortex and adrenal medulla. The cortex is further Layers of adrenal cortex from
subdivided into the following three parts from outside to inside responsible for the secretion g
outside to inside: lomerulosa,
of the hormones mentioned in front of them. f r
asciculata and eticularis
Zona glomerulosa - Mineralocorticoids
Zona fasciculata - Glucocorticoids
Zona reticularis Sex steroids
So, Hyperadrenalism can have 3 distinctive patterns:

1. Cushing syndrome:Excess of glucocorticoids

2. Hyperaldosteronism: Excess of mineralocorticoids Administration of exogenous

3. Adrenogenital syndrome: Excess of sex steroids (androgens) corticosteroids is the com-
monest cause of Cushing syn-
drome.
CUSHING SYNDROME
It has four important causes

1. Primary hypersecretion due to increased ACTH (also called Cushing disease), seen in
women of 20-30 years due to an ACTH producing microadenoma. Concept

2. Adrenal over-secretion due to adenomas or carcinomas (adrenal Cushing syndrome): Pituitary Cushing: ACTH,
There is no effect of ACTH, so, also known as ACTH independent Cushing syndrome. Cortisol

3. Secretion of Ectopic ACTH: Small cell cancer of the lung, carcinoid tumors.
Adrenal Cushing: ACTH,

4. Administration of exogenous corticosteroids Cortisol
Morphology: Ectopic Cushing: ACTH,
Cortisol
In adrenal gland, there can be presence of:

1. Cortical atrophy- Seen with exogenous glucocorticoids which cause feedback
Endocrine System
inhibition of ACTH leading to cortical atrophy except in zona glomerulosa (it functions
independent of ACTH). In Cushing Syndrome, there

2. Diffuse hyperplasia is presence of light basophilic

3. Nodular hyperplasia material due to accumulation of
intermediate keratin filaments in
Diagnosis the cytoplasm called as Crooke
hyaline change in the pituitary.
There is an increased 24 hour free cortisol level in the urine with loss of normal diurnal
pattern of cortisol secretion. For differentiating between the causes of Cushing syndrome,
we use dexamethasone suppression test. (See Review of Pharmacology Chapter-6 by the same
authors for details)
ADREN OGENITAL SYNDROME

It is an adrenal disorder due to excessive production of androgens resulting in virilization. It
can be caused either by an adrenocortical carcinoma or more commonly congenital adrenal
hyperplasia (CAH). CAH represents a group of autosomal-recessive inherited metabolic
errors in which there is deficiency of the enzyme/s necessary for synthesis of cortisol.
Steroidogenesis channeled into other pathways lead to increased production of androgens,
which accounts for virilization. Cortisol deficiency induced increased secretion of ACTH
results in adrenal hyperplasia. CAH can manifest as the following three syndromes:

1. Salt wasting syndrome Total absence of 21-a hydroxylase. Almost 90% of cases of CAH

2. Simple virilising adrenogenitalism Presents as genital ambiguity due to partial are due to 21 hydroxylase
deficiency leading to defective
deficiency of 21 a hydroxylase.
conversion of progesterone to

3. Non classic adrenogenitalism Asymptomatic or may manifest as hirsutism. 11-deoxycorticosterone.
Morphology
Adrenals are hyperplastic bilaterally with nodular cortex that is brown (as there is absence
of lipid).
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Cli i n cal features

In 21-a hydroxylase deficiency, excessive androgenic activity causes signs of masculinization
in females which may range from clitoral hypertrophy and pseudohermaphroditism in
infants, to oligomenorrhea, hirsutism, and acne in post pubertal females. In males, androgen
excess is associated with enlargement of the external genitalia and precocious puberty in
prepubertal patients and oligospermia in older males.
HYPERALDOSTERONISM
The condition is characterized by elevated aldosterone levels leading to retention of sodium
and excretion of potassium and hydrogen ions.
Primary aldosteronism: Diastolic
hypertension is present and
there is renin secretion
Secondary aldosteronism: Diastolic

hypertension is absent and
there is renin secretion
Endocrine System
Causes Causes
Adrenocortical adenoma (Conn syndrome): - Commonest causeQ Decreased renal
Concept Primary adrenocortical hyperplasia Due to overactivity of
aldosterone synthase gene, CYP11B2
perfusion
Hypovolemia and edema
The adjacent adrenal cortex in Glucocorticoid remediable hyper aldosteronism due to fusion (CHF and cirrhosis)
adenoma producing aldoster- between CYP11B1 (11b hydroxylase) and CYP11B2 (Aldosterone Pregnancy
one is not atrophic (it is atroph- synthetase) genes
ic in adenoma causing Cushing Morphology: Adrenal adenomas are usually unilateral (more common on the left as
syndrome). compared to right). The aldosterone producing adenoma has the presence of eosinophilic
laminated cytoplasmic inclusions called as spironolactone bodies seen after treatment with
spironolactone.
Clinical features include hypokalemia induced polyuria, polydipsia and muscle
weakness. There may be associated metabolic alkalosis because of excessive aldosterone
secretion. Edema is uncommon in primary hyperaldosteronism because of escape effect.
Abrupt withdrawal of corti-
costeriods is the most common
cause of acute adrenocortical
ADRENA L INSUFFICIENCY
insufficiency. It can be due to primary adrenocortical insufficiency (primary hypoadrenalism) or ACTH
deficiency induced reduced adrenal stimulation (secondary hypoadrenalism).
1. Primary acute adrenocortical insufficiency: It can be seen after stress, sudden
withdrawal of steroids or massive adrenal hemorrhage. If the acute adrenal
insufficiency is associated with bilateral hemorrhagic infarction of the adrenal glands
associated with a Neisseria infection (septicemia) in a child, it can result in disseminated
TB is the most common cause of intravascular coagulation and rapidly developing hypotension and shock in the
Addisons disease in India patient which is called Waterhouse-Friedrichsen Syndrome. The hemorrhage in
this condition usually begins in the medulla and then involves the cortex.
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Endocrine System
2. Primary chronic adrenocortical insufficiency (Addison disease): It is a slow and

progressive disease resulting from adrenocortical hypofunction. Idiopathic atrophy
Concept
In secondary adrenocortical
(by autoimmune mechanism) is the commonest cause of adrenal destruction. insufficiency disease, the hyper-
Autoimmune adrenalitis is associated with Autoimmune Polyendocrine Syndrome pigmentation of primary Addison
(APS) 1 and 2. The loss of adrenal cortex can also be due to tuberculosis, sarcoidosis, disease is lacking because mel-
AIDS, hemorrhage, trauma and metastatic involvement. anotropic hormone levels are low.
Clinical features include initial manifestations of progressive weakness and easy
fatigability, gastrointestinal disturbances like anorexia, nausea, vomiting, weight loss
and diarrhea. In patients with primary adrenal disease, increased circulating levels of
ACTH precursor hormone stimulate melanocytes, with resultant hyperpigmentation
of the skin particularly of sun-exposed areas and at pressure points, such as neck,
Zellballen pattern is a feature of
elbows, knees, and knuckles.
the carotid body tumor which is
3. Secondary adrenocortical insufficiency: It occurs secondary to any disorder of a prototype of parasympathetic
the hypothalamus and pituitary, such as metastatic cancer, infection, infarction, or paraganglioma.
irradiation. Further, in adrenal insufficiency secondary to pituitary malfunction,
marked hyponatremia and hyperkalemia are not seen.
Pheochromocytoma is rule of
ADRENA MEDL ULLA 10s tumor.
The adrenal medulla is composed of neuroendocrine cells called chromaffin cells and their
supporting cells called sustentacular cells. The organ is responsible for the secretion of Concept
epinephrine and nor-epinephrine and is controlled by the autonomic nervous system.
Earlier, it was mentioned that 10%
are familial but latest Robbins
H O H O O YTOMA
P E C R M C says 25% of the individuals
with pheochromocytoma and
It is a tumor of the adrenal medulla which produces catecholamines. The patients usually have paraganglioma have a germline
Endocrine System
severe headache, anxiety, increased sweating, tachycardia, palpitations and hypertensive mutation.
episodes. The tumor is associated with a rule of 10s consisting of

10% are bilateralQ

10% are extra-adrenalQ N
ME III has three M

10% are malignantQ Medullary thyroid carcinoma

10% occur in childrenQ Medulla of adrenal (pheochro-

10% are not associated with hypertensionQ mocytoma)
Mucosal neuroma
The tumor morphology shows the presence of small or large tumors that have yellow tan color that
turns brown on incubation. There is presence of nests of chief or chromaffin cells with sustentacular
N
ME II has two M (and one P)
Medullary thyroid carcinoma
cells (called zellballenQ) with abundant cytoplasm which contains catecholamine granules. The nuclei Medulla of adrenal (pheochromo-
of the cells have salt and pepper appearance of the chromatin. The immunomarkers for this tumor cytoma)
include chromogranin and synaptophysin in chief cells and S-100 for sustentacular cells. Parathyroid hyperplasia
The definitive diagnosis of malignancy is based exclusively on the presence of metastasis.Q

N
ME I has three P
Pituiatry tumors
The investigations reveal the presence of elevated urinary excretion of free catecholamines Pancreas tumors (insulinoma,
and their metabolites such as vanillylmandelic acid (VMA) and metanephrines. gastrinoma)
Parathyroid tumors (hyperplasia)
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pancreas screen 10 years previously. Compared to Antara, Raju is
more likely to
1. Amylin is secreted by which group of cells of
(a) Not have the HLA-DR3 or HLA-DR4 allele
pancreas? (All India 2012)
(b) Become euglycemic with oral hypoglycemic agents

(a) Alpha cells
(c) Develop ketoacidosis

(b) Beta cells
(d) Have relatively high endogenous insulin levels

(c) D cells 8. A 62 year-old woman Omvati with advanced, metastatic

(d) PP cells (Pancreatic polypeptide) lung cancer develops profound fatigue and weakness
2. Diabetes is diagnosed by which of the following and alternating diarrhea and constipation. Physical
criteria? (AIIMS Nov 2011) examination demonstrates hyperpigmentation of

(a) The level of fasting glucose is 100 mg/dL and that skin, even in areas protected from the sun. Tumor
involvement of which endocrine organ is most strongly
of postprandial glucose is 140 mg/dL

(b) The level of fasting glucose is > 125 mg/dL and that suggested by this patients presentation?

(a) Adrenal gland
of post prandial glucose is > 199 mg/dL

(c) The level of plasma insulin is 6 IU/dL
(b) Endocrine pancreas

(d) The HbA1c level is 5.5%
(c) Ovaries
3. All statements are true about Nesidioblastosis except?

(d) Pituitary gland

(a) Hypoglycemic episodes are seen (AI 2011) Most Recent Questions

(b) Occurs more commonly in adults than in children
Endocrine System

(c) Histopathology shows hyperplasia of Islet cells 8.1. Insulin resistance in liver disease is due to:

(d) Diazoxide is used in treatment
(a) Decreased insulin release
4. Insulin increases glucose entry into skeletal muscle,
(b) Steatosis
adipose tissues and liver cells by: (DPG 2011)
(c) Hepatocyte dysfunction

(a) Increasing the number of glucose transporter GLUT2
(d) Decreased C peptide level
in all these tissues 8.2. According to ADA guidelines, the diagnosis of diabetes

(b) Increasing the number of GLUT4 in muscle and adi- is made when the fasting blood glucose is more than
pose tissue and glucokinase in liver cells

(c) Increasing the number of GLUT3 in skeletal muscle

(a) 126 mg/dl
(b) 100 mg/dl
and adipose tissues and GLUT4 in liver cells

(c) 140 mg/dl
(d) 200 mg/dl

(d) Increasing the number of GLUT1 in muscle, GLUT3 8.3. Mauriacs syndrome is characterized by all except
in adipose tissues and GLUT4 in liver cells
(a) Diabetes
(b) Obesity
5. The term fetal adenoma is used for: (UP 2003)

(c) Dwarfism
(d) Cardiomegaly

(a) Hepatoma liver 8.4. Necrobiosis lipoidica is seen in

(b) Fibroadenoma breast
(a) Diabetes insipidus

(c) Follicular adenoma of thyroid
(b) Lyme disease

(d) Craniopharyngioma
6. Which of the following is used to measure control of

(d) Symmonds disease
blood sugar in diabetes mellitus? (UP 2005)

(a) HbA r d para r d
thy oi , thy oi

(b) HbS

(c) HbA2 9. Which of the following term describes hyperthyroidism

(d) HbA 1C
following intake of iodine in patients suffering from
7. Two diabetic patients are seen by an endocrinologist, endemic goiter? (All India 2012)
Dr. Saket. The first patient is a 16-year-old boy Raju
(a) Wolff-Chaikoff effect
who 2 years previously had presented with polyuria
(b) Jod-Basedow effect
and polydipsia. The second patient is a 65-year-old
(c) Graves disease
woman Antara whose diabetes was identified by the
presence of hyperglycemia on a routine blood glucose

(d) Hashimotos thyroiditis
620
Endocrine System
10. A 17 year old girl who was evaluated for short height 19. Hurthle cells are seen in: (Delhi PG-2005)
was found to have an enlarged pituitary gland. Her T4
(a) Granulomatous thyroid disease
was low and TSH was increased. Which of the following
(b) Hashimotos thyroiditis
is the most likely diagnosis? (AIIMS Nov 2011)
(c) Papillary carcinoma of thyroid

(a) Pituitary adenoma
(d) Thyroglossal cyst

(b) TSH-secreting pituitary tumor
20. Which of the following histological type of carcinoma

(c) Thyroid target receptor insensitivity
thyroid most commonly metastasizes to lymph nodes?

(d) Primary hypothyroidism

(a) Medullary (Delhi PG-2005)
11. All are true about Hashimotos thyroiditis except:
(b) Anaplastic

(a) Follicular destruction (AIIMS Nov 2011)
(c) Papillary

(b) Lymphocytic infiltration
(d) Follicular

(c) Oncocytic metaplasia
21. Struma ovarii is composed entirely of

(d) Orphan Annie eye nuclei

(a) Mature thyroid tissue (Karnataka 2006)
12. Hypothyroidism is seen in: (AI 2011)
(b) Immature-thyroid tissue

(a) Hashimotos Thyroiditis
(c) Primary ovarian carcinoid tissue

(b) Graves disease

(c) Toxic Multinodular Goitre
22. Oncocytes are found in all of the following except:

(d) Struma ovarii

(a) Thyroid (DNB-2000, 2003, 2006, 2007)
13. All are true about Hashimotos thyroiditis except:
(b) Pancreas

(a) Follicular destruction (AIIMS May 2010)
(c) Pituitary

(b) Lymphocytic infiltration
(d) Pineal body

(c) Oncocytic metaplasia
(e) None of the above

(d) Orphan Annie eye nuclei
23. Hurthle cells are seen in: (DNB- 2000, 2005)
14. MC thyroid cancer is: (AI 2008)
(a) Hashimotos thyroiditis

(a) Papillary carcinoma
(b) Granulomatous thyroiditis
Endocrine System

(b) Follicular carcinoma
(c) Carcinoma of thyroid

(c) Medullary carcinoma
(d) Acute thyroiditis

(d) Anaplastic carcinoma
24. Calcitonin is a marker of thyroid: (UP 2001)
15. Which of the following gene defect is associated with
(a) Papillary carcinoma
development of medullary carcinoma of thyroid?
(b) Medullary carcinoma

(a) RET Proto-oncogene (AI 2004)
(c) Anaplastic carcinoma

(b) FAP gene
(d) Adenocarcinoma

(c) Rb gene 25. In Hashimotos thyroiditis, there is infiltration of:

(d) BRCA 1 gene
(a) Macrophages (UP 2003)

(b) Neutrophils
16. Medullary carcinoma of the thyroid is associated with
(c) Leukocytes
which of the following syndrome: ` (AI 2003)
(d) Eosinophils

(a) MEN I
26. Myasthenia gravis is associated with: (UP 2006)

(b) MEN II

(a) Hypergammaglobulinemia

(c) Li-Fraumeni syndrome

(b) Thymoma


(c) Squamous cell carcinoma
17. The expression of the following oncogene is associated
(d) Hepatic adenoma
with a high incidence of medullary carcinoma of
thyroid: (AIIMS Nov 2005) 27. In MEN II B syndrome includes all except:

(a) p 53
(a) Hyperparathyroidism (UP 99, 2007)

(b) Her 2 neu
(b) Marfanoid features

(c) RET proto oncogene
(c) Medullary thyroid carcinoma

(d) Rb gene
(d) Pheochromocytoma
18. DeQuervains thyroiditis is also known as: 28. Plunging goiter is (RJ 2000)

(a) Granulomatous thyroiditis (Delhi PG-2006)
(a) Solitary nodule

(b) Struma lymphomatosa
(b) Colloid goiter

(c) Acute thyroiditis
(c) Retro-sternal goiter

(d) Hashimoto thyroiditis
(d) Medullary ca
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29. All are parts of MEN-I except: (RJ 2006) Most Recent Questions

(a) Pituitary tumor

(b) Parathyroid tumor 36.1. Most common thyroid cancer after radiation exposure

(c) Pancreatic tumor is:

(a) Papillary cancer

(d) Medullary carcinoma of thyroid

(b) Medullary cancer
30. Psammoma bodies are seen in all except:
(c) Follicular cancer

(a) Papillary carcinoma of thyroid (AP 2002)
(d) Anaplastic cancer

(b) Papillary adenoma of colon
36.2. Medullary carcinoma of the thyroid is associated with

(c) Meningioma
which of the following syndrome:

(d) Papillary cancer of the ovary (a) MEN I
31. Papillary carcinoma associated with aggressiveness are (b) MEN II
all except: (AP 2006)
(c) Fraumeni syndrome

(a) Follicular variant

(b) Unencapsulated 36.3. Which thyroid carcinoma has amyloid?

(c) Tall cell variant (a) Papillary (b) Follicular

(d) Oxyphilic (Hurthle) cell type (c) Medullary (d) Anaplastic
32. Which thyroid carcinoma is of C-Cell origin: 36.4. Which is not seen in MEN I:

(a) Medullary carcinoma (Kolkata 2003) (a) Parathyroid adenoma

(b) Follicular carcinoma (b) Pancreatic cancer

(c) Papillary carcinoma (c) Prolactinoma

(d) Anaplastic carcinoma (d) Medullary carcinoma thyroid
33. All of the following regarding thyroid carcinoma are 36.5. Werner syndrome is:
true except: (Kolkata 2003) (a) MEN I (b) MEN IIA

(a) Prognosis of follicular carcinoma is worse than pap- (c) MEN IIB (d) AIP
Endocrine System
illary carcinoma 36.6. Orphan Annie eye nuclei appearance is characteristic

(b) Medullary carcinoma is autosomal recessive of:

(c) Anaplastic carcinoma causes local invasion early
(a) Papillary carcinoma thyroid

(d) Medullary and papillary carcinoma both spread by
(b) Carcinoma pituitary
lymphatic route
(c) Paraganglioma
34. Hurthle cell tumor is: (Kolkata 2005)

(d) Meningioma

(a) Papillary carcinoma 36.7. The laboratory screening test which suggests normal

(b) Follicular carcinoma thyroid function is

(c) Medullary carcinoma
(a) TSH
(b) Free T4

(d) Colloid carcinoma
(c) T3
(d) Free T3
(e) Ionizing radiation in early decades is a major risk 36.8. Psammoma bodies are seen in?
factor (a) Papillary carcinoma thyroid
35. About papillary carcinoma of thyroid, all are true (b) medullary carcinoma thyroid
(c) follicular carcinoma thyroid
except: (Kolkata 2005)
(d) anaplastic carcinoma

(a) Prognosis better

(b) Psammoma body present in 50% cases

(c) Early metastasis with poor prognosis pituitary

(d) Spreads by the lymphatic route
37. Which of the following is true about pituitary tumor?
36. A 51-year-old man Sonu with a history of recurrent (a) It present in 10% of brain tumors. (PGI Dec 2005)
calcium-containing renal stones presents to the (b) Erodes the sella and extends into surrounding area
emergency room with excruciating flank pain and blood (c) Prolactinoma is least common
in the urine. This patient is likely to have which of the
following underlying disorders?

(d) It is differentiated by reticulin stain

(a) Anemia of chronic disease
adrenal gland

(b) Chronic Proteus infection

(c) Hyperparathyroidism
38. Addisons disease was first reported by Thomas

(d) Hyperaldosteronism
Addison. It is still being widely reported from various
622
Endocrine System
parts of the world/throughout the world. Which of 48. Submucosal neuroma is associated with: (AP 2004)
the following is the most common cause of Addisons
(a) MEN I
(b) MEN II A
disease in India? (AIIMS Nov 2011)
(c) MEN II B

(a) Post-partum pituitary insufficiency
49. Most common site of pheochromocytoma after adrenal

(b) Tuberculous adrenalitis
gland is: (AP 2005)

(c) HIV

(a) Hilum of kidney

(d) Autoimmune adrenal insufficiency

(b) Organs of Zuckerkandl
39. All are true statements about pheochromocytoma
(c) Neck
except? (AI 2011)
(d) Urinary bladder

(a) 90% are malignant
50. True about adrenal pheochromocytoma is: (AP 2006)

(b) 95% occur in the abdomen

(a) Chromaffin negative

(c) They secrete catecholamines

(b) Mostly malignant

(d) They arise from sympathetic ganglia

(c) Bilateral in 10% of cases
40. All the following familial syndromes are associated
(d) Unilateral in 10% of cases
with development of pheochromocytomas except:
51. Most common cause of Cushings syndrome is:

(a) Sturge-Weber syndrome (AIIMS Nov 2002)

(a) Pituitary adenoma (AP 2006)

(b) Von Recklinghausen disease

(b) Adrenal adenoma

(c) MEN type II

(c) Exogenous steroids

(d) Prader-Willi syndrome

(d) Ectopic ACTH
41. The most common cause of Addisons disease is:
52. Which of the following is not estrogen dependant

(a) Autoimmune adrenalitis (AIIMS May 2002)

carcinoma: (Kolkata 2003)

(b) Meningococcal septicemia

(a) Lobular carcinoma breast

(c) Malignancy

(b) Follicular thyroid carcinoma

(d) Tuberculosis

(c) Endometrial leiomyosarcoma
42. Most important histopathological indicator of
(d) Carcinoma prostate
malignancy in Pheochromocytoma is:
Endocrine System
53. A 40-year old man with central obesity, buffalo hump

(a) Pleomorphism (Delhi PG-2005)
and vertical purple striae on the abdomen has fasting

(b) High mitotic activity
blood glucose is in the high normal range. Plasma levels

(c) Vascular invasion
of ACTH and cortisol are both increased compared

(d) None
to normal. An overnight high-dose dexamethasone
43. Which of the following is most often involved in test produces 75% suppression of cortisol levels. This
multiple endocrine neoplasia I: (DNB- 2007) patient most likely has

(a) Pituitary
(b) Pancreas
(a) Addisons disease

(c) Parathyroid
(d) Thyroid
(b) an ectopic ACTH-secreting tumor
44. All are true about pheochromocytoma except:

(c) Conns syndrome

(a) 25% are malignant (UP 2002)

(d) Cushings disease

(b) Variety of APUDOMA

(c) Histological type is chromaffin cells

(d) Most common neuroendocrine hormone secreting 53.1. Tumor that follows rule of 10 is:
tumor

45. In Cushing syndrome, the tumor is associated with
(b) Oncocytoma

(a) Increased level of epinephrine (UP 2004)
(c) Lymphoma

(b) Decreased level of epinephrine
(d) Renal cell carcinoma

(c) Elevated levels of cortisol
53.2. Ectopic pheochromocytoma may originate from which

(d) Increased level of norepinephrine
of the following?
46. Vanillylmandelic acid (VMA) is increased in
(a) Organ of Zuckerkandl

(a) Hyperparathyroidism (UP 2008)
(b) Bladder

(b) Pheochromocytoma
(c) Filum terminale

(c) MEN-I
(d) Meckel diveticulum

(d) Addisons disease
53.3. Which one of the following is not seen in pheochromo-
47. Most common cause of Cushings syndrome is cytoma?

(a) Exogenous corticosteroids (RJ 2002)
(a) Hypertension

(b) Pituitary tumor
(b) Episodic palpitations

(c) Adrenal adenoma
(c) Weight loss

(d) Adrenal carcinoma
(d) Diarrhea
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4. Assertion: Postpartum thyroiditis presents as a painful

53.4. In Conns syndrome, all the following are seen, except

(a) Hypokalemia
(b) Hypernatremia enlarged thyroid gland

(c) Hypertension
(d) Edema Reason: Postpartum thyroiditis is preceded by a viral
53.5. Dilutional hyponatremia is seen in: infection (measles, mumps etc)
(a) Addisons disease
5. Assertion: Graves disease is most common cause of
(b) Diabetes insipidus
(c) Diuretic therapy endogenous hyperthyroidism.
(d) None Reason: Autoantibodies like TBIG may lead to reduced
thyroid function
assertion and reason Questions 6. Assertion: Myocardial infarction is the commonest cause
110. Will have two statements, assertion and reason. Read ofReason:
death in diabetes
Uncontrolled blood glucose leads to capillary
options. dysfunction in target organs

(a) Both assertion and reason are true and reason is cor- Assertion:
7. Skin hyperpigmentation is a feature of
rect explanation of assertion. Addisons disease

(b) Both assertion and reason are true and reason is not Reason: ACTH precursor has amino acid sequence
the correct explanation of assertion. similar to melanocyte stimulating hormone.

Assertion: Non ketotic hyperosmolar is a commoner
8.

complication than diabetic ketoacidosis in type 2 diabetes.
1. Assertion: C peptide levels are used as a surrogate Reason: Insulin has a fat sparing effect preventing fatty
marker for insulin secretion acid oxidation.
Reason: C peptide and insulin are secreted in equal

9. Assertion: MEN 2A (Sipple syndrome) is characterized
amounts after cell stimulation
by pheochromocytoma, medullary carcinoma of thyroid
2. Assertion: Pheochromocytoma is also referred to as rule
Endocrine System
and parathyroid hyperplasia.

of 10 tumor
Reason: MEN 2A is associated with a loss of function
Reason: Pheochromocytoma is seen in 10% familial cases
mutation in RET proto-oncogene

3. Assertion: FNAC is not useful for diagnosing follicular
10. Assertion: Amyloid deposition is associated with
thyroid cancer
Reason: Capsular invasion is the definitive feature medullary variant of thyroid cancer
differentiating follicular adenoma from follicular ReasonT he altered cacitonin secreted by parafollicular
carcinoma cells gets deposited in the thyroid stroma
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Endocrine System
E xplanations
1. Ans. (b) Beta cells (Ref: Robbins 9/e p446, 8th/442, 1130)
Amylin is secreted by b cells of the pancreas. It reduces food intake and weight gain by acting on central neurons in
the hypothalamus.
2. Ans. (b) The level of fasting glucose is > 125 mg/dL and that of post prandial glucose is > 199 mg/dL (Ref: Harrison
18th/2970, Robbin 9/e p1106)
3. Ans. (b) More common in adults than in children (Ref: Nelson Pediatrics 18th/660-662; Robbins, 9/e p1121)
Congenital hyperinsulinism was formerly termed as Nesidioblastosis.
It is also known as diffuse Islet cell hyperplasia.
It can occur in adults also but more commonly seen in neonates and children.
Hypoglycemic episodes occur due hyperinsulinemia.
Medical management includes Frequent feedings, Diazoxide and Somatostatin.
4. Ans. (b) Increasing the number of GLUT4 in muscle and adipose tissue and glucokinase in liver cells (Ref: Harrison
17th/2278-9, 2282 Robbins 8th/1134, 9/e p1112)
Insulin acts by binding to its receptor and stimulating intrinsic tyrosine kinase activity, leading to receptor autophospho-
rylation and the recruitment of intracellular signaling molecules, such as insulin receptor substrates (IRS). Activation of
the phosphatidylinositol-3-kinase (PI-3-kinase) pathway stimulates translocation of glucose transporters (e.g., GLUT4) to
the cell surface, an event that is crucial for glucose uptake by skeletal muscle and fat. Activation of other insulin receptor
signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin-
Endocrine System
responsive cells.
Glucokinase catalyzes the formation of glucose-6-phosphate from glucose, a reaction that is important for glucose sensing by the beta
cells and for glucose utilization by the liver. As a result of glucokinase mutations, higher glucose levels are required to elicit insulin
secretory responses, thus altering the set point for insulin secretion, responsible for Maturity Onset Diabetes of Young-1 (MODY-1).
5. Ans. (c) Follicular adenoma of thyroid (Ref: Robbins 9/e p1093, 8th/1118; 7th/1175, Harsh Mohan 6th/810)
6. Ans. (d) HbA 1C (Ref: Robbins 8th/1138, 9/e p1115)
7. Ans. (c) Develop ketoacidosis (Ref: Robbins 8th/1145, 9/e p1113-1114)
Raju probably has type 1 (juvenile onset) diabetes mellitus, while Antara probably has type 2 (maturity onset) diabetes
mellitus. These two types of diabetes differ in many respects. Ketoacidosis is more likely to develop in type 1 diabetes.
Type 1 diabetes has a strong association with HLA-DR3 and HLA-DR4 (option A), while type 2 does not have any strong
HLA associations.
Type 1 is usually apparently due to viral or immune destruction of beta cells, while type 2 is apparently usually due to
increased resistance to insulin; consequently the 65-year-old, rather than the 16-year-old, is more likely to have relatively
high endogenous levels of insulin (option D).
Type 2 diabetes can often be controlled with oral hypoglycemic agents (option B), while type 1 diabetics generally require
insulin. Note that some type 2 diabetics also may require insulin as the disease evolves.
8. Ans. (a) Adrenal gland (Ref: Robbins 8th/1156-1157, 9/e p1130-11131)
This is Addison disease, in which severe adrenal disease produces adrenocortical insufficiency. Causes include auto-
immune destruction, congenital adrenal hyperplasia, hemorrhagic necrosis, and replacement of the glands by either tumor
(usually metastatic) or granulomatous disease (usually tuberculosis). The symptoms can be subtle and nonspecific (such
as those illustrated), so a high clinical index of suspicion is warranted. Skin hyperpigmentation is a specific clue that may
be present on physical examination, suggesting excess pituitary ACTH secretion. (The ACTH precursor has an amino
acid sequence similar to MSH, melanocyte stimulating hormone.) Most patients have symptoms (fatigue, gastrointestinal
distress) related principally to glucocorticoid deficiency. In some cases, however, mineralocorticoid replacement may also
be needed for symptoms of salt wasting with lower circulating volume.
Except in the case of primary pancreatic cancer, complete tumor replacement of the endocrine pancreas (option B) would be
uncommon. In any event, pancreatic involvement would be associated with diabetes mellitus.
Involvement of the ovaries (option C) by metastatic tumor (classically gastric adenocarcinoma) would produce failure of menstruation.
Involvement of the pituitary gland (option D) could produce Addisonian symptoms, but the pigmented skin suggests a primary
adrenal problem rather than pituitary involvement.
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8.1. Ans. (b) Steatosis (Ref: Robbin 8/e p1136, Joslins Diabetes Mellitus 14/e p436)
Insulin resistance is defined as the failure of target tissues to respond normally to insulin. It leads to decreased uptake of
glucose in muscle, reduced glycolysis and fatty acid oxidation in the liver, and an inability to suppress hepatic gluconeo-
genesis.

The loss of insulin sensitivity in the hepatocytes is likely to be the largest contributor to the pathogenesis of insulin resistance
in vivo.
Obesity is the most important factor in the development of insulin resistance.
In type 2 diabetes patients, the presence of hepatic steatosis is associated with reduced insulin stimulated glucose uptake. Increased
hepatic fat accumulation results in impaired peripheral insulin action.Joslin pg 436
8.2. Ans. (a) 126 mg/dl (Ref: Robbins 9th/1106)
8.3. Ans. (a) Diabetes (Ref: internet)
Mauriac syndrome is a rare complication of type 1 diabetes mellitus in children associated with hepatomegaly, growth
impairment and cushingoid features.
8.4. Ans. (c) Diabetes mellitus (Ref: Harrison 18th/chapter 53)
Lesions of necrobiosis lipoidica are found primarily on the shins (90%), and patients can have diabetes mellitus or develop
it subsequently. Characteristic findings include a central yellow color, atrophy (transparency), telangiectasias, and a red to
red-brown border. Ulcerations can also develop within the plaques. Biopsy specimens show necrobiosis of collagen and
granulomatous inflammation.
9. Ans. (b) Jod-Basedow effect (Ref: Harrison 18th/2930, 2932)
Jod Basedow effect is characterized by excessive thyroid hormone synthesis caused by increased iodine exposure.
Wolff Chaikoff effect is iodide dependent suppression of the thyroid.
10. Ans. (d) Primary hypothyroidism (Ref: Robbins 8th/1109-1110, 9/e p1083-5)
Analyzing all options,
In pituitary adenoma/TSH secreting pituitary tumor increased TSH with increased T3/4 would be seen. (excludes
Endocrine System
a and b)
In thyroid hormone resistance increased T as well as T with low TSH will be seen. (option c excluded)
4 3
Primary hypothyroidism is due to defect in the thyroid gland itself. This is associated with high TSH with low T4
will be seen.
11. Ans. (d) Orphan Annie eye nuclei (Ref: Robbins 8th/1111, 9th/1087)
Robbins writesThe nuclei of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically
clear or empty appearance, giving rise to the designation ground-glass or Orphan Annie eye nuclei.
Salient features of Hashimoto Thyroiditis (Chronic Lymphocytic Thyroiditis)
Most common type of thyroiditisQ
Most common cause of hypothyroidism in areas having sufficient iodine levels.
Genetic association
Associated with HLA-DR5, HLA-DR3 and chromosomal defects like Turner and Down syndrome.
Gland morphology
Diffusely enlarged gland with intact capsule.
Microscopic finding
Presence of well developed germinal centers and extensive lymphocytic infiltration
AtrophiedQ thyroid follicles lined by epithelial cells having abundant eosinophilic and granular cytoplasm called Hurthle cells.Q (this is
a metaplastic response of epithelium to the ongoing injury)
Chronic inflammation with lymphocytic infiltrationQ of the thyroid gland (the latter responsible for the term struma lymphomatosa).
Clinical findings
Painless enlargement of thyroid gland in a middle aged female.
Associated with type 1 diabetes, SLE, Sjogren syndrome, myasthenia gravis, increased risk of B cell lymphoma
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Endocrine System
12. Ans. (a) Hashimotos thyroiditis (Ref: Harrison 17th/2230, Robbins 9th/1087)
Hashimotos thyroiditis is a cause of hypothyroidism whereas other diseases mentioned like Graves disease, toxic Multi-
nodular goiter and struma ovarii result in hyperthyroidism.
Causes of Hypothyroidism
Autoimmune hypothyroidism: Hashimotos thyroiditis, atrophic thyroiditis
Iatrogenic: 131I treatment, subtotal or total thyroidectomy, external irradiation of neck for lymphoma or cancer
Drugs: iodine excess (including iodine-containing contrast media and amiodarone), lithium, antithyroid drugs, p-aminosalicyclic
acid, interferon-alpha and other cytokines, aminoglutethimide
Congenital hypothyroidism: absent or ectopic thyroid gland, dyshormonogenesis, TSH-R mutation
Iodine deficiency
Infiltrative disorders: amyloidosis, sarcoidosis, hemochromatosis, scleroderma, cystinosis, Riedels thyroiditis
Causes of hyperthyroidism
Graves disease
Toxic multinodular goiter
Toxic adenoma
Functioning thyroid carcinoma metastases
Activating mutation of the TSH receptor
Activating mutation of Gsa (McCune-Albright syndrome)
Struma ovarii
Drugs: iodine excess (Jod-Basedow phenomenon)
13. Ans. (d) Orphan Annie eye nuclei (Ref: Robbins 8th/1111, 9/e p1096)
Robbins writesThe nuclei of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically
clear or empty appearance, giving rise to the designation ground-glass or Orphan Annie eye nuclei.
14. Ans. (a) Papillary carcinoma (Ref: Robbins 7th/735-736, 9/e p1095)
15. Ans. (a) RET proto-oncogene (Ref: Harrisons 17th/2361, Robbins 7th/1182, 9/e p1095)

Medullary carcinoma of thyroid (MCT) pheochromocytoma and hyperparathyroidism are present in MEN-2A where-
Endocrine System
as the association of MCT, pheochromocytoma, mucosal neuroma and Marfanoid habitus is designated MEN-2B.

Most patients of MEN-2 have mutations of RET-proto-oncogene.

This gene is located on chromosome 10q11.2.

Most common germline mutation of RET is at codon 634 and is associated mostly with MEN 2A.

Most common somatic mutation of RET is at codon 918 and is mostly associated with MEN 2B.

Other genes given in the question can be remembered from their name only:

FAP: Familial adenomatous polyposis

Rb: Retinoblastoma

BRCA1: Breast cancer
16. Ans. (b) MEN II (Ref: Robbins 7th/1222, 9/e p1099)
Multiple endocrine neoplasia (MEN) syndromes are a group of genetically inherited diseases resulting in proliferative le-
sions (hyperplasia, adenoma and carcinoma) of multiple endocrine glands.
MEN I (Wermers Syndrome) N
ME II A (Sipples syndrome) ME N II B
Parathyroid hyperplasia/adenoma Parathyroid hyperplasia/adenoma Medullary carcinoma of thyroid
Pancreatic islet cell hyperplasia/adenoma/ Medullary carcinoma of thyroid Pheochromocytoma
carcinoma Pheochromocytoma Mucosal and gastrointestinal neuromas
Pituitary hyperplasia/adenoma Mutant gene is RET Marfanoid features
Mutant gene is MEN 1 Mutant gene is RET
17. Ans. (c) RET proto-oncogene (Ref: Robbins 7th/294, 295, 9/e 1099)
RET proto-oncogene is mutated in MEN-2A and MEN-2B syndromes. These are associated with medullary carcinoma of
thyroid.
18. Ans. (a) Granulomatous thyroiditis (Ref: Robbins 7th/1170, 9/e p1088)
DeQuervains thyroiditis is also referred to as granulomatous thyroiditis or subacute thyroiditis. (For details, see text)
19. Ans. (b) Hashimotos thyroiditis (Ref: Robbins 7th/1169, 76, 81, 9/e p1087)
Hurthle cells (Oncocytes) are epithelial cells with abundant eosinophilic, granular cytoplasm.
Hurthle cells are seen in following conditions:
Hashimotos thyroiditis
Hurthle cell adenoma of thyroid
Hurthle cell carcinoma of thyroid
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Hurthle cells are eosinophilic due to abundance of mitochondria.

Hurthle cells are also called Ashkanazy cells or oxyphil cells.
20. Ans. (c) Papillary (Ref: Robbins 7th/1180, 9/e p1097)
Most papillary carcinoma present as asymptomatic thyroid nodules, but the first manifestation may be a mass in
cervical nodes.
Follicular carcinoma has little propensity for lymphatics but high for vascular invasion and spreads to bones, lungs
and CNS.
In anaplastic Ca direct spread (extensive local invasion) is more common than vascular.
21. Ans. (a) Mature thyroid tissue (Ref: Robbins 7th/1100, 9/e p1030)
Struma ovarii is a specialized teratoma which is always unilateral and is composed of mature thyroid tissue. It may
manifest itself with the features of hyperthyroidism.
22. Ans. (d) Pineal body (Ref: Internet)
Oncocytes are large cells with small irregular nuclei and dense acidophilic granules due to the presence of abundant
mitochondria. These are found in oncocytomas of the kidney, salivary glands, and endocrine glands (thyroid, parathyroid,
pituitary, adrenal cortex and pancreatic islets).
23. Ans. (a) Hashimotos thyroiditis (Ref: Robbins 8th/1112, 9/e p1087)
24. Ans. (b) Medullary carcinoma (Ref: Robbins 9/e p1099, 8th/1125; 7th/1178)
25. Ans. (c) Leucocytes (Ref: Robbins 9/e p1087, 8th/1112; 7th/1169-1170)
26. Ans. (b) Thymoma (Ref: Robbins 8th/636-637, 9/e p1236)
27. Ans. (a) Hyperparathyroidism (Ref: Robbins 9/e p1136-1137, 8th/1162; 7th/1222)
28. Ans. (c) Retro-sternal goiter (Ref: Robbins 8th/1117, 9/e p1092)
29. Ans. (d) Medullary carcinoma of thyroid (Ref: Robbins 8th/1162, 9/e p1136)
Endocrine System
30. Ans. (b) Papillary adenoma of colon (Ref: Robbins 9/e p1096, 1314, 1025, 8th/38,1122; 7th/859)
31. Ans. (a) Follicular variant (Ref: Robbins 9/e p1096-1097, 8th/1120-1122; 7th/1179)
32. Ans. (a) Medullary carcinoma (Ref. Robbins 8th/1121, 9/e p1099)
33. Ans. (b) Medullary carcinoma is autosomal recessive (Ref. Robbins 8th/1124-1126, 9/e p1095)
34. Ans. (b) Follicular carcinoma (Ref: Robbins 8th/1123, 9/e p1098)
35. Ans. (c) Early metastasis with poor prognosis (Ref: Robbins 8th/1121-1122, 9/e 1097)
36. Ans. (c) Hyperparathyroidism (Ref: Robbins 8th/962, 9/e p1103)
The patients history of recurrent urolithiasis with calcium-containing stones implies a disorder in the regulation of
calcium concentration. Hyperparathyroidism is associated with increased parathormone (PTH) levels, which can produce
hypercalcemia, hypercalciuria, and, ultimately, renal stones.
Anemia of chronic disease (option A) does not produce calcium stones. The patient presents with a chronic condition and
hematuria but the urinary blood loss is not usually significant enough to produce an anemic state.
Hyperaldosteronism (option D) results in potassium depletion, sodium retention, and hypertension. Primary hyperaldos-
teronism (Conns syndrome) is associated with adrenocortical adenomas in 90% of patients and is characterized by decreased
renin. Secondary hyperaldosteronism results from excessive stimulation by angiotensin II that is caused by excess renin
production (plasma renin-angiotensin levels are high). Neither condition is associated with renal stones.
36.1. Ans. (a) Papillary cancer (Ref: Robbins 8/e p1121, 9/e p1095)
There is a marked increase in the incidence of papillary carcinomas among children exposed to ionizing radiation
(particularly during the first 2 decades of life).
Deficiency of dietary iodine (and so, goiter) is linked with a higher frequency of follicular carcinomas.
36.2. Ans. (b) MEN II (Ref: Robbins 8/e p1162, 9/e p1137)
MEN-2A, or Sipple syndrome, is characterized by pheochromocytoma, medullary carcinoma, and parathyroid
hyperplasia.
MEN-2B has significant clinical overlap with MEN-2A. Patients develop medullary thyroid carcinomas, which are
usually multifocal and more aggressive than in MEN-2A, and pheochromocytomas. However, unlike in MEN-2A,
primary hyperparathyroidism is not present
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Endocrine System
36.3. Ans. (c) Medullary (Ref: Robbins 8/e p1125, 9/e p1099)
Acellular amyloid deposits, derived from altered calcitonin polypeptides, are present in the adjacent stroma in many cases
of medullary thyroid cancer.
36.4. Ans. (d) Medullary carcinoma thyroid (Ref: Robbins 8/e p1162, 9/e p1136)
MEN-1, or Wermer syndrome, is characterized by abnormalities involving the parathyroid, pancreas, and pituitary glands; thus
the mnemonic device, the 3Ps
Parathyroid: Primary hyperparathyroidism is the most common manifestation of MEN-1
Pancreas: Endocrine tumors of the pancreas like gastrinomas associated with Zollinger-Ellison syndrome and insulinomas
Pituitary: The most frequent anterior pituitary tumor encountered in MEN-1 is a prolactinoma.
36.5. Ans. (a) MEN I.see earlier explanation(Ref: Robbins 8/e p1162, 9/e p1136)
36.6. Ans. (a) Papillary carcinoma thyroid (Ref: Robbins 8/e p1122, 9/e p1096)
The nuclei of papillary carcinoma cells contain finely dispersed chromatin, which imparts an optically clear or empty
appearance, giving rise to the designation ground-glass or Orphan Annie eye nuclei.
36.7. Ans. (a) TSH (Ref: Robbins 9th /1083)
36.8. Ans.(a) Papillary carcinoma thyroid (Ref: Robbins 9th /1096)
37. Ans. (a) It is present in 10% of brain tumors; (b) Erodes the sella and extends into surrounding area (c) It is differentiated
by reticulin stain; (Ref: Harrison 16th/208I; Robbins 7th/1l59; 9/e p1075, Brains Neurology 11th/558)

10% of all intracranial neoplasms are pituitary tumors.

Benign adenomas are most common.

The most common pituitary adenoma is microadenoma and about 70% microadenomas are prolactinoma.

The tumor can erode the sella and extends into surrounding area and gives rise to local mass effect.

Cellular monomorphism and absence of significant reticulin network distinguishes pituitary adenomas from non-
neoplastic anterior pituitary parenchyma.
38. Ans. (b) Tuberculous adrenalitis (Ref: Robbins 9/e p1130, 8th/1155-6, API 7th/1073, Harrison 18th/2955)
Endocrine System
The commonest cause of Addisons disease is as follows:

In developing countries TuberculosisQ

In developed countries Autoimmune (Idiopathic atrophy)Q
39. Ans. (a) 90% are malignant (Ref: Robbins 8th/1159, 9/e p1134)
Pheochromocytoma is a tumor of the adrenal medulla which produces catecholamines. The patients usually have severe
headache, anxiety, increased sweating, tachycardia, palpitations and hypertensive episodes.
Features of rule of 10sin pheochromocytoma
10% are bilateralQ
10% are extra-adrenalQ
10% are malignant Q
10% occur in children Q
10% are not associated with hypertension Q
Please note
Earlier, it was mentioned that 10% are pheochromocytoma are familialQ but latest Robbins says 25% of the individuals with
pheochromocytoma and paraganglioma have a germline mutation
40. Ans. (d) Prader Willi syndrome (Ref: Robbinss illustrated 7th/1219, 9/e p1134)
Pheochromocytoma is associated with the following familial syndromes.
MEN syndromes type II and type III
Von Hippel Lindau syndrome
Von Recklinghausen disease
Sturge Weber syndrome Famibial paraganglioma 1/3/4
41. Ans. (a) Autoimmune adrenalitis (Ref: Harrison, 17th/2263, Robbins 9/e p1134)
Addisons disease must involve >90% of the glands before adrenal insufficiency develops.
Idiopathic atrophy due to autoimmune adrenalitis is the most common cause of Addisons disease in the worldwhereas
tuberculosis is the most common cause of the same in India.
42. Ans. (d) None (Ref: Robbins 7th/1221, 9th/1135)

The histological pattern in pheochromocytoma is quite variable. The tumors are composed of polygonal to spindle-
shaped chromaffin cells, clustered with their supporting cells into small nests or alveoli (Zellballen), by a rich vascular
network.
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Cellular and nuclear pleomorphism is often present, especially in the alveolar group of lesions and giant and bizarre
cells are commonly seen.
Mitotic figures are rare and do not imply malignancy.
Both capsular and vascular invasion may be encountered in benign lesions. Therefore the diagnosis of malignancy in
pheochromocytoma is based exclusively on the presence of metastases. These may involve regional lymph nodes as
well as more distant sites, including liver, lung and bone.
43. Ans. (c) Parathyroid (Ref: Robbins 8th/1161-1162, 9/e p1136)
44. Ans. (a) 25% are malignant (Ref: Robbins 9/e p1134, 8th/1159-1160; 7th/1219)
45. Ans. (c) Elevated levels of cortisol (Ref: Robbins 9/e p1125, 8th/1150; 7th/1207)
46. Ans. (b) Pheochromocytoma (Ref: Robbins 8th/1161, 9/e p1136)
47. Ans. (a) Exogenous corticosteroids (Ref: Robbins 8th/1148, 9/e p1125)
48. Ans. (c) MEN II B (Ref: Robbins 9/e p1137, 8th/1163; 7th/1222)
49. Ans. (b) Organs of Zuckerkandl (Ref: Robbins 9/e p1134, 8th/1159-1161; 7th/1221)
50. Ans. (c) Bilateral in 10% of cases (Ref: Robbins 9/e p1134, 8th/1159-1161; 7th/1219)
51. Ans. (c) Exogenous steroids (Ref: Robbins 9/e p1125, 8th/1148; 7th/1207)
52. Ans. (b) Follicular thyroid carcinoma (Ref: Robbins 8th/1120-1121, 9/e p1095)
53. Ans. (d) Cushings disease (Ref: Robbins 8th/1148-1150, 9/e p1125)
This patient presents with Cushingoid signs and symptoms due to hypercortisolism. While the acute effect of cortisol is
to produce lipolysis, patients with chronically increased cortisol levels develop a characteristic central obesity and buffalo
hump. The mechanism for the redistribution of body fat is an interaction between cortisol and insulin. The weight gain
with hypercortisolism usually results from increased appetite. Cortisol excess causes protein catabolism, which leads to
poor wound healing, decreased connective tissue, and fragile blood vessels. The combination of thin skin and fragile blood
Endocrine System
vessels leads to abdominal stretch marks (striae) the are characteristically purple in color. Increased gluconeogenesis and
decreased peripheral insulin sensitivity lead to elevated blood glucose. The hypercortisolism due to a functional tumor in
the adrenal cortex (primary hypercortisolism) has low plasma ACTH level.
The patient in the question has increased cortisol and increased ACTH. This could result from either a functional ACTH-secreting
tumor in the pituitary (Cushings disease) or an ectopic tumor (such as a small cell carcinoma of the lung, choice B). To distinguish
between these two, we administer high doses of the potent synthetic glucocorticoid, dexamethasone. High-dose dexamethasone
should suppress ACTH secretion from the pituitary by at least 50%; secretion from an ectopic tumor typically is not suppressed by
dexamethasone.
Addisons disease (choice A) is primary adrenal insufficiency, with increased plasma ACTH (producing hyperpigmentation) and
decreased plasma cortisol and aldosterone compared to normal.
Conns syndrome (choice C) results from hypersecretion of aldosterone by the adrenal cortex. In Cushings disease, it is due in part
to the mineralocorticoid-like effects of high plasma cortisol.
53.1. Ans. (a) Pheochromocytomadiscussed earlier in detail. (Ref: Robbins 9/e p1134, 8/e p524-5)
53.2. Ans. (a) Organ of Zuckerkandl (Ref: Robbins 9th/1134)
Ten percent of pheochromocytomas are extra-adrenal, occurring in sites such as the organs of Zuckerkandl and the carotid
body.
53.3. Ans. (d) Diarrhea (Ref: Robbins 9th/1135, Harrison 18th/2963)
The dominant clinical manifestation of pheochromocytoma is hypertension, observed in 90% of patients. Approximately
two thirds of patients with hypertension demonstrate paroxysmal episodes, which are described as an abrupt, precipitous
elevation in blood pressure, associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of
apprehension.
53.4. Ans. (c) Hypernatremia > (d) Edema (Ref: Sircar pg 532, Harrison 18th/2950)
Harrison mentions that. The clinical hallmark of mineralocorticoid excess is hypokalemic hypertension; serum sodium
tends to be normal due to the concurrent fluid retention, which in some cases can lead to peripheral edema.
Sircar Physiology writes. Edema is not seen because of the escape mechanism: escape from the sodium retaining effects
of hyperaldosteronism.
53.5. Ans. (b) Diabetes insipidus
Please dont get confused with the diuretic therapy because it can lead to increased ADH release and thus, may lead to
hyponatremia.
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Endocrine System
N
EXPLA ATIO S TO A N ssertion and Reason QUESTIONS
Explanations(1-10): While solving assertion reason type of questions, we can use a particular method.
1. First of all, read both assertion (A) and reason (R) carefully and independently analyse whether they are true or
false.
2. If A is false, the answere will directly be (d) i.e. both A and R are false. You can note that all other options (i.e. a,
b or c) consider A to be true.
a
Preproinsulin produced in rough endoplasmic reticulum is delivered to the Golgi apparatus where it is cleaed to
generate mature insulin and C peptide. Both are stored in secretory granules and equimolar quantities are secreted
after cell simulation.
Most important stimulus for insulin synthesis and release is glucose itself.
Pheochromocytoma is also referred to as rule of 10 tumor. It is associated with the following:
10% are bilateralQ
10% are extra-adrenalQ
10% are malignant Q
10% occur in children Q
10% are not associated with hypertension Q
Most of the earlier texts mention that 10% of these tumors are familial but Robbins 8th/1159 clearly says that it has been
Q
modified.
As many as 25% of the individuals with pheochromocytoma and paraganglioma have a germline mutation.
Endocrine System
FNAC is not useful for diagnosing follicular thyroid cancer because it can not distinguish between follicular adenoma
from follicular carcinoma. The most reliable feature of follicular cancer is demonstration of capsular invasion or vascular
invasion. This is best done with careful histologic examination after specimen resection.
Intact capsule encircling the tumor is the hallmark of the benign tumor. Robbins 8th/1119
4. Ans. (d) Both assertion and reason are false. (Ref: Robbins 8th/1113, 9/e p1088)
Postpartum thyroiditis/subacute lymphocytic thyroiditis is a variant of Hashimotos thyroiditis. It presents as a painless
enlargement of the thyroid and transient hyperthyroidism (lasting about 2-8 weeks). Investigations reveal elevated levels of T3
and T4 and reduced TSH.
How to differentiate between Hashimoto and subacute lymphocytic thyroiditis?
Hurthle cell metaplasia and fibrosis are not prominent as in Hashimotos thyroiditis.
(Granulomatous Thyroiditis (De Quervain Thyroiditis) is more commonly seen in females preceded by a viral infection
(caused by coxsackie virus, mumps, measles). The thyroid gland is diffusely enlarged with intact capsule.
Clinical features are pain in neck, sore throat, fever, fatigue, anorexia, myalgia, enlarged thyroid and the presence of transient
hyperthyroidism lasting for 2-6 weeks. It may be followed by asymptomatic hypothyroidism but recovery is seen in most
of the patients.
5. Ans. (b) Both assertion and reason are true and reason is not the correct explanation of assertion. (Ref: Robbins 9/e p1089,
8th/1114-5)
Graves disease is most common cause of endogenous hyperthyroidism. This disease is characterized by breakdown in self
tolerance to thyroid auto-antigens (most importantly TSH receptor). The antibodies seen in these patients are as follows:
Thyroid stimulating immunoglobulin: lead to hyperthyroidism
Thyroid growth stimulating immunoglobulin: lead to hyperthyroidism
TSH binding inhibitor immunoglobulin (TBIG): lead to episodes of hypothyroidism in some patients.
6. Ans. (b) Both assertion and reason are true and reason is not the correct explanation of assertion. (Ref: Robbins 8th/1138-9,
9/e p1117)
Myocardial infarction is the commonest cause of death in diabetes. It is caused by atherosclerosis of the coronary arteries.
Large and medium sized vessel involvement is responsible for macrovascular disease (MI, stroke and lower extremity
gangrene).
Capillary dysfunction in target organs leads to microvascular disease (not macrovascular disease) leading to diabetic retin-
opathy, neuropathy and nephropathy.
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Hyperpigmentation is quite characteristic of primary adrenal disease (Addisons disease) especially at pressure points
and sun exposed areas. This is caused by elevated levels of pro-opiomelanocortin (POMC), which is derived from anterior
pituitary and is a precursor of ACTH and melanocyte stimulating hormone (MSH).
8. Ans. (a) Both assertion and reason are true and reason is correct explanation of assertion. (Ref: Robbins 9/e p1115, 8th/1143)
Hyperosmolar nonketotic coma is due to the severe dehydration resulting from sustained osmotic diuresis in patients
(commoner in elderly) who do not drink enough water to compensate for urinary losses from chronic hyperglycemia.
These patients dont develop ketoacidosis and its symptoms (nausea, vomiting, respiratory difficulties) because of elevated
portal insulin levels. The fat sparing effect of insulin prevents the formation of ketone bodies by inhibiting the fatty acid
oxidation in the liver.
MEN 2A (Sipple syndrome) is characterized by pheochromocytoma, medullary thyroid carcinoma and parathyroid
hyperplasia. It is associated with a gain of function (not loss of function mutation) in RET proto-oncogene.
Loss of function mutations in RET cause intestinal aganglionosis and Hirschprung diseaseQ.
Amyloid deposition is associated with medullary thyroid cancer. The chemical nature of the amyloid in this condition is
ACal. It is because of the deposition of the altered form of calcitonin which gets deposited in the thyroid stroma.
Endocrine System
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CHAPTER 17 Musculoskeletal System

The bone is a type of connective tissue which is composed of cells (osteoclasts and osteoblasts)
and the extracellular matrix. The extracellular components of bone consist of a solid mineral
phase (consisting of calcium and phosphate) and an organic matrix consisting of type I
collagen (9095%), serum proteins such as albumin, cell attachment/signaling proteins such
as thrombospondin, osteopontin and fibronectin, calcium-binding proteins such as matrix
glial protein and osteocalcin and proteoglycans such as biglycan and decorin.
The mineral phase of bone is deposited initially in intimate relation to the collagen fibrils
and is found in specific locations in the holes between the collagen fibrils. This architectural Cleidocranial dysplasia is caused
arrangement of mineral and matrix results in a two-phase material well suited to withstand by heterozygous inactivating
mechanical stresses. mutations in Runx2.
PTH and 1, 25-dihydroxyvitamin

CELLS OF BONE D activate receptors expressed
by osteoblasts to assure mineral
Osteoblasts synthesize and secrete the organic matrix. They are derived from cells of homeostasis.
mesenchymal origin. As an osteoblast secretes matrix, which is then mineralized, the cell
becomes an osteocyte. Mineralization is a carefully regulated process dependent on the
activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing
inhibitors of mineralization. Core-binding factor A1 (CBFA1, also called Runx2) regulates
the expression of several important osteoblast proteins including osterix, osteopontin, bone
sialoprotein, type I collagen, osteocalcin, and receptor-activator of NFB (RANK) ligand.
Runx2 expression is regulated, in part, by bone morphogenic proteins (BMPs).
Osteoclasts carry out resorption of bone. Macrophage colony-stimulating factor (M-CSF) plays a
critical role during several steps in the pathway and ultimately leads to fusion of osteoclast progenitor
cells to form multinucleated, active osteoclasts. RANK ligand, expressed on the surface of osteoblast Concept
progenitors and stromal fibroblasts binds to the RANK receptor on osteoclast progenitors and stimu
lates osteoclast differentiation and activation. Alternatively, a soluble decoy receptor, referred to as Most hormones that influence
osteoprotegerin, can bind RANK ligand and inhibit osteoclast differentiation. Several growth factors osteoclast function do not
and cytokines (including interleukins 1, 6, and 11; TNF; and interferon-gamma modulate osteoclast directly target this cell but instead
differentiation and function. influence M-CSF and RANK
ligand signaling by osteoblasts.
Remodeling of bone Both PTH and 1,25(OH)2D

increase osteoclast number
The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising and activity, whereas estrogen
a group of osteoclasts and osteoblasts. In cortical bone, the BMUs tunnel through the tissue, decreases osteoclast number
whereas in cancellous bone, they move across the trabecular surface. The process of bone and activity by this indirect
remodeling is initiated by contraction of the lining cells and the recruitment of osteoclast mechanism.
precursors. These precursors fuse to form multinucleated, active osteoclasts that mediate Calcitonin, in contrast, binds to
bone resorption. Osteoclasts adhere to bone and subsequently remove it by acidification its receptor on the basal surface
(protons secreted by type II carbonic anhydrase) and proteolytic digestion (by cathepsin K). of osteoclasts and directly
As the BMU advances, osteoclasts leave the resorption site and osteoblasts move in to cover inhibits osteoclast function.
the excavated area and begin the process of new bone formation by secreting osteoid, which
is eventually mineralized into new bone. After osteoid mineralization, osteoblasts flatten and
form a layer of lining cells over new bone.
Remodeling of bone occurs along lines of force generated by mechanical stress.
Biochemical markers of bone resorption

a. Amino and carboxy terminal crosslinking telopeptide of bone collagen

b. Pyridinoline
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Concept
c. Free lysyl-pyridinoline

d. Tartarate-resistant acid phosphatase (TRAP)
Tetracycline is absorbed into
bone and so, it is used as a

e. Hydroxyproline (not very specific)
marker of bone growth for
biopsies in humans. Tetra Biochemical markers of bone formation
cycline binds to newly formed a. Bone specific alkaline phosphatase
bone at the bone/osteoid (un
b. Procollagen type IC and IN propeptide
mineralized bone) interface
where it shows as a linear fluo c. Osteocalcin
rescence. Tetracycline labe d. Alkaline phosphatase (not very specific)
ling is used to determine the
amount of bone growth within PAGETS DISEASE (OSTEITIS DEFORMANS)
a certain period of time, usually a
period of approximately 21 days. Pagets disease (osteitis deformans) can be characterized as a collage of matrix madness. It is
Tetracycline is incorporated into
marked by regions of furious osteoclastic bone resorption, which is followed by a period of hectic
mineralizing bone and can be
detected by its fluorescence. bone formation. The net effect is a gain in bone mass. It has the following three stages:

i. Initial osteolytic stage
In double tetracycline labeling,
a second dose is given 1114

ii. Mixed osteoclastic-osteoblastic stage
days after the first dose, and the

iii. Burnt-out quiescent osteosclerotic stage.
amount of bone formed during Pagets disease usually begins after the age of 40 years and is more common in whites. It
that interval can be calculated by has been linked to slow virus infection by paramyxovirus. It can be involving one bone or
measuring the distance between monostotic (tibia, ilium, femur, skull, vertebra, humerus) in about 15% of cases and affecting
the two fluorescent labels. multiple bones or polyostotic (pelvis, spine, skull) in the remainder. The axial skeleton or
proximal femur is involved in upto 80% of cases.
On radiography, the Pagetic bone is typically enlarged with thick, coarsened cortices
and cancellous bone. There is increased serum alkaline phosphatase and increased urinary
Musculoskeletal System
excretion of hydroxyproline. The most common symptom is pain. Bone overgrowth in the
craniofacial skeleton may produce leontiasis ossea and the weakened Pagetic bone may lead to
invagination of base of skull (platybasia).
The histologic hallmark is the mosaic pattern of lamellar bone which is produced by prominent
cement lines that anneal haphazardly oriented units of lamellar bone. The involved bones are weak
Pagets disease: Weak but thick, and fracture easily.
vascular bone
The complications of the disease include arteriovenous shunts within the marrow
Mosaic pattern of lamellar bone resulting in high output cardiac failure and increased risk of development of sarcomas like
seen microscopical
osteosarcoma, chondrosarcoma, etc. Secondary osteoarthritis and chalk-stick type fractures
are the other complications in Pagets disease.
BENIGN TUMORS OF THE BONE
Osteoma
Subperiosteal osteomas are benign tumors affecting most often the skull and facial bones.
They are usually solitary and are detected in middle-aged adults. Multiple osteomas are seen
in the setting of Gardners syndrome.
Osteoid osteoma and osteoblastoma

Osteoid osteoma and osteoblastoma are terms used to describe benign bone tumors that have
identical histologic features but that differ in size, sites of origin, and symptoms. Osteoid
Concept osteoma is less than 2 cm in size and usually affects patients in their teens and twenties.
They usually involve the femur or tibia, where they commonly arise in the cortex and less
Osteoblastoma differs from osteoid
osteoma in that it more frequently
frequently within the medullary cavity. Osteoid osteomas are painful lesions. The pain is
involves the spine; the pain is characteristically nocturnal, and is dramatically relieved by aspirin.
dull, achy, and not responsive Microscopically, there is a central nidus of osteoid surrounded by dense sclerotic rim
to salicylates; and it does not of reactive cortical bone. X-ray shows the presence of central radiolucency surrounded by a
induce a marked bony reaction. sclerotic rim.
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Osteochondroma (Exostosis)
It is a benign bony metaphyseal growth capped with cartilage originating from the epiphyseal
growth plate. It is seen in adolescent males as a firm, solitary growth at the end of long bones.
It may be asymptomatic or may cause pain and deformity. Rarely, it may undergo malignant
transformation.
Multiple osteochondromas occur in multiple hereditary exostosis, which is an autosomal
dominant hereditary disease.
There is inactivation of both copies of the EXT gene in growth plate chondrocytes in
the pathogenesis of osteochondromas. Multiple osteochondromas become apparent during
childhood.
Chondroma
Chondromas are benign tumors of hyaline cartilage that usually occurs in bones of
endochondral origin. These can be
Enchondroma: When origin is intramedullary

Subperiosteal or juxtacortical: Originate from the surface of bone
Enchondromas are most common intraosseous cartilage tumors. Their favored sites are
short tubular bones of hand and feet.
Enchondromas are composed of well-circumscribed nodules of cytologically benign Olliers disease is a syndrome
hyaline cartilage. The center of the nodule can calcify whereas peripheral portion may of multiple enchondromas (or
undergo enchondral ossification. The unmineralized nodules of cartilage produce well- enchondromatosis)
circumscribed oval lucencies that are surrounded by a thin rim of radiodense bone
(O ring sign).
Maffucis syndrome is associa
Patients with Olliers disease may undergo malignant transformation to chondrosarcoma whereas tion of soft tissue hemangiomas
those with Maffucis syndrome have increased risk of ovarian cancer and brain gliomas. with enchondromatosis.
MALIGNANT TUMORS OF THE BONE
Osteosarcoma
It is the most common primary malignant tumor of the bone. It has a bimodal age distribution
with almost 75% occurring in patients younger than age 20. The second peak occurs in the
elderly with conditions like Paget disease, bone infarcts, and prior irradiation. It is more
commonly seen in the males with increased risk of the development in patients with familial
retinoblastoma.
The patients usually have localized pain and swelling. It arises from the metaphysis of
the long bones with the knee being the most commonly affected site. The tumor is a large,
firm white-tan mass with necrosis and hemorrhage. Microscopically, there is presence of
anaplastic cells producing osteoid and bone.
The tumor frequently breaks through the cortex and lifts the periosteum, resulting in
reactive periosteal bone formation. The triangular shadow between the cortex and raised The formation of bone by the
tumor cells is characteristic of
ends of periosteum is known radiographically as Codmans triangle.
osteosarcoma.
Chondrosarcoma
These are group of tumors that produce neoplastic cartilage.

Similar to chondroma, chondrosarcoma can be:

Intramedullary

Juxtacortical

Chondrosarcomas are second most common malignant matrix-producing tumor of bone The classic X-ray findings in
clude bone destruction, sunray
(Most common is osteosarcoma)
Histologically, Chondrosarcomas are composed of malignant hyaline and myxoid

pattern due to radiating opacities
in the tumor like sunrays and
cartilage. Spotty calcifications may be present and central necrosis may create cystic Codmans triangle.
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spaces. Tumors vary in cellularity and cytological atypia. Malignant cartilage

infiltrates the marrow space and surrounds pre-existing bony trabeculae.
Chondrosarcomas commonly arise in central portions of skeleton (including pelvis,
shoulder and ribs). In contrast to chondroma, chondrosarcoma rarely involve the
distal extremities. The clear cell variant of chondrosarcoma characteristically originates
from Epiphysis of tubular long bones.
Osteoclatoma or Giant cell tumor of bone

It is a malignant tumor containing multinucleated giant cells mixed with stromal cells. It
is more commonly seen in the females and the most commonly affected age group is 20-40
years. The tumor involves the epiphysis of the long bones usually around the knee (distal femur
and proximal tibia). Microscopically, there is presence of osteoclast like giant cells (having 100
or more nuclei) distributed in a background of mononuclear stromal cells. Most of the tumors
are solitary.
Radiographically, giant cell tumors are large, purely lytic, and eccentric, and erode into the
subchondral bone plate. The overlying cortex is frequently destroyed, producing a bulging
soft tissue mass delineated by a thin shell of reactive bone. This gives rise to the soap bubble
appearance. The tumor has high rate of recurrence after excision.
Ewings sarcoma and primitive neuroectodermal tumor (PNET)

Ewing sarcoma and PNET are primary malignant small round cell tumors of bone and soft
Other giant cell lesions include: tissue. Both Ewings sarcoma and PNET are the same tumor, differing only in their degree
of neural differentiation. Tumors that demonstrate neural differentiation by any analysis are called
Brown tumor seen in hyper - PNETs, and those that are undifferentiated are known as Ewings sarcoma.
parathyroidism
Giant cell reparative granuloma Of all bone sarcomas, Ewings sarcoma has the youngest average age at presentation and approxi
Chondroblastoma mately 80% patients are younger than age 20 years. Boys are affected slightly more frequently than
Pigmented villonodular synovitis girls. The classic translocation is t(11;22)(q24;q12) and the most common fusion gene (EWS-FLI1)
generated acts as a dominant oncogenes to stimulate cell proliferation. The presence of p30/32, a
product of mic-2 gene, is a cell surface marker form Ewings sarcoma.
Ewings sarcoma and PNET usually arise in the diaphysis of long tubular bones,
especially the femur and the flat bones of the pelvis.
The tumor is composed of sheets of uniform small, round cells that are slightly larger than
lymphocytes having scant cytoplasm, which may appear clear because it is rich in glycogen. There is
presence of Homer-Wright rosettes (where the tumor cells are arranged in a circle about a
central fibrillary space) which are indicative of neural differentiation.
The presence of p30/32, the

product of the mic-2 gene They present as painful enlarging masses, and the affected site is frequently tender,
warm, and swollen with the patients having systemic findings like fever, increased ESR,
(which maps to the pseudo

autosomal region of the X and Y anemia and leukocytosis (all of which results in the tumor resembling infection). X-ray
chromosomes) is a cell-surface shows the characteristic periosteal reaction producing layers of reactive bone deposited in
marker for Ewings sarcoma an onion-skin pattern.
(and other members of a family
of tumors called PNETs).
Note: Metastatic tumors are the most common form of skeletal malignancy.
SOFT TISSUE TUMORS
Sy novial sarcoma
These tumors forms about 10% of all soft tissue sarcomas. Less than 10% of them are intra-
articular. 60-70% involve the lower extremities especially around knee and thigh. The
histologic hallmark of biphasic synovial sarcoma is the dual lining of differentiation of the
tumor cells (e.g. epithelial-like and spindle cells). The calcified concretions can be present
which help in the diagnosis radiologically.
Immunohistochemically, these tumor cells yield positive reactions for keratin and
epithelial membrane antigen (differentiating from most other sarcomas). Most synovial
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sarcomas show a characteristic chromosomal translocation t(X ; 18) producing SYT-SSX1 or -

SSX2 fusion genes. This specific translocation is associated with poor prognosis.
Architectural Patterns in Soft Tissue Tumors

Pattern Tumor Type
Fascicles of eosinophilic spindle cells intersecting at right angles Smooth muscle
Short fascicles of spindle cells radiating from a central point (like spokes on Fibrohistiocytic
a wheel)storiform
Nuclei arranged in columnspalisading Schwann cell
Herringbone Fibrosarcoma
Mixture of fascicles of spindle cells and groups of epithelioid cellsbiphasic Synovial sarcoma
Y Y
INFLAMMATOR M OPATHIES
The inflammatory myopathies represent the largest group of acquired and potentially
treatable causes of skeletal muscle weakness. They are classified into three major groups:
polymyositis (PM), dermatomyositis (DM), and inclusion body myositis (IBM).
Criteria for Diagnosis of Inflammatory Myopathies

Criterion Polymyositis Dermatomyositis Inclusion body myositis
Myopathic muscle Yes Yes Yes; slow onset, early
weakness involvement of distal
muscles, frequent falls
Electromyographic Myopathic Myopathic Myopathic with mixed
findings potentials
Muscle enzymes Elevated (up to 50- Elevated (up to 50- Elevated (up to 10-fold) or
fold) or normal fold) or normal normal
Muscle biopsy Primary inflammation Perifascicular, Primary inflammation with

findings with the CD8/MHC-I perimysial, or CD8/MHC-I complex;
complex and no perivascular infiltrates, vacuolated fibers with
vacuoles perifascicular atrophy amyloid deposits;
cytochrome oxygenase
negative fibers; signs of
chronic myopathy
Rash or calcinosis Absent Present Absent
Y
MUSCULAR D STROPHIES
The muscular dystrophies are a heterogeneous group of inherited disorders, often beginning
in childhood, that are characterized clinically by progressive muscle weakness and wasting.
The two most common forms of muscular dystrophy are X-linked: Duchenne muscular
dystrophy (DMD) and Becker muscular dystrophy (BMD). BMD is less common and much
less severe than DMD.
DMD and BMD are caused by abnormalities in a gene encoding a protein termed dystrophin.
Dystrophin and the dystrophin-associated protein complex form an interface between

the intracellular contractile apparatus and the extracellular connective tissue matrix. The role
of this complex of proteins is transferring the force of contraction to connective tissue, so,
myocyte degeneration occurs in the absence of dystrophin.
Muscle biopsy specimens from patients with DMD show minimal evidence of dystrophin by both
staining and Western blot analysis. BMD patients have a mutation causing a reduced amount of
altered dystrophin.
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Histopathologic abnormalities common to DMD and BMD include

Variation in fiber size due to the presence of both small and enlarged fibers
Duchenne Muscular Dystrophy
(DMD)

Increased numbers of internalized nuclei
Doesnt Make Dystrophin (no

Degeneration, necrosis, and phagocytosis of muscle fibers
formation)
Regeneration of muscle fibers

Proliferation of endomysial connective tissue

DMD cases also often show enlarged, rounded, hyaline fibers that have lost their
normal cross-striations, believed to be hypercontracted fibers, this finding is rare
in BMD. In later stages, the muscles eventually become almost totally replaced
Panfascicular atrophy: char by fat and connective tissue. Cardiac involvement consists of interstitial
acterized by the muscle fiber fibrosis, more prominent in the subendocardial layers.
atrophy often involves an entire
fascicle and is seen with spinal

Boys with DMD are normal at birth, and early motor milestones are met on time.
Walking is often delayed and weakness begins in the pelvic girdle muscles and then
muscular atrophy.
extends to the shoulder girdle giving rise to Gowers sign (child uses his hands to
climb upon himself on getting up from the floor). Enlargement of the calf muscles
associated with weakness, a phenomenon termed pseudohypertrophy caused initially
by an increase in the size of the muscle fibers later by an increase in fat and connective
Perifascicular atrophy: seen tissue. Cognitive impairment is a component of the disease. Serum creatine kinase
with dermatomyositis. is elevated during the first decade of life but returns to normal in the later stages
of the disease, as muscle mass decreases. Death results from respiratory insufficiency,
pulmonary infection, and cardiac decompensation.

Boys with BMD develop symptoms at a later age than those with DMD. The onset
occurs in later childhood or in adolescence, and it is accompanied by a slower and
Becker Muscular Dystrophy
(BMD) variable rate of progression. Cardiac disease is frequently seen in these patients.
Badly Made Dystrophin (reduced
formation of an altered protein)
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1. A 10 year old girl presents with a tibial mass. Histo 8. A 9-year-old girl has difficulty in combing hairs and
pathological examination reveals a small round cell climbing upstairs since 6 months. She has Gowers
tumor. Which of the following molecular findings is
sign positive and maculopapular rash over metacarpo

most likely to be present? (AII India 2012) phalangeal joints. What should be the next appropriate

(a) 22q translocation investigation to be done? (AIIMS Nov 2008)

(b) 11q deletion
(a) ESR

(c) 7p translocation
(b) RA factor

(d) n-myc amplification
(c) Creatine kinase
2. Which of the following is the most specific test for

(d) Electromyography

rheumatoid arthritis? (AII India 2012) 9. Antibody found in myositis is? (AIIMS Nov 2008)

(a) Anti Ig M antibody (a) Anti-Jo 1

(b) Anti CCP antibody (b) Anti scl 70

(c) Anti Ig A antibody (c) Anti Sm

(d) Anti IgG antibody (d) Anti Ku
3. Onion bulb appearance of nerve ending on biopsy is 10. CD-99 is for: (AIIMS May 2008)
seen in (AIIMS Nov. 2010) (a) Ewings sarcoma
(a) Diabetic neuropathy (b) SLL
(b) Amyloid neuropathy (c) Dermatofibroma protruberans
(c) Leprous neuritis (d) Malignant histiocytic fibroma
(d) Chronic inflammatory demyelinating polyneuropa-
thy (CIDP) 11. Bone resorption markers are all except:
(AIIMS May 2008)
4. The rate of newly synthesized osteoid mineralization is (a) Tartarate resistant alkaline phosphatase (TRAP)
best estimated by (AIIMS Nov. 2010) (b) Osteocalcin
(a) Tetracycline labeling (c) Crosslinked-N-telopeptides
(b) Alizarine red staining (d) Urine total free deoxypyridinoline
(c) Calceine stain
(d) Von Kossa stain 12. A 50-year-old lady presented with a 3-month history of
pain in the lower third of the right thigh. There was no
5. Which of the following is false in relation to Osteo local swelling; tenderness was present on deep pressure.
sarcoma? (DPG 2011) Plain X-rays showed an ill-defined intramedullary
(a) Pagets disease and prior irradiation are pre-dispos- lesion with blotchy calcification at the lower end of
ing factors the right femoral diaphysis, possibly enchondroma
(b) Rb gene mutation is associated with hereditary vari- or chondrosarcoma. Sections showed a cartilaginous
ant tumor. Which of the following histological features (if
(c) C-myc gene implicated in the genesis seen) would be most helpful to differentiate the two
(d) Codmans triangle is the characteristic X-ray finding tumors? (AIIMS May 2006)
6. Cytogenetics for synovial cell sarcoma is: (AI 2008) (a) Focal necrosis and lobulation
(a) t (X: 18) (b) Tumor permeation between bone trabeculae at peri
(b) t (17, 9) phery
(c) t (9, 22) (c) Extensive myxoid change
(d) t (11, 14) (d) High cellularity
7. MIC-2 mutation associated with: (AIIMS Nov 2009) 13. Dystrophic gene mutation leads to: (AIIMS May 2003)
(a) Myasthenia gravis
(a) Osteosarcoma
(b) Ewing sarcoma (b) Motor neuron disease
(c) Alveolar soft tissue sarcoma (c) Poliomyelitis
(d) Dermatofibrosarcoma protuberance (d) Duchennes muscular dystrophy
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14. Giant cells are seen in: (PGI Dec 2006) 24. Osteoclast are stimulated by: (RJ 2005)
(a) Osteoclastoma (a) Thyroxine
(b) Chondroblastoma (b) PTH
(c) Chordoma (c) Calcitonin
(d) Osteitis fibrosa cystica (d) Estrogen
15. Biphasic pattern on histology is seen in which tumor? 25. Large intracytoplasmic glycogen storage is seen in
(a) Rhabdomyosarcoma (Delhi 2010) which malignancy? (AP 2006)
(b) Synovial cell sarcoma (a) osteosarcoma
(c) Osteosarcoma (b) Mesenchymal chondrosarcoma
(d) Neurofibroma (c) Ewings sarcoma
(d) Leiomyosarcoma
16. An epiphyseal bone lesion is: (Delhi 2009 RP)
(a) Osteogenic sarcoma 26. Osteoblastoma resembles histologically:
(b) Chondroblastoma (a) Osteosarcoma (Kolkata 2002,2003)
(c) Ewings sarcoma (b) Osteoid osteoma
(d) Chondromyxoid fibroma (c) Chondroblastoma
(d) Chondrosarcoma
17. Mosaic pattern of lamellar bone histology is found in:
(a) Osteopetrosis (Delhi PG-2006) 27. Syncytial osteoclastic giant cells are seen in All Except:
(b) Osteoid osteoma (a) Osteosarcoma (Kolkata 2002,2003)
(c) Osteitis deformans (b) Ewings sarcoma
(d) Osteomalacia (c) Chondroblastoma
(d) Aneurysmal bone cyst
18. Which one of the following inflammatory markers of
muscle biopsy is diagnostic of polymyositis? 28. Hyaline cartilage contains which type of collagen:
(a) CD8/MHC-I complex (Karnataka 2006) (a) Type I (Kolkata 2008)
(b) Vascular cell adhesion molecules (b) Type II
(c) Intracellular adhesion molecules (c) Type III

(d) Membrane attack complex (d) Type IV
19. Bone tumor arising from epiphysis is: (DNB 2001) 29. Tophi in gout are found in all regions, except:
(a) Osteogenic sarcoma (a) Bone (Bihar 2004)
(b) Ewings sarcoma (b) Skin
(c) Chondromyxoid fibroma (c) Muscle
(d) Giant cell tumor (d) Synovial membrane
20. The commonest malignant bone tumor is: (DNB 2001) 30. Which of the following is true about psoriatic arthritis?
(a) Multiple myeloma (a) Involves distal joints of hand and foot
(b) Osteosarcoma (b) Pencil in cup deformity (Bihar 2004)
(c) Ewings sarcoma (c) Sacroiliitis
(d) Giant cell tumor (d) All of the above
21. Characteristics microscopic features of osteogenic Most Recent Questions
sarcoma is: (UP 2000)
(a) Osteoid formation 30.1. Dystrophin is lacking in:
(b) Osteoid formation by mesenchymal cells with pleo- (a) Polio
morphism (b) Duchennes muscular dystrophy
(c) Codmans triangle (c) Peroneal muscular atrophy
(d) Predominant osteoclast (d) Spinal muscular atrophy
22. Ground glass appearance is found in: (UP 2001) 3 0.2. Ewings sarcoma arises from:
(a) Inverted papilloma (a) G cells
(b) Fibro calcification (b) Totipotent cells
(c) Fibrous dysplasia of bones (c) Neuroectodermal cells
(d) Chronic osteomyelitis (d) Neurons
23. Pagets disease increases the risk of: (RJ 2003) 3 0.3. Most common malignant bone tumor
(a) Osteoma (a) Osteogenic sarcoma
(b) Osteosarcoma (b) Secondaries
(c) Fibrosarcoma (c) Osteoma
(d) All (d) Enchondroma
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30.4. A 42 year-old woman Paro presents with slowly progressive

30.8. Which of these is characteristic of Gout?
syndrome comprising of features like pain and tender-
(a) Podagra
(b) Anasarca
ess on rising
ness in multiple joints, with joint stuffin
(c) Cheiroarthropathy
(d) Calcinosis cutis
in the morning. Joint involvement is symm etric, with
the proximal interphalangeal and metacarpophalangeal
joints especially involved. The physician finds presence ASSERTION AND REASON QUESTIONS
ed joints. Which of the
of tenderness in all the inflam
following laboratory abnormalities is most likely asso- 14. Will have two statements, assertion and reason. Read
ciated in this patient? both of them carefully and answer according to these
(a) Antibodies to double-stranded DNA options.
(b) IgM anti-IgG antibodies
(a) Both assertion and reason are true and reason is
(c) HLA-B27 antigen correct explanation of assertion.
(d) Urate crystals and neutrophils in synovial fluid
(b) Both assertion and reason are true and reason is not
the correct explanation of assertion.
30.5. In the giant cell tumor of the bone, the cell of origin is:
(a) Fibroblast cells

(b) Osteoclast and precursors

(c) Osteoblast and precursors 1. Assertion: Patients with Duchenes muscular dystrophy
(d) Sinusoidal cells have difficulty in walking.
30.6. Paget disease of the bone is also called: Reason: Altered dystrophin is responsible for muscular
(a) Osteitis fibrosa weakness in muscular dystrophy.
(b) Brittle bone disease 2. Assertion: Osteosarcoma is associated with the radio
(c) Fibrous dysplasia logical appearance of Codmans triangle.
(d) Osteomalacia Reason: The tumor results in reactive periosteal bone
formation.
30.7. Polyarticular rheumatoid arthritis is diagnosed when 3. Assertion: Great toe is the most commonly affected joint
more than _ joints are involved? in gout.
(a) Two Reason: Uric acid is deposited in less temperature
(b) Three 4. Assertion: Reiter syndrome is a n example of seronegative
(c) Four spondyloarthropathy
(d) Five Reason: Reiter syndrome is associated with HLA B-27
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E xplanations
1. Ans. (b) 22q translocation (Ref: Robbins 8th/1232)
Ewing sarcoma and primitive neuroectodermal tumor are primary malignant small round-cell tumors of bone and soft
tissue. Both differ in their degree of differentiation. PNETs demonstrate neural differentiation whereas Ewing sarcomas
are undifferentiated. Analyzing some features of Ewing sarcoma with the data in stem of the question:
Arises in diaphysis and metaphysis (mass in the tibia in question)
Most patients are 10 to 15 years old (10 year old girl)
Approximately 95% of patients with Ewing tumor have t(11;22)Q (q24;q12) or t(21;22)Q (q22;q12)
Microscopically there are sheets of small round cells that contain glycogen.
Please note that the option b (11q deletion) given in the question should not be confused with the answer because in Ewing sarcoma
we find 11q translocation and not deletion

Other features of Ewing sarcoma
Second most common pediatric bone sarcomas after osteosarcomas.

Boys are affected slightly more frequently than girls.

The common chromosomal abnormality is a translocation that causes fusion of the EWS gene on 22q12 with a member of the ETS

family of transcription factors usually the FL1 gene on 11q24, and the ERG gene on 21q22.
The presence of Homer-Wright rosettes (tumor cells circled about a central fibrillary space) indicates neural differentiation. Please
see the answer section of chapter 4 for an informative summary on rosettes.
Periosteal reaction produces layers of reactive bone in onion skin fashion.

Treatment includes chemotherapy and surgical excision
2. Ans. (b) Anti-CCP antibody (Ref: Robbins 8th/1237-1240, Harrison 17th/2088)
Rheumatoid factor is an IgM antibody reactive with the Fc portions of the patients own IgG. However, it is not
specific for rheumatoid arthritis as it can also be seen in a wide range of autoimmune disorders, inflammatory disease
and chronic infection.
Anti cyclic citrullinated peptide antibody (anti CCP antibody) test is more specific than rheumatoid factor for
diagnosis of rheumatoid arthritis. It is more commonly seen in the aggressive disease.
Key points about rheumatoid arthritis
It is a type IIIQ hypersensitivity reaction (immune complex disease).

Clinical features include symmetrical arthritis affecting the small joints of the hands and feet (though typically sparing the
distal interphalageal jointQ)
Rheumatoid nodulesQ are the most common cutaneouHs lesions in RA.
Presence of pannusQ (synovial mass with inflammatory cells, granulation tissue and fibroblasts).
Felty syndromeQ is RA+ spenomegaly+neutropenia
Caplan syndromeQ is RA + pneumoconiosis
Radiographic hallmarks are juxta-articular osteopeniaQ and bone erosions with narrowing of the joint space from loss of articular
cartilage.

3. Ans. (d) Chronic inflammatory demyelinating polyneuropathy (CIDP) (Ref: Robbins 8th/1259)
Segmental demyelination occurs in the absence of primary axonal abnormality when there is dysfunction or death of the
Schwann cell (in hereditary motor and sensory neuropathy) or damage to the myelin sheath (in Guillain Barre syndrome).
The process affects some Schwann cells while sparing others. The disintegrating myelin is engulfed initially by Schwann
cells and later by macrophages. The denuded axon provides a stimulus for remyelination, with cells within the endoneu-
rium differentiating to replace injured Schwann cells. These cells proliferate and encircle the axon and, in time, remyelinate
the denuded portion. Remyelinated internodes, however, are shorter than normal and have thinner myelin in proportion
to the diameter of the axon than normal internodes.
On transverse section, repetitive cycles of demyelination and remyelination cause an accumulation of tiers of Schwann cell
processes that appear as concentric layers of Schwann cell cytoplasm and redundant basement membrane that surround a
thinly myelinated axon (onion bulbs).
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CIDP
CIDP can result from altered triggering of T cells by antigen-presenting cells.
Most cases occur in adults, and males are affected slightly more often than females.
Onset is usually gradual, sometimes subacute; in a few, the initial attack is indistinguishable from that of GBS. An
acute-onset form of CIDP should be considered when GBS deteriorates >9 weeks after onset or relapses at least three
times.
Symptoms are both motor and sensory in most cases. Weakness of the limbs is usually symmetric but can be
strikingly asymmetric.
Death from CIDP is uncommon.
Biopsy typically reveals little inflammation and onion-bulb changes (imbricated layers of attenuated Schwann cell
processes surrounding an axon) that result from recurrent demyelination and remyelination
The diagnosis rests on characteristic clinical, CSF, and electrophysiologic findings. The CSF is usually acellular with
an elevated protein level. Electrodiagnostically, variable degrees of conduction slowing, prolonged distal latencies,
temporal dispersion of compound action potentials, and conduction block are the principal features.

Treatment: If the disorder is mild, management can be awaiting spontaneous remission otherwise high-dose IVIg,
PE, and glucocorticoids are all effective.
4. Ans. (a) Tetracycline labeling (Ref: Bancroft 6th/358)
Tetracycline is absorbed into bone and so, it is used as a marker of bone growth for biopsies in humans. Tetracycline binds to newly
formed bone at the bone/osteoid (unmineralized bone) interface where it shows as a linear fluorescence. Tetracycline labeling is used
to determine the amount of bone growth within a certain period of time, usually a period of approximately 21 days. Tetracycline is incor
porated into mineralizing bone and can be detected by its fluorescence. In double tetracycline labeling, a second dose is given 1114
days after the first dose, and the amount of bone formed during that interval can be calculated by measuring the distance between the
two fluorescent labels.

5. Ans. (c) C-myc gene implicated in the genesis (Ref: Robbins 8th/1225)
Osteosarcoma is defined as a malignant mesenchymal tumor in which the cancerous cells produce bone matrix. It is the most
common primary malignant tumor of bone, exclusive of myeloma and lymphoma.
It has a bimodal age distribution; 75% occur in patients younger than age 20. The smaller second peak occurs in the elderly, who
frequently suffer from conditions like Paget disease, bone infarcts, and prior irradiation.
The tumors usually arise in the metaphyseal region of the long bones of the extremities, and almost 60% occur about the knee
Genetic mutations seen with osteosarcoma are that of RB gene, p53, CDK4, p16, INK4A, CYCLIN D1, and MDM2.
The formation of bone by the tumor cells is characteristic of Osteosarcoma
Osteosarcoma typically present as painful and progressively enlarging masses.
Radiographs of the primary tumor usually show a large, destructive, mixed lytic and blastic mass that has permeative margins. The
tumor frequently breaks through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation.
The triangular shadow between the cortex and raised ends of periosteum is known radiographically as Codman triangle

6. Ans. (a) t (X: 18) (Ref: Robbins 7th/1323)
7. Ans. (b) Ewings sarcoma (Ref: Harrison 17th/613)
8. Ans. (c) Creatine kinase (Ref: Harrison 17th/2699)
The diagnosis of the patient is most likely to be dermatomyositis (DM) as suggested by proximal muscle weakness
(Gowers sign positive) and skin rash.
The clinical picture of the typical skin rash and proximal or diffuse muscle weakness has few causes other than DM.
However, proximal muscle weakness without skin involvement can be due to many conditions other than PM or
IBM.
Gowers sign is a medical sign that indicates weakness of the proximal muscles, namely those of the lower limb. The
sign describes a patient that has to use his or her hands and arms to walk up his or her own body from a squatting
position due to lack of hip and thigh muscle strength.
Inflammatory myopathies
The inflammatory myopathies are classified into three major groups: Polymyositis (PM), dermatomyositis (DM), and
inclusion body myositis (IBM).
DM affects both children and adults and women more often than men.
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Features Associated with Inflammatory Myopathies
Characteristic Polymyositis Dermatomyositis Inclusion Body Myositis

Age at onset >18 yr Adulthood and childhood >50 yr
Familial association No No Yes, in some cases
Extramuscular manifestations Yes Yes Yes
Associated conditions
Connective tissue diseases Yes Scleroderma and mixed connective Yes, in up to 20% of cases
tissue disease (overlap syndromes)
Systemic autoimmune diseases Frequent Infrequent Infrequent
Malignancy No Yes, in up to 15% of cases No
Viruses Yes Unproven Yes
Drugs Yes Yes, rarely No
Parasites and bacteria Yes No No
Dermatomyositis
DM is a distinctive entity identified by a characteristic rash accompanying, or more often preceding, muscle weakness. The
rash may consist of
A blue-purple discoloration on the upper eyelids with edema (heliotrope rash),
A flat red rash on the face and upper trunk, and erythema of the knuckles with a raised violaceous scaly eruption
(Gottrons sign).
The erythematous rash can also occur on other body surfaces, including the knees, elbows, malleoli, neck and anterior
chest (often in a V sign), or back and shoulders (shawl sign), and may worsen after sun exposure.
Dilated capillary loops at the base of the fingernails are also characteristic. The cuticles may be irregular, thickened, and
distorted, and the lateral and palmar areas of the fingers may become rough and cracked, with irregular, dirty horizontal
lines, resembling mechanics hands. The weakness can be mild, moderate, or severe enough to lead to quadriparesis.
At times, the muscle strength appears normal, hence the term dermatomyositis sine myositis. When muscle biopsy is performed in such
cases, however, significant perivascular and perimysial inflammation is often seen.

DM usually occurs alone but may overlap with scleroderma and mixed connective tissue disease. Fasciitis and thickening
of the skin, similar to that seen in chronic cases of DM, have occurred in patients with the eosinophilia-myalgia syndrome
associated with the ingestion of contaminated L-tryptophan.
The CK level usually parallels disease activity, it can be normal in some patients with active IBM or DM, especially when
associated with a connective tissue disease. The CK is always elevated in patients with active PM. Along with the CK, the
serum glutamic-oxaloacetic and glutamate pyruvate transaminases, lactate dehydrogenase, and aldolase may be elevated.
Muscle biopsy is the definitive test for establishing the diagnosis of inflammatory myopathy and for excluding other neu-
romuscular diseases. Inflammation is the histologic hallmark for these diseases; however, additional features are charac-
teristic of each subtype.
As biopsy is not given in the options, we will mark CK as the answer.
9. Ans. (a) Anti-Jo 1 (Ref: Harrison 17th/2038)
Some medically important autoantibodies:
Anti-actin antibodies coeliac disease, autoimmune hepatitis, gastric cancer
Anti-ganglioside antibodies
Anti-GD3 -
Guillain Barr syndrome
Anti-GM1 Travelers diarrhea
Anti-GQ1b Miller-Fisher syndrome
Anti-glomerular basement membrane antibody (Anti-GBM antibody) Good pasture syndrome

Anti-Hu antibody Small cell lung carcinoma
Anti-Jo 1 antibody (anti-histidyl-tRNA synthetase) Polymyositis
Anti-liver/kidney microsomal 1 antibody (anti-LKM 1 antibodies) Autoimmune hepatitis
contd...
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contd...
Anti-mitochondrial antibody Primary biliary cirrhosis
Anti-neutrophil cytoplasmic antibody (ANCA) Ulcerative colitis
Antinuclear antibody (ANA)
Anti-p62 antibodies in Primary biliary cirrhosis
Anti-sp100 antibodies in Primary biliary cirrhosis
Anti-glycoprotein210 antibodies in Primary biliary cirrhosis
Anti-ds DNA antibody SLE
Anti-extractable nuclear antigen antibodies (Anti-ENA antibodies)-
Anti-Ro antibody Sjgren syndrome
Anti-La antibody Sjgren syndrome
Anti-PM/Scl (anti-exosome) antibody scleroderma + polymyositis/dermatomyositis.
Anti-Scl 70 antibody Sclerosis and scleroderma
Anti-topoisomerase antibodies
Anti-transglutaminase antibodies
Anti-centromere antibodies
Anti-tTG Coeliac disease
Anti-eTG Dermatitis herpetiformis
10. Ans. (a) Ewings sarcoma (Ref: Harrison 17th/614, 615)

CD 99 is a marker associated with the diagnosis of Ewings sarcoma.
Granulosa cell tumour is also often found to be associated with CD 99.
IMMUNOHISTOLOGICAL MARKERS FOR SOME CANCERS
CD-99 Ewings/PNET, ovarian granulose cell tumors
LCA [CD-45] Lymphoma
CD15 Hodgkins lymphoma
Adenocarcinoma
Desmin Sarcoma
Vimentin Sarcoma
CD 31- Kaposis sarcoma
Angiosarcoma
-
Thyroid transcription factor 1 Thyroid carcinoma, lung adenocarcinoma
CD-68 and HAM 56 Malignant fibrous histiocytoma
CD117 Gastrointestinal stromal tumors (GIST)
HMB-45 Melanoma
-
CD 103 Hairy cell leukemia
11. Ans. (b) Osteocalcin (Ref: Harrison 17th/2368)

Osteocalcin is a protein secreted by osteoblasts. It is made virtually only by osteoblasts. Thus, it is a bone formation
marker, i.e. osteoblastic marker.
Biochemical markers of bone resorption Biochemical markers of bone resorption
a. Amino and carboxy terminal crosslinking telopeptide of bone a. Amino and carboxy terminal crosslinking telopeptide of bone
collagen collagen
b. Pyridinoline b. Pyridinoline
c. Free Lysyl-pyridinoline c. Free Lysyl-pyridinoline
d. Tartarate-resistant acid phosphatase (TRAP) d. Tartarate-resistant acid phosphatase (TRAP)
e. Hydroxyproline (not very specific) e. Hydroxyproline (not very specific)
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12. Ans. (b) Tumour permeation between bony trabeculae at periphery (Ref: Robbins 8th/1227-1230; Sternbergs pathology
4th/276, 281)
Chondromas are benign tumors of hyaline cartilage that usually occurs in bones of endochondral origin. These can
be:
Enchondroma: when origin is intramedullary
Subperiosteal or juxtacortical: Origin from the surface of bone
Ollier disease is a syndrome of multiple enchondromas (or enchondromatosis)
Maffucis syndrome is associated of soft-tissue hemangiomas with enchondromatosis.
Enchondromas are composed of well-circumscribed nodules of cytologically benign hyaline cartilage. Centre of the
nodule can calcify whereas peripheral portion may undergo enchondral ossification.
Chondrosarcoma These are group of tumors that produce neoplastic cartilage
Similar to chondroma, chondrosarcoma can be:
Intramedullary
Juxtacortical
Chondrosarcomas are second most common malignant matrix-producing tumor of bone. (Most common is
osteosarcoma).
Histologically, chondrosarcomas are composed of malignant hyaline and myxoid cartilage. Spotty calcifications may
be present and central necrosis may create cystic spaces. Tumors vary in cellularity and cytological atypia.
Malignant cartilage infiltrates the marrow space and surrounds pre-existing bony trabeculae.
Chondrosarcomas commonly arise in central portions of skeleton (including pelvis, shoulder and ribs). In contrast to
chondroma, chondrosarcoma rarely involve the distal extremities.
Clear cell variant of chondrosarcoma characteristically originate from epiphysis of tubular long bones.
13. Ans. (d) Duchennes musculars Dystrophy (Ref: Robbins 8th/1268-1269)
Mutation in Dystrophin gene leads to Duchene muscular dystrophy.
Important points about DMD
It is an X-linked recessive disease.

Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle giving rise to Gowers sign (child uses his
hands to climb upon himself on getting up from the floor).
Enlargement of the calf muscles associated with weakness, a phenomenon termed pseudohypertrophy caused initially by an
increase in the size of the muscle fibers later by an increase in fat and connective tissue.
Serum creatine kinase is elevated during the first decade of life but returns to normal in the later stages of the disease, as muscle
mass decreases.
Death results from respiratory insufficiency, pulmonary infection, and cardiac decompensation.
Histologically, there is degeneration, necrosis, and phagocytosis of muscle fibers and proliferation of endomysial connective tissue.
14. Ans. (a) Osteoclastoma. (Ref: Robbins 7th/1302)
Osteoclastoma (giant cell tumor) is so named because it contains a profusion of multinucleated osteoclast-type giant cells.
This tumor is supposed to have a monocyte lineage and the giant cells are believed to form via fusion of the mononuclear
cells.
Other giant cell lesions include:
Brown tumor seen in hyperparathyroidism
Giant cell reparative granuloma
Chondroblastoma
Pigmented villonodular synovitis.

15. Ans. (b) Synovial cell sarcoma (Ref: Harrison 17th/2184; Robbins 7th/1317)
Synovial cell sarcoma arise from primitive mesenchymal tissue that differentiate into epithelial and spindle cells.
16. Ans. (b) Chondroblastoma (Ref: Robbins 8th/1228)
Chondroblastoma is a rare benign tumor occurring in young patients in their teens with a male-to-female ratio of 2:1.
Most arise near the knee.
Chondroblastoma has a striking predilection for epiphyses and apophyses (epiphyseal equivalents, i.e., iliac crest).
Chondroblastomas are usually painful.
Radiographically, they produce a well-defined geographic lucency that commonly has spotty calcifications.
The tumor cells are surrounded by scant amounts of hyaline matrix that is deposited in a lacelike configuration; nodules
of well-formed hyaline cartilage are distinctly uncommon.
When the matrix calcifies, it produces a characteristic chicken-wire pattern of mineralization.
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Osteogenic sarcoma and chondromyxoid fibroma arises from metaphysis whereas Ewing sarcoma arises from medullary
cavity.
17. Ans. (c) Osteitis deformans (Ref: Robbins 7th/1285)
T he histologic hallmark in osteitis deformans (Pagets disease) is mosaic pattern of lamellar bone.
T his pattern which is likened to a jig saw puzzle, is produced by prominent cement lines that anneal haphazardly
oriented units of lamellar bone.
18. Ans. (a) CD8/MHC I complex (Ref: Robbins 7th/1343)
Polymyositis is an example of inflammatory myopathy which is characterized by the presence of symmetrical proximal
muscle weakness and elevated muscle enzymes. It is diagnosed with the help of T cell infiltrates within the muscle fascicles
(endomysial involvement). The presence of CD8/MHC I complex is required for the diagnosis of this condition.
Note: It differs from dermatomyositis by the absence of rash (no cutaneous involvement) and its occurrence mainly in the elderly. In
DM, there is presence of perifascicular atrophy (defined by the presence of groups of atrophic fibers at the periphery of the fascicles).

In another inflammatory myopathy called inclusion body myositis, there is presence of endomysial inflammation,
basophilic granular deposits around the edge of slit-like vacuoles (rimmed vacuoles) and loss of fibers (being replaced
with fat cells and connective tissue). There is characteristically presence of amyloid deposits and cytochrome oxygenase
negative fibers are seen.
19. Ans. (d) Giant cell tumor (Ref: Robbins 8th/1233)
20. Ans. (a) Multiple myeloma (Ref: Robbins 8th/609-611)
21. Ans. (b) Osteoid formation by mesenchymal cells with pleomorphism (Ref: Robbins 8th/1226; 7th/1294-1296)
22. Ans. (c) Fibrous dysplasia of bones (Ref: Robbins 8th/1231; 7th/1300-1301)
23. Ans. (b) Osteosarcoma (Ref: Robbins 8th/1216)
24. Ans. (b) PTH (Ref: Robbins 8th/1207-1208)
25. Ans. (c) Ewings sarcoma (Ref: Robbins 8th/1232; 7th/1295,1298,1301)
26. Ans. (b) Osteoid Osteoma (Ref: Robbins 8th/1224)
27. Ans. (a) Osteosarcoma (Ref: Robbins 8th/1226,1228,1234)
28. Ans. (b) Type II (Ref: Robbins 8th/1235)
29. Ans. (a) Bone (Ref: Robbins 8th/1243-1244; 7th/1312)
30. Ans. (d) All of the above (Ref: Robbins 8th/1241; 7th/1310)
3 0.1. Ans. (b) Duchennes muscular dystrophy (Ref: Robbins 8/e p1268)
Mnemonic: DMD
Duchennes muscular dystrophy: Does not Make Dystrophin
Mnemonic: BMD
Beckers muscular dystrophy: Badly Made Dystrophin
30.2. Ans. (c) Neuroectodermal cells.see text for details .(Ref: Robbins 8/e p1232)
30.3. Ans. (b)Secondaries.(Ref: Robbins 8/e p1235)
Metastatic tumours are the most common form of skeletal malignancy..(Ref: Robbins)
3 0.4. Ans. (b) IgM anti-IgG antibodies (Ref: Robbins 8th/1238-9)
Symmetric polyarthritis with involvement of the proximal interphalangeal and metacarpophalangeal joints in a female
patient are characteristics of rheumatoid arthritis. Rheumatoid factor, an IgM antibody directed against the Fc portion of
IgG, is found in about 80% of affected individuals.
The most specific antibody for rheumatoid arthritis is anti-CCP (cyclic citrullinated peptide) antibody.
30.5. Ans. (c) Osteoblast and precursors (Ref: Robbins 9/e p1203)
The neoplastic cells of giant cell tumor are primitive osteoblast precursors but they represent only a minority of the tumor
cells. The bulk of the tumor consists of non-neoplastic osteoclasts and their precursors.
30.6. Ans. (a) Osteitis fibrosa (Ref: Robbins 9/e p1189)
Paget disease is a disorder of increased, but disordered and structurally unsound, bone mass.
30.7. Ans. (d) Five joints or more (Ref: Robbins 9/e p1209; Harrison 18/e p )
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Rheumatoid arthritis is characterized by is a chronic inflammatory disorder of autoimmune origin that may
affect many tissues and organs but principally attacks the joints, producing a non suppurative proliferative and
inflammatory synovitis. The earliest involved joints are typically the small joints of the hands and feet.
The initial pattern of joint involvement may be monoarticular, oligoarticular (less than 4 joints), or poly-articular
(>5 joints), usually in a symmetric distribution.
30.8. Ans. (a) Podagra (Ref: Robbins 9/e p1216)
Podagra is the involvement of the great toe in a patient with gout. As the book mentions; most first attacks are monoarticular;
50% occur in the first metatarsophalangeal joint.
EXPLANATIONS TO ASSERTION AND REASON QUESTIONS

Explanations (1-4): While solving assertion reason type of questions, we can use a particular method.

1. First of all, read both assertion (A) and reason (R) carefully and independently analyse whether they are true or false.

2. If A is false, the answere will directly be (d) i.e. both A and R are false. You can note that all other options (i.e. a, b or c)
consider A to be true.

a
1. Ans. (b) Both assertion and reason are true and reason is not the correct explanation of assertion. (Ref: Robbins 8th/1268-9)
Patients with Duchenes muscular dystrophy have difficulty in walking. This is attributed to the absence of the skeletal
muscle contractile protein dystrophin in these patients.
Altered dystrophin is responsible for muscular weakness in patients of Beckers muscular dystrophy.
Mnemonic:
Doesnt Make Dystrophin (no formation)
Duchenne Muscular Dystrophy (DMD)
Badly Made Dystrophin (reduced formation of an altered protein)
Becker Muscular Dystrophy (BMD)

2. Ans. (a) Both assertion and reason are true and reason is correct explanation of assertion. (Ref: Robbins 8th/1226)
Osteosarcoma is associated with the radiological appearance of Codmans triangle because the the tumor frequently breaks
through the cortex and lifts the periosteum, resulting in reactive periosteal bone formation.
The formation of bone by the tumor cells is characteristic of osteosarcoma.
3. Ans. (a) Both assertion and reason are true and reason is correct explanation of assertion. (Ref: Robbins 8th/1243)
Great toe is the most commonly affected joint in gout because uric acid gets supersaturated in the peripheral joints
(ankle and toes) especially so in the lower temperatures.
4. Ans. (b Both assertion and reason are true and reason is not the correct explanation of assertion. (Ref: Robbins 8th/1241)
The seronegative spondyloarthropathies include the following: Mnemonic: PAIR
P: Psoriatic arthritis
A: Ankylosing spondylitis
I: Inflammatory bowel disease (Crohn disease and ulcerative colitis) associated arthritis
R: Reiter syndrome

These are called seronegative because they are not associated with specific autoantibodies although they are associated
with HLA B-27 as well as a triggering infection.
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CHAPTER 18
1. SALIVARY GLAND TUMORS
Miscellaneous
About 65 to 80% of the salivary gland tumors arise within the parotid, 10% in the submandibular
gland, and the remainder in the minor salivary glands, including the sublingual glands. The
likelihood of a salivary gland tumor being malignant is inversely proportional to the size of the gland
which means the tumors in minor salivary glands are more likely to be malignant and those
in parotid are mostly benign.
These tumors usually occur in adults, with a slight female predominance except Warthin
tumor which occur more often in males than in females.
Pleomorphic Adenoma or Mixed Tumors
They are the most common benign tumors that are derived from a mixture of ductal
(epithelial) and myoepithelial cells, and therefore they show both epithelial and
mesenchymal differentiation. About 60% of tumors in the parotid are mixed tumors.
Radiation exposure increases the risk. Most pleomorphic adenomas present as
rounded, well-demarcated masses rarely exceeding 6 cm.
The epithelial elements resemble ductal cells or myoepithelial cells and are typically
dispersed within a mesenchyme-like background of loose myxoid tissue containing
islands of chondroid and, rarely, foci of bone.
Tumors present as painless, slow-growing, mobile discrete masses.
A carcinoma arising in a pleomorphic adenoma is referred to as a carcinoma
ex pleomorphic adenoma or a malignant mixed tumor. The incidence of malignant
transformation increases with the duration of the tumor.
Warthins Tumor (Papillary Cystadenoma Lymphomatosum)
It is the second most common benign salivary gland neoplasm. It arises almost
always in the parotid gland and occurs more commonly in males than in females,
usually in the fifth to seventh decades of life. About 10% are multifocal and 10%
bilateral. It is more common in smokers.
Most Warthins tumors are round to oval, encapsulated masses, 2 to 5 cm in diameter.
On microscopic examination, the cystic spaces are lined by a double layer of neoplastic
epithelial cells resting on a dense lymphoid stroma. The double layer of lining cells
is distinctive, with a surface palisade of columnar cells having an abundant, finely
granular, eosinophilic cytoplasm, imparting an oncocytic appearance, resting on a
layer of cuboidal to polygonal cells.
Mucoepidermoid Carcinoma
They occur mainly (60 to 70%) in the parotids. They are the most common form of primary
malignant tumor of the salivary glands. Mucoepidermoid carcinomas can grow up to 8 cm in
diameter, lack well-defined capsules and are often infiltrative at the margins. It is associated
with a balanced translocation, t(11;19) producing a fusion gene made-up of MECT1 and
MAML2.
The basic histologic pattern is that of cords, sheets, or cystic configurations of squamous,
mucous, or intermediate cells. The hybrid cell types often have squamous features, with
small to large mucus-filled vacuoles, best seen with mucin stains.
Two other salivary gland tumors include: Adenoid cystic carcinoma and acinic cell
tumor.
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Adenoid cystic carcinoma is a relatively uncommon tumor. In 50% of cases, it is found in the mi-
nor salivary glands (in particular; the palate). These tumors have a tendency to invade perineural
spaces. They have high chances of recurrence and eventually, 50% or more disseminate widely to
distant sites such as bone, liver, and brain.
The acinic cell tumor is composed of cells resembling the normal serous acinar cells of
salivary glands. Most arise in the parotids and the small remainder arises in the submandibular
glands. They rarely involve the minor glands. Most characteristically, the cells have apparently
clear cytoplasm, but the cells are sometimes solid or at other times vacuolated. The cells are
disposed in sheets or microcystic, glandular, follicular, or papillary patterns. There is usually
little anaplasia and few mitoses. On histologic evaluation, they are composed of small cells
having dark, compact nuclei and scant cytoplasm. These cells tend to be disposed in tubular,
solid, or cribriform patterns. The spaces between the tumor cells are often filled with a hyaline
material thought to represent excess basement membrane.
2. OTHER IMPORTANT TUMORS
a. Neuroblastoma
It is the most common extracranial solid tumor of childhood and the most frequently
diagnosed tumor of infancy.
Most cases are sporadic. Familial cases (1-2%) result from germline mutation in
anaplastic lymphoma kinase (ALK) gene.
Most common site of origin is adrenal medulla (40%) followed by para-vertebral sympathetic
chain in abdomen (25%) and posterior mediastinum (15%).
Adrenal neuroblastomas are malignant neoplasms arising from the sympathetic
neuroblasts in the medulla of the adrenal gland. There are two clinical types, based
Miscellaneous
on the differences in distribution of metastasis. First (Pepper type) occurs in the

stillborn and in young infants and metastasizes to the liver and regional lymph
nodes, then the lungs, and late in the course, the calvarium and other flat bones.
The second (Hutchinson) type is characterized clinically by secondary growth in the
orbit, meninges, skull and long bones and occurs in children up to 15 years of age.
Histologically, it is one of the small round blue cell tumor. It shows central
space filled with eosinophilic fibrillary material called neuropil surrounded by
concentrically arranged tumor cells (Homer-Wright pseudorosettes).
Note: Other small round cell tumors can be remembered as (Sofia LOREN)
Sophia Small round cell tumors
L Lymphoma
O Oat cell carcinoma
R Rhabdomyosarcoma
E Ewings Sarcoma
N Neuroblastoma
Tumor cells are positive for neuron specific enolase and contain dense core granules.
Maturation of some of the cells (to form ganglion cells) along with presence of
primitive neuroblasts is called ganglioneuroblastoma. Even better differentiation
with few neuroblasts is designated ganglioneuroma.
Only presence of ganglion cells is not enough for designation of maturation. Presence
of Schwannian stroma, mature Schwann cells and fibroblasts is a histologic pre-
requisite for the designation of ganglioneuroblastoma and ganglioneuroma.
Metastasis develops early and widely. Hematogenous spread may occur to liver,
lungs, bone marrow and bones.
About 60-80% children present with stage 3 or 4 tumors.
Apart from stage 1, 2, 3 and 4, stage 4S (special stage) is present in neuroblastoma.
It signifies localized primary tumor with dissemination limited to skin, liver and/or
bone marrow. Stage 4S is limited to infants < 1 year.
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Miscellaneous
Prognostic Factors
Factor Favorable Unfavorable
1. Stage 1, 2A, 2B, 4S 3, 4
2. Age <18 months >18 months
3. Histology
Schwannian stroma Present Absent
Gangliocytic differentiation Present Absent
Mitotic rate Low High
Mitotic karyorrhexis index <200/5000 cells ( 4%) >200/5000 (> 4%)
Intramural calcification Present Absent
4. DNA Ploidy Hyperdiploid or near triploid Near diploid
5. N-Myc Not amplified Amplified
6. Genetics
17q gain Absent Present
1p loss Absent Present
11q loss Absent Present
TRKA expression Present Absent
TRKB expression Absent Present
MRP expression Absent Present
CD44 expression Present Absent
Telomerase expression Absent Highly expressed
Note:
Age for prognosis in 7th edition of Robbins was 1 year, in 8th edition, this has been changed to 18
months.
Chromosome 11q loss, TRKB expression are included in prognostic factors in 8th edition of Rob-
bins.

Miscellaneous
b. Retinoblastoma
Retinoblastoma is the most common malignant eye tumor of childhood.

90% cases are diagnosed before 7 years. Hereditary retinoblastoma when affecting
both eyes is called bilateral retinoblastoma.
Bilateral retinoblastoma + pineal gland tumor in suprasellar or parasellar region is
called Trilateral retinoblastoma
These tumors arise from neuroepithelium of the retina

A characteristic feature is Flexner Wintersteiner rosettes consisting of clusters
of cuboidal or short columnar cells arranged around a central lumen. The
nuclei are displaced away from the lumen and photoreceptor like elements are
produced from it. Retinoblastoma also shows Homer Wright rosettes which are
radial arrangement of cells around a central tangle of fibrils.

Fleurettes representing photoreceptor differentiation of tumor cells is also seen.
c. Wilms Tumor
Wilms tumor is the most common primary renal tumor of childhood in USA. The risk of
Wilmss tumor is increased in association with at least three recognizable groups of congenital
malformations:

1. WAGR syndrome, characterized by aniridia, genital anomalies, and mental retardation
and a 33% chance of developing Wilms tumor. Patients with WAGR syndrome
carry constitutional (germline) deletions of two genes WT1 and PAX6, both located
at chromosome 11p13.
2. Denys-Drash syndrome, which is characterized by gonadal dysgenesis (male pseudo
hermaphroditism) and early-onset nephropathy leading to renal failure. The charac
teristic glomerular lesion in these patients is a diffuse mesangial sclerosis. These
patients also have germline abnormalities in WT1. In addition to Wilms tumors,
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these individuals are also at increased risk for developing germ-cell tumors called
gonadoblastomas.
3. Beckwith-Wiedemann syndrome, characterized by enlargement of body organs
(organomegaly), macroglossia, hemihypertrophy, omphalocele, and abnormal large
cells in adrenal cortex (adrenal cytomegaly). The genetic locus involved in these
patients is in band p15.5 of chromosome 11 called WT2. In addition to Wilms
tumors, patients with Beckwith-Wiedemann syndrome are also at increased risk for
developing hepatoblastoma, adrenocortical tumors, rhabdomyosarcomas, and pancreatic
tumors.
Morphology
Grossly, Wilmss tumor tends to present as a large, solitary, well-circumscribed mass and
on cut section, the tumor is soft, homogeneous, and tan to grey with occasional foci of
hemorrhage, cyst formation, and necrosis. Microscopically, Wilmss tumors are characterized
by the classic triphasic combination of blastemal, stromal, and epithelial cell types observed in the
vast majority of lesions.
d. Histiocytosis
Langerhans cell histiocytosis (LCH) has the following entities:

1. Letterer-Siwe syndrome (multifocal multisystem LCH)

2. Pulmonary Langerhans cell histiocytosis: most often seen in adult smokers and can
regress spontaneously on cessation of smoking.

3. Eosinophilic granuloma.

Hand-Schuller-Christian triad is composed of calavrial bone defects, diabetes insipidus
and exophthalmos.

The tumor cells express HLA-DR, S-100, and CD1a.
Miscellaneous
The presence of Birbecks granules in the cytoplasm is characteristic which have a tennis-
racket appearance under the electron microscope.
e. Mediastinal Tumors
The mediastinum is the region between the pleural sacs. It is separated into three com
partments.

1. The anterior mediastinum extends from the sternum anteriorly to the pericardium
and brachiocephalic vessels posteriorly. It contains the thymus gland, the anterior
mediastinal lymph nodes, and the internal mammary arteries and veins.

2. The middle mediastinum lies between the anterior and posterior mediastinum and
contains the heart; the ascending and transverse arches of the aorta; the venae cavae;
the brachiocephalic arteries and veins; the phrenic nerves; the trachea, main bronchi,
and their contiguous lymph nodes; and the pulmonary arteries and veins.

3. The posterior mediastinum is bounded by the pericardium and trachea anteriorly
and the vertebral column posteriorly. It contains the descending thoracic aorta,
esophagus, thoracic duct, azygos and hemiazygos veins, and the posterior group of
mediastinal lymph nodes.
The most common lesions in the anterior mediastinum are thymomas, lymphomas,
teratomatous neoplasms, and thyroid masses. The most common masses in the middle
mediastinum are vascular masses, lymph node enlargement from metastases or granulomatous
disease, and pleuropericardial and bronchogenic cysts. In the posterior mediastinum, neurogenic
tumors, meningoceles, meningomyeloceles, gastroenteric cysts, and esophageal diverticula are
commonly found.
T hymoma
The thymus is derived from the third and fourth pharyngeal pouches and is located in the
anterior mediastinum. The thymus is composed of epithelial and stromal cells and
lymphoid precursors.
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Miscellaneous

If a lymphoid cell within the thymus becomes neoplastic, the disease that develops
is a lymphoma which is a T cell lymphoblastic lymphomas in most of the cases. If
the epithelial cells of the thymus become neoplastic, the tumor that develops is a
thymoma.

Thymoma is the most common cause of an anterior mediastinal mass in adults.
Thymomas are most common in the fifth and sixth decade. Majority (90% ) of
thymomas are in the anterior mediastinum. Thymomas are epithelial tumors and all of
them have malignant potential. They may have a variable percentage of lymphocytes within
the tumor. The epithelial component of the tumor may consist primarily of round or
oval cells derived mainly from the cortex or spindle-shaped cells derived mainly
from the medulla or combinations thereof.
These tumors present clinically in 40% patients as causing symptoms due to
compression on the mediastinal structures or due to their association with myasthenia
gravis. In addition to myasthenia gravis, other paraneoplastic syndromes, such as
acquired hypogammaglobulinemia, pure red cell aplasia, Graves disease, pernicious
anemia, dermatomyositis-polymyositis, and Cushing syndrome, can be seen.
WHO Histologic Classification of Thymus Tumors

Type Histologic Description
A Medullary thymoma
AB Mixed thymoma
B1 Predominantly cortical thymoma
B2 Cortical thymoma
B3 Well-differentiated thymic carcinoma
C Thymic carcinoma
Miscellaneous
The genetic lesions in thymomas are not well characterized. Some data suggest that
3. SCLERODERMA
There are three major forms of scleroderma: diffuse, limited (CREST syndrome) and
morphea/linear. Diffuse and limited scleroderma are both a systemic disease, whereas the
linear/morphea form is localized to the skin.
Diffuse Scleroderma
Diffuse scleroderma (progressive systemic sclerosis) is the most severe form. It has a rapid
onset, involves more widespread skin hardening, will generally cause much internal organ
damage (especifically the lungs and gastrointestinal tract), and is generally more life-
threatening.
Limited Scleroderma/CREST Syndrome
The limited form is much milder. It has a slow onset and progression. Skin hardening is
usually confined to the hands and face, internal organ involvement is less severe, and a much
better prognosis is expected. In typical cases of limited scleroderma, Raynauds phenomenon
may precede scleroderma by several years. The scleroderma may be limited to the fingersknown
as sclerodactyly.
The limited form is often referred to as CREST syndrome characterized by:
Calcinosis
Raynauds syndrome
Esophageal dysmotility
Sclerodactyly
Telangiectasia
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CREST is a limited form associated with antibodies against centromeres and usually
spares the lungs and kidneys.
Morphea/Linear Scleroderma
Morphea/linear scleroderma involves isolated patches of hardened skin. There generally is

no internal organ involvement.
Diagnosis is by clinical suspicion, presence of autoantibodies (especifically anti-centromere
and anti-scl70/anti-topoisomerase antibodies) and occasionally by biopsy. Of the antibodies,
90% have a detectable anti-nuclear antibody. Anti-centromere antibody is more common in the
limited form (80-90%) than in the systemic form (10%), and anti-scl70 is more common in the diffuse
form (30-40%).
4. DEFICIENCIES AND TOXICITIES OF METALS
Element Deficiency Toxicity

Boron No biologic function determined Developmental defects, male sterility,
testicular atrophy
Calcium Reduced bone mass, osteoporosis Renal insufficiency (milk-alkali syndrome),
nephrolithiasis, impaired iron absorption
Copper Anemia, growth retardation, defective Nausea, vomiting, diarrhea, hepatic
keratinization and pigmentation of hair, failure, tremor, mental deterioration,
hypothermia, degenerative changes hemolytic anemia, renal dysfunction
in aortic elastin, osteopenia, mental
deterioration
Chromium Impaired glucose tolerance Occupational: renal failure, dermatitis,
Miscellaneous
pulmonary cancer
Fluoride Dental caries Dental and skeletal fluorosis,
osteosclerosis
Iodine Thyroid enlargement, cretinism Thyroid dysfunction, acne-like eruptions
Iron Muscle abnormalities, koilonychia, pica, Gastrointestinal effects (nausea, vomiting,
anemia, reduced work performance, diarrhea, constipation), iron overload with
impaired cognitive development, organ damage, acute systemic toxicity
premature labor, increased perinatal
and maternal mortality
Manganese Impaired growth and skeletal General: Neurotoxicity, Parkinson-like
development, reproduction, lipid and symptoms
carbohydrate metabolism; upper body Occupational: Encephalitis-like syndrome,
rash Parkinson-like syndrome, psychosis,
pneumoconiosis
Molybdenum Severe neurologic abnormalities Reproductive and fetal abnormalities
Selenium Cardiomyopathy, heart failure, striated General: Alopecia, nausea, vomiting,
muscle degeneration abnormal nails, emotional lability,
peripheral neuropathy, lassitude, garlic
odor to breath, dermatitis
Occupational: Lung and nasal carcinomas,
liver necrosis, pulmonary inflammation
Phosphorous Rickets (osteomalacia), proximal Hyperphosphatemia
muscle weakness, rhabdomyolysis,
paresthesia, ataxia, seizure, confusion,
heart failure, hemolysis, acidosis
Zinc Growth retardation, altered taste and General: Reduced copper absorption,
smell, alopecia, dermatitis, diarrhea, gastritis, sweating, fever, nausea, vomiting
immune dysfunction, failure to thrive, Occupational: Respiratory distress,
gonadal atrophy, congenital malformations pulmonary fibrosis
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Miscellaneous

1. The immune-cytochemical feature of Langerhans cell 9. Splenic macrophages in Gauchers disease differ from
histiocytosis ispositivity for which of the following? those in ceroid histiocytosis by staining positive for:
(a) CD1a (AI 2012) (a) Lipids (AI 2004)
(b) CD99 (mic-2) (b) Phospholipids
(c) HMB-45 (c) Acid-fast stain
(d) CD117 (d) Iron
2. In the congenital dystrophic variety of epidermolysis 10. A 70 years old male who has been chewing tobacco for
bullosa, mutation is seen in the gene coding for the past 50 years presents with a six months history of a
(a) Laminin 4 (AI 2012) large, fungating, soft papillary lesions in the oral cavity.
(b) Collagen type 7 The lesion has penetrated into the mandible. Lymph
(c) Alpha 6 integerin nodes are not palpable. Two biopsies take from the
(d) Keratin 14 lesion proper show benign appearing papillomatosis
with hyperkeratosis and acanthosis infiltrating the sub
3. The marker for Langerhans cell histiocytosis is: jacent tissues. The most likely diagnosis is: (AI 2004)
(a) CD 1a (AI 2010) (a) Squamous cell papilloma
(b) CD 20
(b) Squamous cell carcinoma
(c) CD 3
(d) CD 30
(c) Verrucous carcinoma
(d) Malignant mixed tumour
4. For examination of fungus from a sample, uniformly 11. Hereditary retinoblastoma develop the following chro
stain by: (AI 2010)
mosomal deletion:
Miscellaneous
(AI 2003)
(a) Alizarin
(a) 13q14
(b) PAS
(b) 11p13
(c) MassonTrichome (c) 14q13
(d) Giemsa (d) 22q11
5. All are components of photoreceptor matrix, except: 12. All the statement about lactoferin are true, except:
(a) MMP (AI 2008) (a) It is present in secondary granules of neutrophil
(b) TIMP (b) It is present in exocrine secretions of body (AI 2003)
(c) SPARC (c) It has great affinity for iron
(d) MIMECAN (d) It transports iron for erythropoiesis
6. Acinic cell carcinomas of the salivary gland arise most 13. Protein involved in intercellular connections is:
often in the: (AI 2006) (a) Connexins (AI 2001)
(a) Parotid salivary gland (b) Integrins
(b) Minor salivary glands (c) Adhesins
(c) Submandibular salivary gland
(d) Sublingual salivary gland
7. In familial Mediterranean fever, the gene encoding the 14. Which of the following stains is used to detect lipid in
frozen section biopsy in histopathology laboratory?
following protein undergoes mutation (AI 2005) (a) PAS (AIIMS Nov 2009)
(a) Pyrin (b) Oil Red O
(b) Perforin (c) NSE
(c) Atrial natriuretic factor (d) Silver Methanamine
(d) Immunoglobulin light chain
15. Young boy presented with multiple flaccid bullae and
8. To which of the following events is good outcome in oral lesions. Diagnostic finding in skin biopsy immuno
Neuroblastoma associated (AI 2004) fluorescence test would be: (AIIMS Nov 2009)
(a) Diploidy (a) Fish net IgG in dermoepidermal junction
(b) N-myc amplification (b) Linear IgG in dermoepidermal junction
(c) Chromosome/p depletion (c) Linear IgG in dermal papillae
(d) Trk A expression (d) Granular IgA in reticular dermis
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16. A 14 years old girl on exposure to cold develop pallor of (c) Neural
extremities followed by pain and cyanosis. In later ages (d) Muscular
of life she is prone to develop? (AIIMS Nov 2008)
(a) Systemic lupus erythematosus
25. Tophus is the pathognomic lesion of which of the
following condition: (AIIMS May 2003)
(b) Scleroderma
(a) Multiple myeloma
(b) Cystinosis
(d) Histiocytosis
(c) Gout
17. Which is false about acrodermatitis? enteropathica? (d) Eales disease
(AIIMS Nov 2008)
26. Which of the following diseases have an underlying
(a) Triad of diarrhea, dementia and dermatitis
mitochondrial abnormality? (PGI Dec 01)
(b) Low serum zinc levels
(a) Krabbes disease
(c) Symptoms improve with zinc supplementation
(b) Fabrys disease
(d) Autosomal recessive
(c) Mitochondrial myopathy
18. Which of the following statement is incorrect? (d) Oncocytoma
(AIIMS Nov 2008) (e) Fanconis syndrome
(a) Selenium deficiency causes cardiomyopathy
(b) Zinc deficiency causes pulmonary fibrosis
27. Foam cells seen in: (PGI Dec 2005)
(a) Alports syndrome
(c) Increased calcium intake cause iron deficiency
(d) Vitamin A deficiency occurs after 6 months to 1year (b) Niemann-Pick disease
of low vitamin A diet (c) Atherosclerosis
(d) Pneumonia
19. A patient presents with mediastinal mass with sheets 28. Which among the following is the best tissue fixative?
of epithelial cells giving arborizing pattern of keratin
reactivity along with interspersed lymphoid cells. The (a) Formalin (Delhi PG-2007)
apt diagnosis would be: (AIIMS May 2008) (b) Alcohol
(a) Thymoma (c) Normal saline
(b) Thymic carcinoid (d) Methylene blue
(c) Primary mediastinal lymphoma 29. All of the following are forms of panniculitis
Miscellaneous
(d) Non-Hodgkin lymphoma except: (Delhi PG-2006)

20. Ultrastructural finding in case of Paraganglioma: (a) Weber-Christian disease
(a) Deposition of glycogen (AIIMS May 2008) (b) Erythema induratum
(b) Enlarged mitochondria (c) Erythema nodosum
(c) Shrunken mitochondria (d) All of the above
(d) Dense core granules 30. Warthin-Finkeldey cells are seen in:
21. Brain natriuretic peptide is degraded by: (a) Measles
(a) Neutral endopeptidase (AIIMS May 2007) (b) Rubella
(b) Elastase (c) Influenza
(c) Collagenase (d) Rickettsial pox
(d) Ompatrilat 31. Pathogenesis is sequence of events in response to:
22. Why fetal cells continue to divide but terminally diffe (Delhi PG-2004)
rentiated adult cells do not divide: (AIIMS Nov 2006) (a) Expression of disease upto clinical manifestation
(a) There are many cyclin inhibitors which prevent cell (b) Expression of disease upto non-clinical manifesta-
to enter into S phase in adult tion
(b) Phosphatase absent in fetal cells (c) The etiological agent for the initial stimulus to the
(c) Proteinase is absent in fetus ultimate expression of disease
(d) Absence of CD kinase (d) None
23. All of the following are examples of a round cell tumor, 32. All
coma
of the following characteristics are true of liposar
except that it: (Karnataka 2009)
(a) Neuroblastoma (a) Is commonly found in the retroperitoneum
(b) Ewings sarcoma (b) Frequently gives rise to embolization in lymphatics
(c) Non-Hodgkins lymphoma (c) Is the most common soft tissue sarcoma
(d) Osteosarcoma (d) Arises very rarely in subcutaneous tissue
24. The tissue of origin of the Kaposis sarcoma is: 33. All of the following are correctly matched except:
(a) Lymphoid (AIIMS May 2005) (Karnataka 2008)
(b) Vascular (a) Russell bodiesMultiple myeloma
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Miscellaneous
(b) Russell bodiesAlcoholic liver disease

(b) Rhabdomyoma
(c) Michaelis Gutmann bodiesLangerhans histio-
(c) Hemangioma
cytosis
(d) Lipoma
(d) Civatte bodiesLichen planus
44. Triad of biotin deficiency is (UP 2005)
34. Most common second malignancy in patients with (a) Dermatitis, glossitis, steatorrhea
familial retinoblastoma is: (Karnataka 2004) (b) Dermatitis, glossitis, alopecia
(a) Teratoma (c) Mental changes, diarrhea, alopecia
(b) Medullary carcinoma (d) Dermatitis, dementia, diarrhea
(c) Osteosarcoma 45. Basophilic stippling is seen in: (UP 2006)
(d) Malignant melanoma (a) Cadmium poisoning
35. Hutchisons secondaries in skull are due to tumors in: (b) Lead poisoning
(a) Lung (DNB-2000, 2003) (c) Chromium poisoning
(b) Breast (d) Iron poisoning
(c) Liver 46. Most common tumor of infancy is (UP 2005, 2007)
(d) Adrenals (a) Lymphangioma
(e) Testes (b) Rhabdomyoma
36. Rosette shaped arrangement of cells are seen in: (c) Hemangioma
(a) Thecoma of ovary (DNB- 2000, 2006, 2007) (d) Lipoma
(b) Ependymoma 47. Pleomorphic adenoma usually arises from
(c) Neurofibroma (a) Parotid gland (UP 2007)
(d) Lymphoma (b) Submandibular gland
37. Spontaneous regression though rare is seen in: (c) Minor salivary gland
(a) Burkitts lymphoma (DNB- 2000) (d) Superficial lobe
(b) Wilms tumor 48. Direct Coombs test detects: (UP 2008)
(c) Neuroblastoma (a) Antigen in serum
(d) Melanoma (b) Antibodies on RBC surface
Miscellaneous
(c) Antigen on RBC surface
38. Peri-oral pallor and Dennies lines are seen in: (d) Antibodies in serum
(a) Atopic dermatitis (DNB- 2008)
(b) Chronic actinic dermatitis 49. In vitamin deficiencies, patient is vulnerable to infec
(c) Blood dyscrasias tion with: (RJ 2000)
(d) Perioral contact dermatitis (a) Measles
(b) Mumps
39. Most common tumor of parotid gland is: (c) Rubella
(a) Pleomorphic adenoma (UP 2001)
(d) Whooping cough
(b) Warthins adenoma
(c) Mucoepidermoid carcinoma 50. Paralytic food poisoning is caused by: (RJ 2000)
(d) Mixed tumor (a) Staphylococci
(b) E. coli
40. MC malignant tumor of parotid glands is: (c) B. cereus
(a) Pleomorphic adenoma (UP 2001) (d) Clostridia
(b) Mucoepidermoid carcinoma
(c) Warthins tumor 51. Which is not present in anterior mediastinum?
(d) Mixed tumor of salivary gland (a) Lymphoma (RJ 2000)
(b) Thymoma
41. Punctate basophilia is found in: (UP 2001) (c) Teratoma
(a) DDT poisoning (d) Neurofibroma
(b) Mercury vapors inhalation
(c) Cyanide poisoning 52. Nonbacterial verrucous endocarditis is associated with
(d) Lead poisoning (a) Rheumatic carditis (RJ 2001)
(b) Rheumatoid arthritis
42. Epulis is (UP-98, 2004) (c) SLE
(a) Tumor of gingiva (d) Infective endocarditis
(b) Tumor of enamel of tooth
(c) Disarrangement of tooth 53. Frozen section biopsy in not used for: (Bihar 2005)
(d) Dysplastic leukoplakia (a) Enzyme
(b) Amyloid
43. Most common tumor of infancy is (UP 2005) (c) Fat
(a) Lymphangioma (d) Proteins
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54. Rodent ulcer is due to: (RJ 2002) 58. Pellagra is characterized by all except: (RJ 2003)
(a) Syphilis (a) Diarrhea (b) Dementia
(b) Burns (c) Dermatitis (d) Diplopia
(c) Basal cell carcinoma
(d) TB 59. Smoking causes all cancers except: (AP 2002)
(a) Liver (b) Pancreas
55. Most common salivary gland tumor in adult is: (c) Bladder (d) Lung
(a) Mucoepidermoid carcinoma (RJ 2003)
(b) Lymphoma 60. Endothelial cells have: (Bihar 2003)
(c) Pleomorphic adenoma (a) Weibel Palade bodies
(d) None (b) Gamma Gandy bodies
56. Soft chancre is caused by: (RJ 2003) (c) Both
(a) Syphilis (d) None
(b) TB
(c) Chancroid
(d) L. donovani 60.1. Which one of the following conditions is NOT
57. Kobners phenomena is seen in: (RJ 2003) associated with occurrence of pellagra?
(a) People eating mainly corn-based diet
(a) Psoriasis
(b) Lichen planus (b) Carcinoid syndrome
(c) Toxic epidermal necrolysis (c) Phototherapy
(d) All (d) Hartnup disease
Miscellaneous
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Miscellaneous
E xplanations
1. Ans. (a) CD1a (Ref: Robbins 8th/631-2)
Entities in Langerhans cell histiocytosis
Letterer-Siwe syndrome (multifocal multisystem LCH)

Pulmonary Langerhans cell histiocytosis: seen in adult smokers and can regress on cessation of smoking.
The tumor cells in Langerhans cell histiocytosis express HLA-DR, S-100Q, and CD1aQ.
2. Ans. (b) Collagen type 7 (Ref: Robbins 8th/1196)
Epidermolysis bullosa are a group of non inflammatory disorders caused by defects in structural proteins which lend
stability to the skin. It can be of the following types:
Simplex type: defect in basal layer of epidermis due to mutation in gene for keratin 14 or 5
Junctional type: blisters occur at the level of lamina lucida
Dystrophic type: blisters beneath the lamina densa due to defect in COL7A1 gene for collagen type VIIQ
Clinical importance
Squamous cell cancersQ can arise in these chronic blisters.
Non-Herlitz junctional epidermolysis bullosa is caused by defect in LAMB3 gene encoding laminin V3.

3. Ans. (a) CD 1a (Ref: Robbins 8th/631-632)
Langerhans cell histiocytosis (LCH) has the following entities:
Miscellaneous
Letterer-Siwe syndrome (multifocal multisystem LCH)
Pulmonary Langerhans cell histiocytosis: most often seen in adult smokers and can regress spontaneously on cessation
of smoking.
Hand-Schuller-Christian triad is composed of calavrial bone defects, diabetes insipidus and exophthalmos.
The tumor cells express HLA-DR, S-100, and CD1a.
The presence of Birbecks granules in the cytoplasm is characteristic which have a tennis-racket appearance under the
electron microscope.
4. Ans. (b) PAS (Ref: Robbins 8th/336, Harsh Mohan 6th/12-13)
PAS (Periodic Acid Schiff) stain is used for Carbohydrates particularly glycogen and all mucins, amoebae and fungi
Other frequently asked stains:
Stains Substance
Congo red with polarizing light Amyloid
Ziehl Neilson stain Tubercle bacilli
Massons Trichrome Extracellular collagen
Perls stain Hemosiderin, iron
Masson-Fontana Melanin, argentaffin cells
Alizarin calcium
Feulgen reaction DNA
Giemsa Campylobacter, leishmaniae, malaria parasites
Silver methanamine is a better stain for fungi and stains Pneumocystis and the fungi black in color.
Mucicarmine is for staining cryptococci
5. Ans. (d) MIMECAN (Ref: Robbins 7th/105, 109-111; Retina; Stephen J.Ryan 4th/140)
Ryan says the retinal pigment epithelial (RPE) cells actively synthesize and degrade extracellular matrix (ECM) com-
ponents. Deposition of ECM molecules is polarized with different components secreted apically and basally. The
apical domain of the RPE cells is embedded in the interphotoreceptor matrix which is produced by RPE and inner
segments of the photoreceptors. Degradation of ECM is regulated by the equilibrium between matrix metalloprotein-
ases [(MMP) and their tissue inhibitors (TIMPs)].
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The normal RPE expresses membrane bound type I (MT1-MMP) and type 2 (MT2 MMP) metalloproteinase as well
as the metalloproteinase inhibitors TIMP-1 and TIMP-3. TIMP-3 accumulates in Brusch membrane and is seen in age
related macular degeneration (ARMD).
Patients with SPARC (ostionectin) (Secreted Protein Acidic and Rich in Cysteine) contributes to tissue remodeling in
response to injury and functions as an angiogenesis inhibitor. SPACR (sialyprotein associated with cones and rodes)
is a glycoprotein identified in human interphotoreceptor matrix.
MIMECAN is a member of small leucine rich proteoglycans (SLRP) gene family. They are essential for normal colla-
gen fibrillogenesis in various connective tissues like cornea. It is not present in photorceptor matrix. It is also known
as osteoglycin.
6. Ans. (a) Parotid salivary gland (Ref: Robbins 7th/794)
Acinic cell tumors of salivary glands are uncommon tumors representing 2 to 3% of salivary gland tumors.
These are composed of cells resembling the normal serous acinar cells of salivary glands.
Most of these arise in the parotids. The remainder arises in submandibular glands.
Most parotid tumors are benign but half of submandibular and sublingual and most minor salivary gland tumors are
malignant.
7. Ans. (a) Pyrin (Ref: Robbins 7th/261, Harrison 17th/2144)
Familial Mediterranean fever (FMF) is a group of inherited diseases characterized by recurrent episodes of fever
with serosal, synovial or cutaneous inflammation and in some individuals, the eventual development of systemic AA
amyloidosis.

The FMF gene is located at 16p13.3 and encodes a protein denoted PYRIN (marenostrin) that is expressed in granu-
locytes, eosinophils, monocytes, dendritic cells and fibroblasts.
Most of the gene mutations responsible for disease occurs in exon 10 of the gene with a smaller group in exon 2 FMF
follows autosomal recessive inheritance.
Treatment of choice for FMF is daily oral colchicine, which decreases the frequency and intensity of attacks and pre-
vents the development of systemic AA amyloidosis.
8. Ans. (d) Trk A expression (Ref: Robbins 7th/503)
Miscellaneous
Neuroblastoma has good prognosis in infants (< 1 year old) regardless of the stage. These tumors are hyperdiploid
or near triploid.
Prognostic factors in Neuroblastoma
Age and stage: Good prognosis in infants regardless of stage. In children > 1 year, stage III and IV poor prognosis as
compared to stage I or II.
Genetics: Hyperdiploid or near triploid and high expression of Trk-A have good prognosis whereas near-diploidly,
deletion of chromosome 1p or 14, gain of chromosome 17q and N-myc amplification is associated with unfavorable
outcome.

3. Tumor markers: Telomerase and MRP expression has poor prognosis whereas CD 44 expression associated with
good prognosis.
Histology: Differentiation (into Schwann cells and gangliocytes), low mitotic rate and intramural calcification has
good prognosis.
Note: Most characteristic cytogenetic abnormality in neuroblastoma is 1p deletion.

9. Ans. (a) Lipids (Ref: Harrison 17th/2548, 2455)
Ceroid histiocytosis also known as neuronal cerebrolipofuschinosis is a group of diseases where lipofuschin, a yellow
brown cytoplasmic pigment is deposited in the neurons. Lipofuschin is a lipid.
In Gauchers disease, all patients have a nonuniform infiltration of bone marrow by lipid laden macrophages termed
Gaucher cellss.
Thus both these disorders have lipids in the macrophages.
GAUCHERS DISEASE
It is autosomal recessive lysosomal storage disorder due to deficiency of enzyme -glucosidase resulting in accumu-
lation of glucosylceramide.
Decreased activity (0-20%) of a-glucosidase in nucleated cells is required for diagnosis.
Type 1 disease do not involve CNS and present as hepatosplenomegaly with skeletal dysplasia whereas Type 2 Gau-
chers disease is a severe CNS disease leading to death by 2 year of age. Type 3 disease has highly variable manifesta-
tions in CNS and viscera.
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Miscellaneous
10. Ans. (c) Verrucous carcinoma (Ref: Robbins 7th/1037; Ackermans surgical pathology 8th/235)
Verrucous carcinomas also referred to as giant condyloma accuminatum or Buschke-Lowenstein tumour is considered an
intermediate lesion between condyloma acuminata and invasive squamous cell carcinoma. It is important to distinguish
verrucuous carcinomas from squamous cell carcinoma as these tend to remain localized and are cured by wide excision,
however they may undergo malignant transformation to invasive squamous cell carcinomas.
Features of verrucuous carcinomas
Predilection for males > 50 years
Predisposed in tobacco users, poor oral hygiene
Grossly, it is a soft, large, wart like (papillomatous) lesion which may show fungation
Microscopically:
Cytological features of malignancy are absent or minimal and rare
Epithelium is thickened and thrown into papillary folds
The folds project both above and below the level of surrounding mucosa and crypt like surface grooves exhibit
marked, pre-keratin plugging.
The deep border of epithelial projections is pushing and not infiltrative.
11. Ans. (a) 13q 14 (Ref: Harrisons 17th/413)
The term contiguous gene syndrome refers to genetic disorders that mimic single gene disorders. They result from deletion
of a small number of tightly clustered genes. Because some are too small to be detected cytogenetically, they are termed as
microdeletion syndromes
The important microdeletion syndromes are:
1. Wilms tumor Aniridia complex (WAGR syndrome) 11p 13
2. Retinoblastoma 13q 14.11
3. Prader-Willi syndrome 15q11-13
4. Angelmans syndrome 15q11-13
5. DiGeorges syndrome/Velo-cardiofacial syndrome 22q 11
Miscellaneous
6. Miller-Dieker syndrome 17p 13
Deletions involving the long arm of chromosome 22 (22q 11) are the most common microdeletions identified to date.

Note: Important microduplication syndromes include Beckwith-Wiedemann syndrome (11p 15) and Charcot- Marie-Tooth syndrome
type IA (17 p 11.2)

12. Ans. (d) It transports iron for erythropoiesis (Ref: Harper 25th/775, Harrison 17th/378,815,847)
Transport of iron for erythropoiesis is done by transferin and not by lactoferin.
Lactoferin is found in specific/secondary granules in neutrophils and in many exocrine secretions and exudates
(milk, tears, mucus, saliva, bile, etc.)
13. Ans. (a) Connexins (Ref: Harrison 17th/2479)
Connexins are complex protein assemblies that traverse the lipid bilayer of the plasma membrane and form a con-
tinuous channel. A pair of connexins from adjacent cells joins to form a gap junction that bridges the 2-4 mm gap
between the cells. These are important for communications in neurons and glial cells.
Adhesions are microbial surface antigens that frequently exist in the form of filamentous projection (pili or fimbria)
and bind to specific receptors on epithelial cell membranes.
Integrins are a family of cell membrane glycoproteins. These are involved in cell adhesion.
14. Ans. (b) Oil Red O (Ref: Harsh Mohan 6th/12-13)
Lipids are detected in histopathology by the use of the following stains:
Oil red O: Mineral oils stain red and unsaturated fats stain pink
Sudan Black B: Unsaturated fats stain blue black
Osmium tetroxide: Unsaturated fats stain brown-black whereas saturated fats are unstained.
Regarding other options:
PAS (Periodic Acid Schiff) stain is for carbohydrates particularly glycogen and all mucins
Silver Methanamine is for fungi
Non-specific esterase (NSE) is for staining myeloblast in patients of Acute myeloid leukemia (AML)
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15. Ans. (a) Fish net IgG in dermoepidermal junction (Ref: Robbins 8th/1192-1193, Harrison 17th/336-339)
The inflammatory bullous lesions may be Pemphigus vulgaris, Bullous pemphigoid and dermatitis herpetiformis.
The presentation of multiple flaccid bullae and oral lesions in a young boy is suggestive of Pemphigus vulgaris. An im-
portant histological finding in pemphigus is acantholysis which is dissolution, or lysis, of the intercellular adhesion
sites within a squamous epithelial surface. The suprabasal acantholytic blister that forms is characteristic of pemphigus
vulgaris. The antibody in pemphigus vulgaris reacts with desmoglein 1 and 3, a component of the desmosomes that ap-
pear to bind keratinocytes together. By direct immunofluorescence, lesional sites show a characteristic netlike pattern
of intercellular IgG deposits.
About other options:
Bullous pemphigoid generally affects elderly individuals. The bullae are tense and oral lesions are present in 10-15% of
affected individuals. The subepithelial acantholytic blister is characteristic of bullous pemphigoid. The antibody in bul-
lous pemphigoid reacts with bullous pemphigoid antigens 1 and 2 (BPAG 1 and 2) present in dermoepidermal junction.
Linear IgG in dermoepidermal junction are seen by direct immunofluorescence. (option B).
Dermatitis herpetiformis is characterized by urticaria and grouped vesicles. The disease results from formation of an-
tibodies against gliadin and is associated with celiac disease. By direct immunofluorescence, dermatitis herpetiformis
shows granular deposits of IgA selectively localized in the tips of dermal papillae. (option D).
Pemphigus foliaceous is having the antibody reacting with desmoglein 1 alone. There is selective involvement of su-
perficial epidermis at the level of the stratum granulosum. It usually affects the scalp, face, chest, and back, and the
mucous membranes are only rarely affected. Linear IgG in dermal papillae is a feature of Pemphigus foliaceous. (op-
tion C).
16. Ans. (b) Scleroderma (Ref: Harrison 17th/2096)
The girl in this case is showing Raynauds phenomenon and is likely to suffer later from systemic sclerosis.
Raynauds phenomenon is characterized by episodic digital ischemia, manifested clinically by the sequential devel-
opment of digital blanching, cyanosis, and rubor of the fingers or toes following cold exposure and subsequent re-
warming. The blanching, or pallor, represents the ischemic phase of the phenomenon and results from vasospasm of
digital arteries. During the ischemic phase, capillaries and venules dilate, and cyanosis results from the deoxygenated
Miscellaneous
blood that is present in these vessels. A sensation of cold or numbness or paresthesia of the digits often accompanies
the phases of pallor and cyanosis.
Raynauds phenomenon is broadly separated into two categories: The idiopathic variety, termed Raynauds disease,
and the secondary variety, which is associated with other disease states or known causes of vasospasm
Raynauds phenomenon occurs in 8090% of patients with systemic sclerosis (scleroderma) and is the presenting
symptom in 30% of patients. It may be the only symptom of scleroderma for many years. Abnormalities of the digital
vessels may contribute to the development of Raynauds phenomenon in this disorder. Ischemic fingertip ulcers may
develop and progress to gangrene and autoamputation. About 20% of patients with systemic lupus erythematosus
(SLE) have Raynauds phenomenon. Occasionally, persistent digital ischemia develops and may result in ulcers or
gangrene. In most severe cases, the small vessels are occluded by a proliferative endarteritis. Raynauds phenomenon
occurs in about 30% of patients with dermatomyositis or polymyositis. It frequently develops in patients with rheu-
matoid arthritis and may be related to the intimal proliferation that occurs in the digital arteries.
Atherosclerosis of the extremities is a frequent cause of Raynauds phenomenon in men >50 years. Thromboangiitis
obliterans is an uncommon cause of Raynauds phenomenon but should be considered in young men, particularly
those who are cigarette smokers. The development of cold-induced pallor in these disorders may be confined to
one or two digits of the involved extremity. Occasionally, Raynauds phenomenon may follow acute occlusion of
large and medium-sized arteries by a thrombus or embolus. Embolization of atheroembolic debris may cause digital
ischemia. The latter situation often involves one or two digits and should not be confused with Raynauds phenom-
enon. In patients with thoracic outlet compression syndrome, Raynauds phenomenon may result from diminished
intravascular pressure, stimulation of sympathetic fibers in the brachial plexus, or a combination of both. Raynauds
phenomenon occurs in patients with primary pulmonary hypertension; this is more than coincidental and may reflect
a neurohumoral abnormality that affects both the pulmonary and digital circulations.
17. Ans. (a) Triad of diarrhea, dementia and dermatitis (Ref: Harrison 17th/449)
Acrodermatitis enteropathica also known as Brandt Syndrome or Danbolt-Cross syndrome is an autosomal reces-
sive metabolic disorder affecting the uptake of zinc, characterized by periorificial and acral dermatitis, alopecia and
diarrhea.
This disease is apparently caused by an inborn error of metabolism resulting in malabsorption of dietary zinc and
can be treated effectively by parenteral or large oral doses of zinc. Zinc deficiency might in part account for the im-
munodeficiency that accompanies severe malnutrition.
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Miscellaneous
Features of acrodermatitis enteropathica start appearing in the first few months of life, as the infant discontinues
breast milk. There are erythematous patches and plaques of dry, scaly skin. The lesions may appear eczematous, or
may evolve further into crusted vesicles, bullas or pustules. The lesions are frequent around the mouth and anus,
and also in hands, feet and scalp. There may be suppurative inflammation of the nail fold surrounding the nail plate-
known as paronychia. Alopecia-loss of hair from scalp, eyebrows and eyelashes may occur. The skin lesions may be
secondarily infected by bacteria such as Staphylococcus aureus or fungi like Candida albicans. These skin lesions are
accompanied by diarrhea.
Without treatment, the disease is fatal and affected individuals may die within a few years. There is no cure for the
condition. Treatment includes lifelong dietary zinc supplementation in the range of greater than 1-2 mg/kg of body-
weight per day.
18. Ans. (b) Zinc Deficiency Causes Pulmonary Fibrosis (Ref: Harrison 17th/449)
Element Deficiency Toxicity
Calcium Reduced bone mass, osteoporosis Renal insufficiency (milk-alkali syndrome), nephrolithiasis, impaired
iron absorption
Selenium Cardiomyopathy, heart failure, striated muscle General: Alopecia, nausea, vomiting, abnormal nails, emotional lability,
degeneration peripheral neuropathy, lassitude, garlic odor to breath, dermatitis
Occupational: Lung and nasal carcinomas, liver necrosis, pulmonary
inflammation
Zinc Growth retardation, altered taste and smell, General: Reduced copper absorption, gastritis, sweating, fever,
alopecia, dermatitis, diarrhea, immune nausea, vomiting
dysfunction, failure to thrive, gonadal atrophy, Occupational: Respiratory distress, pulmonary fibrosis
congenital malformations
19. Ans. (a) Thymoma (Ref: Harrison 17th/89, Devita 6th/1023)

Tumors made up of two different lineage of cells, i.e. lymphocytes and epithelial cells suggests the diagnosis of
thymoma.
Thymoma is the most common cause of an anterior mediastinal mass in adults, accounting for ~40% of all mediastinal
Miscellaneous
masses. Thymomas are most common in the fifth and sixth decade. Some 90% of thymomas are in the anterior me-
diastinum. Thymomas are epithelial tumors and all of them have malignant potential. They may have a variable
percentage of lymphocytes within the tumor, but genetic studies suggest that the lymphocytes are benign polyclonal
cells. The epithelial component of the tumor may consist primarily of round or oval cells derived mainly from the
cortex or spindle-shaped cells derived mainly from the medulla or combinations thereof.
20. Ans. (d) Dense core granules (Ref: Robbins 7th/769; Devita 6th/900)
Paraganglioma is a neuroendocrine tumor and like other neuroendocrine tumors, the ultrastructure shows dense
core granules (neurosecretory granules)
The tumor cells are separated by fibrovascular stroma and surrounded by sustentacular cells.
Chief cells are neuroendocrine cells and are positive for regular neuroendocrine markers, e.g.
Chromogranin
Synaptophysin
euron specific enolase
Serotonin
Neurofilament
The chief cells are S-100 protein negative but the sustentacular cells are S-100 positive and are focally positive for
glial fibrillary acid protein.
Paraganglioma cells are never positive for cytokeratin like other neuroendocrine tumors.
21. Ans. (a) Neutral endopeptidase (Ref: Ganong 22nd/462, , Harrisons 17th/233,2146,2103)
Brain natriuretic peptide (BND) or B type natriuretic peptide is a hormone produced by the ventricles of the heart.
It has been shown to increase in response to ventricular volume expansion and pressure overload.
BNP is a marker of ventricular systolic and diastolic function.
BNP also has a prognostic significance in systemic sclerosis (with pulmonary artery hypertension) and in amy-
loidosis involving the heart.
Atrial natriuretic peptide (ANP) is a hormone released by atrial walls of the heart when they become stretched. Be-
cause in heart failure, there is almost always excessive increase in both the right and left atrial pressures that stretch
the atrial walls the circulating levels of ANP in the blood increase fivefold to tenfold in severe heart failure. The ANF
in turn has a direct effect on the kidneys to increase greatly their excretion of salt and water. Therefore ANP plays a
natural role to prevent the extreme congestive symptoms of cardiac failure.
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Both ANP as well as BNP are metabolized by neutral endopeptidases and the inhibitors of this enzyme (omapatrilat
and sampatrilat) are used for the management of CHF.
22. Ans. (a) There are many cyclin inhibitors which prevent cell to enter into S phase in adult (Ref: Robbins. 7th/42, 43, 308,
309)
After a fixed number of divisions, normal cells become arrested in a terminally non dividing state known as replica-
tive senescence. It occurs due to shortening of telomeres.
Telomeres are short repeated sequences of DNA present at the linear ends of chromosomes that are important for
ensuring the complete replication of chromosomal ends and protecting chromosomal terminals from fusion and deg-
radation. When somatic cells replicate a small section of the telomere is not duplicated and telomeres become progres-
sively shortened. The loss of telomere function leads to activation of p53 dependent cell cycle checkpoints causing
proliferative arrest or apoptosis.
Germ cells, some stem cells and cancer cells continue to divide because in these cells telomere shortening is prevented
by sustained function of the enzyme telomerase that maintains the length of the telomere by nucleotide addition.
23. Ans. (d) Osteosarcoma (Ref: Robbins 7th/500, 8th/475)
Most of the malignant pediatric neoplasms are unique in many respects:
They tend to have a more primitive (embryonal) rather than pleomorphic-anaplastic microscopic appearance, are
often characterized by sheets of cells with small, round nuclei, and frequently exhibit features of organogenesis
specific to the site of tumor origin. Because of this latter characteristic, these tumors are frequently designated by
the suffix -blastoma, for example, nephroblastoma (Wilms tumor), hepatoblastoma, and neuroblastoma.
Owing to their primitive histologic appearance, many childhood tumors have been collectively referred to as
small round blue cell tumors.
The differential diagnosis of such tumors includes

- Neuroblastoma

- Wilms tumor

- Lymphoma

- Rhabdomyosarcoma
- Ewing sarcoma/Primitive neuroectodermal tumor.
Miscellaneous
24. Ans. (b) Vascular (Ref: Harrison 17th/1186-1187, Robbins 7th/548, 550)
Kaposis sarcoma (KS) is a multicentric neoplasm consisting of multiple vascular nodules appearing in the skin, mu-
cous membranes, and viscera.
HHV-8 or KSHV has been strongly implicated as a viral cofactor in the pathogenesis of KS.
Lesions often appear in sun-exposed areas, particularly the tip of the nose, and have a propensity to occur in areas of
trauma (Koebner phenomenon).
Because of the vascular nature of the tumors and the presence of extravasated red blood cells in the lesions, their
colors range from reddish to purple to brown and often take the appearance of a bruise, with yellowish discoloration
and tattooing.

KS lesions most commonly appear as raised macules.
Apart from skin, lymph nodes, gastrointestinal tract, and lung are the organ systems most commonly affected by KS.
Lesions have been reported in virtually every organ, including the heart and the CNS.
In contrast to most malignancies, in which lymph node involvement implies metastatic spread and a poor prognosis,
lymph node involvement may be seen very early in KS and is of no special clinical significance.
A diagnosis of KS is based upon biopsy of a suspicious lesion. Histologically one sees a proliferation of spindle cells
and endothelial cells, extravasation of red blood cells, hemosiderin-laden macrophages, and, in early cases, an inflam-
matory cell infiltrate.
25. Ans. (c) Gout (Ref: Robbins 8th/1243-1246)
Tophi are formed by large aggregations of urate crystals. They are surrounded by macrophages, lymphocytes and foreign
body giant cells. They are characteristic of gout.
They are seen in the
Articular cartilage of joints*
Periarticular ligaments*
Tendons and soft tissues*
Achilles tendon*
Ear lobes*
Most common joint involved in Gout is Big Toe (First metatarsophalangeal joint)
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Miscellaneous
The diagnosis is made by presence of monosodium urate crystal in polarized light which are needle shaped and
strongly negative birefringent crystal.
26. Ans. (c) Mitochondrial myopathy (Ref: Robbins 7th/33, 1342, Harrison 16th/2534, 374)
Mutations in mitochondrial genes cause mitochondrial myopathies causing neurological and systemic involvements like:
Mitochondrial Myopathy
MELAS
Lebers Hereditary Optic Neuropathy
Myoclonic Epilepsy with Ragged Red Fibers syndrome (MERRF)
Chronic progressive external ophthalmoplegia.
Kearns-Sayre syndrome.
27. Ans. (a) Alports syndrome; (b) Niemann-Pick disease; (c) Atherosclerosis; (Ref: Robbins 7th/523, 988 ,163)
Foam cells are lipid laden phagocytes. In Niemann-Pick disease, they are widely distributed in spleen, liver, lymph
nodes, bone marrow, and tonsils.
During atherosclerosis, oxidized LDL is ingested by macrophages forming foam cells.
In Alports syndrome, interstitial cells of kidney may acquire a foamy appearance owing to accumulation of
neutral fats and mucopolysaccharides forming foam cells.
28. Ans. (b) Alcohol (Ref: Harsh Mohan 6th/276)
Formalin is the best tissue fixative.
29. Ans. (d) All of the above (Ref: Robbins 7th/1265, 8th/1199)
Panniculitis is an inflammatory reaction in the subcutaneous fat that may affect principally the connective tissue septa
separating lobules of fat or predominantly the lobules of fat themselves.
The various forms of panniculitis are:
Erythema nodosum: Most common form of panniculitis and usually has an acute presentation. Its occurrence
is often associated with infections (-hemolytic streptococci, TB and less commonly, coccidiodomycosis, his-
toplasmosis and leprosy), drug administration (sulfonamides, oral contraceptives), sarcoidosis, inflammatory
Miscellaneous
bowel disease, and certain malignant neoplasms.
Erythema induratum: Uncommon type of panniculitis that affects primarily adolescents and menopausal wom-
en. It is a primary vasculitis affecting deep vessels with subsequent necrosis and inflammation within the fat.
There is no associated underlying disease.
Weber-Christian disease (relapsing febrile nodular panniculitis): It is a rare form of lobular, nonvascular pannicu-
litis seen in children and adults.
Factitial panniculitis: It is a result of self-inflicted trauma or injection of foreign or toxic substances, is a form of
secondary panniculitis.
Lupus erythematosus may occasionally have deep inflammatory components with associated panniculitis.
30. Ans. (a) Measles (Ref: Robbins 7th/364)
In measles, the lymphoid organs typically have marked follicular hyperplasia, large germinal centers and randomly dis-
tributed multinucleate giant cells, called Warthin-Finkeldey cells, which have eosinophilic nuclear and cytoplasmic inclu-
sion bodies.
Giant cells Giant cells
1. Langhans giant cells 1. TB
2. Sarcoidosis
2. Touton giant cells 1. Xanthoma
3. Tumour giant cells 1. Ca liver
2. Soft tissue sarcomas
4. Foreign body giant cells 1. Leprosy
31. Ans. (c) The etiological agent for the initial stimulus to the ultimate expression of disease (Ref: Robbins 7th/4)
Pathogenesis refers to the sequence of events in the response of cells or tissues to the etiological agent, from the initial
stimulus to the ultimate expression of the disease.
32. Ans. (b) Frequently gives rise to embolization in the lymphatics (Ref: Robbins 7th/1318)
Liposarcomas are one of the most common sarcomas of adulthood and are uncommon in children. They usually arise in the
deep soft tissues of the proximal extremities and retroperitoneum and are notorious for developing into large tumors. Histo-
logically, liposarcomas can be divided into well-differentiated, myxoid, round cell, and pleomorphic variants. The cells in
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well-differentiated liposarcomas are readily recognized as lipocytes. In the other variants, some cells indicative of fatty dif-
ferentiation called lipoblasts are almost always present. The myxoid and round cell variant of liposarcoma has a t(12;16)
chromosomal abnormality.
33. Ans. (c) Michaelis Gutmann bodiesLangerhans histiocytosis (Ref: Robbins 7th/1258, 680-681, 905, 1027-1028,
701-702)
Russell bodies
Inclusions containing immunoglobulins present in the cytoplasm of patients of multiple myeloma; similar inclusions in the nucleus are
called Dutcher bodies.
Mallory bodies
Eosinophilic cytokeratin inclusions seen in alcoholic liver disease (can also be seen in Wilsons disease, Indian childhood cirrhosis,
chronic cholestatic conditions, hepatocellular cancer and primary biliary cirrhosis)
Civatte bodies
Lichen planus is a disease characterized by purple, pruritic, polygonal papules and characterized histologically by dense
lymphocytic infiltrates along dermoepidermal junction. The lymphocytes are intimately associated with basal keratinocytes which
show degeneration and necrosis contributing to saw-toothing of dermo-epidermal junction. Anucleate, necrotic basal cells may get
incorporated into the inflamed papillary epidermis where they are called colloid or Civatte bodies.
Michaelis Gutmann bodies
Seen in Malacoplakia (vesicle inflammatory reaction associated with E. coli infection characterized by raised mucosal plaques and
histologically by infiltration with large, foamy macrophages having laminated mineralized concretions of calcium inside lysosomes
called Michaelis Gutmann bodies).
Langerhans histiocytosis
It is a term used for proliferative disorders of dendritic cells which has three disorders namely Letterer-Siwe syndrome, Hand-Schuller-
Christian disease and eosinophilic granuloma. The presence of Birbecks granules in the cytoplasm is a characteristic feature. These
granules have a rod-like structure and terminal dilated ends (Tennis racket appearance)
34. Ans. (c) Osteosarcoma (Ref: Robbins 7th/299)

Miscellaneous
Patients with familial retinoblastoma are also at greatly increased risk of developing osteosarcoma and some other
soft tissue sarcomas (Robbins pg 299)
Alterations in RB pathway involving INK 4a proteins, cyclin D-dependent kinases and RB family proteins which are
present in normal cells lead on to inactivation of tumor suppressor gene (CRB gene) and associated somatic/inherited
mutations cause the increased risk of other tumors.
35. Ans. (d) Adrenals (Ref: Arch Ophthal. 1939; 22(4):575-580)
Adrenal neuroblastomas are malignant neoplasms arising from the sympathetic neuroblasts in the medulla of the adrenal
gland. There are two clinical types, based on the differences in distribution of metastasis. First (Pepper type) occurs in
the stillborn and in young infants and metastasizes to the liver and regional lymph nodes, then the lungs, and late in the
course, the calvarium and other flat bones. The second (Hutchinson) type is characterized clinically by secondary growth
in the orbit, meninges, skull and long bones and occurs in children up to 15 years of age.
36. Ans. (b) Ependymoma (Ref: Robbins 8th/1334)
37. Ans. (c) Neuroblastoma (Ref: Robbins 8th/477)
38. Ans. (a) Atopic dermatitis (Ref: Robbins 8th/1187-1189)
39. Ans. (a) Pleomorphic adenoma (Ref: Robbins 8th/757; 7th/791)
40. Ans. (b) Mucoepidermoid carcinoma (Ref: Robbins 8th/759; 7th/791)
41. Ans. (d) Lead poisoning (Ref: Robbins 8th/407; 7th/432-433)
42. Ans. (a) Tumor of gingiva (Ref: Robbins 8th/748; 7th/776)
43. Ans. (b) Rhabdomyoma (Ref: Robbins 8th/584; 7th/614)
44. Ans. (b) Dermatitis, glossitis, Alopecia (Ref: Harsh Mohan 6th/254)
45. Ans. (b) Lead poisoning (Ref: Robbins 8th/406-407; 7th/433)
46. Ans. (b) Rhabdomyoma (Ref: Robbins 8th/584; 7th/614)
47. Ans. (a) Parotid gland (Ref: Robbins 8th/757)
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Miscellaneous
48. Ans. (d) Antibodies in serum (Ref: Robbins 8th/653; 7th/736-737)

49. Ans. (a) Measles (Ref: Robbins 8th/432-433)
50. Ans. (d) Clostridia (Ref: Robbins 8th/378-379)
51. Ans. (d) Neurofibroma (Ref: Robbins 8th/730)
52. Ans. (c) SLE (Ref: Robbins 8th/220)
53. Ans. (b) Amyloid (Ref: Robbins 8th/253)
54. Ans. (c) Basal cell carcinoma (Ref: Robbins 8th/1180)
55. Ans. (c) Pleomorphic adenoma (Ref: Robbins 8th/261)
56. Ans. (c) Chancroid (Ref: Robbins 8th/366)
57. Ans. (d) All (Ref: Robbins 8th/1191-1192)
58. Ans. (d) Diplopia (Ref: Robbins 8th/438)
59. Ans. (a) Liver (Ref: Robbins 8th/273; 7th/923)
60. Ans. (a) Weibel Palade bodies (Ref: Robbins 8th/990; 7th/513)
6 0.1. Ans. (c) Phototherapy (Ref: Harrison, Chapter 74. Vitamin and Trace Mineral Deficiency and Excess)
Niacin deficiency causes pellagra which can be due to the following reasons:
People eating corn-based diets
In alcoholics
In congenital defects of intestinal and kidney absorption of tryptophan like Hartnup disease
In patients with carcinoid syndrome
Miscellaneous
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NOTES
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CHAPTER 19 Recent Papers

AIIMS NOVEMBER 2014
1. Which of the following is the most common site of Renal cell cancer
(a)
mucosa associated lymphoid tissue? Adult polycystic kidney
(b)
(a) Duodenum Hydronephrosis with chronic pyelonephritis
(c)
(b) Jejunum (d) Cystic dysplastic kidney
(c) Ileum
(d) Stomach
2. Which of the following is seen in schawannnoma?
(a) Spindle cells
(b) Storiform pattern
(c) Target cells
(d) Antoni A and B pattern
3. A young female presented with a right side thyroid
nodule and was operated. A 2*2 cm thyroid nodule was
resected and the following histology is seen. Which of
the following is the most likely diagnosis?

(a) Follicular goiter

(b) Papillary thyroid cancer

(c) Graves disease

(d) Follicular carcinoma A
5. Apoptosis is induced by which of the following

(a) Iso-protenoids
(b) Glucocorticoids
(c) Mysteric acid
(d) Oleic acid
6. Molecular classification of breast cancer is based on

(a) Gene expression profiling

(b) Expression of hormone receptors like ER,PR, and
HER-2 neu

(c) Histology

(d) Response to chemotherapy
4. A 45 year old patient has a history of recurrent ureteric 7. Immuno-histopathological markers wrongly matched
stones and presents with off and on fever. The patient (a) Desmin-Carcinomas
had to be operated and the appeared of the kidney is (b) Vimentin Sarcomas
given alongside. Which of the following is the most (c) Leukocyte specific antigen-Lymphoma
likely diagnosis? (d) S100-melanoma
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8. Patient has been given penicillin 48 hours ago, with no 13. Which of the following is rarely seen in rheumatic heart
history of drug allergy. Now he develops wheeze and disease?
hemolysis. Antibody for penicillin is positive. Type of (a) Mitral stenosis
hypersensitivity is which of the following: (b) Aortic stenosis
(a) Type I (c) Pulmonary stenosis
(b) Type II (d) Tricuspid stenosis
(c) Type III 14. Which of the following is having a 90% association
(d) Type IV with HLA B27?
9. Which of the following is true regarding Non-specific (a) Ankylosing spondylitis
interstitial pneumonia? (b) Rheumatoid arthritis
(a) Honey combing on CT (c) Psoriasis
(b) Predominant in males (d) Reiter syndrome
(c) Affects elderly age group 15. Angina, dyspnea and syncope is seen in:
(d) Good prognosis (a) Pulmonary stenosis
10. Nurse got a needle prick injury. Which of the following (b) Atrial septal defect
suggests active phase of hepatitis? (c) Ventricular septal defect
(a) IgM anti HBc (b) IgG anti HBc (d) Aortic stenosis
(c) IgG anti HBs (d) IgM anti Hbe 16. All of the following are premalignant except:
11. Which of the following is the function of MHC I and II? (a) Ulcerative colitis
(a) Signal transduction in T cells (b) Peutz Jegher syndrome
(b) Antibody class switching (c) Crohn disease
(c) Antigen presentation to T cells (d) Familial adenomatous polyposis
(d) Increase the secretion of cytokines 17. Fine needle aspiration cytology is not able to detect
12. High calcium intake can lead to which of the following?
(a) Osteoporosis (a) Papillary carcinoma
(b) Osteopetrosis (b) Hashimoto thyroiditis
Recent Papers
(c) Milk alkali syndrome (c) Follicular cancer

(d) Renal failure (d) Medullary cancer
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EXPLANATIONS
1. Ans. (c) Ileum (Ref: Robbins 9th/772)
Direct quote Although extranodal lymphomas can arise in virtually any tissue, they do so most commonly in the GI
tract, particularly the stomach.
However, the question is regarding the most common site for MALT (and not MALToma) for which the answer is ileum.
Also know!
In the stomach, MALT is induced typically as a result of chronic gastritis.
H. pylori infection is the most common inducer in the stomach.
2. Ans. (d) Antoni A and B pattern (Ref: Robbins 9th/1247)

These are benign tumors that exhibit Schwann cell differentiation and often arise directly from peripheral nerves. They are
a component of neurofibromatosis -2 (NF2). Microscopically, they are comprised of an admixture of dense and loose areas
referred to as Antoni A and Antoni B areas, respectively.
The dense eosinophilic Antoni A areas often contain spindle cells arranged into cellular intersecting fascicles. Palisading of
nuclei is common and nuclear-free zones that lie between the regions of nuclear palisading are termed Verocay bodies.
Also know!
The Schwann cell tumors have a uniform immunoreactivity for S-100.
Schwannomas may recur locally if incompletely resected, but malignant transformation is extremely rare.
Storiform pattern is seen in dermatofibrosarcoma protuberans. This is composed of closely packed fibroblasts arranged radially.
3. Ans. (b) Papillary thyroid cancer (Ref: Robbins 9th/1095-6)
Recent Papers
Papillary carcinomas are the most common form of thyroid cancer. They occur most often between the ages of 25 and 50.
It is associated with a previous exposure to ionizing radiation.
Histologically, papillary thyroid cancer is associated with ground glass or Orphan Annie eye nuclei (as shown in the
figure). In this, the nuclei of papillary carcinoma cells contain finely dispersed chromatin. In addition, invaginations of the
cytoplasm may give the appearance of intranuclear inclusions (pseudo-inclusions) or intranuclear grooves. The diagno-
sis of papillary carcinoma can be made based on these nuclear features, even in the absence of papillary architecture.
Concentrically calcified structures termed psammoma bodies are often present, usually within the cores of papillae. This
structure is almost never found in follicular and medullary carcinomas, and so, is a strong indication that the lesion is a
papillary carcinoma.
4. Ans. (c) Hydronephrosis with chronic pyelonephritis (Ref: Robbins 9th/934)
The characteristic changes of chronic pyelonephritis:
The kidneys usually are irregularly scarred; if bilateral, the involvement is asymmetric.
Hallmark feature: coarse, discrete, corticomedullary scars overlying dilated, blunted, or deformed calyces, and flattening
of the papillae. The scars mostly are in the upper and lower poles, consistent with the frequency of reflux in these sites.
Microscopically, the tubules show atrophy in some areas and hypertrophy or dilation in others. Dilated tubules with
flattened epithelium may be filled with casts resembling thyroid colloid (thyroidization). There are varying degrees of
chronic interstitial inflammation and fibrosis in the cortex and medulla.
Other options
Renal cell cancer would be having a mass on the upper or lower pole. There is absence of thyroidisation in this condition.
Adult polycystic kidney would have been The external surface appears to be composed solely of a mass of cysts with
no intervening parenchyma.
5. Ans. (b) Glucocorticoids..repeat question..see chapter 1 for details.

6. Ans. (a) Gene expression profiling (Ref: Robbins 9th/1061)
Invasive carcinomas can be divided based on molecular and morphologic characteristics into several clinically important
subgroups. Breast carcinomas have a wide variety of morphologic appearances. One third can be classified morphologically
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into special histologic types, some of which are strongly associated with clinically relevant biologic characteristics. The
remainder are grouped together and called ductal or no special type (NST).
Recent detailed description of genomic alterations and gene and protein expression in large cohorts of breast cancers has
provided a framework for a molecular classification for this group of breast cancers..Robbins 9th/ 1060
Gene expression profiling measures relative levels of mRNA expressionfigure 23.20 Robbins
7. Ans. (a) Desmin-Carcinomas (Ref: Robbins 9/e p11)
Desmin is a marker of myogenic tumours and not carcinomas (keratin is marker in this cancer).
Lamin A, B, and C: nuclear lamina of all cells
Vimentin: mesenchymal cells (fibroblasts, endothelium)
Desmin: muscle cells, forming the scaffold on which actin and myosin contract
Neurofilaments: axons of neurons, imparting strength and rigidity
Glial fibrillary acidic protein: glial cells around neurons
Cytokeratins: 30 distinct varieties which are present in different cells, hence can be used as cell markers
8. Ans. (b) Type II (Ref: Robbins 9th/205)
Administration of penicillin causing no symptoms in 48 hours with no previous history of allergy rules out type I hyper-
sensitivity reaction.
The patient presented with hemolysis which can be because of antibody formation against red cells. The formation of
autoantibody is a feature associated with type II hypersensitivity reaction. Thus, it becomes the answer over here.
Clinically, antibody-mediated cell destruction and phagocytosis occur in multiple situations:
Transfusion reactions, in which cells from an incompatible donor react with and are opsonized by preformed antibody
in the host
Hemolytic disease of the newborn: antigenic difference between the mother and fetus
Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to
their own blood cells, which are then destroyed.
Certain drug reactions, in which a drug acts as a hapten by attaching to plasma membrane proteins of red cells and antibodies
are produced against the drug-protein complex.
9. Ans. (d) Good prognosis (Ref: Robbins 9th/686)
Recent Papers
Nonspecific interstitial pneumonia

Nonspecific interstitial pneumonia may be idiopathic or associated with connective tissue disease.
Clinical features
Patients present with dyspnea and cough of several months duration.
More likely to be female nonsmokers in their sixth decade of life.
High-resolution computed tomography scan: B/L, symmetric, predominantly lower lobe reticular opacities (honey-
comb pattern is absent).
Patients have a much better prognosis than those with usual interstitial pneumonia.
Having 2 patterns: cellular and fibrosing patterns. Those having the cellular pattern are somewhat younger than
those with the fibrosing pattern and have a better prognosis
In cellular pattern, there is mild to moderate chronic interstitial inflammation, in a uniform or patchy distribution.
In fibrosing pattern, there is diffuse or patchy interstitial fibrotic lesions of roughly the same stage of development
(an important distinction from usual interstitial pneumonia)
Fibroblastic foci, honeycombing, hyaline membranes and granulomas are absent.
10. Ans. (a) IgM anti HBc (Ref: Robbins 9th/833)
IgM anti-HBc antibody becomes detectable in serum shortly before the onset of symptoms, concurrent with the onset of
elevated serum aminotransferase levels (indicative of hepatocyte destruction).
11. Ans. (c) Antigen presentation to T cells (Ref: Robbins 9th/194)
The function of MHC molecules is to display peptide fragments of protein antigens for recognition by antigen specific T
cells.
12. Ans. (c) Milk alkali syndrome (Ref: Robbins 9th/65)
Milk -alkali syndrome is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate.
This is associated with the development of metastatic calcification.
13. Ans. (c) Pulmonary stenosis (Ref: Robbins 9th/558-559)
In chronic disease the mitral valve is virtually always involved. The mitral valve is affected in isolation in roughly two
thirds of RHD, and along with the aortic valve in another 25% of cases. Tricuspid valve involvement is infrequent, and the
pulmonary valve is only rarely affected.
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14. Ans. (a) Ankylosing spondylitis (Ref: Robbins 9th/205)

Direct quote Approximately 90% of patients are HLA-B27 positive; associations have also been found with the IL-23
receptor gene.
Ankylosing spondylitis (also rheumatoid spondylitis and Marie- Strmpell disease)
It causes destruction of articular cartilage and bony ankylosis, especially of the sacroiliac and apophyseal joints (between
tuberosities and processes).
It becomes symptomatic in the 2nd and 3rd decades of life as lower back pain and spinal immobility.
15. Ans. (d) Aortic stenosis (Ref: Robbins 9th/555)
The valve area is approximately 0.5 to 1 cm2 in severe aortic stenosis whereas it is normally approximately 4 cm2. Left
ventricular pressures rises leading to concentric left ventricular (pressure overload) hypertrophy. The hypertrophied myo-
cardium tends to be ischemic (as a result of diminished microcirculatory perfusion, often complicated by coronary athero-
sclerosis), and angina pectoris may occur. Both systolic and diastolic myocardial function may be impaired; eventually,
cardiac decompensation and CHF can ensue. The onset of symptoms (angina, CHF, or syncope) in aortic stenosis heralds
cardiac decompensation and carries an extremely poor prognosis. If untreated, most patients with aortic stenosis will die
within 5 years of developing angina, within 3 years of developing syncope, and within 2 years of CHF onset.

16. Ans .(c) Crohn disease (Ref: Robbins 9th/800-1,806,809)
Robbins pg 806Peutz-Jeghers syndrome is associated with a markedly increased risk of several malignancies. Lifetime risk
is approximately 40% for these, and regular surveillance is recommended.
Pg 809Colorectal adenocarcinoma develops in 100% of untreated FAP patients, often before age 30 and nearly always by age 50.
The risk of colonic adenocarcinoma is increased in patients with long-standing IBD affecting the colon. Please under-
stand that increased risk of cancer is seen in colonic variant of Crohn disease and not otherwise. Ulcerative colitis is
a premalignant condition.

17. Ans. (c) Follicular cancer (Ref: Robbins 9th/1094)
Direct quote Because of the need for evaluating capsular integrity, the definitive diagnosis of adenomas can be made only after
careful histologic examination of the resected specimen. Suspected adenomas of the thyroid are therefore removed surgically to exclude
malignancy.
Recent Papers
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AIIMS MAY 2014

1. In the entire human genome, coding DNA constitutes: 9. Which of the following is not a characteristic feature of
(a) 2% multiple myeloma?
(b) 1% (a) Increased Ig levels in serum
(c) 0.1% (b) Positive ANA
(d) 4% (c) Plasmacytosis
2. Methylation of cytosine leads to: (d) M spike on electrophoresis
(a) Increased expression of gene 10. Anti-neutrophil cytoplasmic antibodies (ANCA) is seen
(b) Decreased expression of gene in:
(c) No effect on gene expression (a) Wegeners Granulomatosis
(d) Mutation (b) Diabetes mellitus
3. The cells of the human body most sensitive to ischemia (c) Rheumatoid arthritis
are: (d) Churg-Strauss syndrome
(a) Neurons
(b) Nephrons
11. Which of the following is not an etiological factor for
pancreatitis?
(c) Cardiac myocyte
(d) Hepatocytes (a) Abdominal trauma
(b) Hyperlipidemia
4. Which of the following regarding cellular events in (c) Islet cell hyperplasia
acute inflammation is not correct? (d) Germline mutations in the cationic trypsinogen gene
(a) PECAM/CD31 is responsible for neutrophil activa-
tion 12. Which of the following is not a part of HELLP syndrome?
Recent Papers
(b) Components of complement can assist in chemotaxis (a) Hemolysis

(c) Neutrophil margination is assisted by selectins (b) Elevated liver enzymes
(d) ICAM-1/VCAM-1 is responsible for neutrophil ad- (c) Thrombocytopenia
hesion (d) Retroplacental hemorrhage
5. Which of the following factors is morphogenic as well 13. A 10-year old child presents with edema, oliguria
as mitogenic? and frothy urine. He has no past history of similar
(a) Fibroblast growth factor complaints. On examination, his urine was positive for
(b) Platelet derived growth factor 3+ proteinuria, no RBCs/WBCs and no casts. His serum
(c) Bone morphogenetic protein albumin was 2.5 g/L and serum creatinine was 0.5 mg/
(d) Insulin-like growth factor dL. The most likely diagnosis is:
6. ARDS is due to a defect/damage in: (a) IgA nephropathy
(a) Type 1 pneumocytes (b) Minimal change disease
(b) Type 2 pneumocytes (c) Acute interstitial nephritis
(c) Clara cells (d) Membranous nephropathy
(d) Endothelial cells 14. A 6-year old girl presents with fever for the past 5 days,
7. Verocay bodies are seen in: generalized erythematous rash, strawberry tongue and
(a) Meningioma cervical lymphadenopathy. The most likely diagnosis
(b) Hemangioma is:
(c) Glioma (a) Kimura disease
(d) Schwannoma (b) Kawasaki disease
(c) Scarlet fever
8. Which of the following is not true regarding IgE (d) Rosie-Dorfman syndrome
antibodies?
(a) It mediates release of histamine and other chemical 15. Which of the following is NOT an example of a
mediators syndrome caused by uniparental disomy?
(b) It is the primary antibody involved in allergic reac- (a) Prader-Willi syndrome
tions (b) Angelman syndrome
(c) It is involved in anti-parasitic immune responses (c) Russell-Silver syndrome
(d) May cross the placenta and fix complement (d) Bloom syndrome
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16. A 27-year old male presents with low backache, that

(c) Gouty arthritis
occurs early in the morning, associated with stiffness,
(d) Ankylosing spondylitis
and persists for more than 30 minutes. On examination, 17. Histopathologically, rosettes are not seen in:
his chest expansion is also restricted. The most probable (a) Retinoblastoma
diagnosis is: (b) Neurocysticercosis

(a) Rheumatoid arthritis (c) PNET

(b) Oteoarthritis
(d) Medulloblastoma
Recent Papers
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EXPLANATIONS
1. Ans. (a) 2% (Robbins 9th /2)
98.5% of the human genome that does not encode proteins.. direct quote from Robbins. So, it means that about 1.5% of
the genome is used for coding proteins. The best answer therefore is option a.
2. Ans. (b) Decreased expression of gene (Robbins 9th/4)
High levels of DNA methylation in gene regulatory elements typically result in transcriptional silencing.
3. Ans. (a) Neurons (Robbins 9th/ 130,1264)
Neurons undergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes. Myocardial cells,
although hardier than neurons, are also quite sensitive and die after only 20 to 30 minutes of ischemiaRobbins
Potential future questions!
The most sensitive neurons in the brain are in the pyramidal cell layer of the hippocampus (especially area CA1, also
referred to as Sommer sector), cerebellar Purkinje cells and pyramidal neurons in cerebral cortex.
4. Ans. (a) PECAM/CD31 is responsible for neutrophil activation (Robbins 9th/ 76-7)
PECAM-1 (platelet endothelial cell adhesion molecule) is associated with transmigration (diapedesis) and not neutrophil
activation.
Other options
Chemotaxis is assisted by bacterial products, complement protein C5a, leukotriene B4 and interleukin
(IL-8).
Selectins are associated with rolling which also contributes to margination.
Recent Papers
Integrins are associated with firm adhesion of the white blood cells. They interact with vascular cell adhesion
molecule 1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1).
5. Ans. (a) Fibroblast growth factor (Robbins 9th/ 19-20; 8th/87-88, Fetal and Neonatal Physiology 4th/867-8)
Fibroblast growth factor (FGF) contributes to wound healing responses, hematopoiesis, and development. They can be
belonging to
Acidic FGF (aFGF, or FGF-1)
Basic FGF (bFGF, or FGF-2): necessary for angiogenesis
FGF-7 is also referred to as keratinocyte growth factor (KGF)
Growth Factor Source Functions
Epidermal growth factor (EGF) Activated marcophages, selivary Mitogenic for keratinocytes and fibroblasts; stimulates karatinocytes
glands, keratinocytes, and many other migration; stimulates formation of granulation tissue
cells
Transforming growth factor- Activated marcophages, keratinocytes, Stimulates proliferation of hepatocytes and many other epithelial cells
(TGF-) many other cells types
Hepatocyte growth factor Fibroblasts, stromal cells in the liver, Enhances proliferation of hepatocytes and other epithelial cells;
(HGF) scater factor endothelial cells increases cell motility.
Vascular endothelial growth Messenchymal cells Stimulates proliferation of endothelial cells; increases vascular
factor (VEGF) parmeability
PLatelet-derived growth factor Platelets, macrophages, endothelial Chemotactic for neutrophils, macrophages, fibroblasts, and smooth
(PDGF) cells, smooth muscle cells, keratino- muscle cells, activates and stimulates proleferation of fibroblasts,
cytes endothelial, and other cells, stimulates ECM protein synthesis
F i b r o b l a s t g r o w t h f a c t o r Macrophages, mast cells, endothelial Chemotactic and mitogenic for fibroblasts; stimulates anglogenesis
(FGFs), including acidic (FGF- cells, many other cell types and ECM protein synthesis.
1) and basic (FGF-2)
Transforming growth factor Platelets, T lymphovcytes, macrophages, Chemotactic for leukocytes and fibroblasts; stimulates ECM protein
b-(TGF-b) endothelial cells, keratinocytes, smooth synthesis; suppresses acute inflammation
muscle cells, fibroblasts
Contd...
676
Recent Papers
Contd...
Growth Factor Source Functions
Keratinocyte growth factor Fibroblast Stimulates keratinocyte migration, proliferation, and differentiation.
(KGF) (i.e., FGF-7)
ECM, EXtracellular membrane
6. Ans. (d) Endothelial cells (Robbins 9th/672)

ALI/ARDS is initiated by injury of pneumocytes and pulmonary endothelium, setting in motion a viscous cycle of
increasing inflammation and pulmonary damage.
Endothelial activation is an important early eventRobbins 9th/672
Also revise
The histologic manifestation of this disease is diffuse alveolar damage (DAD).
7. Ans. (d) Schwannoma (Robbins 9th/ 1247)
Schwannomas are well-circumscribed, encapsulated masses that abut the associated nerve without invading it. Micro-
scopically, they are comprised of an admixture of dense and loose areas referred to as Antoni A and Antoni B areas,
respectively.
The dense eosinophilic Antoni A areas often contain spindle cells arranged into cellular intersecting fascicles.
Palisading of nuclei is common and nuclear-free zones that lie between the regions of nuclear palisading
are termed Verocay bodies.
In the loose, hypocellular Antoni B areas the spindle cells are spread apart by a prominent myxoid extracellular
matrix that may be associated with microcyst formation.
8. Ans. (d) May cross the placenta and fix complement (Harrison 18th/)
IgG (and not IgE) is the antibody which may cross the placental barrier and fix complement.
Recent Papers
Also revise
Heat labile antibody

Has homocytotropism (affinity for cells of the same species)
Is increased in allergic conditions and parasitic infections.
9. Ans. (b) Positive ANA (Robbins 9th/598-601)
Increased serum levels if immunoglobulins, plasmacytosis and M spike on electrophoresis are all seen in multiple myeloma.
For details, see text of chapter 8.
10. Ans. (a) Wegeners granulomatosis (Robbins 9th/511-2)
PR3-ANCAs are also present in up to 95% of cases; they are a useful marker of disease activity and may participate in
Wegeners granulomatosis.
11. Ans. (c) Islet cell hyperplasia (Robbins 9th/884)
Etiological factors in acute pancreatitis
Metabolic
Alcoholism
Hyperlipoprotelnemia
Hypercalcemia
Drugs (e.g., azathioprine)
Genetics
Mutations in genes encoding trypsin, trypsin regulators, or proteins that regulate calium metabolism
Mechanical
Gallstones
Trauma
Iatrogenic injury
Operative injury
Endoscopic procedures with dye injection
Contd...
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Review of Pathology
Contd...
Vasular
Shock
Atheroembolism
Vasculitis
Infections
Mumps
12. Ans. (d) Retroplacental hemorrhage (Robbins 9th/ 866)

The subclinical hepatic disease may be the primary manifestation of preeclampsia, as part of a syndrome of hemolysis, elevated
liver enzymes, and low platelets, dubbed the HELLP syndrome.
13. Ans. (b) Minimal change disease (Robbins 9th / 917)

Presence of edema, proteinuria (frothy urine in stem of question), hypoalbuminemia etc. is suggestive of nephritic
syndrome.
Minimal change disease is the most frequent cause of nephrotic syndrome in children. There is commonly no hyper-
tension or hematuria. The proteinuria usually is highly selective, most of the protein being albumin.
No RBC casts in the urine is suggestive of absence of glomerulonephritis. So, options a and c are ruled out.
Membranous nephropathy causes nephritic syndrome in adults. The best answer therefore is option b
14. Ans. (b) Kawasaki disease (Robbins 9th/510)
Kawasaki disease typically presents with conjunctival and oral erythema and blistering, fever, edema of the hands
and feet, erythema of the palms and soles, a desquamative rash, and cervical lymph node enlargement. Hence, it is
also called as mucocutaneous lymph node syndrome.
It affects infants or children. 80% of patients are 4 years old or younger.
15. Ans. (a) Bloom syndrome (Robbins 9th/314-5)
Recent Papers
Bloom syndrome is characterized by a defect in DNA repair genes as well as developmental defects. It is associated with
increased risk of development of malignancies.
Prader-Willi Syndrome
Characterized by diminished fetal activity, obesity, hypotonia, mental retardation, short stature, and hypog-
onadotropic hypogonadism.
Deletions of the paternal copy of chromosome 15
Angelman Syndrome
Characterized by mental retardation, seizures, ataxia, and hypotonia,

Deletions involving the maternal copy of chromosome 15.
16. Ans. (d) Ankylosing spondylitis (Robbins 9th/1213)
Ankylosing spondylitis causes destruction of articular cartilage and bony ankylosis, especially of the sacroiliac and
apophyseal joints (between tuberosities and processes). It is also known as rheumatoid spondylitis and Marie- Strmpell
disease. Disease involving the sacroiliac joints and vertebrae becomes symptomatic in the second and third decades of
life as lower back pain and spinal immobility. Involvement of peripheral joints, such as the hips, knees, and shoulders,
occurs in at least one third of affected individuals. Approximately 90% of patients are HLA-B27 positive; associations have
also been found with the IL-23 receptor gene.
17. Ans. (b) Neurocysticercosis (Robbins 9th/ 1203,1312, 1339)
Retinoblastoma has the presence of Flexner-Wintersteiner rosettes and fleurettes reflecting photoreceptor differentia-
tion. .(Robbins 9th/1339)
PNET (Primitive Neuro-Ectodermal Tumour): It is composed of sheets of uniform small, round cells that are slightly
larger than lymphocytes. .(Robbins 9th/1203 )
Medulloblastoma: The tumor may express neuronal (neurosecretory) granules, form Homer- Wright rosettes.
(Robbins 9th/1312)
For details see the answer of a question in chapter of Neoplasia
678
CHAPTER 20 E
Hematoxylin and osin (H & ) E
Important Stains and Bodies
This is the most commonly used stain in routine pathology. Hematoxylin, a basic dye stains
acidic structures a purplish blue. Nuclei (DNA), ribosomes and rough endoplasmic reticulum
(with their RNA) are therefore stained blue with H&E. Eosin, in contrast is an acidic dye
which stains basic structures red or pink. Most cytoplasmic proteins are basic and therefore
stained pink or pinkish red. In summary, H&E stains nuclei blue and cytoplasm pink or red.
A Sh
Periodic cid- c iff (P AS)
This stain is versatile and has been used to stain many structures including glycogen, mucin,
mucoprotein, glycoprotein, as well as fungi. PAS is useful for outlining tissue structures
basement membranes, glomeruli, blood vessels and glycogenin the liver.
Romanowsky Stains
These histology stains are used for blood and bone marrow. Examples of Romanowsky
histology stains include Wrights stain, Giemsa stain and Jenners stain. These histology
stains are based on a combination of eosin and methylene blue.
Silver Stains
These histology stains use silver. Argyrphilic tissue has an affinity for silver salts. The silver
salts will be seen in argyrphilic tissues. Silver histology stains are used to show melanin and
reticular fibers.
Sudan Stains
Sudan histology stains are used for staining of lipids and phospholipids. Examples of such
histology stains are Sudan black, Sudan IV, and oil red O.
TYPE OF STAIN Used for staining
Acid Fast Stain Mycobacterial Organisms and other Acid Fast Organisms
Aldehyde Fuchsin Pancreatic Islet Beta Cell Granules
Alician Blue Mucins and Muco-substances
Alizarin Red S Calcium
Bielschowsky Stain (Uses Silver) Reticular Fibers, Neurofibrillary Tangles and Senile Plaques
Cajal Stain Nervous Tissue
Congo Red Amyloid
Cresyl Violet (Nissl Stain) Neurons and Glia
Fontana Massons Melanin and Argentaffin Cells
Giemsa Bone Marrow
Golgi Stain Neurons
Gomori Methenamine Silver (GMS) Fungi
Gram Stain (Taylors) Bacteria
Hematoxylin & Eosin (H&E) General Stain Used in Routine Pathology
contd...
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contd...
Luna Stain Elastin and Mast Cells
Luxol Fast Blue (LFB) Myelin
Massons Trichrome Connective Tissue, Collagen
Mucicarmine Epithelial Mucin
Oil-Red-O (On Frozen Sections) Lipid
Orcien Stain Elastin fibers
Osmium Tetroxide Lipids
Periodic Acid-Schiff (PAS) Glycogen, Fungi
Phosphotungstic Acid- Fibrin, Cross Striations of Skeletal Muscle Fibres
Haematoxylin
Picrosirius Red (polarized) Collagen
Reticulum Silver Reticulum Fibres
Safranin O Mucin, Cartilage and Mast cells
Toluidine Blue Mast Cell Granules
Verhoeff Vangieson (VVG) Elastic Fibres
Von Kossa Calcium Salts
Inclusion Bodies
A. Intra-Cytoplasmic
Rabies Negri bodies
Small pox Guarnieri bodies
Molluscum Contagiosum Henderson Peterson bodies
Fowl pox Bollinger bodies
Trachoma Halberstaedter- Prowazeki bodies
I N
B. ntra- uclear
t
Cowdrey ype A
Herpes Virus Lipschutz Inclusions
Yellow fever Torres Bodies
Cowdrey Type B
Adenovirus (Basophilic)
Poliovirus (acidophilic)
C. Both Intranuclear and Intracytoplasmic

Measles Virus
Other Important Bodies

Asteroid body Sarcoidosis and Sporotrichosis
Ferruginous body Asbestosis
Torres body Yellow fever
Lafora body Myoclonic epilepsy
Michaelis Gutmann body Malacoplakia
contd...
680
contd...
Mallory bodies Primary biliary cirrhosis
Alcoholic hepatitis
Wilsons disease
Chronic cholestasis
Miyagawas Corpuscles Buboes from LGV
Leishman Donovan Bodies Kala Azar
Babes- Ernst Granules Corynebacterium diphtheriae
Donovan Bodies Granuloma Inguinale
Lewis Bodies Parkinsonism
Russell Bodies Multiple Myeloma
Warthin- Finkedely Giant Cells Measles
Owl-Eye Inclusions CMV and Herpes
Keratin Pearls Squamous Cell Carcinoma
Pick Body Picks Disease
Aschoff Bodies Rheumatic Fever
Bodies of Arantius Aortic Valve Nodules
Body of Highmore Mediastinum Testis
Bollinger Bodies Fowlpox
Brassy Body Dark Shrunken Blood Corpuscle in Malaria
Call Exner Bodies Granulosa Theca Cell Tumor

Chromatid Bodies Entamoeba histolytica Pre-cyst
Citron Bodies Clostridium septicum
Civatte Bodies Lichen Planus
Councilman Bodies Hepatitis
Coccoid X Bodies Psittacosis
Creola Bodies Asthma
Gamma Gandy Bodies Congestive Splenomegaly
Guarnieri Bodies Vaccinia
Henderson Peterson Bodies Molluscum contagiosum
Heinz Bodies G 6 PD Deficiency
Hirano Bodies Alzheimers Disease
Levinthal Coles Lille Bodies Psittacosis
Mooser Bodies Endemic Typhus
Moot Bodies Multiple Myeloma
Psammoma Bodies Papillary Carcinoma of Thyroid, Ovary and Salivary Glands,
Meningioma, Mesothelioma
Reilly Bodies Hurlers Syndrome
Rokitansky Bodies Teratoma
Rosss Bodies Syphilis
Rushton Bodies Odontogenic Cyst
Sclerotic Bodies Chromoblastomycosis
Sandstorm Bodies Parathyroid Glands
Schiller Duval Bodies Yolk Sac Tumor
Schaumann Bodies Sarcoidosis
Verocay Bodies Schwannoma
Winkler Bodies Syphilis
Zebra Bodies Metachromatic Leukodystrophy
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IMAGE BASED QUESTIONS
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Image Based Questions

PLATE 1 PLATE 2

Q2. A 34-year-old man presents with the manifestation
Q1. A 25 year old man of African American descent suffered shown in the figure. He has a number of family
from an injury and came back to your clinic with members suffering from the same condition though
the complaint shown in the figure. What is the most the severity is different in different members. What
likely diagnosis? is the likely diagnosis?

(a) Hypertrophic scar
(a) Squamous cell cancer

(b) Normal scar
(b) Basal cell cancer

(c) Keloid (c) Neurofibromatosis 1

(d) Wound contraction
(d) Tuberous sclerosis
PLATE 3 PLATE 4
Q4. A patient presented with acute abdominal pain. He

was operated and the appearance of the spleen is
Q3. A patient having Turner syndrome was having the given in the figure. Which of the following organs
following lesion in the kidney. What is the lesion can have the same appearance in the presence of
depicted? ischemia?

(a) Polycystic kidney
(a) Intestine

(b) Horseshoe kidney
(b) Heart

(c) Medullary cystic disease
(c) Liver

(d) Hepatomegaly
(d) Lungs

Ans. 1. (c) Keloid
Ans. 2. (c) Neuro fibromatosis 1
Ans. 3. (b) Horseshoe kidney
Ans. 4. (bw) Heart
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PLATE 5 PLATE 6
Q5. An old man presented in the medical emergency with Q6. A strict vegetarian presented with complaints of numb-
complaints of severe headache and dizziness. His ness and tingling in her feet. She also had dyspnea,
blood pressure was recorded to be 200/146 mmHg. A reduced ability of exertion and diarrhea. She had
figure of the vascular changes is shown. Which of the inflammation of tongue also. Her blood sample was
following is the most expected change likely to be taken and a peripheral smear was made. What is the
seen in his blood vessels? most likely diagnosis for this lady?

(a) Hyaline arteriolosclerosis (a) Iron deficiency anemia

(b) Hyperplastic arteriolosclerosis
(b) Immune thrombocytopenic purpura
(c) Neutrophilic infiltration
(c) Megaloblastic anemia

(d) Accumulation of plasma proteins in the vessel wall
(d) Aplastic anemia
PLATE 7 PLATE 8
Q7. A young man presented with a chronic non-healing

ulcer. He has episodes of severe pain the digits of
hands and feet as well three episodes of priapism Q8. A 50-year-old female has complaints of painless
earlier. He was immunised earlier because the cervical lymphadenopathy with fever, malaise and
physician told him that he has greater chance of infection weight loss. A lymph node biopsy was taken and the
finding is shown in the figure alongside which has
caused by capsulated organisms. His peripheral smear
cells with owl eye appearance. What is the most
is shown in the figure. What is the likely diagnosis?
likely diagnosis?

(a) Nutritional anemia
(a) Non-Hodgkin lymphoma

(b) Immune hemolytic anemia
(b) Acute lymphadenitis

(c) Hereditary spherocytosis
(c) Hodgkin disease

(d) Acute lymophoblastic leukemia
Ans. 5. (b) Hyperplastic arteriolosclerosis
Ans. 6. (c) Megaloblastic anemia
Ans. 7. (d) Sickle cell anemia
Ans. 8. (c) Hodgkin disease
PLATE 9 PLATE 10
Q10. An old man with 20 years history of smoking presented

with foul smelling sputum, fever and recurrent
Q9. A child presented with a maxillary mass which on pulmonary infections. He died after few days. On
further investigation showed the presence of starry autopsy his lung specimen showed the presence of
sky appearance in the biopsy. The likely diagnosis the airways which were traced to the pleural surface.
of this condition is: This man most probably was suffering from:

(a) Mantle cell lymphoma
(a) Bronchogenic cancer

(b) Marginal zone lymphoma
(b) Chronic bronchitis

(c) Burkitt lymphoma
(c) Bronchiectasis

(d) Hodgkin lymphoma
(d) Emphysema
PLATE 11 PLATE 12
Q12. A 60-year man having uncontrolled diabetes presents

with hypertension and frothiness in the urine.
Q11. A chronic alcoholic had the complaints of yellowing The urinary dipstick test showed the presence
of the skin and sclera, abdominal distension, of proteinuria. A renal biopsy was taken which
hematemesis and alteration of sleep pattern. He demonstrated the characteristic lesions of diabetic
could not be saved. The appearance of his liver is nephropathy. Which of the following is the finding
shown in the figure. The most likely diagnosis is: observed in the photograph?

(a) Gall bladder cancer with secondaries to the liver
(a) Diffuse glomerulosclerosis

(b) Alcholic fatty liver

(c) Cirrhosis
(c) Basement membrane thickening

(d) Primary liver cell cancer
(d) Crescentic glomerulonephritis

Ans. 9. (c) Burkitt lymphoma
Ans. 10. (c) Bronchiectasis
Ans. 11. (c) Cirrhosis
Ans. 12. (b) Nodular glomerulosclerosis
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PLATE 13 PLATE 14
Q13. A patient was incidentally found to have the

presence of renal stone which surprisingly cause
massive destruction of the renal parenchyma. The Q14. The kidneys shown in this image are from a 24-year-
history revealed that he had suffered from multiple old man. What would have been the most likely
episodes of urinary tract infection with Proteus cause of his death?
organism earlier. A photograph of his kidney is revealed
(a) A subarachnoid hemorrhage due to ruptured berry
alongside. The most likely stone is: aneurysm

(a) Calcium oxalate stone
(b) A hypertensive crisis

(b) Triple stone

(c) Uric acid stone
(d) Metastatic renal cell carcinoma

(d) Cystine stone
PLATE 15 PLATE 16
Q16. An old lady suffered from pelvic fracture because

of which she was admitted in the ward and was
immobile for 3 months. One night she complained
of sudden onset of dyspnea and chest pain. On
Q15. The kidney shown in the image was resected from a examination she had increased pulse rate. She
63-year-old man with a history of smoking two pack- expired after 20 minutes. Her autopsy showed the
ages of cigarettes a day for 40 years, who presented picture of the lung as is shown in the figure. What is
with hematuria. What is the most likely diagnosis? the most likely diagnosis for this lady?

(a) Papillary necrosis
(a) Lung cancer

(b) Renal cell carcinoma
(b) Pulmonary thromboembolism

(c) Angiomyolipoma
(c) Varicosities of the vein

(d) Hemangioma
(d) Deep vein thrombosis
Ans. 13. (b) Triple stone Ans. 14. (c) Chronic renal failure
Ans. 15. (b) Renal cell carcinoma Ans. 16. (b) Pulmonary thromboembolism
PLATE 17
Q17. A labourer presented with the complained of

night sweats, evening rise of fever, weight loss
and two episodes of blood in the sputum. His lung
demonstrated the lesion seen in the figure. The most
probable diagnosis is:

(a) Pulmonary thromboembolism

(b) Pulmonary tuberculosis

(c) Bronchiectasis

(d) Bronchogenic cancer
PLATE 18
Q18. The most likely diagnosis in the picture is:

(a) Prader Willi syndrome
(b) Cri du chat syndrome
(c) Down syndrome
(d) Bloom syndrome
Ans. 17. (b) Pulmonary tuberculosis

Ans. 18. (b) Cri du chat syndrome
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Gobind Rai Garg MBBS MD

Sparsh Gupta MBBS MD

The Health Sciences Publisher

Jaypee Brothers Medical Publishers (P) Ltd

Assistant Editors: Mrs Praveen Kumari, Mrs Krishna Gupta

Review of Pathology and Genetics

My parents, wife Praveen,

My family members and

Preface to the Seventh Edition

All references have been updated from Robbins 9th edition

April 2015 Gobind Rai Garg

Preface to the First Edition

Gobind Rai Garg

From the Publishers Desk

Robbins Pathological Basis of Diseases, 9th edition

SYMBOLS USED IN BOXES ON HIGH YIELD POINTS

Questions asked in most recent exam

Important Notes of New Chapter Added in Robbins 9th Edition xiii-xvi

10. Respiratory System 405

Image Based Questions 685

Important Notes of New Chapter Added IN Robbins 9th Edition

CELL AS A UNIT OF HEALTH AND DISEASE

Virchow coined the term cellular pathology

1. Cytochemically dense and transcriptionally inactive heterochromatin and

CELLULAR HOUSEKEEPING (as per 9th edition of Robbins)

Organelles Key points

Important Notes of New Chapter Added in Robbins 9th Edition

Mitochondrial function: key points

Intermembrane space in the mitochondria is the chief site of ATP synthesis.

Important Notes of New Chapter Added in Robbins 9th Edition

Summary of growth factors and the receptors

In response to injury, a cell/tissue can have following consequences:

Mitochondria is the earliest

Swelling of organelles like endoplasmic reticulum results in decreased protein synthesis

Inability to reverse mitochon-

Irreversible cell injury may be necrosis or apoptosis (Programmed cell death)

Mnemonic: Apoptosis can be considered as suicide whereas necrosis as murder. Like

Coagulative Liquefactive Caseous Fat necrosis Fibrinoid Gangrenous

Coagulative necrosis is associated

Caspase 3 is the most important

Condensation of nuclear chro-

Apoptosis affects only single

Apoptotic cells express mol- Diagnosis of apoptosis

Clinical Significance of apoptosis in cancers

3. ADAPTATION: Cells may show adaptation to injury by various processes like

an organ or tissue function of cells organ.

Disorders with protein defects

4. Hyaline change: It is any intracellular or extracellular accumulation that has pink

Ends of the chromosomes are known as telomeres. Enzyme telomerase helps in

Decreased activity of telome-

Fenton reaction: H2O2 + Fe2+

Mechanism of Free Radical Injury

Commonly Used Stains

Multiple Choice Questions

(b) Apoptosis (c) Cell entering replication phase

18. Most pathognomic sign of irreversible cell injury

(b) Inflammatory reaction is present

U/L and alkaline phosphatase is within normal limits. glycogenolysis