Pathology 1 Concept Maps

Block 1

Jandrely Lopez
Material from Dr. Roy’s Lectures
Cell Injury: Growth Adaptation

Physiologic:
Ex. Body builders or uterus growth
in pregnancy Pathologic:
Ex. Left Ventricular Hypertrophy
Increase Cell Size *Not associated with adverse due to HTN
NO increase in cell Number clinical sequelae

Types: Enlarged nucleus (increase in

Non dividing cells:
protein synthesis) and increase in
1. cardiac myosites
cell size
2. skeletal muscle Definition:
3. Nerves

Histology:

Hypertrophy

Mechanism:
Two pathways:
—> PI3K/AKT - important in
1. Stimulation of signal transduction physiologic hypertrophy
Associated Mechanism —> G Protein - important in
pathologic, involves Growth factors
& Vasoactive agents
TNF-B, ILGF1, FGF
—> lead to increase in protein
2. Growth Factor Stimulation synthesis

*In Left Ventricular Hypertrophy is

Switch from Adult —> fetal myosin ANF an increase in Contractile proteins.
a —> B heavy chain —> Normally expressed in fetal heart and is
down regulated at birth
*B is energetically economical
—> In HTN the gene for ANF is Re-expressed

a-adrenergic agonist, endothelin 1

3. Vasoactive agents and angiotensin 2
 Prostatic Hyperplasia
—> age associated
—> due to high levels of prostatic
DHT
Cell Injury: Growth Adaptation Estrogen in Post Menopause
—> anovulatory cycles
—> S&S: Urine stream,
incontinence, urge to urinate,
—> HRT of estrogen maitains nocturia
proliferatuve phase —> for malignancy is MC in Outer
—> chance of cell mutation that zone
increase risk of cancer —> BPH is MC in the inner zone
—> Dysfunctional Uterine bleeding

Endocrine
examples —> Diffuse or focal
—> Parathyroid hyperplasia in chronic
renal failure
—> Thyroid hyperplasia in Grave’s
Physiologic: Disease
1) Hormonal - proliferating glans —> Islets of Langerhans seen in child
—> female breast at puberty or pregnancy of Diabetic Mother
Pathologic:
2) Compensatory - regeneration of liver
Is an increase in hormone or
—> after partial hepatectomy Other
Growth factor stimuli
Bone marrow hyperplasia
—> Polycythemia Vera

Liver hyperplasia
—> Replacing lost tissue
Increase number of cells Types:
Skin
—> Psoriasis

Definition:
*Only on dividing cells like liver,
kidney and RBC

* Differs from neoplasia because is

in response to specific stimuli
Hyperplasia

Histology
Mechanism

—> Glandular proliferation Hyperplasia of endometrium

(Glandular crowding)
—> decrease size in stroma
—> Glandular infolding that cause
decrease gland lumen
1) increase local productions of
growth factors
2) activate intracellular pathways
3) proliferation of mature cells is
stimulated

*sometimes arise from stem cells

prostate hyperplasia
Cell Injury: Growth Adaptation Loss of innervation
Diminished blood supply
—> occluding tumor
—> trauma
—> poliomyelitis
Inadequeate nutrition
—> marasmus
Decrease Workload
—> cast

Loss of endocrine stimulus

causes: —> Hypoparathyroidsm
—> Menopause

Physiologic:
Ex. embriogenesis, notochord and
thyroglossal duct Pressure
Pathologic: —> Cystic Fibrosis in pancreas

Decrease cell size Types:

Decrease cell number

Definition:

Atrophy Histology

Mechanism

1) decrease protein synthesis or increase protein degradation

2) catabolism of organelles and protein
3) Ubiquitin-Proteosome pathway
4) Sometimes accompanied by autophagy
- Increase number of vacuoles with Lipofuscin granules

*differs from cell death because targeted proteins are not essential
 Normal
Cell Injury: Growth Adaptation metaplasia

Histology:
More goblet cells in stomach,
change from gastric pits to intestinal
columnar
Gross:
Finger like projection salmon pink in
color after Zline of esophagus
Histology:
Intestinal columnar - presence of normal
goblet cells

Squamous —> Columnar Histology:

—> distal end of esophagus Intestinal Metaplasia Dome shaped (Umbrella)
—> Barrett’s esophagus —> Stomach pyluris Urothelium to a straight shaped
- caused by GERD & antrum squamous
- Lost of LES tone —> H. Pylori Transitional —> Squamous
—> Replaced by Intestinal —> risk of dysplacia
normal —> inflammation of bladder
Columnar Epithelium —> Schistosoma Haematobium
—> risk of carcinoma
metaplasia —> Risk of squamous cell
carcinoma

Columnar —> Squamous

—> Bronchial mucosal
lining in chronic smokers
—> due to irritation squamous metaplasia
Examples:
Connective tissue Metaplasia
—> Myositis ossificans
- followed by hematoma
Types: - minimal inflammation
- extra skeletal calcification
Reversible change in
which one adult cell is
replaced by another
adult cell
Definition:
Metaplasia Xray:
No connection between ossification
and bone tissue
Vit A deficiency
Mechanism —> Keratomalacia
Histology: - squamous metaplasia
Ciliated columnar with goblet cells
to a more “rugged” squamous

1) Stimulus triggers inflammation

2) Lymphocytes release cytokines
that activate stem cells
3) Re-programming of stem cells
re-populate damage tissue with
another cell type more appropriate
for the new environment
Cell Injury Part 2 Budd Chiari
- Obstruction of hepatic vein
causing hepatomegaly and ascites

Buerger Disease
Testicular torsion Methemoglobinemia CO poisoning
- Cause of limb amputation in
- No proper attachment to tunica - hemoglobin with oxidized heme - higher affinity for heme group
young smokers
vaginales causes testes to freely groups (Fe3+) compites with O2 binding sites.
rotate causing venous torsion and - Chocolate color blood - cherry red discoloration
ischemia

Ischemia
- Obstruction of blood flow Hypoxemia
- Due to: Thrombosis, Embolism, - fall in PaO2 (blood)
Venous and Peripheral artery - Due to CO poisoning, Anemia,
disease. Methemoglobinemia
1) Necrosis 2) Apoptosis
—> eosinophilic staining —> cell shrinks
—> dead cell is replaced by Myelin Figures —> presence of apoptotic bodies
(whorled calcified phsopholipid mass) 1) Watershed areas
—> Retraction artifact
- Anterior cerebral and middle cerebral (global hypoxia)
—> NO INFLAMMATION
Due to: - Superior & inferior mesentery arteries
2) Subendocardial tissue
- farthest from blood supply
3) Renal Cortex & Medulla
- medulla more affected
Oxygen depravation: Susceptible tissues: 4) Purkinje cells in cerebellum
Amorphous densities in mitochondria Hypoxia —> inadequate
-Ex. As seen in Myocardial ischemia
Morphological changes: oxygenation of tissues
FIndings:
Physical: Trauma, Extreme temperatures, Radiation

Chemical:
consequence of continuos injury Irreversible Causes:
1) Oxygen (in high concentration)
2) Mercury: binds to sulfhydryl group of cell membrane
3) Cyanide: poisons mitochondrial cytochrome oxidase and
Types
Cell Injury Infectious agents
blocks oxidative phosphorylation
4) Carbon monoxide: displaces O2 from Hb
- Funcional and morphological 5) Carbon tetrachloride & drugs: free radical injury
changes
- Reversible only if stimilus is
Reversible - Acetaminophen (Tylenol)
Immunologic Reactions
removed • Massive hepatic necrosis
characterized by:
• Renal papillary necrosis
Findings
- Carbon Tetrachloride
Genetic Rearrangements • Massive hepatic necrosis
Light Microscope - Cell Swelling &
Fatty changes - Down Syndrome and Sickle cell 6) Alcohol: mitochondrial toxin
1) Reduced Oxidative
Phosphorilation Electron Microscope - Altered
2) ATP depletion plasma membrane, Mitocondrial
swellign, Dilated RER and Nuclear Nutritional imbalances
alterations - kwashiorkor, Vit Deficiencies,
Nutritional excess and anorexia
nervosa
 Cell Injury Part 2 - Increase membrane permeability
- Loss of membrane potential resulting in No ATP production
- Leakage of CytC activating apoptosis
- ATPases: depletes ATP
- Phospholipases: damages cell membrane
- Proteases: cell membrane damage
leading to: - Endonucleases: fragmentation of DNA
- Caspases: lead to apoptosis
- Increase Cytosolic Calcium
- Decrease pH due to Lactic acid a. Enzyme activation
production b. Re-entry of Calcium to mitocondria makes causing activation of:
- Impaires Na/K Pump = No turgor - Oxidative stress
- Detachment of ribosomes = No - Activation of Phospolipase A2, Proteases, Endonucleases and ATPases
translation
- Calcium ATPase pump fails
which 3) Influx of Intracellular Calcium and Loss of
causes: Calcium Homeostasis
Prolonged depletion causes UPR 1) ATP depletion caused by:
activation - Normal Intracellular calcium levels are low but
- When reduce O2 supply the ischemia and certain toxins increase it
Glycolitic (anaerobic) pathways is 2) Mitochondrial damage
trigerred

Cell Injury: Mechanisms 4) Accumulation of Oxygen-Derived Free Radicals

- free radicals are made in cell during mitochondrial

respiration and when CytP450 helps degrade drugs as
1) ROS - cause lipid peroxidation 5) Defects in Membrane Permeability acetaminophen in liver
on plasma membrane
examples:
Types of damage:
Several mechanisms responsible:
2) Decrease phospholipid synthesis -
due to hypoxia or mytochondrial - Chemical and radiation injury (UV light) 1) Lipids: lipid peroxidation
disfunction - Liver necrosis by drugs (CCl4 or acetaminophen) 2) Proteins: oxidative modification (Cross-linking)
- Ischemia-reperfusion injury (MI) 3) Nucleic Acids: single, and double stranded in DNA mutations
- Retinopathy of prematurity (Tx for NRDS
3) Increase phospholipid breakdown - - Iron overload (Tx B thalassemia major)
increase in lipid breakdown molecules
which have detergent effect on
cytoskeletal defects - Cellular aging
- Microbial killing by phagocytes
membrane 4) Intermediate filaments defects

Examples: Kartagener Syndrome

- Microtubule disorganization leading to
Alcholic hepatits immobilization of cilia in respiratory tract
- Cytokeratins undergoes Ubiquitin - Alzheimer and inhibition of sperm motility
Protease degradation - Disrupted Neurofilaments forming - Bronchiectasis, sinusitis, situsinversus
Parkinson’s disease
- Characterize for Mallory bodies neurfibrillary tangles by abnormally - presence of lewy bodies
hyperphosphorylated Tau protein.
 Dry Gangrene - limb that has loss
blood supply.
- Ex. Diabetics: peripheral arterial
diseases causes narrowing of blood
vessels causing RBC rupture and Wet Gangrene - initially is
Histology: the release of Ion sulfide causes Coagulative necrosis but is
“tombstone” appearance = Cellular the black color. modified by liquefactive action of
outline and NO nucleus 2) Liquefactive
bacterial infection.
Due to:
- Bacterial or fungal infection
- CNS ischemia (hypoxic cell death)
1) Coagulative necrosis - Clinically seen as pus
- Preservation of cellular outlines
3) Gangrenous
- Denaturation of enzymes and
proteins
- Seen in ischemia in all tissues
except brain

Types:
4) Caseous
- Eosinophillic, glassy ceel with - seen in tuberculosis causing
cytoplasmic vacuoles
- Calcification and myelin figures
Necrosis formation of caseating granulomas
- described as “cheesy white”
- Goes Karyolysis, pyknosis and Morphology: 5) Fat necrosis appearance
karyorrhesis. - Eelease of activated pancreatic
- Pathologic, INFLAMMATION lipases into substance of pancreas
6) Fibrinoid
- If necrotic cell debri is not remove and peritoneal cavity
- Immune reactions involving Ag-Ab
provides nidus for calcium - Activated lipase split TAG Acute pancreatitis
complex deposition in vessels
deposition,this is called Dystrophic - Released fatty acids combine with - MCC due to alcohol
- Vascular leakage causes Fibrin to
Calcification calcium to form chalky white areas Pancreatic autodigestion following enzyme activation
go out and imparts Pink color - S&S: increase amylase, lipase, & leukocytosis
or fat saponification.
- seen in autoimmmune disease as -XRay: calcifications
SLE

Cell Injury Part 3

 Pathologic:
- Cell death following injury —> Radiation & Cytotoxic anticancer drugs
- Viral induced cell injury —> Viral hepatitis
- Accumulation of misfolded proteins —> Alzheimer
Physiologic:
- Pathologic atrophy in parenchymal organs following duct obstruction
- Embryogenesis —> ex. loss of Mullerian structure
•Pancreas = Cistic Fibrosis
- Involution of thymus
•Parotid gland = Stensen Stones
- Hormone dependent involution —> endometrial breakdown
•Kidney = Kidney Stones
- Cell deletion —> immature lymphocytes in BM
- CTLs
- Removal of PMN’s in inflammation
•Recognize foreign antigens
- Removal of self reactive lymphocytes
•Activation secretes perforin
•Promotes entry of granzymes
•Activate caspases

causes:

- programmed cell death - Cell shrinkage

- apoptotic cells break up into - Chromatin condensation
fragment called Apoptotic bodies
- NOT associated with Inflammation
Definition:
Apoptosis Morphology:
- Cytoplasmic blebs
- Phagocytosis of apoptotic cells or
cell bodies

Mechanism:

Initiation phase: Execution phase: Removal:

Extrinsic (death-receptor) Intrinsic (mitochondrial) pathway Mediated by proteolytic cascade - Apoptotic cells express
- Death receptors are TNF - Growth factors stimulate production of Anti- - Initiator caspases phosphatidylserine on the surface
—> TNFR1 apoptotic Bcl-2 —> Caspase-8 of plasma membranes
—> Fas (CD95) - When growth stimilus is lost or cell is subjected —> Caspase-9 - Recognized by macrophages
- FasL expressed on T-cells bind to to stress Bcl-2 is loss from mitocondrial - Executioners
Fas membrane —> Caspase-3
- Then provide binding site for FADD -is replaced by pro-apoptotic factors like: Bak, —> Caspase-6
- Triggers activation of caspase 8 Bax and Bim
- Blocked by FLIP (binds to pro- - There is an increase in mitochondrial
caspase 8 - related to HPV) membrane permeability which makes
Cytochrome c leak out into cytoplasm and
Binds to Apaf-1
- This Activates caspase 9 Leading to apoptosis
Cell Injury Part 3
Intracellular accumulation Example: Alcoholic Fatty Change

1) Oxidation of EtOH by Alcohol dehydrogenase

- Increases NADH
—> causes decrease gluconeogenesis
—> increase Lactate = lactic acidosis + hypoglycemia
—> decrease Fatty acid oxidation which increase TAG
levels leading to patty liver

2) Microsomal Ethanol Oxidation System (MEOS)

- is a P450 System that needs oxygen so it created free
radicals that create hepatocyte damage

3) Fat deposition
- presence of glucagon makes fat go to Liver

Oil Red O
pathogenesis:
1) Toxin (alcohol)
stain: 2) Non alcoholic Fatty Liver Disease
(NAFLD)
- Abnormal accumulation of TAG - Diabetes Mellitus, Insulin Resistance,
within parenchymal cells Obesity
definition: causes:
- Liver, heart and muscle Fatty change 3) Protein malnutrition
- Enlarged, yellow and greasy - Kwashiokor
4) DM
5) Anoxia
histology:
In heart:

1) Prologued moderate hypoxia

- as seen in anemia
- Gross: tigered effect
2) Myocarditis
- as seen in diphteria
Intracellular accumulation

Associated with Rh incompatibility

in newborn

- Unconjugated bilirubin
deposits in basal ganglia Kernicterus: Jaundice
nuclei of brain
- Specifically in Globus
pathogenesis:
Bilirubin
Pallidus Scleral icterus
Clinical features:

Decrease Moro reflex

Plasma cells
- have accumulation of Ig in the
cytoplasm
- Known as Russell Bodies
Renal Disease
- Reabsorption droplets in PCT Amyloidosis
renal tubules indicating that - defect in protein folding
proteins are being reabsorbed
examples:

Appear as eosinophilic droplets,

vacuoles, or aggregates in Histology:
cytoplasm Protein
 Cholesterol and Cholesterol Esters histology:
- Cholesterol clefts
- Laden Macrophages
examples:

sites of inflammation and necrosis

atherosclerosis
xanthomas
- In acquired and hereditary
hyperlipidemias
Cell membrane contains lipids that
attract Laden Macrophages to eat
up the dying cell, this causes the
deposition.

HTN DM
- damage endothelial cell cause - Advance Glycation End Product
protein escape to vessel wall (AGE) binds with RAGE receprtors
- causes increase of skeletal on endothelial cell and causes
muscle wall matrix damages.

Extracellular
- Old scars
Intracellular - Long standing HTN
- Protein droplets
- Russell Body
- Alcoholic hyaline (Mallory Body)
causes:
types:

- Alteration within cells or in

extracellular spaces
- Can lead to tissue ischemia due to
definition: Hyaline change Histology:
narrowig of vessel lumen

differential:

No inflammatory cell as in Fibrinoid

Intracellular Accumulation Necrosis

 Metastatic - Deposition of calcium Dystrophic - presents locally in
salts in otherwise normal tissues Pathologic Calcification
always as a Result of hypercalcemia
dying tissues has NORMAL
Calcium levels Intracellular accumulation
1) Coagulative, caseous or
1) Increase PTH liquefactive necrosis
- Hyperparathyroidism 2) Atheromas of advance
- due to tumors and ectopic PTHrp atherosclerosis
2) Resorption of bone tissue 3) Aging or damage heart valves
- tumor bone marrow - rheumatic heart disease
3) Vitamin D related
- Vit D intoxication
- Sarcoidosis
4) Renal Failure
- Retention of phosphate leading to
secondary hyperparathyroidism

Psammoma bodies
- Meningioma
- Papillary carcinoma Thyroid
- Papillary carcinoma Ovary

Diabetes Mellitus
- Cells become insensitive to insulin Glycogen Storage Disease
thus increase storage/deposition of - Von Gierke’s Disease
glucose —> Deficiency of glucose-6-phosphatase

examples:

Periodic Acid Schiff stain: Glycogen

 1) Lipofuscin 2) Hemosiderin
- Wear and tear & aging - Excess Iron
1) Carbon
- Telltale sign of free radical injury - Causes
- Smoking Histology
and lipid peroxidation of cell —> Local: hematoma
- air pollution differential
membrane —> systemic: B thalasemmia
2) Anthracosis in stain
- Yellow-brown granules - Golden yellow/brown
- black discoloration of lungs
- Most commonly seen in the liver
3) pneumoconiosis
and the heart Stain: Prussian blue stain
- coal workers
4) Silicosis
- miners

3) Melanin
Exogenous - when the enzyme tyrosinase
Endogenous catalyzes the oxidation of tyrosine
to dihydroxyphenylalanine in
melanocytes
- brown-black, pigment
Types: - Ex: Addison’s disease, melanoma

Pigments

Intracellular accumulation
 Inflammation part 1 Cardinal Signs of Inflammation:
- Rubor = Redness
—> Vasodilation of arterioles
—> Histamine
- inflammation is the reaction of the - Calor = Heat
vascularized living tissue to local —> Vasodilation of arterioles
1) Vasodilation injury —> Histamine
definition:
- earliest event - linked to the process of repair, is a Inflammation - Tumor = Swelling
—> Increased vascular
- involves arterioles protective response
permeability
- Histamine & NO - Dolor = Pain
2) Increase permeability —> Prostaglandins and Bradykinin
- leakage of protein (immunoglobulins) leads to stasis to PMN’s •PGE2– sensitized nerve
- Due to: endings to effects of bradykinin
a. Formation of endothelial gaps in venules - Loss of Function
—> Histamine, Bradykinin, Leukotrienes, Neuropeptide substance P Chemotaxis
—> Endothelial contraction - movement oriented chemically to foci Leukocyte activation - on arrival at injury
—> Fast - By exogenous (bacterial products) or - signaling pathways activate them;
b. Direct endothelial injury Endogenous agents (C5a, leukotreine activation of enzymes
—> arterioles, capillaries and venules B4, cytokines)
—> toxins, burns and chemical Phagocytosis
—> immediate sustained 1) Recognition and attachment
c. Delayed prologued - opsonization: coating the material to be ingested by phagocytic cells
—> venules & capillaries after leaving vessels - Major opsonins: IgG, C3, C reactive protein, MBL
—> thermal injury, UV light, bacterial toxin 2) Engulfment
—> starts after 2-12hrs Margination on arrival at injury - Formation of phagosome
—> last for hrs - days Rolling - Lysosomal granule fuses with it resulting in release of hydrolytic enzymes
d. Leukocytes mediated injury - mediated by Selectins
Adhesion 3) Killing and degradation
—> venules
—> Pulmonary capillares (ex. Smoker and ARDS - increase PMN’s) - Achieved by Integrins a. Oxygen dependent mechanism —> NADPH oxidase
—> Pathogenesis: adherent leukocytes damage endothelium by - TNF & IL-1 stimulate expression of adhesion molecules by endothelial cells b. Oxygen independent mechanism
Transmigration —> Azurophilic granules : MPO, defensins, acid hydrolyases, elastases
free radical release - PECAM 1
—> Secondary/specific granules: collagenase, major basic protein, etc
- Collagenases
deal with the injurious material

Vascular changes
Leukocyte Adhesion Deficiency 1
-Deficiency of β2integrins
Cellular events -Recurrent bacterial infection
Leukocyte Adhesion Deficiency 2 -Poor wound healing
-Less severe than LAD1 Clinical feature: Delayed separation
-Deficiency of Selectin that binds of the umbilical cord
with neutrophil
- Same S&S of LAD1
Chédiak-Higashi Syndrome
-Mutation in LYST (lysosomal
regulator trafficking) gene
Stimuli for acute inflammation:
Infection, Trauma, Physical and
Acute Inflammation Defects in Leukocytes Function -Inability of neutrophilic granules to
chemical agents, Tissue necrosis, fuse with phagosomes
Foreign bodies & Immune reactions - Recurrent pyogenic infections
(hypersensitivity) - Partial oculocutaneous albinism
and silvery hair due to
abnormalities in melanocytes, nerve
defects & bleeding disorders.

Exudate (Creamy) Myeloperoxidase (MPO)

- High protein concentration Deficiency Chronic Granulomatous Disease
- Cellular debris -Absence of myeloperoxidase - Defect in gene encoding for
- Inflammatory extravascular fluid (Ex. Abcess-Pus) -No production of HOCL (bleach) NADPH oxidase
-Superoxide and hydrogen peroxide - Prone to recurrent infection
Transudate (Clear) are produced (specialy catalase + bacteria like
- Low protein content S.Aureus and pseudomonas)
- Very few cells or none at all - Macrophages aggregate to form
- Ultrafiltrate of blood plasma (Ex. Pulmonary Edema) granuloma (bumpy skin)
-Screening Test
- Nitroblue tetrazolium (NBT) test
—> Normal: WBC turn blue
—> CGD: NOT blue (abnormal)
 C3a Regulatory Proteins
- histamine release from mast cells C1 inhibitor (C1 INH)
- anaphylatoxins
C5a
- blocks activation of C1
- inherited absence: Hereditary Angioedema
- inflammation causes changes in
endothelium Inflammation part 2
- histamine release from mast cells - endothelial cells then activate
- anaphylatoxins Decay Accelerating Factor (DAF) and CD59 coagulation system
- chemotactic factor for leukocytes - linked by GPI achoring proteins - thrombin (which thrombin cleaves Exogenous
C3b - DAF prevents formation of C3 convertase fibrinogen to form fibrin) activates - Endotoxins from Gram negative
- opsonization - CD59 inhibits MAC Protease activated receptors - Super antigens
C5-9 - important disease: Paroxysmal Nocturnal (PARs)
- MAC complex Hemoglobinuria (PNH) - links inflammation and coagulation
Platelet-Activating Factor (PAF) - lysis
Produced by: Pyrogens
Fever Endogenous
- Platelets, Basophils, Mast cells,
-Increase in set point of - Cytokines: IL-1, TNF, IL-6 & IFN
Neutrophils, Macrophages, Endothelial cells
Kininogens + Kalkrein (enzyme) = hypothalamus —> Produce fever by inducing
Causes:
Release of Bradykinin -Vasoconstriction which Decreased synthesis of PGE2
Vasoconstriction, Bronchoconstriction,
- Increases vascular permeability heat loss: body feels cold
Leukocyte adhesion, Chemotaxis
- Contraction of smooth muscles -Shivering

Nitric Oxide Complement System - Dilation of blood vessels Clotting systems Bronchial Asthma
- Produced by endothelial cells, -Chronic inflammatory disease of airways due to Increased
macrophages, and some neurons responsiveness of tracheobronchial tree to stimuli
Kinin system
- Vasodilator and Reduces platelet -Release of mediators: Histamine, Bradykinin, Leukotrienes,
aggregation and adhesion PGE2, PGD2, PAF
outcome
- Bactericidal properties -Clinical Features: Intense bronchoconstriction, Vascular
congestion, Edema, Increased mucus production
Chemoattractants for leukocytes Plasma proteins -Damage to epithelium by: Major Basic Protein from
Examples: eosinophils
Monocyte chemoattractant 1 and Free radicals
(MCP-1)
Eotaxin- selectively recruits
eosinophils
Macrophage Inflammatory Protein
1α (MIP-1α)
Chemokines chemical mediator Acute Inflammation Serous
-Outpouring of thin fluid
TNF & IL-1 -Skin blister
- Produced by activated -Effusions: Pleural, Pericardial,
macrophages Peritoneal
- play role in Cytokines morphology
1) endothelial activation
2) activation of leukocytes and Fibrinous
complement Vasoactive amines Serotonin - severe injuries increased vascular
3) Systemic acute phase response - present in platelets, and certain permeability
Arachidonic acid metabolites neuroendocrine cells - fibrinogen escapes
- functions as a neurotransmitter in - fibrin is formed and deposited in
GIT extracellular space
- fibrinous exudate: meninges,
Lipoxins Purulent pericardium, pleura
Histamine
- Inhibitors of - production of large
Prostaglandins Present in:
inflammation amount of pus - ex:
- Produced by COX-1 and COX-2 - Mast cells, Platelets and Basophils
- Plays role in resolution acute appendicitis,
1) PGE2 – vasodilation, pain, fever - Degranulation by:
of inflammation abscesses Ulcers
2) PGE2a – contraction of uterine and 1) Trauma, cold, heat (solar urticaria)
2) Binding of Ab to mast cell (allergic - bronchial - discontinuity of lining epithelium
bronchial smooth muscle
Leukotrienes asthma) - tissue necrosis, and resultant
3) PGI2 (prostacyclin) –
- Produced by leukocytes 3) Anaphylatoxins (C5a & C3a) inflammation
vasodilation, inhibitor of platelet
1) LTB4– chemotactic factor and Causes:
aggregation
activator of neutrophils - Vasodilation, Increased permeability of venules and
4) TxA2 (thromboxane) –
2) LTC4, LTD4, LTE4– Endothelial activation
vasoconstriction, platelet aggregation,
vasoconstriction, bronchospasm,
bronchoconstriction
increased vascular permeability
 - Promote inflammation (CD4+ T-cells)
B-cells (10-20% in circulation) - TH1 cells – produce IFN-γ
- Develop from bone marrow
Chronic inflammation 1 T-cells (60-70% in circulation)
- Develop in Thymus
- In blood and para-follicular regions
- In follicle regions of lymph nodes
- Recognize antigens through B-
—> defense agaisnts bacteria, virus
and autoimmune diseases
- TH2 cells – secrete IL-4, IL-5, and IL-13
- Recognize antigens by antigen cell antigen receptor complex —> Recruit eosinophils
specific T-cell receptor (TCR) - IgM &IgD are membrane bound —> defense against parasites
on surface of all mature näive B - TH17 cells – secrete IL-17
cells —> Induce secretion of chemokines
—> Recruit neutrophils
—> defense agaisnts bacteria, virus
and autoimmune diseases
types:

Macrophage-Lymphocyte
Interaction
role: -Macrophages display antigen to T-
cells and release IL-12
-IL-12 – stimulates T-cell response
-T-cell releases cytokines and IFN-γ
Lymphocytes - Recruit and activate macrophages
Mobilized in antibody mediated and
cell mediated immune reactions

macrophage
- Derived from bone marrow Classical M1
-Persistent infections: TB and
- Monocytes in blood, macrophages - Host Defense
Syphilis
in tissues - produce cytokines, GF, and other
-Prolonged exposure to potentially Inflammatory cells
- can be activated by IFN Gamma, mediators
toxic agents like Silica or
Atherosclerosis
causes Chronic Inflammation Bacterial endotoxins, chemical type:
- autoimmune diseases as RA and mediator, Tcells, and NK cells
Alternate M2
SLE - Repair
Granulomatous inflammation - induced by IL-4 and IL-13
- secrete GF that promote collagen
Plasma cell synthesis and angiogenesis
- Focal accumulation of activated - Develops from activated B-
macrophages with Epithelioid lymphocyte
appearance - Produces antibodies
- Presence of indigestible matter Mast cell
- Russell bodies
Examples: -Both in acute and chronic
- Tuberculosis: Caseous inflammation
necrosis and Granuloma -IgE to Fc receptor
- Leads to degranulation Eosinophils
- Leprosy (tuberculoid type)
- Anaphylactic reactions -Mediated by IgE
- Syphilis: Gumma
-Stain: Toludine blue -Eotaxin – chemotactic factor for
- Cat-scratch Disease: Stellate
eosinophils
granuloma types: -Granules contain major basic
- Sarcoidosis: Non-caseating
protein
granuloma
- Toxic to parasites
- Crohn’s Disease: Non-
- Cause tissue damage
caseating granuloma
- IL-5 and IL-13
foreign body granuloma immune granulomas
- produced by inert foreign bodies - microbes can produce a cell
- talc, suture, fibers mediated immune response

absence of necrosis, giant cell presence of caseous necrosis,

contains suture material Langhans giant cells
 Clinical importance:
Chronic Inflammation 2
1) Indicates necrosis associated with acute inflammation
(ex. acute osteomyelitis)
2) Increased risk for MI
3)Monitoring Rheumatoid Arthritis
- binds to red cells and causes
them to form stacks (rouleaux) that - act as opsonins and fix
- act as opsonins and fix sediment more rapidly complement
complement

Fibrinogen
CRP Serum Amyloid A protein

- which is an iron regulating

peptide. plays a role in anemia of
chronic disease (ACD)
Hepcidin

Most important proteins

- Neutrophilia
protein synthesis stimulation in —> Mediated by IL-1 and TNF
hepatocytes by: IL-6 (CPR & - Shift to the left
Fibrinogen) and IL-1/TNF for (SAA) —> Elevation of neutrophils/band
cells (>10%)
- Simulates Leukemoid reaction

Acute Phase Reaction

Leukocytosis
- Elevation of body temperature - Absolute increase in lymphocytes
- Caused by prostaglandins —> Viral infections, Mumps, Infectious
-Increase production of (especially PGE2) Fever mononucleosis
prostaglandins due to activation - causes increase of temperature System effects Lymphocytosis —> Chronic infection: tuberculosis,
effect of IL-1 and TNF to COX set point. typhoid, pertussis
enzymes - Hypothalamus sends sympathetic
signal to cause vasocontriction, Septic shock
piloerection and shivering. Severe Bacterial Infection
- Large amounts of organisms and
LPS
Chronic Inflammation - Stimulate production of cytokines;
High levels of TNF &IL-1
- Leads to DIC (Disseminated
example
Intravascular Coagulation)
Supportive test

Psoas abscess - fever, back pain Erythrocyte Sedimentation Rate

and limp. Labs: raised WBC, raised -Helps in supporting a diagnosis of
CRP, raised Erytrocyte chronic inflammation/infection
sedimentation rate and may - Ex. RA, SLE, Tb, Multiple
include a particular organism as Myeloma
causing agent.
Part 1
Quiescent Cells (stable)
- Low level of replication
- easily pushed to into replication Inflammasome
- Liver, kidney, pancreas, - cells have receptors that
- induces production of IL-1
mesenchymal cells, endothelial recognize molecules that are
Labile cells (continually dividing) - also play a role in Gout, metabolic
cells, lymphocytes liberated following cell injury
- Surface epithelium (skin, oral syndrome, atherosclerosis, and
Damage associated molecular
cavity) Alzheimer disease
Nondividing Cells (permanent) patterns:
- Derived from adult stem cells - gain of function mutation:
- Cannot undergo mitosis —> uric acid
Autoimmflammatory syndromes
- Neurons, skeletal muscle, cardiac —> ATP
—> condition where apoptotic
muscle —> reduced intracellular K+
cells bring inflammation
- these activate a multiprotein
cytosolic complex: Inflammasome

Tissue proliferative capacity

Regeneration by proliferation Recognition

- Ability to replace damaged
components and return to normal
state
- occurs in unijured cells
- Ex. Skin, intestine, liver - Both binds to EGFR
Repair
Healing and Repair - two types:
1) EGFR1 (Erb-B1)
Deposition of connective tissue 1) EGF —> seen in lung, head and neck,
- Produced by: platelets, breast cancer and glioblastoma
(scar formation)
2) Erb-B2 (HER2/Neu)
- Occurs in tissue incapable to macrophages —> over expressed in breast cancer
complete restitution or if supporting - Fx: mitogenic for keratinocytes,
structures are severely damaged fibroblasts, also helps in granulation
- Laying down of fibrous tissue Growth factor tissue formation.
(collagen)
- Damage to ECM cause loss of 2) TGF - α
important framework Produced by: macrophages, T
lymphocytes, keratinocytes
Fx: similar to EGF

- Acellular
- Light pink

6) FGF 3) TGF - B
- Produced by: Macrophages, Mast - Produced by: platelets, endothelial, lymphocytes &
cells, Tcells, Endothelial cells, Macrophages
Fibroblasts - Fx: Triggers phosphorylation of cytoplasmic transcription
- Function: Angiogenesis, Wound 4) VEGF factors (Smads)
5) PDGF
repair, Development, - Produced by: mesenchymal cells 1) Growth Inhibition = Increases expression of cell cycle
- Produced by: Platelets,
Hematopoiesis - Fx: 1) Induce endothelial inhibitors
Macrophages, Endothelial cells,
permeability and vasodilation 2) Fibrogenic Agent = Fibroblast chemotxis; Production of
Keratinocytes, Smooth muscle
7) Basic Fibroblast Growth 2) Vasculogenesis (development) collagen, fibronectin, proteoglycans
- Fx: Chemotactic factor,
Factor 3) Angiogenesis (cancer) 3) Anti-inflammatory = Limit and terminate inflammatory
Keratinocyte migration,
- fx: Stimulates angiogenesis 4) Lymphogenesis response (along with IL-10)
Angiogenesis, Inhibit platelet
aggregation, Integrin regulation 5) Hypoxia (ex. Retinopathy of
* Imp for wound healing Preemies)
 Part 2 Ehlers-Danlos Syndrome
- mutation of collagen genes
- MC Type I and Type III
- S&S:
—> skin is thin, velvety, hyperextensible, easily
traumatized and poor wound healing
—> laxity and hypermobility of ligaments and joints
- 3 polypeptide chains (α chains) in —> Mitral valve prolapse, Aortic dissection
triple helical conformation
-Provides framework - Vitamin C is important in
-Type I – skin, bone, & tendon hydroxylation reaction
-Type II – cartilage, intervertebral
disc, vitreous
-Type III – reticular (vessels)
Synthesis: Osteogenesis Imperfecta
-Type IV – basement membrane
- Deficiency in synthesis of type I collagen
types:
Disease: - Mutation in genes encoding for α1&α2 collagen
chains
Collagen
-S&S: Multiple fractures, Blue sclera, Hearing loss and
Dental issues

- Regulates growth, proliferation, movement

of differentiation of cells present within it: Healing and Repair:
Fibroblasts, Myofibroblasts, Adipocytes,
Chondrocytes, Osteocytes, Endothelial cells ECM - Permits recoil
- Ex: Cardiac valves, Large blood
Elastin vessels, Uterus, Skin, Ligaments
definition:
- Composed of central elastin core
associated with mesh-like network
DIsease: of fibrillin
Cytoskeleton Proteoglycans and hyaluronan

Marfan Syndrome
-Maintains shape, polarity, - FBN1 Mutation causes defect in
1. Actin Microfilaments organization of cell Fibrillin 1
- Composed of G-actin and F-actin -Form highly hydrated compressible
- myosin binds to actin in muscle gels - Firbillin is major component of
- Fx: Act as lubricant, Resistance to microfibrils which provide scaffold to
Classes: compressive forces (Joint form elastic fibers.
cartilage), reservoir for GF, role in -S&S: Unusually tall, Long
migration and cell adhesion. extremities and fingers, Ligament
2. Intermediate filaments 3. Microtubules laxity, Kyphosis, Scoliosis, Pigeon
-Composed of glycosaminoglycans
- Types I and II: Cytokeratins —> epithelial cells) chest, Mitral valve prolapse,
attached to a core protein linked to
- Type III: Vimentin, Desmin —> mesenchymal cells) and aortic dissection, Subluxation of
hyaluronan
GFAP —> astrocytes lens, Bilateral ectopialentis
- Type IV: Neurofilaments —> axons of neurons
- Type V: Laminin—> nuclear lamina of all cells
 - 24hrs: blood clot forms and PMN’s arrive
- 24-48hrs: GF’s (EGF &TGF-a) promote movement of endothelial cells and deposition of
basement membrane components Part 3
- Day 3
- Neutrophils are replaced by macrophages to remove debris
- Granulation tissue formation begins. Max occurring between days 3-5.
- Type III collagen formed then replaced by Type I collagen —> TGF-β plays role
- Day 5: Neovascularization, Collagen fibrils bridge incision, Epidermis regains thickness,
Surface keratinization occurs.
- 2nd week: Continued collagen accumulation and fibroblastic proliferation, Disappearance of
leukocyte infiltrate, edema, and increased vascularity
- Month: Scar is made up, Devoid of inflammatory infiltrate, 80% tensile strength restored but
dermal appendages destroyed are permanently lost.
- When there is more extensive loss of cells
and tissue
-Wounds with opposed edged - Larger fibrin clot
- Leaky new vessels -Clean, uninfected, surgical incision with - More necrotic debris and exudate
- Edema sutures - Intense inflammation
- Fibroblast laying New collagen Granulation tissue -Wound Contraction due to Myofibroblasts
- Inflammatory cells especially M2s - by day 3 after injury fibroblast and —> Fibroblasts that partially differentiate via
vascular endothelial cells proliferate PDGF and TGF-B to smooth muscle
First intention - Large amount of scar formation

Hallmark of healing Second intention -Balance between ECM synthesis &

Inflammation, Proliferation and degradation = remodeling
Maturation - with the porpuse of change granulation
tissue into scar tissue
- Degradetion of collagen and other
1) Injury
2) Cot formation = stops bleeding
overview: Healing and Repair: Tissue remodeling
ECM proteins is done by MMP’s
—> produce by: macrophages,
and provides framework for
migrating cells
Wound fibroblasts, neutrophils and synovial
cells under the influence of PDGF, FGF,
3) Inflammatonry response arrives
IL-1 and TNF
3) Proliferation of granulation tissue
—> inhibited by TIMPs
and vascular endothelium Repair in other tissues
5) Collagen deposition Local
1) Blood supply: limbs in diabetis
Fibrosis Factor that influence healing (PAD) and varicose veins
2) Local infection: persistent tissue
Liver Brain injury and inflammation (S.aureus)
- Can regenerate if cytoarchitecture 1) Gliosis 3) Foreign Body
is intact - Astrocytes (glial cell) proliferate in 4) Hematoma
- Fibrosis is used to denote the - Hepatocytes are quiescent response to injury
excessive deposition of collagen - Mechanisms - Responsible for repair and scar
- Major cytokine involved in fibrosis 1) Proliferation of remaining formation
is TGF-β hepatocytes Systemic
-Ex: liver cirrhosis, scleroderma, 2) Repopulation from progenitor 1) Anemia
idiopathic pulmonary fibrosis, etc cells (cells of hering) 2) Genetic disorders
3) Metabolic Status: DM
4) Nutrition: Vit C deficiency
5) Steroids: inhibits TGF-B and
inflammatory response

Cirrhosis: characterized by presence of

regenerating nodules and fibrosis. Ex. viral hepatitis
 Part 4

Keloid
- Scar tissue grows beyond the
boundary of the original wound and
do not regress
- Dense fibrocollagen: type III Microscopy: overlying epidermis is normal. Thickened
produced by myofibroblast dermis composed of dense collagen. Relatively
Hypertrophic scar
- Little vascularity avascular.
- excessive amount of collagen
- raised scar

Inadequate formation of Healing and Repair: Desmoid tumor/Aggressive

granulation fibromatoses
- leads to wound dehiscence Complications - nterface between benign
(splitting) and ulcer proliferation and malignancy
- vomiting, coughing, ileus causes - Seen in C-section
dehiscence and rupture - Tends to recur but no metastases

Contraction
Excessive contraction results in
deformities Ex. Burns
- Impair joint movement
part 1
Right heart failure
Left heart failure Causes: following a left 3. Lymphatic obstruction
Causes: Ischemic heart sided failure or in patients - Deveolpmental: Milroy’s disease, cystic hygroma (Turners)
disease, Hypertension, with lung pathology (COPD, 2. Reduced plasma osmotic pressure - Acquired:
valvular diseases & Pulmonary hypertension or (hypoproteinemia) a. Inflammatory
Myocardial diseases Pulmonary -Nephrotic Syndrome: b. Filariasis
Morphology: Hypertrophy of thromboembolism) —> heavy proteinuria —> Parasite (W. bancrofti, B. malayi)
the heart & Pulmonary edema Morphology: Liver —> hypoalbuminemia —> Elephantiasis
Clinical aspect: Dyspnea, congestion and portal —> decrease colloid osmotic pressure c. Breast carcinoma
Cough, Orthopnea, venous hypertension - Cirrhosis —> Peau d’ orange - Obstruction of breast lymphatics
Paroxysmal nocturnal Clinical: Elevated JVP, —> decrease syntheis of albumun
dyspnea, atrial fibrilation, ascites, congestive —> ascites: fluid accumulation in
azotemia. hepatomegaly. peritoneal cavity
- Protein loss enteropathy
—> loss of serum proteins into the
types: intestine 4. Sodium and water retention
- Association with left heart failure
which causes activation of Renin-A2-
Heart Failure Aldosterione system
- decreased cardiac output and - Increase salt and water retention
tissue perfusion (forward failure) 1. Increase hydrostatic pressure: - Causes expansion of interstitial and
- pooling of venous blood in system - Local: impaired venous flow (ex. intravascular volumes
overview: DVT) - Could also end in azotemia due to
(backward failure)
- May lead to pulmonary edema - Generalized: Ex. CHF leading to impaired excretion of Nitrogenous
Pulmonary edema products.
causes

- Subcutaneous edema
- Dependent edema
Starling Forces
—> Affects legs when standing
1) Increase in Plasma hydrostatic
-Transudate —> Sacrum when lying
pressure and/or a decrease in
—>Protein poor fluid - Pitting edema
oncotic pressure
—> Seen in body cavities —> Edema due to renal
2) cause fluid to diffuse out of
—> Dependent pitting edema dysfunction tends to be peri orbital.
capillaries
—> ex. CHF 3) accumulates in interstitial space
- Exudate
—> Protein rich fluid Morphology:
—> Tissue swelling
—> Ex. inflammation
-Lymphedema pathophysiology
—> Protein rich fluid types of fluid:
—> Non-pitting edema
—> Ex. Lymphatic obstruction
Hemodynamic Part 1:
- Increase fluid in intertitial space Definition: Edema Acute pulmonary edema
- Anasarca: severe and - due to increase hydrostatic
generalized edema pressure
Lung:
- S&S: exertional dyspnea,
Brain: orthopnea, Paroxysmal nocturnal
dyspnea
Papilledema: optic disc blurring on - Gross: heavy lungs, frothy & blood
fundoscopy. Due to elevated tinged fluid.
intracranial pressure (ICP). - Clinical feature: Xray with Kerley B
Edema of brain lines and patchy lession, cough and
Increase in intra-axonal pressure
- due to traumatic brain injury, frothy spytum.
due to edema.
ischemic stroke, tumors, meningitis
- Gross: brain is swollen, narrowed
sulci, distended gyri, flattening
against the skull
- cause increase of Intracranial
pressure
—> S&S: headache, change in
pupil reaction, eizure, ataxia,
Note the flattened gyri and change in behavior & Papilledema
narrowed sulci
Part 2

Congestion of Liver
Congestion of the lungs - Seen in cardiac failure
- Seen in cardiac failure - Damming of blood in IVC
- Increased hydrostatic pressure - Distention of central vein and
due to backed up pressure in
pulmonary blood vessels
Hemodynamic Part 1: sinusoids
- Necrosis and degeneration near
Liver:
- Causing leakage of fluid into
alveoli
Lungs: Chronic Passive central vein
- Fatty change in periportal
- RBC leak into alveoli Congestion hepatocytes,
and are Phagocytosed by —> hepatocytes near the arterioles
macrophages are better oxygenated than the ones
“Heart failure cells” —> RBC near the central vein.
Heart failure cells—> Macrophages debris inside macrophages.
containing hemosiderin (Stain with Prussian
blue)

“Nutmeg liver”
- enlarged and congested
- central regions of hepatic lobules are red
brown surrounded by uncongested tan brown
areas

Petechiae
- 1 to 2 mm hemorrhages Purpura
- Locally increased in intravascular pressure - ≥ 3mm hemorrhages
- Low platelet count - low platelet count Ecchymosis:
- trauma - non-raised lesions on skin (bruise)
- vascular inflammation (vasculitis) - larger than purpura

Hematoma: accumulation of blood

within tissues
Cardiac tamponade: pericardium
Hemodynamic Part 1: Large hemorrhages within body
cavities
cut open to show blood contained
within pericardial sac
Extravasation of blood following Definition: Hemorrhage - Ex. hemopericardium,
vessel rupture hemoperitoneum, hemothorax
1
Part 1

Final common pathway

- Factor V, X, II (Prothrombin) and I
1) Arteriolar vasocontriction by neurogenic mechanism (fibrinogen)
2) Primary Hemostasis = formation of platelet plug
—> Injury to endothelium
—> Sub-endothelium vWF and collagen is exposed
—> Promotes platelet adherence and activation
- Platelets attach to vWF via Gp1b receptor (Von Willebrand factor) Intrinsic pathway
Extrinsic pathway
—> Forming hemostatic plug - Exposed subendothelial
- Damage tissue releases
3) Secondary hemostasis = deposition of fibrin collagen activates Factor XII
Thromboplastin —>
—> Tissue factor (a pro coagulant expressed by subendothelial cells) is - Partial Thromboplastin
activates Factor VII
exposed. time (PTT) assesses the
- Prothrombon time (PT)
—>Tissue factor bonds and activates Factor VII function of the pathway (XII,
assesses the function of - Activation of Fibronolytic cascade
—> Which triggers the activation cascades that makes Thrombin. XI, IX, VIII, X, V, II)
extrinsic pathway (Factors limits the coagulation to the site of
—> Thrombin cleaves fibrinogen to fibrin
VII, X, V, II & fibrinogen) injury 1) Anti-platelet effect
- Thrombin also: activates platelets and has pro inflammatory effects
- Achieved trough Plasmin, which - Prostacyclin (PGI2) and
- Fibrinogen is attached to Platelets via Gp2b3a
comes from plasminogen (tPA Nitric Oxide —> Prevent
—> Fibrin creates a meshwork, activates and brings more platelets
activates plasminogen), and its platelet adhesion/aggregation
- TxA2 made by platelets also helps in Aggregation
4) Clot stabilization and resorption action is to break down fibrin.
—> polymerized fibrin and platelet aggregates undergo contraction
—> a solid permanent plug is formed series of reactions that lead to
—> counter regulatory mechanism are started deposition of fibrin clot 2) Anti-coagulant effects
Limiting factors a. Heparin like molecules
- ex: Tissue plasminogen activator limits clotting to the site of injury and
leads to clot resorption. - activates Anti-Thrombin III which
inhibits Thrombin
Endothelium has Anti-thrombotic b. Thrombomodulin
Events: Functions for procoagulation- - Activates Protein C which inactivates
Coagulation system anticoagulation balance Factor Va and Factor VIIIa
- Is Vit K dependent and requires protein
S as cofactor
Regulated process that occurs at
the site of vascular injury and
culminates in the formation of a
clot. definition:
Hemodynamic part 2: 3) Fibronolytic effects
Tissue Type Plasminogen
Hemostasis Activator (t-PA)
- Cleaves plasminogen to form
plasmin
- Plasmin —> cleaves fibrin to
degrade thrombi
Part 2
Factor V Leiden Mutation
- Mostly Caucasians
- Amino acid substitution causes
structural difference in Factor V,
this form is resistant to Protein C
inactivation.
- S&S: increase tendency for
2) Stasis or turbulence of blood
thrombosis specially during
flow
pregnancy (due to its natural Antibodies against phospholipids
- Both causes endothelial activation
physiology of being a pro- bound to plasma proteins causes:
and pro-coagulant activity 3) Blood hyper-coagulability
thrombotic state). 1) Inactivation of anticoagulants
- Bring platelets in contact with - non common activation of the coagulation system
endothelium Causes: 2) Initiate release of pro
- Turbulence: causes endothelial injury Primary (genetic) Antiphospholipid Syndrome inflammatory cytokines
Diseases: Pathogenesis:
and dysfunction Factor V mutation (Leiden mutation) (Hughes Syndrome)
- Stasis: important in formation of Protein C deficiency - Antiphosopholipid antibodies
venous thrombi Homozygous Homocystinuria (very rare) - S&S: Recurrent fetal loss, Cardiac DVT, pulmonary embolism, CVA,
- Ex: prolonged bed rest & valve vegetations, migranes, Libman Sacks
Thrombocytopenia. Clinical features:
aneurysms Secondary (acquired) endocarditis, Coronary heart
Antiphospholipid antibody syndrome - higher in African-Americans and diease, Pregnancy loss
Prolonged bed rest, MI, atrial fibrillation, cancer, Hispanics
- Association with SLE (10-30%)

1) Endothelial injury - Anti-phospholipid antibodies

Dx:
- Endothelial injury leading to platelet (aCL test)
activation leads to thrombus formation.
- Endothelial injury exposes vWF and Tissue
factor
- This change is referred to as Endothelial Virchow triad
Activation or Endothelial Dysfunction where
endothelium becomes prothrombotic.
- Ex: ulcerated plaques in atherosclerosis,
Vasculitis, heart chamber following MI or
exposes subendothelium Arrow:
Artherial trombi
adherent
- Present within cardiac chambers or
thrombi at
aortic lumen
Pathogenesis: the apex of
- Adhere to the wall = Mural Thrombi
(L) ventricle
- Are occlusive
- ex: coronary, cerebral, femoral

Intravascular mass formed from

blood components adherent to the Definition:
Hemodynamic part 2: Morphology:

vessel wall Thrombosis

Phlebothrombosis
- Venous thrombosis
- forms luminal cast
- contains more enmeshed red
- Thrombus formed in heart or cells, and less platelets
aorta, - referred to as ‘red’ or ‘stasis’
- show lamination: ‘lines of Zahn’ thrombi
- Alternating ‘pale’ areas of platelets
admixed with some fibrin and
‘darker’ layer containing more red Postmortem clots
cells - characterized by chicken fat and
currant jelly pattern on gross
morphology
- can be mistaken for ante mortem
thrombi
Part 3

Embolic obstruction of small

Sudden death (Cor Pulmonale) - end-arteriolar pulmonary
when emboli obstructs more than branches - lead to infarction or
60% or more of the pulmonary hemorrhage
circulation

Paradoxical - emboli pass into the Hampton’s hump Infarction

(L) side of heart through an inter-
ventricular defect Xray:
Types:
Fat embolism
- Associated with mid shaft fracture of long
Pulmonary Thromboembolism bones
- 95% comes form Deep Vein of the - Rupture of bone marrow vascular sinuses
leg - Pathogenesis:
- Caused by: DVT & Pro-thrombotic 1) Mechanical: obstruction of pulmonary
Saddle - thrombus sits
states, Progressive right heart microvasculature
astride the pulmonary
failure. 2) Biochemical: fatty acids released from fat
bifurcation
- Pathophysiology: globules toxic to endothelium
1) Respiratory compromise - due - S&S: pulmonary insufficiency, neurologic
to lack of perfusion symptoms, anemia (hemolysis)
2) Hemodynamic compromise - & thrombocytopenia 24-72hrs after trauma
increase blood flow resistance by
the obstruction

A detached intravascular solid,

liquid, or gaseous mass that is Definition:
Hemodynamic part 2:
Presence of fetal squames. lanugo
carried by the blood to a site of
distant from its point of origin
Embolism Stain: Oil Red O
hair, fat from vernix caseosa and
mucin, within pulmonary circulation

Amniotic fluid embolism

Air Embolism
- Amniotic fluid, fetal cells, hair or other debris enter into
- Gas bubbles within circulation can obstruct vascular flow (>100cc)
maternal circulation leading to cardiorespiratory collapse
- Causes:
Pathogenesis:
1) Decompression sickness
- Tear in placental membranes or uterine veins leads to
- Air breathing under high pressure dissolved in blood and tissues
small volume of amniotic fluid gets transferred to maternal
- Diver ascends too rapidly causing Nitrogen to come out of solution and form gas
circulation (1 to 2 ml) during labor or early post-partum.
bubbles (may be due to Nitrogen Narcosis)
- amniotic fluid contents: mucin, fetal debris, vernix, lanugo,
- S&S: Muscle and joint pain (bends), Lung Issues (chokes) (Edema, Atelectasis,
and squamous cells
Hemorrhage)
Causes:
2) Severe chest trauma
1) Mechanical: obstruction
- if require positive pressure ventilation are at risk
2) Biochemical: endothelial injury leading to stimulation of
- High ventilatory pressures, especially >50 cm H2O, may force air from an injured
inflammatory cascade. Also,
bronchus into an adjacent injured vessel.
mucin may act as “procoagulants” and triggers
- Chronic Form: Caisson disease, ischemic necrosis in muscles, and bones ( ‘avascular
disseminated intravascular coagulation (DIC)
necrosis’)
- S&S: on mother - hypotension, dyspnea, pulmonary
edema, cardiac arrest, shock (DIC)
Part 4

Red Infarct in heart: This

pattern of infarct is
associated with
reperfusion injury.
1) Thrombus/emboli arising from
Remember: classically in
arterial occlusion (ie. MI, cerebral
MI, you find ‘pale’ infarct.
pulmonary, bowel infarction)
2) Local vasospasm
4) Compression of blood vessel
5) Venous thrombosis
Ex: Testicular torsion - testicle rotates
on its spermatic cord. Cuts off blood
supply. If more than 12 hrs.
orchidectomy is required Red infarction:
6) Ovarian Torsion - occurs in loose tissues with
collaterals
- ex. liver, lungs, intestines,
- Important: red infarction may be
Causes:
seen following reperfusion

is an area of ischemic necrosis

caused by occlusion of either the definition: Hemodynamic part 2: Morphology:
arterial supply or the venous White (pale) infarction:
drainage in a particular tissue Infarct - solid organs
- ex. heart, kidney
spleen

Septic infarction:
- Causes: intravenous drug abuse,
infective endocarditis
- bacterial vegetation from heart
dislodge and causes embolus
- spleen, kidney, brain,
- infarcted area can be converted to
an abscess

infective “vegetations” on heart

valve
 1) decrease cardiac output
2) decrease left ventricular end
diastolic pressure - Cold skin
1) Hemorrhage causing loss of
3) increase peripheral vascular - hypotension Inflammatory
RBC and plasma
resistance - crease urine output - LPS on microbes triggers pro inflammatory response of innate immune system (i.e.. TLR, PAMPs)
OR
4) Decreased mixed venous oxygen - Normal Hb levels at early stages - Innate response leads to release of TNF, IL-1, IFNg and IL-12 which up-regulate expression of
2) Loss of plasma volumen due
content - increase AN gap —> metabolic adhesion molecules
to extravascular fluid
sequestration or GI, urinary and acidosis due to increased anaerobic - Complement cascade is also triggeres (via C3a & C5a)
insensible losses. glycolysis - Endothelial cell injury causes activation of coagulation system
- >20% blood volumen loss results Pathogenesis: Counter inflammatory
in shock - possible mechanism include a shift from pro-inflmamtory (Th1) to anti inflammatory (Th2)
- expllains immune suppresed states seen in sepsis
Due to: Clinical features:
Sepsis accompanied by
hypotension that cannot be 1) Inflammatory and counter
corrected by fluid infusion inflammatory responses - Endothelial injury leads to widespread
- Failure of myocardial pump owing
vascular leakage and edema which affects
to intrinsic myocardial damage,
tissue perfusion.
extrinsic pressure or obstruction to Hypovolemic shock definition: Causing agent
- This interfere with intravenous fluid
flow 2) Endothelial activation and administration
- Examples: MI, Ventricular rupture, injury
leading to: - Also, the NO produced by activated
Arrhythmia, Cardiac tamponade & Pathogenesis:
Cardiogenic shock Septic Shock endothelium causes vasodilation which
Pulmonary embolism
resultes in systemic hypotension.
results in:
Clinical features:
Causes:
3) Metabolic abnormalities - Sepsis leads to insulin resistance and
- hypotension, neurologic, weak hyperglycemia.
rapid pulse, tachypnea, warm skin - Gluconeogenesis is driven by TNF, IL- 1,
and flushed initially (due to glucagon and GH.
peripheral vasodilation), - Also presence of pro-inflammatory cytokines
Hypoperfusion caused by reduction
in either cardiac output or effective definition:
Hemodynamic Part 3: - ARDS, renal insufficiency
- Complication: Disseminated
suppress insulin and promotes insulin
4) Organ dysfunction resistance in the liber by decrease expression
circulating blood volume Shock intravascular coagulation (DIC)
- Multiorgan failure
of GLUT 4.

- Systemic hypotension, interstitial edema, and

small vessel thrombosis decrease oxygen
Acute Tubular Injury/ Morphology: delivery to tissues
Necrosis Waterhouse-Friderichsen - high levels of cytokines decreases
- Characterized by acute syndrome myocardial contractility
Kidney
renal failure Adrenal - Bacterial infection (Neisseria - Increased vascular permeability, and
- Caused by: meningitidis), leading to sepsis endothelial injury lead to ARDS
Lung
1) Ischemia - Causes rapidly progressive ultimately all these lead to failure of multiple
2) Direct Toxic injury hypotension, disseminated and organs
- Morphology: focal tubular Acute Respiratory Distress Syndrome intravascular coagulation (DIC)
epithelial Necrosis, occlusion - Injury to pneumocytes and pulmonary - Results in rapidly developing
of tubular lumen by casts. endothelium adrenocortical insufficiency
- PCT and the ascending - Injury causes endothelial activation and associated with massive bilateral
thick limb are vulnerable inflammation cascade is activated. adrenal hemorrhage
- Leads to accumulation of intralveolar fluid
due to leaky pulmonary capillaries
The damage and necrosis of Type II alveolar
pneumocytes cause formation of ‘hyaline
membrane (Pink Stuff)
 Transthyretin (ATTR)
Part 1 2) AA (amyloid associated)
- From non-Ig protein synthesized
- Normal fx is to bind and transport
thyroxine and retinol
by the liver - Mutant form is deposited in
- Seen in inflammation genetic diseases like Familial
- Derived from proteolysis of SAA amyloid polyneuropathies
(acute phase reactants) - Also seen in: hearts of aged
3) Aβ amyloid
- Produced by the β-amyloid people
precursor protein (Alzheimer
disease CNS) Prion protein
1) AL (amyloid light chain)
- Derived from Ig light chains - Misfolded protein
produced by plasma cells - Clump in extracellular space
- Plasma cell tumors (contains - Causingprion disease
complete Ig light chain: ʎ and ƙ)
- Ex. Multiple Myeloma β2-microglobulin
Major Forms: Other forms: - Component of MHC class 1
molecules and a normal serum
protein (Aβ2m)
- Which is seen to complicate the
course of patients on long term
1) Composed of continuous hemodialysis
nonbranching fibrils - 95% consists of fibril protein
- Affinity for Carpal Tunnel
2) Characteristic cross β-pleated - Remaining 5% being P component
accumulation
sheet conformation and other glycoproteins
3) That stain with Congo red
staining

Chemical nature: 1) Normal proteins that have a

Physical nature: tendency to fold improperly

pathologic proteinaceous -Normally abnormal folded protein

substance, deposited in the are degraded intracellularly by
extracellular space in various proteosomes or extracellularly by Types:
tissues and organs of the body in a
Definition:
Amyloidosis Pathogenesis: macrophages.
- In amyloidosis this ‘quality control’
2) Mutant protein that are prone for
wide variety of clinical settings misfolding, and subsequent
fails, leading to accumulation aggregation

Immune dyscrasias with amyloidosis: Medullary carcinoma thyroid

- AL type amyloid with systemic distribution - MEN syndrome
- Produces abnormally large quantity of Classification - Originates from calcitonin-
‘M’ (monoclonal) protein both Ig molecules and light secreting neuroendocrine
chains are seen. Endocrine Amyloidosis parafollicular (C cells) of the thyroid.
- Light chains that may escape in urine is referred to
as “Bence-Jones” protein Systemic Amyloidosis
- Ex. multiple myeloma, plasma cell malignancy Localized Amyloidosis Diabetes Mellitus (Type II)
senile cerebral (Alzheimer) - islets of Langerhans

Reactive systemic amyloidosis: Hereditary Amyloidosis

- AA type, systemic distribution
- Seen in Tb, Bronchiectasis, osteomyelitis, Alzheimer disease:
Hemodialysis-associated
Rheumatoid arthritis, ankylosing spondylitis, -Deposition of Aβ amyloid derived
amyloidosis:
inflammatory bowel disease (Crohn’s and from precursor protein (APP)
- Deposition of β2-microglobulin due to
ulcerative colitis) long term hemodialysis
- Also, heroin abusers who inject the drug - β2-microglobulin present in serum of
subcutaneously patients with renal failure
- And non-immunocyte derived tumors like is not filtered through dialysis membrane Familial amyloid
Renal cell carcinoma, Hodgkin lymphoma -Therefore remain in circulation and gets cardiomyopathy:
deposited in tissues - Mutant ATTR deposition is noted
patients present with ‘carpal tunnel in 4% of African-American
syndrome’ - Presents as restrictive
Familial Mediterranean fever: cardiomyopathy
- ‘Autoinflammatory’ condition
- Due to abnormally high
production of IL-1, in response to
inflammatory stimuli
- S&S: fevers, and inflammation of
serosal surfaces
- The gene encodes for: Pyrin
- There is widespread AA type Familial amyloidotic
amyloidosis polyneuropathies:
- Deposition of amyloid in peripheral
and autonomic nerves
composed of mutant ATTR
(transthyretin)
Part 2

Kidney
Micro:
- Deposits seen in glomeruli,
interstitial peritubular tissue,
Micro: arteries/arterioles
-Pink on routine H & E stain - Clinically present as nephrotic
- Highlighted using: Congo Red syndrome
stain
- Polarizing microscopy: apple
green birefringence Spleen
Gross:
- enlarged, deposits may be of two types:
Gross: 1) Limited to splenic follicles, with tapioca like
- Involved organs tend to be granules: “sago spleen”
enlarged
-Waxy appearance, firm in
Amyloidosis: 2) Deposits involve wall of the splenic sinuses,
and connective tissue framework of red pulp:
Presentation in:
consistency Morphology “lardaceous spleen”
-Painting the cut surface with iodine
gives a yellow color Heart:
- Restrictive cardiomyopathy
Diagnosis: Other tissues: - Characterized by restrictive filling,
- Tongue: large deposits : normal or reduced LV and right
“tumor forming amyloid of the ventricular (RV) volumes, and
tongue” normal or nearly normal systolic (LV
- Carpal tunnel syndrome and RV) function.
Tissue biopsy:
- Abdominal wall
- Rectal
- The heart is firm
and rubbery with a
waxy cut surface.
- The atria are
markedly dilated and
the left atrial
endocardium,
normally smooth, has
yellow-brown
amyloid deposits
that give texture to
the surface.
Pathology 1 Concept Maps
Block 2

Jandrely Lopez
Material from Dr. Roy’s Lectures
 Part 1

Desmoplastic round cell

tumor
- Intra abdominal tumor
- Highly aggressive, complete
resection us not possible due
to infiltration of abdominal
structures

Example Cystadenoma:
Fibroma
- Exhibits cystic spaces into which papillary ingrowths
- Common benign tumor arising
Osteoma of neoplastic epithelium protrude.
Parenchyma –-> proliferating mostly in oral cavity
Stroma –-> supporting tissue - Ex: Papillary cystadenoma of ovary is a typical
neoplastic cells - Proliferation of fibrous tissue
- Desmoplasia —> abundant example.
collagenous stroma

Adenomas:
- Composed of solid glandular tissue.
- May not show glands, but show cells
Mesenchymal
resembling the respective tissue.
Components: - Adenomas that grow into lumen becomes
pedunculated to form ‘polyps’.
An abnormal mass of tissue, the
growth of which exceeds and is
uncoordinated with that of the
normal tissues and persists in the definition:
Neoplasia Part 1: Bening Tumors
Fibroadenoma:
- Suffix “oma” to cell of origin Origin
same excessive manner after the
cessation of the stimuli which has Nomenclature - Most common benign breast tumor (breast mouse)
- Epithelial component of breast is hormonally responsive
evoked the change - Autonomous Epithelial - Fibroadenomas are grouped with “proliferative changes
without atypia” (mildly increased risk of subsequent cancer)
Malignant Tumors
- Suffix of “-carcinoma” or “-
sarcoma”

Inductal Papilloma Breast Laryngeal papilloma:

- Growth within a dilated duct - “Finger-like” off-shoots from lining
Origin - Composed of Fibrovascular cores Papilloma (verruca vulgaris):
- Referred to as ‘squamous epithelium
- 80% produce a nipple discharge - Most common cause is HPV
- Discharge is bloody if stalk papilloma’
Bone Marrow Epithelial infection.
undergoes torsion - Caused by HPV infection
Lymphoid Mesenchymal

Leukemia: Adenocarcinoma stomach: Squamous cell carcinoma of

- Malignancy of blood cells Lymphoma: - Large ulcerated area with esophagus:
- Sometimes there can be difficulty - Malignant tumor involving Sarcoma: surrounding loss of rugal folds - Associated with smoking and
in differentiating one from the other. lymphoid cells. - Less common than carcinoma - Microscopy reveals irregular alcohol.
- Enlarged lymph node shows -Typically radio-resistant glands lined by cells with atypical - Common in African Americans
homogenous white color. - Special stains: vimentin, desmin features
- Histopathology is definite for - Ex: osteosarcoma, fibrosarcoma,
making a diagnosis. liposarcoma
- MC B-cell type.

Osteosarcoma
- Common tumor of bone
- Formation of bone or osteoid by tumor cells
- Clinical Associations:
1) Pediatric age
2) Retinoblastoma, Li-Fraumeni syndrom,
fibrous dysplasia, Paget’s Disease
3) Sites: distal femur, proximal tibie,
proximal humerus
4) Located at bone metaphysis
 Part 2

Pleomorphic adenoma:
- Mixed Tumor
- Benign
- Frequently arise from parotid gland
- Admixture of epithelial and stromal elements
- Histogenesis: myoepithelial/ductal reserve
cell origin
Teratoma: - Sites: parotid (80%), submandibular (10%),
1) Mature Teratoma remaining from minor salivary glands Neuroblastoma:
- Benign
- Also known as cystic or dermoid cysts - Incidence is 2yro
- Lined by skin-like structures - Arise from the neural crest cells and show
- Often contain hair, sebaceous material, different levels of differentiation.
adipose, cartilage, thyroid, teeth, etc. - Usually in adrenal medulla or sympathetic
2) Immature Teratoma chain
- Malignant - Increased production of catecholamines
- Contains embryonal tissue - Spontaneously regress
Divergent differentiation from
3) Monodermal Teratoma single cell line
- Unilateral
- Struma ovarii
a. Mature thyroid tissue that can cause Ewing’s Sarcoma
Tumors representing more
hyperthyroidism - Malignant bone tumor
than one germ layer
- Carcinoid - Primitive round cells with obvious
a. Arises from intestinal tissue differentiation
b. Can produce 5-HT causing carcinoid
syndrome
Neoplasia Part 1: - 2nd MC bone sarcomas in children
- Arise from the diaphysis of long tubular
Special types: Embryological blast: primitive/embryonal
Nomenclature bones (femur, flat bones of pelvis)
- Layers of reactive bone deposited in onion-
skin fashion
Ectopic rests of normal tissue - translocation (11q24 ; 22q12) – in frame
fusion of EWS gene on chr 22 to the FLI1
Mass of disorganized, but mature gene
Choristoma: specialized cells or tissue
- Example: pancreatic tissue in indigenous to that site
stomach wall, gastric mucosa in
Meckel diverticulum's
- Most common epibulbar and -Wilm’s Tumor – malignant tumor arising
orbital tumors in children. from kidney
Hamartoma: -Medulloblastoma – malignant tumor
- tumor like malformation arising from 4th ventricle
1) Tissues present are those -Retinoblastoma – malignant tumor
specific to the part from which arising from eye
arises -Hepatoblastoma – malignant tumor
2) Growth is coordinated with that arising from liver
of the surrounding tissues
- Example: Solitary pulmonary
nodule

medulloblastoma
 Part 3

Differentiation
Neoplasia Part 1: Anaplasia
Characteristics
The extent to which neoplastic cells
resemble comparable normal cells Poor differentiation i.e. Well differentiated
on: morphological/functional adenocarcinoma:
1) Morphology - resemblance to differentiation is absent. shows glandular pattern, however
parent cell cells exhibit features of malignancy
2) Function - ability to produce
parent cell function (ex. mucin)

Benign tumors are mostly well

differentiated and do not Malignant tumors can range from
difference well differentiated to poorly
metastasize.
differentiated

- Well differentiated malignant

tumors differ from benign tumors on
several morphologic features

- Malignant tumors whether well or

poorly differentiated have a high
risk of invasion and metastasis

Anaplastic adenocarcinoma:
shows poor differentiation and
bears no semblance to parent
tissue
 Part 4

Malignant tumors
- Show nuclear hyperchromatism Malignant tumors Benign tumors
(dense staining) - Ratio approaches 1:1 - Ratio remains normal Malignant tumors
- This feature does not help to - Best observed in ie. o ranges from 1:4 to - Abnormal/bizarre mitosis
differentiate malignant tumors from aspiration cytology 1:6 - Tripolar, quadripolar, stellate
benign study

Benign tumors
Nuclear:Cytoplasmic Ratio - Normal bipolar spindle type

Hyperchromatism
Mitosis

Malignant tumors
- Variation in size and shape of the
cells and nuclei
Neoplasia Part 1:
Pleomorphisim
Morphology Loss of polarity
Malignant tumors
- Epithelial lined structures lose
Benign tumors
- Does not show pleomorphism normal orientation
- Show regular cell size and nuclear
size

Problem area
Tumor Necrosis Tumor Giant Cells

Thyroid Adeoma vs. Adenocarcinoma

- Tumor cells having 2+ nuclei
- Poses diagnostic challenge - Seen in rapidly growing tumors
- Common in sarcomas
- Adenoma - Numerous follicles of varying - Develop in ischemic areas, mostly
sizes encapsulated within the thyroid in central areas
- Adenocarcinoma - May look extremely well- - Ischemia is noted following
differentiated (look benign) treatment (chemo/radiation)
- Diagnosis rests on:
1) Capsular invasion and/or
2) Vascular invasion

Adenoma

Adenocarcinoma - capsular invasion

 Carcinoma in situ – when entire
thickness of the epithelium is
involved Part 5
- is a Pre-invasive lesion but not
1/3 thickness Full thickness
always progresses to malignancy 2/3 thickness
Intact Basement Membrane

- Disordered growth seen in

epithelial lines structures
definition
Neoplasia Part 1: Described as (A) mild, (B)
moderate, (C) severe/carcinoma
- Often occurs in metaplastic
epithelium Dysplasia in situ

example

Cervical Dysplasia

Determined by…
Uterine leiomyomas (benign)
1. Doubling time of tumor cells
-Benign tumor arising from smooth
- Minimal detectable weight = 1 gm
muscle of uterus
- Maximum weight compatible with life = 1 kg
-Hormonal dependent
2. Fraction of tumor cells that are in the replicative pool (growth
-Exception to rule that malignant
fraction)
tumors grow faster than benign
- Rapid growing tumors have a growth fraction of about 20% Exception tumors
- Ex High Growth = leukemias, lymphomas, small cell
- Increased growth during
carcinoma of lung
pregnancy
- Ex low growth fraction = carcinoma colon, carcinoma breast
-After menopause, leiomyomas
- Anti-cancer meds target cells in cell cycle i.e The Higher
may atrophy and be replaced by
growth fraction, more likely the medication will work
fibrous tissue or calcify
3. Rates at which cells are shed and lost in the growing lesion

Rate of Growth

1. Malignant change in the target

cell (transformation)
2. Growth of the transformed cells Phases of Growth
Neoplasia Part 1:
3. Local invasion
4. Distant metastases Biology
Part 1 metastatic breast carcinoma spreading
to lung shows cannon ball appearance

- Most malignant tumors

metastasize
- Except Gliomas, basal cell
Hemangioma is an carcinomas (skin)
unencapsulated benign tumor

Exception
- Spread of tumors that are
physically discontinuous with the Jelly belly
primary tumor
Bening tumor
- All benign tumors DO NOT invade
or metastasize and have fibrous definition 1) Seeding of body cavities and Pseudomyxoma peritonei
tissue capsule surfaces - Mucin producing tumor associated
- Malignant cells exfoliate & invade example:
with appendix and ovaries
body cavity tissue (peritoneal cavity)
Neuroma encapsulation

Local invasion Neoplasia 2 Metastasis

Sentinel lymph node:

Pathways of spread - Is the first lymph node in a
2) Lymphatic spread
regional lymphatic basin that
- Common pathway for initial
receives lymph flow from the
spread for carcinomas and
primary tumor
Malignant tumors sarcomas
4) Others - Ex. Breast Cancer -
- Infiltrate and destroy the Rotter’s LN
surrounding tissue as they are
Causes for LN enlargement
poorly demarcated Perineural invasion is
- However a “pseudocapsule” may not a route of spread
be seen in a slowly expanding Krukenberg Tumor –
malignant tumor. gastric tumors giving rise 3) Hematogenous spread
to tumor deposits on - Veins commonly involved 2) Reactive hyperplasia: drainage
Carcinoma head of pancreas infiltration
surface of ovaries 1) Spread and growth of cancer
- Liver and lungs most frequently of tumor cell debris or tumor
bilaterally. cells
involved antigen, or both
- Example: vertebral metastases
in carcinoma thyroid and prostate
(Baston paravertebral venous
plexus)

Metastatic lymph node: Presence of Reactive Hyperplasia of Lymph

Pseudocapsule but still malignant
glandular elements in the lymph nodes: architecture is still
node preserved, however, there is
reaction by macrophages

Tumor emboli in blood vessel. A

case of primary lung cancer.

Radiology: Pancoast tumor

Clinical: Horner syndrome
 Part 2
Solar keratosis Crohn’s Disease:
Gross: cobblestone appearance
Histology: non-caseating granuloma
in small bowel mucosa.

Normal histology of breast ducts Epithelial hyperplasia: breast duct

- Pernicious anemia —> atrophic gastritis of stomach

- Solar keratosis of skin —> quamous cell carcinoma Helicobacter pylori
- Sjorgen Syndrome, Hashimoto’s thyroiditis—> MALT
lymphoma
- Atypical hyperplasia of ductal epithelium —> Breast cancer
- Leukoplakia of oral cavity, vulva, and penis —> squamous
cell carcinoma
- Chronic irritation of sinus orifice —> squamous cell carcinoma
- Barrett’s Esophagus —> adenocarcinoma esophagus
- Dysplastic Nevus —> malignant melanoma
- Myelodysplastic Syndrome —> AML
Autosomal Dominant
- Regenerative nodules in cirrhosis —> hepatocellular
Retinoblastoma
carcinoma
Familial Adenomatous Polyposis
- Villous adenoma rectum —> adenocarcinoma
(FAP)
Normal Atrophic gastritis: note patchy - Complete hydatidiform mole —> choriocarcinoma
Li-Fraumeni Syndrome
areas of atrophic mucosa - Endometrial hyperplasia —> adenocarcinoma endometrium
Hereditary Non Polyposis Colon
- Scar tissue in lung —> adenocarcinoma
Cancer (HNPCC)
BRCA1 & BRCA2
2) Precancerous conditions

- Usually due to germline Examples

Nonhereditary Predisposition
Conditions Neoplasia 2 Familial Cancer mutations in a tumor
suppressor gene

Autosomal Recessive
Xeroderma Pigmentosum (XP)
1) Chronic inflammation and Ataxia Telangiectasia
cancer Bloom Syndrome
Fanconi Syndrome

- Activated immune cells produced

ROS that are genotoxic
- Growth factors and cytokines
increase pool of tissue stem cells
- This alterations for long periods
may allow cells to mutate and
Metaplasia may occur.
- Examples: Crohn’s Disease, H.
pylori gastritis, Ulcerative colitis
& Viral Hepatitis
1
Part 1

-Gastro Intestinal Stromal Tumor

(GIST)
- Mesenchymal tumor of GIT
- Arise from interstitial cells of Cajal

Cholangiocarcinoma:
- Encountered in three anatomic Example:
regions: intrahepatic, extrahepatic
PI3K mutations:
(ie, perihilar), and distal
- Activates AKT downstream
extrahepatic. c-KIT mutation:
- PI3K is negatively regulated by
- MC are Perihilar tumors also - Gain of function mutation of c-KIT
PTEN
called Klatskin tumors seen in 75 to 80% of all cases of Alteration of Non- TK receptors
- PI3K and PTEN are frequently Neuroblastoma
GIST 1) CML - t(9,22) ABL
mutated together - N-MYC is amplified
- ex: breast carcinoma, endometrial 2) JAK2 mutation - Polycythemia
- 3rd MC pediatric malignancy
carcinoma vera, essential thrombocytosis & Burkitt Lymphoma t(8; 14) - Adrenal glands, posterior
Primary Myelofibrosis - c-MYC (chr 8) is a master mediastinum, neck, or pelvis
examples: transcriptional regulator - Presence of N-MYC amplification
Adenocarcinoma colon - Gets translocated to a Ig is a poor prognostic indicator
- Gross: ulceroproliferative lesion on promoter (chr 14) - Referred to as
luminal surface. RAS mutations: small round blue cell tumors
- Microscopy: ulceration and infiltrating ERBB2 (Her-2/Neu): is amplified in
- 90% of pancreatic 20 to 25% of all breast cancers
glands with features of malignancy examples:
adenocarcinoma, and - HER2 gene is located in
cholangiocarcinoma chromosome 17q
- 50% of colon, endometrial, and
thyroid
Amplification and overexpression - Mutations can affect transcription
Point mutation factors that drive growth promoting
genes
BRAF mutations:
Hairy cell leukemia
Melanoma

Signal transducing proteins Transcription factors

- Mutations of Growth factor
receptors can make them - Defects in G1/S Checkpoint are important as
constitutively active independent of these can lead to dysregulated growth
stimulation. - Types of mutation at G1/S
- Promoting independent cellular 1) Gain of function (oncogenes that promote)
growth Growth factor receptors - ex: cyclin D1 in Mantle cell lymphoma
- oncogenic versions of receptors Cyclins & cyclin 2) Loss of function (oncogenes that inhibit)
are associated with constitutive Types of proto- dependent kinases - ex: -
growth factor independent oncogen mutation a. Germline mutation of p16 (CDKN2A) in
tyrosine kinase activity familial melanoma.
b. Somatic inactivation of CDKN2A in 95%
of pancreatic adenocarcinoma, glioblastoma,
esophageal carcinoma
Glioblastomas:
- Tumors with autocrine loop - Oncogenes – genes that promote
- Express Growth Factor: PDGF, autonomous growth in cancer cells
and its receptor-
- Cancer cells acquire the ability to - Created from proto-oncogenes
(PDGFR) Example: Growth factors
synthesize growth factors to which which get mutated and encode
- Glioblastoma Multiforme is Grade
they are responsive (autocrine) proteins growth in the absence of
IV Astrocytoma. (most aggressive) normal growth signals.

1) Self-sufficiency in growth signals

Neoplasia 3:
Molecular Basis
 Sporadic mutation of CDKN2A is
Germline mutation of CDKN2A - Pancreatic adenocarcinoma, Endometrial adenocarcinoma
- Familial melanoma cholangiocarcinomabladder
cancers, head and neck cancers,
and Acute Lymphoblastic Leukemia
(ALL)
Part 2
CDKN2A
- Encodes for: p16/INK4a, & p14/
ARF
Lobular carcinoma breast p16/INK4:
- is a cyclin-dependent kinase
inhibitor
- blocks CDK4/cyclin D-mediated
phosphorylation of RB, reinforcing Carcinoma Pancreas:
the RB checkpoint - Tumor arising from head of
pancreas.
- Infiltrating ductal carcinoma
Somatic mutation: Germline loss of E-cadherin (pancreas), arises from small ducts
- Breast carcinoma (Lobular), (CDH1): Cowden syndrome:
Squamous cell carcinoma of - Familial gastric carcinoma - AD
esophagus
- Frequent benign growths
- Increased incidence of epithelial
TGF β Pathway cancers: breast, endometrium, and Neurofibromatosis 1
- Normally an inhibitor of cell proliferation thyroid. - Neurofibromas (benign)
Somatic mutation: - Initiates intracellular signals that involve - Café-au-lait
E-cadherin
- 50% of hepatoblastomas, and proteins of the SMAD family Lisch nodules (hamartomas in iris)
- Important for Intercellular
approximately 20% of - Normally turn on anti-proliferative genes - Association with
adhesiveness
hepatocellular carcinomas - Mutation leads to loss of function pheochromocytoma
- Loss of cell to cell contact disrupts
interaction between E- cadherin - Mutations of type II TGF-β – colon,
and β-catenin stomach and endometrial cancer PTEN
Familial Adenomatous Polyposis - Mutational inactivation of SMAD4 – - Regulates PI3K/AKT pathway
- This permits β-catenin to
(FAP) pancreatic cancer - Without PTEN PI3K/AKT becomes
translocate into the nucleus
- Germline mutation activated
triggering cell proliferation Neurofibromin NF1
- Thousands of adenomatous - PTEN is inactivated in both
polyps develop in the colon during - Involves downregulation of the
endometrial hyperplasia, and RAS signal transduction pathway
teens to early 20s Adenomatous polyposis coli (APC endometrial carcinoma
- Polyps turn malignant giving rise - Therefore, considered a tumor-
gene)
to colon cancer suppressor gene
- Down regulates growth-promoting
- At least 100 polyps necessary for signaling pathways Neurofibromatosis 2
diagnosis - Mechanism of Action: Germline mutations:
• Component of WNT signaling - Benign bilateral schwannomas of acoustic
pathway nerve
• Major role in controlling cell fate, - Causes paralysis and deafness
adhesion, and cell polarity during Neurofibromin 2 NF-2 Somatic mutations:
embryonic development - Sporadic meningiomas and ependymoma
• Holds β-catenin activity in check
Li-Fraumeni syndrome
- Germline mutation of TP53
- 25 fold greater chance of developing a Von Hippel-Lindau (VHL)
malignant tumor by age 50 - Mutations on chromosome 3
p53
- Sarcomas, breast cancer, leukemias, associated with
- Guardian of the genome”
brain tumors, and carcinomas of the 1) Hereditary renal cell cancers,
- Most frequently mutated gene (loss of
adrenal cortex 2) Pheochromocytomas,
function) in human cancers
3) Hemangioblastomas of CNS,
Mechanism of action:
Examples: 4) Retinal angiomas
Somatic mutation of TP53: - Activation of temporary cell arrest
5) Renal cysts
- Very common - Induction of permanent cell arrest
- Are found in more than 50% of - Triggering of programmed cell death
cancers (apoptosis)

WT1 Hemangiolastoma of CNS

Pheochromocytoma
Chromosome 11p13 Renal cell carcinoma
- Transcriptional activator of
Retinoblastoma genes involved in renal & gonadal
- Rb gene Chr locus 13q14 differentiation
- 60% Sporadic —> children born - Associated with Wilms Tumor
with 2 normal copies of RB gene development
but both are lost through somatic Rb
mutation - Prevent excessive cell
- 40% Inherited —> children are growth by inhibiting cell cycle
progression until a cell is BRCA-1 and BRCA-2 genes
born with one defective and one
ready to divide - Function as transcription
normal copy of RB gene —> regulation, cell cycle control,
normal copy is lost through somatic protecting DNA
mutation - Loss of Tumor Suppressor Genes Leads to failure 0 Associated with breast carcinoma
—> higher chance to develop of growth inhibition and ovarian cancers in pre-
osteosarcoma - RB and p53, are part of a regulatory network that menopausal women
recognizes genotoxic stress and responds by - BRCA-1 —>Breast, Ovarian,
shutting down proliferation Prostate cancer
Other: RB somatic mutation can - BRCA-2 —> Breast (men and
lead to: Glioblastoma, small cell women), ovarian, prostatic,
Glioblastoma: Gr. IV astrocytoma, known carcinoma of lung, breast cancer & pancreatic, bile duct cancers
for being aggressive, large size, and bladder cancer 2) Insensitivity to growth inhibitory
hemorrhage
signals: Tumor suppressor genes

Neoplasia 3:
Molecular Basis
 Part 3

B cell lymphoma (follicular -All cancers contain immortal cells

lymphoma) - Neoplastic cells may result from
via:
- 85% has a t(14;18) translocation mutations in the genes that regulate
1) Evasion of senescence
tha5 leads to overexpression of example apoptosis - Growing cancers stimulate
2) Evasion of mitotic crisis
Bcl-2 - Bcl-2 is an anti apoptotic factor neoangiogenesis because they
3)Capacity for Self-renewal
- This upregulates anti-apoptotic - Tumor can escape apoptosis by require oxygen, nutrients, and a
- Increased telomerase activity
properties altering apoptosis route to remove waste products
-Endothelial cells secrete growth
factors: Insulin like growth factor
and PDGF
- Angiogenesis is controlled by a
balance between promoters and
4) Evasion of Apoptosis 5) Limitless replicative potential inhibitors

1) Invasion of Extracellular Matrix (ECM)

- Must breach basement membrane and
6) Sustained angiogenesis cross interstitial connective tissue and Enter
circulation
Steps:
3) Altered cellular metabolism Neoplasia 3: 1) Detachment of tumor cells from each other
(not discussed) •E-cadherin function is lost
Molecular Basis 2) Attachment to matrix components
3) Degradation of ECM/Basment Membrane
7) Ability to invade & metastasize
Two phases: •Metalloproteinases (MMPs) = Proteolytic
enzyme used by tumor to remodel and
8) Ability to evade the host degrade ECM
immune response 4) Migration of Tumor Cells

Genomic Instability 2) Vascular dissemination and homing of

tumors
- In circulation, tumor cells are clumped
Recombination Repair Mismatch Repair together
Nucleotide Excision Repair (NER) - Mismatch-repair factors correct the - Tumor emboli at distant sites involve
defect that may occur in a family of adhesion molecules
- Hypersensitivity to DNA genes (CD44 molecule expressed on Tcells are
damaging agents like: Ionizing - if mutated, errors accumulate and used by tumor cells in selective sites)
radiation or DNA crosslinking Xeroderma pigmentosum may cause activation of proto- - Common Pathways:
agents - Defective DNA repair genes oncogenes or inactivatation tumor •Prostatic adenocarcinoma —> bone
- Increased risk of skin cancers suppressor genes •Bronchogenic carcinoma —> adrenals
—> UV radiation causes cross and brain
linking or pyrimidine residues •Neuroblastoma —> liver and bones
1) Ataxia-telangiectasia
- Mutation in ATM Hereditary nonpolyposis colon
—> ATM normally Recognizes cancer (HNPCC) syndrome
dsDNA breaks caused by ionizing - Also called as Lynch syndrome
radiation - Familial carcinomas of the colon,
2) Bloom syndrome predominantly the cecum and
3) Fanconi Anemia proximal colon
- Mutations in MSH2 or MLH1
- Common mismatch repair defects
occur in microsatellites
Clinical Features: Lesions seen in
proximal colon with no pre-existing
polyps
 Initiation
Basal Cell Ca (BCC):
- Exposure to sufficient dose of Promoters
Part 1 - Do not require no metabolic
carcinogenic agent
- Causes permanent, irreversible
- Induce tumors in initiated
cells
conversion to become carcinogenic change in DNA - Alone are nontumorigenic
- Said to be weak carcinogens - Cannot give rise to a tumor
- Drugs: cyclophosphamide,
chlorambucil, busulfan, melphalan
- Cause of “second” malignancy
Betel nuts comes decades later Ultraviolet Rays
- Contain alkaloid arecoline - MC Acute myeloid leukemia - UVB most important for skin
Steps:
- Mutagenic, cytotoxic, and (AML) cancer
genotoxic effects - Types: Squamous cell
carcinoma, Basal cell carcinoma,
Melanoma
Direct acting compounds
Naturally Occurring Carcinogens - Mechanism: UV absorbed by
- Ex: Aflatoxin B1 1) Chemical Carcinogenesis DNA leads to crosslinking of
pyrimidine bases. If NER is
- Mycotoxin from some strains of
overwhelmed genomic mutations
Aspergillus flavus - Require metabolic conversion to can occur.
- Associated to Hepatocellular produce “ultimate carcinogen”
carcioma - Conversion of pro-carcinogen into Indirect acting agents categories:
carcinogen (procarcinogens)
- Metabolized by Cytochrome
P-450 dependent mono- Ionizing Radiation
Aromatic Amines oxygenases 2) Radiant energy - Exposure to radiation
- Ex: Β-napthylamine (found in - Can lead to: Leukemia in
children, Papillary carcinoma
Aniline dye & Rubber industry) Miscellaneous agents thyroid, Breast, lung, salivary gland
- Associates with Transitional cell
Carcinoma of bladder
—> Bladder mucosa secretes b-
Polycyclic hydrocarbons (fossil
fuels)
Nitrites (food preservatives)
– Carcinoma stomach
Neoplasia 4: cancers.

glucuronidase which Splits the - Metabolized by CYP1A1 to

compound into ultimate carcinogen benzopyrene
- Found in: Tobacco smoke &
Diethylstilbestrol (DES)
Broiling of animal fat/fish Asbestos
- Drug used for threatened
- Associated with lung carcinoma – Malignant mesotheliomas
Vinyl chloride (PVC) abortion
and bladder malignancies - Asbestos bodies
- Angiosarcoma of liver - Risk of breast cancer in
mothers Human T-Cell Leukemia Virues
- Risk of adenocarcinoma of Type I (HTLV1)
- Risk ofT-cell leukemia/lymphoma
vagina and cervix in daughters
- Caribbean and Japan Bening wart - HPV genome is
born - Tropism for CD4+ cells maintained in an ‘episomal’ form
- Virus contain Tax gene – activates (non integrated in DNA, but within
transcription of host genes like the nucleus)
PI3K/AKT pathway & NF-κB
—> Interferes with DNA repair
mechanism creating genomic
instability

Human Papilloma Virus (HPV)

- Squamous cell carcinoma of cervix and anogenital region
- HPV infects immature squamous cells but viral replication
occurs in maturing squamous cells.
- Serotypes
Karposi Sarcoma Herpes Virus (KSHV/ - HPV type 1: plantar warts
HHV8) 3) Oncogenic viruses and - HPV type 6 & 11: anogenital warts
- Highly associated with AIDS
- Sexually transmitted microbes - HPV type 16 & 18: cervical dysplasia/cancer
koilocytosis
•Koilocytes – cells with wrinkly appearance
Morphology Types: Viral proteins E6 & E7
- Stages of lesions: 1) Classic KS - Interfere with tumor suppressors
1) Patches – red/purple macules - Uncommon in USA - E7 binds to hypophosphorylated (active) RB and promotes
on distal lower extremites - Associated with malignancy/altered degradation and inhibits p21 & p27
2) Raised Plaques – dermal immunity - E6 binds to and promotes degradation of p53 and
accumulations of dilated, jagged - NOT associated with HIV infection upregulates telomerase ie. immortality
vascular channels lined and 2) Endemic African KS Helicobacter pylori
surrounded by plump spindle cells - Occurs in HIV-seronegative individuals - Gastric carcinomas/lymphomas
3) Nodular – sheets of plump, younger than 40 (MALTomas)
proliferating spindle cells in dermis 3) Transplant Associated KS - Treat with antiobiotics and
or subcutaneous tissues, - Solid organ transplant recipients omeprazole
encompassing small vessels and In setting of T-cell immunosuppression
slit-like spaces containing red cells 4) AIDS Associated KS Epstein Barr Virus (EBV)
- AIDS defining illness Hepatitis B Virus (HBV)
- Causes:
- Involves lymph nodes and - Chronic viral injury leads to
1. Burkitt lymphoma (C-MYC t 8-14)
dissemination to viscera compensatory proliferation of
2. B-cell Lymphoma
- Patients die of opportunistic infections hepatocytes
3. Hodgkin Lymphoma
- Presence of growth factors,
4. Nasopharyngeal Carcinoma
cytokines, chemokines, and
- Pathogenesis
oxygen free radicals hepatocytes
- Transmission through close human contact, saliva
become mutagenic
- Infects B cells by binding CD21
- Leads to Activation of NF-κB in
-Infection may take one of two forms:
hepatocytes that blocks apoptosis
1) minority of B cells undergo lysis
- HBx activates transcription factors
2) majority, EBV establishes a latent infection
- EBNA1 – binds EBV genome to host chromosomes
Hepatitis C Virus (HCV)
during mitosis
- Far East and Africa
- Latent membrane protein 1 (LMP1) – drives B-cell
- Activates growth promoting signal
activaton and proliferation and activates NF-κB and
transduction pathways
JAK/STAT pathways
- EBNA2 – promotes B-cell activation and replication
1
Paraneoplastic syndromes (cont d)

2
Part 2
Prostate adenocarcinoma —> osteoblastic +
Multiple myeloma or breast cancer —> osteoclastic +

2) Production of calcemic humoral

substances by extraosseous neoplasms:
1) osteolysis induced by cancer: - Considered as Paraneoplastic
- Can be by a primary in bone, such as Multiple - Ex: Squamous cell carcinoma of lung
Myeloma, or metastatic to bone from any primary release parathyroid hormone-related protein
lesion (PTHRP) causing hypercalcemia.
- Is NOT considered as paraneoplastic - Others: carcinomas of the breast, lung,
Cushing syndrome
kidney, and ovary
- 50% associated with small cell carcinoma of Bone metastasis —> Plasma cells—> release
lung factors —> osteoclast (+)—> increased Ca 2+. Tumor —> release factors (PTHRP) —>
—> high growth fraction
Osteoclast (+) —> increase Ca 2+.
—> seen In smokers
—> tumor has properties to secrete endocrine
like molecules like high ACTH
- Excessive production of corticotropin/ Two ways:
corticotropin-like peptides (product of pro- SIADH
opiomelanocortin) - Common cause of Ectopic ADH
- Cushing syndrome as a paraneoplastic synd producing by tumors
show raised serum levels of both pro- Hypercalcemia - Ex: small cell carcinoma of lung
opiomelanocortin and corticotropin - Something that increase the levels (SCLC)
- Immunostain positive for Chromogranin of Ca2+ Clinical Features:
- Asymptomatic
- Identified by the presence of
hyponatremia on routine testing
- S&S: weakness, lethargy, nausea,
confusion, depressed mental
status, and seizures
- Tumor that cause S&S that cannot
be explained by the position of the
tumor or by the elaboration of
hormones indigenous to the tissue Definition:
Neoplasia 4:
where the tumor is.
- May be the earliest manifestation
of an occult neoplasm Paraneoplastic
Eaton-Lambert syndrome
- Rare myasthenia disorder
Carcinoid syndrome - Reduction in neurotransmitter release from
- Benign tumor that release presynaptic terminals
serotonin and bradykinin Acanthosis nigricans
Others: Table - Develops in association with tumors like small
- S/S: Sudden blushing and - hyperkeratosis and cell carcinoma of lung (broncheogenic
sweating, diarrhea, sensation of hyperpigmentation of axilla, neck, carcinoma)
redness, or flushing. flexures, anogenital area Clinical Features:
- Investigation finds a single nodule - Related to GIT tumors (Gastric - Muscles of the trunk, shoulder girdle, pelvic
in the lung. carcinoma) girdle, and lower extremities are weak
- Unlike MG, there may be a temporary increase in
muscle power during the first few contractions
- Weakness may precede discovery of the tumor

Polycythemia
- Increase in RBCs mass. Venous Thrombosis (Trousseau
- Ex: Renal cell carcinoma (well phenomenon)
differentiated) produce - Related to pancreatic carcinoma
erythropoietin, go to BM and -Inflammation of the vessels, or
Increase RBC mass. phlebotrombus, of the popliteal
- S/S: dizziness, vertigo, headache, vessels.
redness, DVP (produce a
thrombus).
 Part 3
1) Union Internationale Contre le Cancer
(UICC)
- Based on TNM Classification
•T – refers to primary tumor size & invasion
(T1-T4) higher the T more large and invasive
•N – refers to regional lymph nodes involved
(N0-N3)
Grading (Pathologist) •M – refers to distant metastatic disease
- Histologic determination refering from no metastases to presence of
to degree of cellular metastases (M0-M1)
Staging (Clinician) systems:
differentiation 2) American joint Committee on Cancer
- Based on the results on
- Based on nuclear pleomorphism, (AJCC
Anorexia and weight loss (cancer noninvasive evaluation (physical
cellularity, necrosis, cellular
cachexia) examination and various imaging
invasion, number of mitoses
- Equal loss of both fat and lean studies)
- Graded I – IV based on increasing
muscle - Size, extent of spread to regional
anaplasia
- Elevated basal metabolic rate lymph nodes, presence/absence of
- Evidence of systemic inflammation blood borne metasteses
(e.g. increase in acute phase
reactants)

Grading and staging

Anemia in Cancer
- Anemia of chronic disease

Clinical features Neoplasia 4:

of malignancy:
Autoimmune Hemolytic Anemia
CD 30 = Lymphomas
- Due to formation of IgM cold
agglutinins
Lab diagnosis of cancer Cytokeratins = epithelial origin

Desmin/Vimentin = sarcoma
Disseminated Intravascular Immunohistochemistry
Coagulation (DIC) - using known specific monoclonal
- Trigger by release of antibodies
procoagulant factors - useful in: categorization of
Ki-67 = Cell proliferation
- Ex: in Adenocarcinoma colon undifferentiated malignant Prostatic specific antigen (PSA) =
- nuclear non-histone protein
Carcinoma pancreas (Mucin tumors like anaplastic carcinomas, bone metastases
secretion) lymphomas, melanomas, sarcomas

Glial fibrillary acidic protein

(GFAP) = Astrocytoma Thyroglobulin = carcinoma thyroid
S-100 = Melanomas and neural
origin tumors

Estrogen/Progesterone receptors
= Breast carcinoma
- if ER is positive HER2 will be
negative (50%-65% of cases)
- ER cancers are termed luminal

HER2 = Breast carcinoma

- Common in Li-fraumeni
- ER negative, HER2 positive (triple
negative, accounts for 20-25%
cases)
Tumor markers
- Substances
that can be Hydaditiform moleà choriocarcinoma
detected in B-hcg
high amounts MENà RET
in the serum,
urine, or tissue
with certain hepatocellular
types of cancer
- Serve as CEA
biochemical
indicators of
presence of
tumor
PSA
-May facilitate
diagnosis in the
event of an
unknown
primary

1
Part 4

Pancoast's syndrome
- Superior sulcus tumors in the
apex of the lung invade adjacent
structures
Horner syndrome:
- Lesion of the central or peripheral
sympathetic nervous system
- Leads to small (miotic) pupil
associated with mild ptosis and
sometimes loss of sweating
(anhidrosis)
Pouch of Douglas
- Rectouterine pouch or cul-de-sac
- Tumor deposits (pelvic
Sister Mary Joseph node malignancies, gastric, and
- Metastasis manifesting as a
periumbilical nodule secondary to
Neoplasia 4: pancreas) may be found in this
space
abdominal or pelvic cancers (ex:
Gastric carcinoma) Clinical Importance Blumer’s shelf:
- A finding felt in rectal examination
- Spread to the umbilicus that indicates that a tumor has
metastasized to the Pouch of
Douglas
12
Part 1

Biochemical Tests
- Serum Iron Concentration: Low
- TIBC (total iron binding
capacity): increased
- % Saturation (% transferrin
bound by iron): decreased
- Serum Ferritin: decreased
- Erythrocyte Iron: decreased
- Erythrocyte Zinc
Protoporphyrin (FEP): increased
Lab Diagnosis Bone Marrow
Hb: reduced - Hyperplastic Clinical Features
Hematocrit: reduced - Microcytic Maturation - Fatigue, light headedness,
RBCs: - Gold Standard (loss of stainable palpitation, pounding in ears
- MCV decreased iron) seen by prussion blue stain - Decreased work performance Pathogenesis
- MCH decreased - Pica - IL-1 & TNF, IFNγ
- MCHC decreases - Smooth red tongue with —> Stimulate hepcidin synthesis which Inhibits release of
Reticulocyte Hb: reduced Incidence
burning sensation iron from storage pool
- Koilonychia (spoon shaped - Very common —> Block intestinal absorption of iron
Peripheral Smear - Associated with chronic disease infections
concavity of nails) —> Impair erythropoietin response in BM
RBCs or non-infectious inflammatory disorders and
- Hair loss - Ferritin synthesis and iron stores increase
- Microcytic certain types of malignancy
- Restless legs
- Hypochromic Examples:
- Growth impairment
- Anisocytosis (variation in size) 1. Chronic microbial infections (TB,
- Angular cheilitis
- Poikilocytosis (variation in osteomyelitis, pelvic inflammatory diseases,
shape - pencil cells) bacterial endocarditis, lung abscess). Others:
Plummer-Vinson syndrome Malaria, HIV Lab Diagnosis
1) Microcytic hypochromic 2. Chronic immune disorders (Rheumatoid - Normocytic normochromic anemia
- Occurs only when iron stores are exhausted after anemia arthritis, SLE, vasculitic syndromes) progressed to microcytic
supply of iron fails to meet demand 2) Atrophic glossitis 3. Neoplasms (Hodgkin lymphoma) hypochromic
Caused by: 3) Esophageal webs - Prominent 4. Alcoholism - MCV: normal to reduced
1. Dietary Lack ridges hypopharynx and esophagus - Serum Iron: reduced
2. Impaired Absoprtion leading to dysphagia - Serum Ferritin: increased
3. Increased Requirements (Growth, Menstruation, Pathogenesis: - TIBC: decreased
Pregnancy) Treatment
4. Chronic Blood Loss (Peptic ulcer, Hemorrhoids, - Oral Iron Tablets
Carcinoma stomach/colon, Asprin, Ulcerative colitis, - Iron-carbohydrate complex
Esophageal varices, Hookworm infestation) - Blood transfusion
2) Anemia of Chronic Disease

-Pathologic iron deposits in erythroblast

Absorption mitochondria seen as ring sideroblast
Hereditary
- In Duodeno -Due to:
—> X-linked – ALA synthetase-2
Two pathways 1) Insufficient generation of heme as a result of
Acquired
1) Uptake of Heme iron primary defect in heme biosynthetic pathway or
1) Iron deficiency anemia - Primary
-  Ferrous (Fe 2+) derived from food of animal origin 2) Defects in mitochondrial functions that
—> Myelodysplastic Syndrome
- Imported into mucosal enterocytes by divalent metal ion Biology: involve iron pathways
Secondary
transporter 1 (DMT1 —> creates imbalance between mitochondrial
—> Chronic alcoholism
- Once inside the porphyrin ring is enzymatically cleaved iron import and utilization
—> Drugs (Isoniazid)
by heme oxygenase Introduction: - Leading to ineffective erythropoeisis
—> Pyridoxine (B6) deficiency
-  the liberated iron then may follow the same pathway as
—> Lead poisoning
the non-heme iron
2) Dietary Non-Heme Incidence Introduction: causes:
- Ferric (Fe 3+) hydroxide which is Loosely bound to - Young children and women - Defect in heme synthesis within
organic molecules Iron Balance mitochondria,
- First is Reduced by CYBRD1 then imported into - Gained through diet absorption - Protoporphyrin is absent so iron
enterocytes by DMT1 - Loss through loss of epithelial begins to acumulate within
Causes:
cells of GIT, epidermal loss of 3) Sideroblastic Anemia Pathogenesis: mitochondria
skin - Iron laden mitochondria appear as
a ring around the nucleus
Then Iron is exported from enterocyte to plasma via —> Ringed sideroblasts
Ferroportin (FPN1)

Lab Findings
Iron is transported in plasma by Transferrin Peripheral blood smear
- Is synthesized in liver - May be normocytic, macrocytic, or even microcytic
- only one-third of the available transferrin binding sites are -  red cells referred to as dimorphic (normocytic +
occupied Treatment:
- Supportive measures microcytic)
- thus leaving a large capacity to deal with excess iron Microcytic Anemias -  Pappenheimerbodies
- Withdrawal of alcohol
MCV: < 80 - Withdrawal of drug (treat with MCV:
pyridoxine) - usually low
Iron delivered to erythroid precursors Bone Marrow:
- Ultimately taken up by mitochondria and incorporated into -  Erythroid hyperplasia, abnormal forms
heme -  “Ring sideroblasts” (15 to 100%), raised hemosiderin
RBC Disorders 1 Special test: expression of mitochondrial ferritin
Biochemical:
Macrophage Iron Recycling - TIBC: decreased
- Alveolar macrophages phagocytose erythrocytes - Serum Iron: increased
- Convert iron to 1 of 2 storage forms - Serum Ferritin: increased
1) Ferritin – stores iron and releases it in controlled - Lead/alcohol in serum
fashion
2) Hemosiderin
Part 2 Normal
-RBC lifespan: 120 days
-Phagocytosis of old RBCs in
spleen, liver and bone marrow
1. Release of Hb
—> Split into globin & heme
—> Sent to protein pool
2. Heme oxygenase cleaves
porphyrin ring of heme producing
Intravascular Hemolysis Extravascular Hemolysis biliverdin
- Acute Process - Exaggeration of normal RBC 3. Billiverdin is reduced to
- Destruction of RBCs within removal billirubin
circulation - Premature phagocytosis of RBCs 4. Billirubin forms complex with
- Release of free Hb - Example: hereditary spherocytosis albumin and is transported to liver
- Examples: incompatible blood
transfusion, malaria, sepsis, PNH)

Pathological
- Shortened RBC life span
- Leads to compensatory bone
marrow hyperplasia (6x to 8x)
Intrinsic abnormality - If compensation is not successful
RBC Breakdown anemia occurs
1) Membrane Defects
site: -  In ‘Compensated hemolytic
- Hereditary Spherocytosis
2) Hb Defects disorders’- anemia is absent,
- Sickle Cell Disease reticulocytosis & erythroid
- Thalassemias hyperplasia of bone marrow are
3) Enzyme Defects seen
- G6PD Deficiency
4) Acquired
- Paroxysmal Nocturnal Hyperbilirubinemia and jaundice
Introduction to Hemolytic
hemoglobinuria - Absence of jaundice does not
Anemias
Causes: -Result from an increase in the rate exclude the diagnosis of hemolytic
of RBC destruction anemia
Evidence of Increased Plasma haptoglobin
Extrinsic abnormality Hb Breakdown - Synthesized by liver and binds to
1) Acquired free Hb in plasma to prevent Hb
•Immune Mechanisms from passing through glomerulus
- Hemolytic disease of the into urine
newborn - Reduced in both intrinsic and
- Incompatable blood transfusion extrinsic hemolysis
- Drug induced Features of Accelerated
•Non-Immune Hematopoiesis Evidence of Intravascular hemolysis
- Mechanical-micro angiopathic Plasma hemopexin
hemolytic anemia (MAHA) - Synthesized by liver and binds to free heme
Reticulocytosis and ferriheme in plasma
- Cardiac Prosthetic Valve - Presence of nucleated red cells in —> Ferriheme
2) Miscellaneous peripheral blood smear 1. Unbound Hb
- Infections - Normal is 0.2 – 2.0% 2. Converted to methemoglonin, then
- Burns - Bone marrow hyperplasia 3. disassociates into ferriheme and globin
- Lead Poisoning LDH: increased - Reduced in intravascular hemolysis
Extra medullary hematopoiesis
(liver, spleen, LN) 1) Methemalbumin and depletion of hemopexin indicate
Cholelithiasis severe hemolysis
Skeletal abnormalities Process:
a) Hb from RBC is released into plasma
b) Hb exceeds the haptoglobin capacity so unbound Hb is
converted to methemoglobin,
c) Which disassociates to ferriheme & globin
d) If the binding capacity of hemopexin is exceeded ferriheme
binds to albumin forming methemalbumin,
2) Presence of hemoglobinuria
- Occurs when Hb reabsorpitive capacity of tubules in kidney is
exceeded
- Urine color can range from being pink to black
3) Presence of hemoglobinemia
- When plasma Hb is increased
- Causes pink/red color to plasma

Reticulocytes show Reticulocytes with supravital stain

‘polychromatophelia’
Part 3

Lab Diagnosis
Hb: severe anemia
RBCs: low MCV
Peripheral Blood Smear
- Ansiopoikilocytosis
- Microcytic, hypochromic
-Target cells
- Fragmented red cells
Hydrops Fetalis - N-RBCs
- Deletion of all four α chains Reticulocyte Count: increased
- Most severe form Bilirubin in plasma
- Deficient synthesis of B chain
- In fetus, γ chains form tetramers, Hb Barts Hb Electrophoresis:
- Lack of adequate HbA (α2 β2) production
- Very high affinity for oxygen, no oxygen - HbA2: increased
-  Excess free α chains in comparison to
delivered to tissues - HbF: increased
reduced β chains:
- MCV: decreased - HbA: low or absent
-  Insoluble precipitated α chains aggregates
- RBC count: increased Bone Marrow: expanded
in rbc
- Fetal distress in 3rd trimester followed by intra
- Damages cell membrane, vulnerable to
unterine death
HbH Disease phagocytosis (extra-vascular hemolysis) Clinical Features
- Mother has toxemia of pregnancy
- Deletion of three α chains - Low HbA synthesis is —> poorly - Marked pallor, jaundice
(hypertension, fluid retention with or without
Severe hemolytic disease hemoglobinized ‘microcytic hypochromic’ red - Growth retardation
proteinuria), polyhydroamnios or
cells - Splenomegaly
oligohydroamnios
Leading to: - Skeletal system abnormalities
Beta Thalassemia Major
-Ineffective erythropoiesis (chipmunk facies)
- Genetic mutation leads to Total
-Increased absorption of dietary iron - Gall stones
absence (β0 thalassemia) of β-
-Iron overload - Infections
globin chains
α Thalassemia Trait - Hair on end/crew cut Xray
- Deletion of two α chains Types:

Treatment
Pathogenesis: - Blood tranfusion
Silent Carrier
- Deletion of a single α chain - Splenectomy may help
Types:

Alpha Thalassemia
Beta Thalassemia
Pathogenesis Beta Thalassemia Minor
-Reduced or absent synthesis of α
(Thalassemia trait) Lab Diagnosis
globin chains
- Moderate reduction in the Hb: mild microcytic anemia
-Affects HbA, HbA2, and HbF
Types: synthesis of β chain (β+ RBCs: low MCV
- There is 4 α globin chain loci
thalassemia) Peripheral Blood Smear:
- Deletions cause disease
- Anemia is mild  but becomes - Slightly Microcytic hypochromic
evident during pregnancy - Target cells
Is an example of an hemolytic
4) Thalassemias - Tear drop cells
anemia
- N-RBCs
TIBC: normal
Serum iron: normal to slightly increased
Serum ferritin: normal to slightly increased
Differentiation from iron Serum FEP: normal
deficiency anemia Reticulocyte Count: increased
Causes:
- Iron deficiency anemia improves Bilirubin in plasma
with iron therapy, whereas Hb Electrophoresis:
-  β Thalassemia trait or minor - HbA2: increased
Microcytic Anemias worsened by iron therapy - HbF: increased
MCV: < 80 -  Estimation of serum iron, ferritin - HbA: mild decrease
and transferrin are important

RBC Disorders 1
55
 Increased cellularity

Part 1 Megaloblastic
maturation of
Macrocytic red cell erythroid series. N/C
asynchrony

Glossitis (smooth, sore (beefy)

Hypersegmented
neutrophils and
Howell-Jolly bodies

Blood smear/Clinical Images:

Neurological:
Subacute combined degeneration of the spinal cord:
Megaloblastic anemia Clinical features:
- Degeneration of ascending and descending spinal tracts Differential Vit B12 Differential Folic Acid
- Anemia (lemon tint) - Same
- Demyelination of the dorsal and lateral spinal tracts
- Mild icterus - Remember: No neurological symptoms
- Sx: bilateral peripheral neuropathy characterized by paresthesia
- Glossitis (smooth, sore (beefy)
(numbness and tingling), loss of vibratory sense, loss of fine touch,
due to loss of papillae
and loss of proprioception (Romberg test)
- May lead to spastic ataxia

Megaloblastic anemia Labs:

Hb: Reduced
Peripheral blood smear:
Red cells: macrocytic change (typically oval;
Lab Biochemical tests: ovalocytes), and Howell-Jolly bodies
1) Serum bilirubin: Mild increase White blood cells:
2) Serum cobalamin: Decreased levels Differential Vit B12 hypersegmented neutrophils are seen
Differential Folic Acid
3) Serum Homocysteine: Increased (not specific) MCV: Increased (›100) - Same
4) Methylmalonic acid: increased in serum and urine.
Bone marrow: - Remember: increased homocysteine, but normal
*Seen only in cobalamin deficiency and not in Folate defn
- Increased cellularity methylmalonic acid
5) Antibodies to IF: present in most cases
6) Schilling test: assays vit B12 absorption by measuring - Megaloblastic change seen in all erythroid
urinary radioactivity, after an oral dose of radioactive Vit B12 precursors
7) Urine: increased methylmalonic acid - Cytoplasm: regular hemoglobinization (N/C
asynchrony)
- Granulocytic series: giant metamyelocytes
- Platelets: abnormally large, multilobation of
nuclei
Pernicious Anemia:
- Is an immune mediated disease Neural tube defects
- Antibodies against intrinsic factor (IF): (anencephaly, spina bifida)
1) Type I Ab, blocks the binding of vitB12 to Lab:
IF - Alpha fetoprotein levels in
2) Type II Ab, blocks the binding of vitB12-IF maternal serum is elevated
complex to ileal receptors Labs - Best detected during 14th
3) Type III Ab, are produced against α and β
Labs to 20th week of gestation
subunits of the gastric proton pump
- Leads to:
1) Chronic atrophic gastritis (pre-cancer Pathogenesis:
state)
2) Achlorhydria (reduced gastric acid) Complications: - Decreased Intake: malnutrition,
infants/elderly & alcoholism
- Malabsorption: Celiac disease
Atrophic Glands, Lymphocyte infiltration - Decrease Intake: Vitamin B12 Deficiency Major Types due to: - Drug inhibition: methotrexate,
Folic Acid Deficiency causes:
vegetarianism 5-Fluorouracil
- Impaired absorption: Causes: - Increased requirement:
Pernicious anemia, pregnancy, lactation,
gastrectomy, Chron’s or TB Absorption process: disseminated malignancies
(ileitis, ileal resection), Fish Absorption process:
tapeworm, Bacterial overgrowth Introduction
in diverticula - Vit B12 and Folic Acid play a role in - Synthesized by micro organisms and plants
- Intake from animal protein origin - Rich source: liver, kidney, yeast, fresh green
- Increase requirement: conversion of homocysteine to
- Absorption is mediated through leafy vegetables
pregnancy, Hyperthyroidism, methionine in DNA synthesis
gastric intrinsic factor which (asparagus, broccoli, spinach, lettuce, & lima
cancer
travels with it until is taken by the
- Its defiency leads to: RBC 2: beans)
1) Impaired DNA synthesis - delays
Ileum
nuclear maturation ie. less division leads to Megaloblastic Anemia - Absorbed mostly from duodenum & upper
- Transported via transcobalamin jejunum
larger cells
protein to wherever is needed. - Body stores are approximately 5 mg of folate
2) Ineffective erythropoiesis ie. mild
- Stored in mainly in Liver - Takes aprox 4 months before Folic Acid stores
destruction within marrow, and apoptosis.
- Takes a few years before vit B12 are completely depleted
stores are completely depleted
1
Part 2

Burr cells

Direct toxic effect of red cell

precursors
- Direct effect of alcohol on
developing red cells
- Antibodies against
acetaldehyde modify red cells
Treatment: - Produces a non-megaloblastic
- Recombinant EPO macrocytosis, but here there is mild
anemia

Blood Smear
RBC: Macrocytes, Burr cells
Platelets: Slightly increased but might have Blood picture:
Impaired platelet function leading to defective - Macrocytes noted, tend to be thin,
hemostasis, characterized by: and rounded
- Prolonged bleeding time - MCV does not exceed 115 fl
- Defective platelet adhesion, secretion, and - Remember: life span of the red
aggregation. cells are not reduced
Chronic renal failure
Alcoholism
Pathogenesis:
1) Reduced erythropoietin (major cause)
2) Suppression of erythropoeisis, Intro:
3) Shortened red cell survival - Liver disease are associated with
alcohol
- Macrocytes are seen, however not
associated with anemia because no
Causes:
impairment of DNA synthesis
occurs
Non-megaloblastic vs.
megaloblastic
- Round Macrocytes rather than
ovalocytes
- Absence of hypersegmented RBC 2:
Intro:
neutrophils Non - Megaloblastic Anemia
- No pancytopenia
- No neurological features
- Alcohol MCC
Lab/Clinical finding Pernicious Other vit B12 Folic Acid
Anemia Deficiencies Deficiency
Achlorhydria present absent absent

Autoantibodies present absent absent

Chronic atrophic gastritis present absent absent

Gastric ca. risk é none none

Hypersegmented neutrophils present present present

MCV é é é

Neurologic features present present none

pancytopenia present present present

Plasma homocysteiene é é é

Urine methylmalnic acid é é normal

Part 3

No platelets, no Neutrophils

1) Extrinsic immune mediated

suppression of marrow
progenitors
- Enviromental insult (virus, 2) Intrinsic abnormality of stem
drug) cells
- Activates TH1 T cells produces - Characterized by karyotype
that produce: IL-1, TNF, IFN aberration
gamma - Which transforms to myeloid
- Which suppress hematopoietic malignancy (MDS & AML)
Causes stem cells& kill hematopoietic
1) Benzene progenitors
- Used as solvent in glue and petrochemical industry
2) Radiation
- Ionizing radiation to entire body Lab diagnosis
3) Drugs - Pancytopenia
- Antibiotics (sulfonamides, chloramphenicol) - Absolute neutrophil count:
- Pain killers (phenylbutazone) reduced
- Anti-convulsants (hydantions, carbamazepine) - Relative lymphocytosis
4) Pancytopenia Bone marrow:
- Simultaneous presence of anemia, leukopenia and - Marked reduction in cellularity
thrombocytopenia Pathogenesis (less than 25%)
- Increase fatty marrow

Introduction:
-Characterized by autoimmune
attack against hematopoietic stem
cells
-Reduction in number of stem Aplastic Anemia
Importance:
cells - Need to exclude other causes
-Inability to produce normal Myelodysplastic syndrome,
numbers of mature cells leukemias, hairy cell leukemia
Clinical features
Corrected reticulocyte count/ - Pallor, weakness, easy bruising,
Reticulocyte count index < 3% infections
- Used to estimate the degree of effective erythropoiesis
- Reference range in adults is 0.5%-1.5%
- In an Anemic State the homeostatic mechanisms of the body bring recovery by
accelerating erythropoiesis
- Reticulocyte count provides an initial assessment of whether the cause of
anemia is due to impaired RBC production or to increased loss in peripheral
RBC 2:
circulation.
- In an anemic patient a correction index must be done to blood reticulocyte
Normocytic Anemia
count because it may “look” elevated when in relation to the reduced number of
RBC.
MCV: 80-100
Corrected reticulocyte Count Labs:
1) More than 3% = good marrow response
anemia is caused by peripheral RBC destruction
2) Less than 3% = poor marrow response cause being Aplastic anemia.
 Vaso-occlusive complications
1) Vaso-Occlusive Crisis
- Abnormal adherence to vascular endothelium ie.sticky
- Promoted by inflamation mediator (Like TNF & IL-1)
Clinical Features: - Leads to stagnation of red cells in micro-circulation
Nocturnal hemoglobinuria 2) Hand-foot Syndrome
Labs - Micro-infarction of carpal and tarsal bones leading to painful
- Passage of red/brown urine in morning Susceptibility to infections
Hb: low and swollen appearance of hand/feet
- Respiratory acidosis during sleep augments complement - Differential diagnosis: osteomyelitis - Congestion and poor blood flow
Serum haptoglobin: decreased
attachment 3) Acute Chest Syndrome in spleen.
Reticulocyte Count: increased
Chronic hemolysis - Fever, cough, and chest pain following lung infection - Leading to Infarction and
Urine Analysis: hemoglobinuria,
- Hemosideruria 4) CNS
hemosiderinuria autosplenectomy
- Intravascular hemolysis - Seizures/strokes due to hypoxia
Bone Marrow: hyperplastic, - Abrupt onset of hemiparesis/aphasia/seizures - Loss of splenic functions
Iron deficiency made them prone to infections
reduced iron stores 5) Retinopathy: loss of visual acuity or sometimes blindness
- Lost in urine
Flow Cytometry: detects
Bleeding
granulocytes with missing anchors Chronic Sequestration Crisis
- Due to thrombocytopenia (from lack of GPI anchoring
for complement inhibitors Severe Anemia hyperbilirubinemia - Massive sequestration in spleen
DAF) Lab
Screening: Sucrose Hemolysis - Rapid splenic enlargement
- hepatic vein/portal/cerebral —> Budd Chiari Hb: decreased
Test - Hypovolemic shock
Risk of thrombosis Treatment: Peripheral Blood Smear
HAM test positive
- Due to release of aggregating factors from damaged - Corticosteroids - normoocytic normochromic
platelets - Eculizumab: inhibit activation of - Sickled cells Aplastic Crisis
Development of AML (rare) MAC compex Sickling test: positive when - Failure of erythropoiesis due to
treated with 2% sodium infection by parvovirus B19
metabisulfite Clinical Features: - Worsening anemia
Hb Electrophoresis
Pathogenesis Others:
Prenantal DNA Screening:
1) Mutation in Phosphatidyl-Inositol Glycan class A1 (PIGA) - Gall stones
recombinant DNA technique
genes on X chromosome prepared from amniotic fluid cells - Chronic leg ulcers
- Leads to GPI defect: membrane anchor for proteins, including - Renal (renal papillary necrosis,
DAF are not well bound Pathogenesis loss of concentration, dilution of
2) Decay Accelerating Factor (DAF)/CD55 - Distorted/rigid cells block small blood urine)
- Its Loss leads to greater binding of complement to RBCs Paroxysmal Nocturnal hemogloblinuria vessels - Eye: sludging of blood in
3) Membrane inhibitor of reactive lysis/CD59 (PNH) —> Leads to ischemia conjunctival vessels, sickle
- Intravascular hemolysis, - Repeated ‘sickle-unsickle’ leads to retinopathy
4) C8 binding protein
- intermittent hemoglobinuria (occurs during the Fragile RBCs - Fat embolism
- Results in in intravascular hemolysis due to activation of the
night) - Deoxygenation of HbS leads to Hbs
membrane attack complex C5b-C9 - Defect in RBC membrane aggregation and formation of sickle
- Complement induced by: Pathogenesis
•Fall in pH cell shape - When a G6PD def RBC when exposed to
•Infections —> Seen inn microcirculation Sickle cell anemia (HbS) oxidants, causes oxidation of sulfhydryl
-Heterozygous HbS undergoes Functions of G6PD:
•Surgery -Point mutation at 6th codon of group on Hb chain.
sickling only under severe hypoxic state - Glucose 6 phosphate
•Strenuous exercise β-globin chain - Hb denatures and form ‘Heinz body’
-Homozygous HbS express all dehydrogenase reduces NADP
- Glutamate—> valine - This damages cell membrane
features of sickle cell disease to NADPH while oxidizing
-HbS: 90 – 95% - Results in intravascular hemolysis
glucose 6 phosphate
-HbA: absent - In spleen macrophages pluck out Heinz
- NADPH then provides reducing
-HbA2: 1-3% bodies (bite cells).
equivalents needed for
-HbF: >5% Hemolysis follows oxidant stress, like:
Treatment conversion of oxidized
1) Drugs: Anti-malarials malarials
- Splenectomy glutathione —> reduced
(primaquine, chloroquine, sulfonamides,
- Immunization glutathione
nitrofurantoins)
- Antibiotics - This protects against oxidant
Hemogloblinopathies: 2) Infections: Viral hepatitis, Pneumonia,
Clinical features/complications: injury neutralizing compounds
Typhoid fever
anemia, splenomegaly, jaundice, such as H2O2
3)Fava bean
gall stones
Aplastic crises: Lab Diagnosis
- Acute parvovirus infection Hb: decreased in RBC
- Virus kills red cell progenitors Hereditary Spherocytosis Peripheral blood smear
worsening anemia, reduced - Intrinsic defects in RBC membrane - normocytic anemia
G6PD deficiency
reticulocytes - Resulting in RBC which are - Heinz bodies
- Hereditary deficiency of G6PD
Hemolytic crises spherical and less deformable ie. - Bite cells
- Mild hemolysis
- Increased splenic destruction of become rigid G6PD levels: low
Enzyme defects: - Mostly intravascular hemolysis
spherocytes - Vulnerable to splenic sequestration Plasma free Hb: increased
- Enlarged tender spleen and distortion Membrane defects: hemogobinemia
- jaundice and darkening of urine Haptoglobin: reduced
Clinical Features Hemoglobinuria
Labs - Acute Hemolysis 2-3 days
Hb: decreased following oxidant stress & lasting
Reticulocyte count: increased Causes: about 7 days
Peripheral blood smear: Pathology:
- Normocytic anemia - Mutation in spectrin, or
- Spherocytes: show absence of mutation in ankyrin Corrected Reticulocyte count > 3%
central pallor - Increased permeability to sodium
Osmotic fragility test: - Results in increase glycolytic rate
- Increased osmotic fragility (more work)
- Spherocytes rupture easily - Depletes ATP
Other tests: - Shape change causes red cells to RBC 3:
Increased serum unconjugated become spherical
bilirubin - These cells are trapped within the Normocytic Anemia
LDH: increased splenic sinusoids
- pH falls, inhibiting glycolysis MCV: 80-100
- Phagocytosis
G6PD Deficiency
 LE cells represent phagocytosis by thickening capillaries, thrombus
neutrophils of apoptotic bodies formation, and wire loop lesions

Part 1
Kidney:
- Deposition of both in situ as well as circulating
immune complexes
- Classification
Class I: minimal mesangial lupus nephritis
1) Immune complexes Class II: mesangial proliferative lupus nephritis
- Immune complexes Initiate inflammatory Class III: focal lupus nephritis Skin
response Class IV: diffuse lupus nephritis (MC) - Erythema (Butterfly/malar rash)
- Type III hypersensitivity Class V: membranous lupus nephritis accentuated by sunlight
- There is Low levels of complement due to Class VI: advanced sclerosing lupus nephritis - Vacuolar degeneration of basal
consumption cells in epidermis
2) Autoantibodies - Perivascular inflammation
- Specific for red cells/white cells/platelets Blood vessels: - Vasculitis with fibrinoid necrosis
- Opsonized cells expose their nuclei to ANA - acute necrotizing
- Damaged,denatured nuclei shows like —> LE vasculitis
- presence of CVS:
bodies/Hematoxylin bodies
fibrinoid necrosis Libman-Sacks endocarditis
3) Anti-phospholipid antibody syndrome
- Non-bacterial verrucous
- Risk of thrombus formation
endocarditis (fibrinous)
- Pericardial friction rub on
auscultation
Morphology
Environmental Factors
Exposure to UV rays
Pathology damage
- Apoptotic cells induce immune
response by activating
- keratinocytes to produce IL-1
- Leads to inflammation Clinical Features
Estrogen - Young Women
- May stimulate B cells to produce - Butterfly Rash
Immunological Factors - Recurrent early fetal loss
anti-DNA antibodies
-Defective elimination of self- Systemic Lupus Erythematosus - Photo sensitivity
reactive B cells in BM or defect in (SLE) - Fever, headache, seizures
peripheral tolerance Causes Pathogenesis : - Multisystem disease - Serious renal involvement
- Production of auto antibodies due - Presence of ‘autoantibodies’ —>
to defective CD4+ T cells specific anti nuclear antibodies: ANA
Genetic Factors
for nucleosomal antigens - Type III - deposition of immune Diagnosis
- HLA-DQ associated with anti-
dsDNA, anti-SM, and complexes - Anti-nuclear Antibodies
antiphospholipid antibodies - Targets: skin, joints, kidney, and - Anti-dsDNA & Anti-SM IgG
- Deficiency of early complement serosal membranes (most useful)
factors: C2, C4, C1q - LE Cells
- Immunofluoresence in skin/renal
biopsies
- Proteinuria

Autoimmunity
-Loss of self tolerance due to:
Immune Factors 1) Inheritance of susceptibility
definition:
- CD4+ Helper T Cells initiate autoimmune response
- React with arthritogenic agent
genes or 2) Environmental triggers
-There is presence of Self reactive
Immunopatholgy
- Cytokines produced by T cells stimulate inflammation lymphocytes
Example:
Lab Investigations
1. IFN-γ – activate macrophages & synovial cells
- Rheumatoid Factor (RF)
2. IL-17 – recruit neutrophils & macrophages
(MC IGM)
3. TNF & IL-1 – stimulate secretion of proteases that destroy
- Increased serum C3
hyaline cartilage
- Antibodies to CCPs
4. RANKL – Expressed on activated T cells and stimulate
bone absorption
- Secondary follicles in synovium produce autoantibodies
Against citrullinated paptides (CCPs) (Presence is
Diagnostic) Rheumatoid Arthritis (RA)
- 80% of RA patients have serum IgM, or IgA autoantibodies - Chronic inflammatory disease
characterized by symmetric, peripheral Clinical Features Swan-neck deformity = Hyperextension of
(rheumatoid factor)
polyarthritis - Small joints of hands and feet the PIP joint with flexion of the DIP joint
-Inflammatory synovitis resulting in - Early morning stiffness
Genetic - Damage metacarpophalangeal (MCP), and proximal
destruction of cartilage and ankylosis
- 50% of the risk for RA, is genetic Causes Pathogenesis: interphalangeal (PIP)
of joints
- HLA-DRB1 alleles are linked to RA - Flexor tendon tenosynovitis:
—> hallmark of RA
Morphology —> decreased range of motion,
Environmental: —> reduced grip strength
smoking may promote citrullination Blood Vessels —> “trigger” fingers
of self-antigens - Ulnar deviation Boutonnière deformity - flexion of
Joints Rheumatoid Vasculitis
- Baker cyst the PIP joint with hyperextension of
- Synovial cell hyperplasia and the DIP joint
—> Distension of local bursa posteriorly and
proliferation
Skin inferiorly to the knee
Pathologic hallmarks - Inflammatory infiltrates (with
Rheumatoid Nodules - Anemia of Chronic Disease
lymphoid follicles)
- Firm, non-tender, round to oval - Carpal Tunnel Syndrome
- Vascularity due to angiogenesis
- Fibrinopurulent exudate on the skin lesions at sites of pressure
synovial and joint surfaces - Central fibrinoid necrosis
surrounded by epithelioid cells
-Synovial inflammation and
and numerous lymphocytes and
proliferation, focal bone erosions, and
plasma cells
thinning of articular cartilage
- Chronic inflammation leads to synovial
lining hyperplasia and the formation of
Pannus
Pannus – thickened cellular membrane of
granulation-reactive fibrovascular tissue
that grows over the articular cartilage
- Causes erosion
- Bridges opposing bone to form fibrous
ankylosis

synovial thickening, & chronic

inflammation Left: marked synovial hypertrophy with
formation of villi.
Right: subsynovial tissue containing a
dense lymphoid aggregate is seen
 stretched parchment-like skin, claw
Raynaud's phenomenon hand
- Episodic vasoconstriction in the
fingers and toes
- Triggered by exposure to cold,
Part 2 emotional stress, and vibration
- Starts with pallor, followed by
cyanosis, eventually erythema
develops
- Sasoconstriction, ischemia, and
reperfusion

Skin
- Diffuse, sclerotic atrophy beginning with fingers then to
neck and face
- Histology shows:
- edema, CD4+ T cell infiltrates, swelling and
degeneration of collagen (eosinophilic staining).
- Capillaries show thickened basal lamina and partial
occlusion
- Increasing fibrosis of dermis
- Increase compact collagen, and thinning of epidermis,
loss of rete pegs
Clinical Features - CREST syndrome
-Unknown antigen in skin activate
- Dryness of mouth (xerostomia) •Calcinosis cutis
Labs: CD4+ T cells in genetic predispose
and eyes (keratoconjuctivitis •Raynaud’s phenomenon
-Histological diagnosis: lip biopsy/ pt
sicca) •Esophageal dysfunction
salivary gland biopsy -Bring inflammatory cells
- Dental caries •Sclerodactly
- Presence of antibodies in serum: (macrophages) and fibroblasts
- Parotid Enlargement •Telangiectasia
SS-A(Ro), SS-B(La), positive RF - Release cytokines TGF-β, IL-13
Causes:
Intimal proliferation, endothelial Gastro-Intestinal Tract
Salivary glands: activation, and injury leading to - Progressive atrophy
- Periductal and perivascular lymphocytic fibrosis. - Collagenous fibrous replacement of muscularis
infiltration i.e inflammation - Rubber hose-like inflexibility to lower 2/3 of esophagus
Sjögren Syndrome’
- Lymphoid follicles with germinal centers - May lead to Barrett’s esophagus
- Chronic, slowly progressive
may appear Morphology:
autoimmune disease characterized
- Causing ductal lining hyperplasia, this Morphology: by lymphocytic infiltration of Musculoskeletal System
leads to obstruction (i.e. decrease exocrine glands resulting in Etiology: - Inflammation of synovium with
secretion) xerostomia & dry eyes hypertrophy and hyperplasia
- Later there is acinar atrophy, fibrosis, - Marginal zone lymphoma is a well Kidney - NO joint destruction
and hyalinization (pressure atrophy) known risk - Vascular lesions
Systemic Sclerosis - Hypertension due to
(scleroderma) intimal thickening
Pathogenesis: 1) Chronic inflammation
(autoimmune),
2) Widespread damage to small
- Inflammation predominated by Heart
CD4+ Helper T Cells along with B Immunopathology blood vessels, and
3) Progressive interstitial and
- Pericarditis with effusion Lungs
cells and plasma cells - Myocardial fibrosis - Interstitial fibrosis
perivascular fibrosis in skin and
- Leads to fibrosis of lacrimal and - Thickening of intramyocardial - Pulmonary hypertension
multiple organs
salivary gland arterioles (electrical
- Causing decrease in tears and abnormalities)
saliva (sicca syndrome)
- Others Anti-nuclear antibodies:
- Rheumatoid Factor
- SS-A (Ro)
- SS-B (La) Clinical Features:
- HLA association: HLA-B8 and Diagnosis - Female (50-60yro)
HLA-DR3 - Presence of ANA in all patients - Cutaneous changes ie. thick skin
- Anti-DNA topoisomerase I (anti- - Raynaud’s phenomenon
Scl 70) - Dysphagia, abdominal pain,
Dermatomyositis
- Anti-Centromere antibody malabsorption, anemia
Pathogenesis: - Genetically determined
- HTN
autoimmune disorder that target
- Respiratory problems
skeletal musculature and/or skin
- Myocardial fibrosis, arrhythmia

- Autoimmune damage to small blood Morphology: Clinical Features

vessels leading to telangiectasia seen in
- Slow onset of muscle weakness
nail folds, eyelids, and gums
- Myalgia
- Vascular damage contribute to muscle Muscle biopsy: - Difficulty getting up from chair, climbing stairs
injury - Mono-nuclear inflammatory cells, - Elevated serum creatine kinase levels
- Deposition of complement C5b-9 is seen around perimysial connective tissue - Lilac colored upper eyelids (Heliotrope rash)
in biopsy of muscle/skin and around blood vessels - Gottron papules – scaling erythematous eruption or
Associated antibodies: - Perifasicular atrophy of muscle dusky red patches over knuckles/elbows/knees
1) Anti-Mi2 – Gottron papules Immunohistochemistry: - Dysphagia
2) Anti-Jo1 – interstitial lung disease, non- -Inflammatory cells stain positive for - Interstitial lung disease
erosive arthritis, skin rash CD4+ T-helper cells
3)Anti-P155/P140 – paraneoplastic and -Deposition of C5b-9 in capillary
juvenile cases of dermatomyositis vessels

heliotrope rash

Gottron sign, are a hallmark

cutaneous feature of DM
Pathology 1 Concept Maps
Block 3

Jandrely Lopez
Material from Dr. Roy’s Lectures
 Warm Antibody Type
- IgG Ab active at 37°C
- Leads to extravascular hemolysis (spleen) Cold agglutinin type
Causes: - IgM Ab active below 37°C
1) Primary (idiopathic) Types:
2) Secondary Acute
- Autoimmune disorders (SLE) - Mycoplasmal infection
- Drugs (Penicillin, α-methyl dopa) - Infectious Mononucleosis
- Lymphoid neoplasms (CLL) - EBV, CMV, Influenza, HIV
Pathogenesis: Chronic
1) RBCs are coated with IgG autoantibodies with or - Idiopathic
without complement proteins - Lymphoid neoplasm (Lymphoplasmacytic lymphoma)
2) These IgG coated RBC are attached to spleen Pathogenesis:
Lab Findings: macrophages or Liver Kupffer cells via Fc receptors. 1) IgM binds to RBC and fixes complement at low temperatures
Hb: reduced 3) Macrophage then partially phagocytize the RBC by 2) When IgM/C3b-coated RBC circulates to warmer tissues the Agglutination of red cells. This is
Peripheral smear: Spherocytes (extravascular) Reticulocytes: increased removing RBC membrane IgM dissociates, from a case of “cold reactive”
Peripheral blood smear: 4) These cells then become spherocytic RBCs 3) Leaving complement C3b (opsonin) on the original RBC
- Polychromatophils 5) Leading to Extravascular hemolysis 4) This leads to removal of affected RBC by phagocytes in spleen,
- Nucleated red cells liver, and bone marrow
- Extravascular = spherocytes - Raynaud’s phenomenon may be seen
- Intravascular = schistocytes
Serum bilirubin: raised
Hemoglobinuria: intravascular
Haptoglobin: reduced
Direct Coomb’s Test Coombs test: positive Cold Hemolysisn type
- Detects presence of antibody or - IgG Ab active below 37°C
complement coated red cells - Rare, occurs in children following
- Anti IgG or complement is added viral infections
to patients red cells General: Classification:
- Agglutination occurs if red cells
are coated with IgG or
complement

-Characterized by presence of
autoantibodies directed against
autologous RBC and shortened
Indirect Coomb’s Test RBC survival Introduction: Immune Hemolytic Anemia
- Detects presence of antibodies in - Coomb’s Test –> direct
patient’s serum Hemolytic disease of newborn:
antiglobulin test (DAT) which is
- Anti IgG and test RBCs are mixed ABO incompatibility
essential for diagnosis
with patient’s serum - Occurs almost exclusively in infants with blood
- Agglutination occurs if serum group A or B who are born to group O mothers
antibodies are present Others: who have presence of anti-A & anti-B IgG type
Microangiopathic hemolytic anemia antibodies (only 1% of O individuals produce it)
- Mechanical hemolytic anemias - Hemolysis occurs by non-complement mediated
- RBC are traumatized with contact with endothelium, phagocytosis of IgG coated red cells
fibrin, etc Rh-incompatibility - Normally anti-A and anti-B antibodies are of the
- “Intravascular” hemolysis - D antigen is the cause of Rh incompatibility IgM type,
Causes: Pathogenesis: which is incapable of crossing the placenta so
Platelet thrombi 1) Rh (D antigen) negative mother gets disease is not present.
- Hemolytic uremic syndrome (HUS) immunized by Rh antigen when becomes
- Thrombotic thrombocytopenic purpura (TTP) pregnant with Rh positive fetus.
Fibrin thrombi 2) IgG antibodies created by previously
- Disseminated intravascular coagulation (DIC) immunized mother pass through placenta and
- HELLP synd. (Hemolytic, Elevated transaminases, destroy fetal RBCs
Low platelets, associated with preeclampsia) Clinical Features
Aortic stenosis - Hemolytic anemia
Lab Diagnosis - Unconjugated hyperbilirubinemia
-Normocytic anemia - Risk of developing kernicterus
-Decreased Haptoglobin —> caused by reduced albumin synthesis
-Hemoglobinuria due to impaired liver function leading to
-Hemosiderinuria increase of serum unconjugated bilirubin
-Schistocytes
 ABO HEMOLYTIC DISEASE OF
CHARACTERISTICS Rh HEMOLYTIC DISEASE OF NEWBORN
NEWBORN
Incidence Uncommon Common
Mother must be group O and the baby
Blood group association Mother can be any blood group
must be group A or B

ABO HDN is protective against Rh

Mother must be Rh negative and the
Rh association sensitization with the exception of an
baby must be Rh positive
O Rh-positive baby

Mild to no anemia at birth; severe

Anemia at birth Frequent and often severe
anemia uncommon

Jaundice first 24 hours Frequent; moderate to severe Mild

Common; sign of accelerated

Hepatosplenomegaly Uncommon
erythropoiesis causing EMH

If the mother is Rh negative and has an

Baby can be affected if the mother is
Rh-positive baby, the baby is not
First pregnancy blood group O and the baby is blood
affected, but the mother is at great
group A or B
risk for developing anti-D antibodies.

If the mother has anti-D and the baby

Each pregnancy is at risk for ABO HDN
Later pregnancies is Rh positive, the baby is at risk for Rh
if the mother is blood group O
HDN

Direct Coombs test on cord blood Strongly positive Weakly positive

Indirect Coombs test on cord blood Positive Usually positive

Present (part of the RBC membrane is

Spherocytes in the peripheral blood Not present (RBCs fully phagocytosed)
removed by macrophages)
 1) Inadequate or ineffective
granulopoeisis
2) Accelerated removal or destruction of
Part 1 - Suppression of hematopoietic stem cells
• Aplastic anemia
• Marrow infiltration
neutrophils
- Immunologically mediated
- Suppression of committed granulocytic • SLE
precursors - Splenomegaly
• Drugs • Splenic sequestration
- Diseases associated with ineffective - Increased peripheral utilization
hematopoiesis • Bacterial
• Megaloblastic anemia • Fungal
• Myelodysplastic syndrome • Rickettsial
- Rare Congenital
• Kostmann’s Syndrome

Causes: Values:
Normal Neutrophil Count: 1,500 – 8,000 cells/mm3
Neutropenia: < 1,500 cells/mm3
Mild Neutropenia: 1,000 – 1,500 cells/mm3
Moderate Neutropenia: 500 – 1,000 cells/mm3 Neutropenia: absence of neutrophils
Severe Neutropenia: < 500 cells/mm3
Agranulocytosis: < 100 cells/mm3

Lab Diagnosis:
- Total white cell count: reduced
- Peripheral blood smear: neutropenia
- Absolute neutrophil count: reduced
Bone Marrow:
- Hypocellular: MC. Drug induced. Hypocellularity, increase in fat cells
- Hypercellular: occasionally, when
there is increased peripheral
destruction of neutrophils (ex. SLE,
megaloblastic anemias)
Leukopenia
-Decrease in number of circulating
WBCs
-Normal WBC count: 4,000 to
11,000 cell/mm3
Introduction: WBC & LN #1 Neutropenia & Agranulocytosis
-Mostly from reduced neutrophils candida albicans, oral mucosa
(neutropenia).

Clinical features:
Prone to serious infections, Like:
- Ulcerating necrotizing lesions of
gingiva, floor of mouth, buccal
mucosa
- Life threatening infections in
lungs, kidneys Fungal infections
Treatment: 1) Candida
- Granulocytic transfusions 2) Aspergillus
- Recombinant granulocyte
growth factors: G-CSF, GM-
CSF
2
 Part 2

Morphology: Clinical Features:

- Enlarged lymph nodes - Lymph node enlargement
- Prominent lymphoid follicles - Tender on palpation
Leukoerythroblastic Reaction containing large germinal - Inflammation of overlying skin
- Immature granulocytes and erythroid precursors centers Location:
Leukemoid Reaction - Macrophages containing - Occipital LN = scalp infection
enter peripheral blood
- Elevated WBC count (50,000 cells/mm3) due to inflammatory particulate debris - Preauricular LN = conjunctival
Pathogenesis:
state or chronic infection - Centers of follicles may show infections & cat scratch disease 1) Follicular Hyperplasia
- Due to bone marrow infiltration
- Immature granulocytes appear in peripheral blood —> “Shift to the necrosis - Posterior Cervical LN = Caused by Activation of humoral immune responses
- Example: Amyloidosis, Gaucher’s, Leukemia,
left” toxoplasmosis Morphology:
Metastatic Cancers, Marrow fibrosis
Lab Findings: - Inguinal LN = STDs - Formation of “secondary follicle”
Peripheral blood smear:
Lap Score (leukocyte alkaline phosphatase) = Increase —> Large round to oblong B cell rich germinal center
- immature granulocytes, and nucleated red cells
- Differential: Low in CML surrounded by mantle zone (resting B cells)
Peripheral smear = Band cells & metamyelocyte - Lymph node architecture is maintained
Acute Non-Specific Lymphadenitis - Presence of Tingible Body Macrophages =
- Reactive changes occurring in lymph nodes when macrophages containing nuclear debris inside
presented with microbiologic agents, cell debris, phagocytosed apoptotic bodies
foreign bodies Clinical:
Special Types: - Mostly involve anterior cervical lymph (dental, tonsils) - Associated with : rheumatoid arthritis, toxoplasmosis,
nodes and inguinal early stages of HIV
-  Acute mesenteric lymphadenitis —> mimic
appendicitis
2) Paracortical Hyperplasia
- Caused by activation of cellular immune
Leukocytosis Chronic Non-Specific Types: responses involving T-cell region
- Increase in total white count. Lymphadenitis Morphology:
Neutrophilic Leukocytosis: Neutrophilia, is the most common - Expansion of paracortical/interfollicular regions of
- Morphologic variants.
- Caused by acute bacterial infection/ -Pathogenesis: lymph nodes
Lymphadenitis
sepsis 1) Size of precursor pool (BM, thymus, - Presence of immunoblasts
- Enlarged LN due to various
Morphological patterns of Neutrophils: circulation, peripheral tissues) (activated T Lymphocytes)
reasons
—> Toxic Granulations 2) Rate of release of cells from - Hypertrophy of sinusoidal and vascular
- Numerous dark purple granules storages pools 3) Sinus Histiocytosis endothelial cells
—> Döhle Bodies 3) Proportion of cells that are adherent Morphology: Clinical:
1) Increased production in the marrow
- Light blue smudge within mature to blood vessel wall (marginal pool) - Distension and prominence of Associated with:
-  chronic infection/inflammation (IL-1, TNF)
neutrophils, seen along with toxic Causes: 4) Rate of extravasation of cells from lymphoid sinusoids 1) Use of Dilantin
-  Hodgkin lymphoma
granulations blood into tissues - Hypertrophy of endothelial cells 2) Acute viral infections
-  CML
lining sinuses 3) Vaccinations
2) Increased rate of release from BM
- Increased number of
-  endotoxemia (sepsis)
macrophages
-  infection
Clinical:
Infectious Mononucleosis Examples: -  hypoxia
- Associated with lymph nodes
-EBV infection transmitted via contact with body secretion 3) Decreased margination
draining cancers
-Involves tonsils (B Lymphocytes expressing CD21) - exercise
Pathogenesis: - catecholamines
-Two ways: 1)Infection leading to lysis or 2) EBV establishes 4) Decreased extravasation
latent infection, during which viral genes are expressed: Lymphocytosis: - Glucocorticoids
—> EBNA1: binds EBV to chromosomes causing latency - Accompanies monocytosis in
—> EBNA2 & LMP1: drives b cell proliferation and activation disorders associated with
—> T-cell response to infected B cells appear as atypical immunologic stimulation, viral
cells, Downey Cells infections & bordetella pertusis
Sx: Fever, Pharyngitis, Lymphadenopathy, Splenomegaly infection
(risk of splenic rupture), Glandular Fever, Young age
Lab Investigation
- WBC increased
- Downey Cells
- Paracortical Lymphoid hyperplasia
- Positive antiviral capsid antigen test
- Monospot test is positive Proliferative Disorders
—> If negative in patient who has same features, it is likely
to be CMV
(Reactive/Inflammatory)

Types:
Submental: metastases from squamous cell
ca. floor of the mouth
Cervical: head & neck tumors
Virchow’s node (left supraclavicular):
stomach, pancreas cancers
WBC & LN #1 Lymph Node Metastasis Axillary: breast cancers
Hilar: lung cancers
Mediastinal: lung cancers, Hodgkin
lymphoma (nodular sclerosing), T- cell ALL
Para-aortic: testicular, Burkitt Lymphoma
Inguinal: vulva, penis can
Downey cell
 Bone marrow aspiration: Leukemic
blasts

Immunophenotyping: B cell type ALL AML Lymphoblasts in CSF

vs T cell Type - Lymphoblasts: may contain 1 to 2 - Myeloblasts: may contain 2 to 5
Blast Indicator: Terminal nucleoli, show dense chromatin nucleoli
Deoxynucleotidyl transferase (TdT) Stains: Stain:
•Expressed by pre B and pre T Myeloperoxidase: Negative Myeloperoxidase: Positive
cells ie present in both types Sudan Black: Negative Sudan Black: Positive
Pre B Cell Indicator: CD10, CD19, PAS: Positive PAS: Negative
PAX5, t(12;21)
Peripheral blood smear: leukemic Pre T Cell Indicator: CD2, CD3,
blast. Note presence of Nucleoli. CD4, CD7, NOTCH1
Differential: Lymphoblast (ALL)
vs. Myeloblast (AML)
Biochemical:
Serum LDH: increased
Triad: Anemia, Neutropenia, Serum Uric Acid: increased
Thrombocytopenia X-ray:
WBC: elevated Thymic enlargement on chest
Platelet: decreased Mediastinal lymph node Testicular biopsy: shows leukemic infiltration
Hb: decreased Lab Diagnosis: enlargement
Hodgkin lymphoma: note- Reed- Peripheral smear: circulating leukemic
Sternberg cell CSF:
blast cells CNS and Testes are sanctuary
Bone marrow necessary for diagnosis sites
- Leukemic blast cells (more than 20%)

Acute Lymphoblastic Leukemia (ALL) Clinical Features: anemia,

- MC childhood malignancy neutropenia and thrombocytopenia,
—> Peak age 2-6 years old abrupt stormy onset, bone marrow
Leukemia -Group of neoplasms composed of immature depression, bone pain and
- Neoplastic disease that results precursor B (pre B) or T (pre T) lymphocytes tenderness, generalized
from incomplete maturation of - 85% are B cell type lymphadenopathy, CNS T-ALL: anterior mediastinal lymphadenopathy
hematopoietic precursors and its - T cell Type affect older kids, involves the thymus manifestations
uncontrolled proliferation. and has poor prognosis.
-Crowds the marrow to displace the Risk Factors:
Treatment:
remaining normal cells - Down syndrome
- Induction, consolidation,
-Presence of “blasts” in peripheral - T-cell type ALL: NOTCH1 mutation in 70% of cases
Lymphoma maintenance, and central nervous
blood. (> 20% in the BM) - B-cell type ALL: PAX5 mutation, or t(12;21) involving
-Proliferations arising as discrete system (CNS) prophylaxis
- Lead to increase TWC ETV6/RUNX1, which promote maturation arrest.
tissue masses (in LN)
- B-cell ALL with t(9; 22): this creates a fusion gene.
-Two main categories:
Seen in mostly in adults, carrying poor prognosis.
1) Hodgkin Lymphoma
Non Hodgkin Lymphoma: diffuse 2) Non-Hodgkin Lymphoma
large cell type. (NHL)
Pathophysiology:

Plasma Cell Neoplasms

Intro Proliferative Disorders WBC & LN #2: Types:
1) Acquired genetic alteration inhibit
terminal myeloid differentiation
(Neoplastic): 2) marrow is replaced by undifferentiated
-Composed of tumors containing
terminally differentiated B-cells
-Arise mostly from bone marrow
1) Neoplastic Proliferation of White cells Acute leukemias ‘blasts’ with features of early myeloid
differentiation
with rare involvement of lymph - MC chromosomal translocations:
nodes t(15;17) with M3
inv 16 with M4
t(8;21) with M2
Etiological and Pathogenetic Factors in Acute Myelogenous Leukemia (AML)
AML following MDS
White Cell Neoplasms - Tumor of hematopoietic progenitors caused by
1) Chromosomal translocation and other acquired oncogenic mutations that impeded
acquired neoplasms differentiation leading to accumulation of immature M3: Acute Promyelocytic Leukemia (APL)
2) Inherited Genetic Factors: Down myeloid blasts in bone marrow - Young adult, males
syndrome, Bloom Syndrome, Fanconi Anemia -Mostly Adults Pathogenesis:
& Ataxia telangiectasia Risk Factors: 1) t(15;17)
3) Viruses: HTLV-1, EBV, KSHV/HHV-8) Radiation exposure, chronic benzene exposure, 2) Fusion gene leading to chimeric protein composed of retinoic acid
4) Chronic Immune Stimulation: chemotherapeutic drugs (Direct acting alkylating receptor-α (RARα) and PML
H pylori —> MALToma agents:cyclophosphamide), smoking, Down synd, 3) Fusion protein interferes with the terminal differentiation of
Gluten sensitivity enteropathy —> intestinal T- Bloom synd, Fanconi anemia. AML following MDS granulocytes
Cell lymphoma - Responds to all-trans retinoic acid (ATRA) or Arsenic Trioxide
Immune deficiency —> B-cell Lymphoma treatment.
5) Latrogenic Agents: Radiation, Class: Other Features:
Chemotherapy, Cigarette smoking - Bleeding tendencies, risk of DIC (coagulation factors depleted)
- Features of BM failure
Clinical Features: - Auer rods present in histology
- Fever, Splenomegaly, Hepatomegaly Lab Investigations:
- Lymphadenopathy, Sternal tenderness, Total WBC ct:
Evidence of infection, Hemorrhage - Increased
- Easy bruising - Normal or decreased only in MDS M5: Acute Monocytic Leukemia
- Petechiae pts —> stem cell is being damage Features:
- Prolonged bleeding so Cell production will be affected. - Gum hypertrophy due to
Specific: - Anemia, Thrombocytopenia cutaneous and gingival infiltration
M3: GI, intrapulmonary, intracranial Peripheral blood smear: Atypical - Positive for non-specific
hemorrhages myeloid cells, Circulating blasts esterase (NSE)
M5: gingival infiltration, meningeal involvement Bone marrow: >20% blasts - Poor prognosis
M7: increased association with Down MPO positive stain - CNS involvement
Syndrome Sudan Black Positive Stain - Bleeding tendency
 Hairy cells peripheral smear BM: increase amount of fibers TRAP stain

Smudge cells due to the cell fragility.

Lab Investigations:
Hb: decreased (anemia)
Total WBC: decreased
Platelet count: decreased “pancytopenia”
Peripheral blood smear: neutropenia, presence
of hairy cells
Bone Marrow: “dry tap”
- bone marrow is enmeshed in extra cellular
matrix (Collagen + Reticulin)
- Leukemic cells have hair-like structure on Clinical Features
surface of cytoplasm - Massive splenomegaly
Immunophenotype: CD19, CD20, Surface IgG, - Pancytopenia & splenic sequestr
CD11c, CD25, and CD103 - Prone for infection
Lab Investigations: Special Stain: TRAP (tartrate-resistant acid (Mycobacterium avium
Hb: decreased late in disease phosphatase) intracellulare)
WBC ct: markedly elevated
(100,000 cells/mm3)
Peripheral Blood Smear: Treatment:
Lab Investigations:
Lymphocytosis & Smudge Cells Hairy Cell Leukemia Cladribine (2-CDA) inhibits
CBC: leukocytosis
Immunoglobulin: Low level of -Rare chronic lymphoproliferative adenosine deaminase (ADA) and
Peripheral blood smear: lymphocytosis,
surface Ig disorder of B lymphocytes increases level of toxic
abnormal lymphoid cells described as
Markers: CD19, CD20, CD5, CD23 -Prominent cytoplasmic hair-like deoxyadenosine
“flower cells” seen
Positive projections Biochemical: Hypercalcemia
Pathogenesis: Skin Biopsy: T-cell markers positive
- Point mutation in BRAF (CD4)
- Overexpression of cyclin D1 (cell Serum: HTLV-1
Chronic Lymphocytic Leukemia cycle regulator) Adult T cell Leukemia / Lymphoma Radiology: ‘lytic’ bone lesion
Clinical Features (CLL) - Lympho-proliferative disorder seen in adults,
- Asymptomatic = accidental -Most common type of leukemia in associated with HTLV 1 infection
diagnosis Western world Pathogenesis:
- Tiredness -Risk increases with age (>60 yro) - HTLV-1 has tropism for CD4+ T cells
- Weight loss
- Generalized lymphadenopathy
-More common in males
Pathogenesis:
WBC & LN #3: - Viral genome contains tax gene
- This works as a transcriptor for the viral gene, alters
Clinical Features:
- Rapidly progressive disease
- Clonal B cells are arrested in an - Lymphadenopathy
- Hepatosplenomegaly
- Hypogammaglobulinemia =
predispose to infections
intermediate stage between pre-B cells
and mature B cells in the B-cell
Chronic Leukemias host genes and interact with the host cell signaling.
- Leading to increase pro-growth signaling, cell
- Hepatosplenomegaly
- Skin lesions
survival & genomic instability - Hypercalcemia
- AIHA or Thrombocytopenia differentiation pathway. - Also, leukemic cells express FoxP3 (marker for
- Leads to accumulation of functionally - Lytic bone lesions
Tregs), which suppress the immune system leading to - High mortality
incompetent lymphoid cells (clonal B susceptibility for opportunistic infections
cells)

Richter syndrome Mycosis Fungoides / Sézary

- Transformation leads into syndrom
aggressive rapidly enlarging lymphoma - Different manifestations of tumor
- Which is a “diffuse large B cell arising from CD4+ T helper cells Lab Investigations:
lymphoma” - Common type of cutaneous T- Immunophenotype:
- Transformation is associated with cell lymphoma Mature T cell markers: CD2, CD3,
poor prognosis (survival less than a CD4, on skin biopsies
year following transformation)

Histology:
Clinical features: - Infiltration of epidermis and dermis
- Progresses patch —> plaque by neoplastic T cells
—> tumor phase - “Band like patchy infiltrate” in
- Simultaneously have more than upper dermis
Sézary Syndrome
one type of lesion - Pautrier abscesses= Collections
- Referred to as generalized
of neoplastic lymphocytes in
exfoliative erythroderma
epidermis
- Tumor dissemination to
other organs and spill over
into peripheral blood
- Leukemic phase of
Mycosis Fungoides
- Progressing rapidly to more
advanced stages
 numerous granulocytes; mature neutrophils seen,
and numerous platelets Basophils & large platelets

Bone marrow aspirate smear showing an increase in

myeloid elements including basophils and eosinophil

Lab Diagnosis
Total WBC: > 100,000 cells/mm3
Platelet count: increased initially then
thrombocytopenia
Peripheral blood smear:
- Moderate anemia Lab Diagnosis:
- Myeloid series in all stages of development ie RBC ct: increased
myelocytes, metamyelocytes, and band forms Hb: increased
Bone Marrow: Hematocrit: increased
- Marked hypercellularity Leukocytosis, thrombocytosis
- Myeloblasts < 5% (increase over 10% signifies Clinical Features Peripheral Blood Smear:
onset of accelerated phase) - Massive Splenomegaly - Increased basophils
- Increased basophils and eosinophils - Blast crisis or accelerated phase Clinical Features:
- Large platelets
- Collagen proliferation - Rapidly increasing percentage of - Headache, Dizziness, Tinnitus
Bone Marrow:
Biochemistry: blasts (myeloblasts) - Visual disturbances
Pelger huet cells - Hypercellular
Hyperuricemia (leading to Gout) - resembles acute leukemia - Ruddy color of skin
- Marrow fibrosis
LAP score is low - anemia,thrombocytopenia, - Deep vein thrombosis
- Hyperuricemia
basophilia - Transient ischemic attack, .
-  enlarging spleen -  Pruritus (release of histamine from
-  less favorable prognosis mast cells/basophils), ‘aquagenic
pruritus’
2. Polycythemia vera
Treatment: -  Peptic ulceration (histamine release)
- Adult males
Imatinib mesylate - hyperuricemia (gout)
Pawn ball megakaryocytes 1. Chronic Myeloid Leukemia (CML) - Neoplasm arising in a multipotent myeloid stem cell
- Blocks the effects of BCR-ABL - Complications: myelofibrosis, acute
- Adults between 25 to 60 yrs Pathogenesis:
fusion product leukemia
Pathophysiology: - Increased marrow production of erythroid,
- Also used for Gastrointestinal granulocytic and megakaryocytic elements
- Translocation involving ABL gene on stromal tumor (GISTs) - There are Decreased EPO levels
chromosome 9 and BCR gene on
Chromosome 22 - Erythroid proliferation NOT regulated by
- Philadelphia chromosome t(9;22) erythropoietin
Lab Investigations: associated with increased cell division - JAK2 mutation in chromosome 9 leads to
- Pancytopenia (abnormal stem cell being and inhibition of apoptosis excessive proliferation independent of Growth
—> apoptosis) - Activation of downstream pathways Factor
- Neutropenia like: RAS, JAK/STAT, AKT (enhances - Also, BM is really sensitive to EPO so even the little
- Thrombocytopenia cell survival) quantity present drives red cell expansion.
Peripheral Blood Smear:
- Hypogranular granulocytes
- Pelger-Huet Cells (bilobed neutrophils)
Bone Marrow:
- Dysplastic maturation affecting all non- Myeloproliferative Disorders
lymphoid lineage -Neoplastic cell proliferation Lab Diagnosis:
- Erythroid series: Ringed sideroblasts & associated with cell maturation WBC: mild elevation
Megaloblastoid cells involving all cell lines Hb: reduced
- Classified based on predominant 3. Primary myelofibrosis
- Myeloid series: Pseudo-Pelger-Huet Peripheral blood smear:
cell type -Disease of adults 50+ years old
cells. Myeloblasts < 20% in bone marrow - N-RBC
-Associated with JAK-2 mutation -Rapid development of obliterative
- Megakaryocyte: Pawn ball - Tear drop RBCs (dacrocytes)
-Increased cell turnover marrow fibrosis
megakaryocytes - Early granulocytes
Ring sideroblasts -Marrow Fibrosis - Extra medullary hematopoiesis
- Leukoerythroblstosis
-Transformations to AML (shifts to spleen)
Bone Marrow:
Myelodysplastic Syndrome Pathogenesis:
- Initially hypercellular, but
-Group of clonal stem cell disorders - JAK-2 mutation
becomes hypocellular with
characterized by maturation defects associated - Neoplastic megakaryocytes
progression fibrosis of marrow with atypical
with ineffective hematopoiesis release fibrogenic factors: PDGF
Clinical course: - Difuse Fibrotic megakaryocytes.
-Incidence: Older age, Benzene, alkylating and TGF-β
-  Older age group (> 60 - Atypical megakaryocytes Fibrosis→ spindle nuclei
agents, Radiation - Leads to extensive deposition of
years) Biochemistry: Hyperuricemia
-  Weakness,infections,
Types:
1) Idiopathic Primary MDS
WBC & LN #4: collagen

hemorrhages
- Progression to AML
2) Therapy related MDS (t-MDS)
Being treated by a malignancy
MDS and Myeloproliferative Disorders 4. Essential Thrombocytosis
- Clonal hematopoietic stem cell Clinical Features:
- T- MDS has very poor prognosis disorder characterized by an - Anemia
- usually takes 2 to 8 years following genotoxic
exposure isolated thrombocytosis and - Splenomegaly
Pathogenesis: associated with thrombotic and - Fatigue
-  Mutations in genes involved in control of gene hemorrhagic complications - Night sweats
splicing, and epigenetic regulators -Females 50 – 70yro - Gout
-  Example: TET2 mutations (Tumor suppressor) Pathogenesis: - Survival rate 3-5 years
-JAK2 mutation leading to Lab Diagnosis:
proliferation of platelets WBC: elevated
Platelet ct: elevated
Clinical Features: Peripheral Smear:
- DVT, portal & hepatic vein - Basophilia
thrombosis - Leukocytosis
- Myocardial infarction - Thrombocytosis (increase)
- Bleeding tendencies - Large platelets
- Splenomegaly Bone Marrow:
- Erythromyalgia - Increased cellularity
- Intense burning or throbbing pain - Megakaryocytic hyperplasia
of hand and feet Bleeding time: abnormal/
- Induced by exercise prolongued
- Associated with warmth, Platelet defects: present
duskiness, and mottled erythemia
 LN Biopsy: distribution of cyclin
D1 positivity around germinal Lymphmatoid polyp: Cyclin
centers D1 positivity (dark brown)

“lymphmatoid polyp”

gastric ulcer. CD 19 is positive

MALTomas Pathology:
- begin as polyclonal immune
reactions
- acquire an initiating mutation in Hallmark cells Doughnut cells
Lab Diagnosis: the B-cell clone
CBC: normal Clinical Features: - more mutations are gained that
Bone marrow: frequently - Painless lymphadenopathy make these cells autonomous
involved - Splenomegaly -  NF-kB activation promotes growth
Lymph node biopsy - Extranodal involvement: Waldeyer and survival of these transformed
Starry sky - Loss of architecture ring and GIT B-cells
- Few reactive germinal centers - GIT: present as “lymphmatoid -  MALTomas are indolent and tends
Immunophenotype: CD19, CD20, polyp” Lab:
to remain localized at the site of
CD5, CD23 NEGATIVE & Up- - Poor prognosis/Rarely curable Immunophenotype: CD19, CD20
origin for years
regulation of cyclin D1 due to
t(11;14)

Marginal zone Lymphoma

Mantle cell Lymphoma -A distinct B cell neoplasm with variable
- Europe clinical features including Lab Investigation:
- 5th to 6th decade of life Clinical course:
- Extra nodal marginal zone MALToma CBC: normal
- Males -  Eradication of H. pylori results in
Labs investigation: —> Stomach, orbit, intestine, lung, Skin Biopsy: large anaplastic cells,
Pathology: tumor regression in gastric
CBC: normal thyroid, salivary gland, bladder, CNS Hallmark cells (Horseshoe nuclei)
Burkitt Lymphoma - tumor cells resemble the MALTomas
Bone marrow: very rarely involved —> seen arising from areas involved in Lymph Node:
Categories: mantle zone B lymphocytes -  5 year survival rate is about 75%
mmunophenotype: CD19, CD20, B-cell chronic inflammation (Sjörgen syndrome, - Loss of architecture
expression of IgM 1) African (endemic): Hashimoto’s thyroiditis, Helicobacter - Presence of large anaplastic cells,
Diagnosis: based on tissue biopsy & - eastern equatorial Africa pylori) Hallmark cells and Doughnut cells
karyotyping - Age 4 to 7 years, —>  these remain localized for a long time - CD30 positive
Morphology: -M>F —> may regress, if inciting agent is
- Tissues show infiltrate of intermediate- - Association with malaria eradicated
sized lymphoid cells 2) Sporadic (non endemic): abdominal
-  High mitotic index, extensive apoptotic masses, involving the ileocecal region.
cell death 3) Aggressive form associated with HIV
- “Starry sky” = Benign macrophages Pathogenesis:
- t(8; 14): myc gene on chromosome 8. Anaplastic Large-cell Lymphoma
are scattered within the tumor tissue
forming B-cell lymphomas WBC & Lymph nodes, Part 5: - Uncommon
- Children and young adults
Non- Hodgkin Lymphoma (NHL) T-cell lymphomas
- Rearrangement of ALK (2p23)
gene triggers JAK/STAT pathway

Diffuse Large B-cell Lymphoma (DLBCL)

Lab Investigations: Follicular Lymphoma
-Mostly middle aged people
CBC: normal - middle aged, males and females
-Aggressive
Bone Marrow: involved late Pathogenesis:
-Increased incidence with HIV
Serology: HIV -  Translocation 14; 18
-May involve extra nodal sites (brain, GIT,
Elevated LDH: due to increased -  leads to overexpression of bcl-2
liver)
tumor burden -  inhibition of apoptosis
Special subtypes:
CT scan: organ involvement, 1)  Immunodeficiency associated (BM
abdominal LN transplantation/HIV infection)
Tissue biopsy: 2)  Primary Effusion Lymphoma (PEL)
Lymph node morphology: Large (advanced HIV infection) Clinical Features:
lymphoid cells Lab Investigation:
Pathogenesis: - Painless generalized
ImmunophenotypeCD19, CD20, CBC: within normal limits
- Dysregulation of BCL-6 lymphadenopathy
Surface Ig, Negative TdT Lymph node biopsy
- normally required for the formation of - Incurable
- Loss of architecture
normal germinal centers - Median survival rate 7-9 years
- Follicle like pattern
- Positive stain for bcl-2 Transformation:
lymph node contains Bone Marrow: involvement seen in - Transforms to diffuse large B
large cells with 85% of cases cell lymphoma which has poor
enlarged nuclei, Clinical Features: prognosis
Spleen/Liver: involved
open chromatin, and - Rapidly enlarging lymph nodes at
prominent nucleoli Immunophenotype: CD19, CD20,
single nodal or extranodal site (GIT, CD10, Bcl-2 Positive
skin, brain)
- Aggressive tumors but respond to
therapy
- Anti-CD20 antibody for therapy

Primary Effusion
Lymphoma (PEL):
Aspiration cytology reveals
large pleomorphic cell.
Stain positive for
Immunoglobulin follicle-like structures
No GC & No tingible bodies
 Lacunar variant cells are seen
within retraction artifact
- IgG genes of RS have undergone V(D)J
recombination and somatic hypermutation
-  This establish that the RS cell taken origin from
the germinal/post-germinal center B-cell
-  However, RS cell fail to express most B-cell
specific markers
-  NF-kB activation helps these abnormal RS from
Reed-Sternberg cell
being removed through apoptosis
-  RS cells produces cytokines: IL-5, IL-10,
1L-13, and TGF-β (Fibrosis, eosinophils)
-  Which creates a reactive response in the
surrounding cells
Immunophenotype:
- CD15, CD30 positive
-  mostly involve lower cervical,
supra clavicular and mediastinal
lymph nodes
Pathogenesis:
Classification:
Characterized by:
1)  Nodular sclerosis (good
- Reed-Sternberg cell = residing in Nodular sclerosis, HL
prognosis)
a mixed infiltrate of non-neoplastic - Involvement of the lower cervical,
WBC & Lymph nodes, Part 5: 2)  Mixed cellularity
cells definition: supraclavicular, and mediastinal
3)  Lymphocyte rich (good
- Bimodal distribution, 15 to 34 Hodgkin Lymphoma prognosis) lymph nodes
years and second peak after 50 -  MC in adolescents and young
4)  Lymphocyte depletion (poor
years females
prognosis)
Clinical Course: 5)  Lymphocyte predominan
- Painless lymph node enlargement
- Neck, supraclavicular, axilla Morphology:
- Mediastinal lymph node - RS cell variant: ‘lacunar cell’
- Fever: Pel-Epstein fever = persist for - Are seen in a reactive background
days to weeks, followed by afebrile composed of T-cells, eosinophils,
intervals and then recurrence plasma cells, macrophages,
- Night sweats fibrous bands, circumscribing the
- Weight loss lymph node into nodular areas
- Anemia of chronic disease(ACD)
- Increased risk of second
malignancy AML in survivors
 increased number of abnormal
plasma cells (BM)
plasma cell with grape-like
cluster is a Mott cell

Peripheral blood
Clinical Course:
smear: rouleaux Lab Diagnosis: 1) Infiltration of organs by plasma cells (Bones)
formation CBC: anemia, thrombocytopenia 2) Production of excessive immunoglobulins
Peripheral blood smear: 3) Suppression of normal humoral immunity
- Rouleaux formation (RBCs = “Stack of coins”). Renal Failure:
- Increased viscosity due to presence of immunoglobulins - Deposition of proteinaceous tubular casts
- Pale blue background (Bence Jones Proteins)
- Nephrocalcinosis: metastatic calcification
Bone Marrow:
- AL type amyloidosis from light chains
> 30% plasma cells - Hypercalcemia: Neurologic changes,
Abnormal plasma cells: Flame cells, Mott Cells, Russell Bodies, Dutcher Bodies Weakness, Pathologic fractures, Lethargy,
Bleeding Manifestations: Constipation, Polyuria
- Abnormal platelet function -Poor prognosis due to infections, renal failure
- Prolonged bleeding time
ESR: Increased
Urine: Proteinuria, Bence-Jones proteins
Radioimaging: Punched out lesions (osteolytic) in Spine, ribs, skull, pelvis, femur
Immunophenotype: positivity for CD138 & CD56 (when negative = poor prognosis)
Serum Electrophoresis: M spike due to IgG
> 3g/dL Ig in serum Lab Diagnosis:
> 6g/dL Bence Jones proteins in urine CBC: normal
Monoclonal Gammopathy of Uncertain Serum calcium levels: normal
Multiple Myeloma Significance (MGUS) Peripheral blood smear: Rouleaux
-Age dependent monoclonal tumor of bone marrow plasma cells Incidence: formation seen
-Significant end organ damage that can include lytic bone lesions, - 3% of people over 50 yrs. Bone Marrow:
loss of kidney function, low immunity, & amyloid deposits - 7% over 70 yrs. - Increase in lymphoid cells
Risk Factors: - Intermediate forms between lymphocytes
Pathogenesis: - More in African Americans
-  radium, benzene, radiation. and plasma cells (lymphoplasmacytic
- Neoplastic plasma cells and normal stromal cells in bone marrow Diagnosis:
Earlier days there was an cells)
produce IL-6 - Asymptomatic: detection is incidental
association with Thorostat - Russell bodies
- This growth factor promote proliferation and survival of myeloma - Isolated M spike with no lytic bon lesions, no
-  others: cigarette smoking, - Increase in mast cells Clinical Course:
cells. hypercalcemia, no Bence-Jones proteins
hair dye (?), mercury - Weakness
- Neoplastic plasma cells also produce factors which destroy the bone: - Bone marrow shows < 10% plasma cells
- Weight loss
MIP 1α which upregulates NF-kB ligand RANKL - 1% develop symptomatic plasma cell disorder
Lymphoplasmacytic lymphoma - Visual disturbances
-  these serve as ‘osteoclast activating factors’
(Waldenström macroglobinemia) - Hemostatic disturbance
- Leading to pathological fractures, and hypercalcemia
- Older population Retina:
- Malignancy of B-cells characterized by - Hemorrhages
monoclonal IgM - Cotton wool exudates
- Proliferation of B cell clone that synthesizes and secretes a homogenous Pathology: - Lymphadenopathy
immunoglobulin or its fragments 1) mutation in MYD88 - Hepatomegaly
—> since this is homogeneous, would migrate in serum protein electrophoresis 2) malignant lymphoplasmactyoid cells - Splenomegaly
to produce “spike” (M spike) secrete monoclonal IgM - Hyperviscosity
- Monoclonal immunoglobulin identified in blood are called as M component
—> Monoclonal Ig (M component) have high molecular weight
Introduction WBC & Lymph nodes, Part 6 3) causing hyperviscosity - Anemia due to marrow infiltration and
4) Tumor dissemination to lymph nodes, autoimmune hemolytic anemia due to cold
—> Seen only in plasma or extracellular fluid spleen, and liver agglutinins
—> Is Excluded from urine in absence of glomerular damage - Peripheral neuropathy due to IgM high
- Neoplastic Plasma cell produce Excess of Light chains (Bence-Jones affinity for myelin
proteins-multiple myeloma) or complete Ig (Lymphoplasmacytic lymphoma)
Langerhans Cell Histiocytosis
- Proliferation of immunophenotypical and functional
Langerhans cell which are immature dendritric cells
- Contain racquet shaped structures: Birbeck granules,
S-100 positive, CD1a positive
- Present in skin, oral mucosa
- Derived from bone marrowzx

Eosinophilic granuloma
Multifocal multisystem - Benign histiocytosis
(Letterer-Siwe disease) types:
- Unifocal lytic lesions: skull,
- < 2 years of age ribs, femur
- Cutaneous lesions trunk, scalp - Excellent prognosis
hepatosplenomegaly, Hand-Schuller-Christian
- Lymphadenopathy, lung, - Children
- Osteolytic lesions: skull, pelvis, - Presents with fever, localized
long bones rash on scalp and in ear canal
- Anemia/thrombocytopenia Triad:
- Repeated infections 1) Lytic lesions in skull
2) Diabetes insipidus
(invasion of posterior pituitary
stalk)
3) Exophthalmos (infiltration
of the orbit)


11

10

 schistocytes (arrow), scant platelets,

polychromatophils (reticulocytes)

Part 1

Lab Findings:
Hb: reduced
Platelet count: reduced Clinical Features:
Hemoglobin: reduced
2) Chronic ITP: - Abdominal pain, and vomiting by
Haptoglobulin: reduced
- Young to middle aged women 27th of gestation
Peripheral blood smear: schistocytes
Pathogenesis: -headache, visual disturbance,
Lab Findings: Fibrin Degradation Product & D-
-  formation of ‘auto antibodies’ directed against weakness, and jaundice
Hb: reduced Dimers: present
‘platelet membrane -edema with secondary weight ga
WBC: leukocytosis Bleeding Time: prolonged
glycoproteins’ Platelet count: reduced Coagulation Studies: PTT and PT are
1) Acute ITP: - IgG antibodies directed against GpIIb/IIIa, seen in Bleeding time: prolonged normal
- Children, usually following viral infection (within 6 80% of patients Coagulation studies: normal (PTT is Serum Creating: raised
weeks). Labs:
- These antibodies act as opsonins; are recognized by normal) Urine Analysis: proteinuria
- MC Varicella zoster and EBV Pathogenesis: CBC: thrombocytopenia
IgG Fc receptors on phagocytes results in platelet Peripheral blood smear: Stool Sample: EHEC on soribitol-
- Formation of anti platelet antibodies (GpIIb/ Hb: decreased
destruction, mostly in spleen schistocytes, low platelets MacConkey agar
IIIa) Reticulocyte count: increased Peripheral blood
Lab findings: Urine: hematuria, proteinuria
- Self limited (resolves in 6 months) smear: schistocytes, reduced number of platelets
Platelet count: decreased ADAMTS 13 assay: not reliable
- Tx: steroid therapy indicated Hemolytic uremic syndrome Liver Function Tests:
Bleeding time: prolonged
Lab findings: - MC in children -increased serum bilirubin
PTT: normal
- Thrombocytopenia - Due to consumption of under cooked -abnormal liver enzyme levels Haptoglobulin:
Bone marrow: slight increase in megakaryocytes and
- Bleeding time: prolonged Thrombotic thrombocytopenic red meat, unpasteurized milk, decreased Fibrinogen: decreased
dermal blood vessels with a coolar rule out leukemia
- Coagulation study: normal purpura contaminated water D-dimers: increase
of inflammatory infiltrate. Blue arrow Clinical Features:
Clinical Features: - Mostly women Pathogenesis:
shows a blood vessel obliteratedby - Easy bruising, Menorrhagia, Bleed from mucus
-  Petechial hemorrhages, epistaxis Pathogenesis: - Gastroenteritis caused by E.coli strain
inflammation & fibrinoid necrosis membranes, Subconjunctival/retinal hemorrhages
-  80% have a spontaneous recovery with - Deficiency ADAMTS 13 (vWF 0157:H7 produce shiga like toxin which
- Transplacental transfer of IgG to fetus HELLP
completely normal platelet counts in 2-8 wks metalloprotease) binds and damages endothelial cells in
- Patients responds to corticosteroids - Hemolysis Elevated Liver enzymes Low Platelets
- Normally degrades vWF glomerulus
-Life-threatening condition that can potentially complicate
- So there would be excess of vWF - Endothelial injury exposes the
pregnancy
- This increases platelet adhesion in underlying thrombogenic GBM triggering
Subtypes: - Association with Preeclampsia
areas of endothelial injury platelet activation and aggregation,
Pathogenesis:
- Therefore thrombus formation occurs and cytokine activation.
-In preeclampsia, defective placental vascular
Primary ITP Secondary ITP with minimal endotheilal injury Clinical Triad:
remodeling occurs during weeks 16-22
2 clinical sub types: Acute or Causes: - Resulting in thrombocytopenia 1) acute renal failure,
-Results in inadequate placental perfusion
Chronic 1) MC Drug induced Clinical Pentad: 2)thrombocytopenia,
-Hypoxic placenta then releases placental factors
- Acute is usually self-limiting, seen 2) Aplastic anemia Leukemias 1) fever 3) microangiopathic hemolytic anemia
which then binds to VEGF and PGF preventing them from
in children 3) Bone marrow infiltration 2) thrombocytopenia Treatment:
binding its receptors
Lab Investigation: - Chronic shows recurring bleeding 4) Hypersplenism 3) renal failure - antibiotics
-Result in hypertension, proteinuria, and increased
Platelet count: normal over months and years 5) SLE 4) microangiopathic hemolytic anemia - plasmapheresis
platelet activation and aggregation
Bleeding time: normal 5) neurological symptoms
-Activation of the coagulation cascade causes its
Coagulation workup: normal consumption.
Urine: proteinuria, microscopic Types: -Causing thrombocytopenia, hemolytic anemia, and liver
hematuria dysfunction, in addition to microangiopathic hemolysis
Skin Biopsy: IgA, C3, Fibrin
deposits Immune Thrombocytopenic purpura Clinical Features:
Renal Biopsy: IgA, C3 deposits - Platelets undergo premature - Bleeding tendency seen early in
destruction due to auto antibody/ life or early childhood
Microangiopathic hemolytic anemia
immune complex deposition on their - Purpura, epistaxis, gingival
Henoch-Schönlein purpura membrane hemorrhages, menorrhagia
- Childhood and adolescence (90% below - Patients must avoid anti-platelet
10 years) treatment (aspirin)
- Follows infections
Pathogenesis:
- Systemic hypersensitivity disease of Reduced platelet number
unknown cause Bernard-Soulier syndrome Lab:
-  Deposition of immune complexes (IgA) - Autosomal recessive, consanguinity Total platelet count: decreased
-  Widespread inflammatory reaction of the - Defective adhesion (usually mild)
capillaries and small vessels 1) Increased fragility of the blood - Platelets have abnormality of Peripheral blood smear: giant
- Leading to purpuric rash (buttocks & lower vessels membrane GpIb complex platelets
limbs), abdominal colic, polyarthralgia, - Do not cause serious bleeding - Failure to bind vWF and thrombin Bleeding time: prolonged
2) Platelet deficiency and Defective platelet function - Characterized by thrombocytopenia, Coagulation studies: normal
acute glomerulonephritits problems
-  petechiae, purpuras Bleeding disorders dysfunction and giant platelets Platelet aggregation: abnormal
-  Platelet count, bleeding time, Pathogenesis: study, due to defective adhesion to
Others causes: coagulation tests (PT, PTT) are - Defective adhesion of platelets to collagen in vitro
1) Moyamoya Disease Normal. Glanzmann Thrombasthenia subendothelium cause Severe Ristocetin test: abnormal
-chronic cerebral vasculopathy - Familial, autosomal recessive, bleeding tendency
-occlusion of the terminal portion of the consanguinity
internal carotid arteries, or the proximal aspect Others: - Defective aggregation
of middle/anterior cerebral -  Bleeding tendency due to
artery abnormalities of platelet receptor
-an abnormal vascular network of collaterals GpIIb-IIIa
develop Pathogenesis:
2) Perivascular tissue Drugs: - Genetic defect in GpIIb-IIIa prevent
- Ehlers Danlos Syndrome - aspirin causes platelet normal assembly and processing of
- Marfan Syndrome aggregation defect the functional fibrinogen receptor and
- Osteogenesis Imperfecta - inhibits COX pathway, which binding after platelet activation
- Pseudoxanthoma elasticum blocks synthesis of thrombaxane A2 -  Therefore results in a problem with
- Scurvy (TXA2) platelet aggregation
3) Vasculitis Uremia:
- reduction in ADP induced
platelet aggregation Lab diagnosis:
Infections Total platelet count: normal Clinical Features:
- in the setting of DIC Peripheral blood smear: normal - Bleeding tendency more in
looking platelets homozygous mutations
Bleeding time: prolonged - Purpura, epistaxis, gingival
Platelet aggregation: abnormal hemorrhages, menorrhagia
study
Coagulation studies: normal


61

64

Part 2

Morphology:
thrombi seen in various organs Lab diagnosis:
- Brain Platelet count: decreased
- Heart PT: prolonged
- Lungs PTT: prolonged
- Kidneys Fibrinogen levels: reduced
Associated with: Peripheral blood smear: schistiocytes,
Lab investigations:
1. Waterhouse-Friderichsen reduced platelets, polychromatophils
Platelet count: normal
syndrome (Neisseria meningitidis Fibrinogen degradation products and
Bleeding time: normal
sepsis) D- Dimers are present
Prothrombin time: normal
2. Sheehan postpartum pituitary
Partial Thromboplastin Time:
necrosis
prolonged
Factor VIII levels: reduced
Treatment:
- Treat underlying cause
- Volume replacement
DIC - Correction of hypotension/
Clinical features: - Complex systemic thrombohemorrhagic disorder oxygenation
- Easy bruising, hemorrhage - Consumption coagulopathy - Heparin
following trauma or operative Causes:
procedures 1) Obstetric complications (abruptio placentae,
- Spontaneous hemorrhages to Hemophilia B amniotic fluid embolism, abortion, intra uterine death)
knee joints (hemarthroses) -  Decrease in Factor IX activity 2) Infections (sepsis)
- Chronic hemophilic arthritis Hemophilia A -  Also called as Christmas disease 3) Neoplasms (Mucin secreting adenoca, AML:M3)
(soft tissue hematomas & - Mutation in Factor VIII -  X linked recessive 4) Massive tissue injury
hemarthroses) -  X-linked recessive trait 5) Snake bite (viper)
- Hematuria - Affects males (and homozygous Pathogenesis:
- Bleed into CNS (most serious females) - Pathologic activation of the coagulation or
Remember: - Presents with spontaneous - Impairment of clot inhibiting mechanism
-  clinically Hemophilia A & B are hemorrhages - Triggered by:
indistinguishable 1) Release of tissue factor, or procoagulants
2) Widespread injury to endothelial cells
- Once triggered, there will be formation of thrombin and
so widespread deposition of fibrin in microcirculation
Lab: results microthrombi in circulation and later on ischemia.
Platelet count: normal
Bleeding time: prolonged, (this is
due to a platelet adhesion defect) Vitamin K Deficiency
PT: normal PTT: increased von Willebrand disease Normal function:
vWF activity: reduced - Autosomal dominant disease - Vit K is a cofactor in carboxylation of Factor II
Factor VIII activity: reduced - Types 1 and 3 are due to quantitative (prothrombin), Factor VII, Factor IX, Factor X, protein C, and
Ristocetin test: abnormal defects of vWF, whereas Type 2 is due protein S
- Ristocetin binds vWF and to a qualitative defect of vWF -Made by colonic bacteria and activated by the liver microsomal
therefore leads to platelet - Normally, vWF stabilizes Factor VIII, enzyme epoxide
aggregation (normal) 3) Derangement of coagulation
makes its half-life increase -Gamma-carboxylation allows Vit K dependent procoagulants
-  therefore, reflects the vWF Pathogenesis: to actively bind to calcium in fibrin clot formation
activity of the sample 1) Defect of platelet function leading to Deficiency states:
prolonged bleeding 1) Newborns: receive intramuscular Vit K at birth, as bacterial
2) Coagulation defect due to deficiency colonization of gut does not happen until day 5- 6 and breast
Clinical Features:
- Spontaneous bleed from mucous
of factor VIII activity in plasma. Bleeding disorders milk is deficient in Vit K
2) Antibiotic therapy: broad-spectrum antibiotics removes
membrane: epistaxis bacteria from gut, therefore Vit K synthesis would be impaired
- Bleed from trivial wounds, 3) Malabsorption: Vit K is a fat-soluble vitamin
menorrhagia, dental procedures,
minor surgeries
88
Part 1

Communicating (non-obstructive):
Causes:
1) Increased CSF production
—> choroid plexus papilloma
Cerebral Aqueduct stenosis 2) Problems with reabsorption of
- Cause for obstructive CSF
hydrocephalus Non-communicating (obstructive): —> post-meningitic scarring
Pathogenesis: - Blockage to CSF outflow from the
-  Stenosis (narrowing) ventricles Hydrocephalus ex vacuo:
-  cause accumulation of CSF in the Causes: Cause:
ventricles 1) stenosis of the Aqueduct of 1) Dilation of the ventricular system
Clinical Features: Sylvius. with compensatory increase in CSF
-  Enlarging head circumference —> This causes paralysis of upward volume secondary to loss of brain
-  Bulging fontanelles, and gaping gaze (Parinaud syndrome). volume as a consequent to cerebral
cranial sutures 2) Tumor in the 4th ventricle atrophy (Alzheimer disease)
-  Setting sun sign —> ependymoma, medulloblastoma

Types:

Subfalcine (cingulate) herniation:

-  Unilateral or asymmetric
expansion of a cerebral hemisphere
displaces the cingulate gyrus under
Hydrocephalus
the falx
- Excessive CSF
- May lead to compression of the
- Enlargement of ventricles
anterior cerebral artery and its
—> before closure of cranial sutures
branches
(infancy) = enlargement of head
circumference
—> after infancy = produces
enlargement of lateral ventricles and
raised intracranial pressure, without Transtentorial (uncal) herniation:
increase in head circumference - Medial aspect of the temporal lobe is
compressed against the free margin of the
Cerebral Edema tentorium
Types: - Third cranial nerve gets compressed
1) Vasogenic (pupillary dilation and eye is deviated
- Blood-brain barrier disruption Raised intracranial pressure & herniation down and out)
- Increased vascular permeablity - Increased intracranial pressure cause CSF - Can lead to Duret hemorrhages
- Leads to influx of fluid and solutes from intravascular compartment displacement of brain tissue past rigid dural folds (falx - in mid brain and pons
into intercellular space. and tentorium) or through the openings in the skull - linear or flame shaped lesions
- It can be Localized (Inflammation or Neoplasms) or Generalized CNS #1 Causes: Types: - midline or paramedian location  due to
2) Cytotoxic 1) Generalized brain edema distortion or tearing of penetrating veins
- Intracellular edema secondary to neuronal, glial, or endothelial cell 2) Tumors, abscesses, hemorrhages and arteries supplying
membrane injury
- Associated with generalized hypoxic/ischemic insults, trauma or
metabolic derangement which prevents maintenance of normal
membrane ionic gradient Tonsillar herniation:
-  Displacement of cerebellar tonsils
(coning) thru’ foramen magnum
-  It causes brain stem compression
& compromises respiratory and
cardiac centers in medulla
- Causes: posterior fossa masses
 Part 2

Arnold-Chiari malformation
-Congenital structural defects in
cerebellum
Dandy-Walker malformation Types:
-Partial or complete absence of Type II:
cerebellar vermis - Downward displacement of
- Hugely dilated 4th ventricle cerebellar vermis and tonsils
- Absent cerebellum through foramen magnum
Pathogenesis: - Small posterior fossa
- Absence of cerebellum, a cystic - Hydrocephalus
Anencephaly space develops - Meningomyelocele
- Malformation of the anterior end - Lined by ependyma - Syringomyelia
of neural tube - Platybasia
- Cerebrum and cerebellum are Type I:
absent - Asymptomatic
- hindbrain is present
- Polyhydramnios in mother due to
absence of fetal swallowing of Syringomyelia
amniotic fluid - Cystic degeneration of the central
parts of the spinal cord
-Associated with Arnold-Chiari
Type I
Causes: Neural tube defects
CNS #1: Clinical Features:
- Folic acid deficiency Spina Bifida types: - Failure of a portion of the neural Malformations & - Bilateral loss of pain and
- Exposure to agents tube to close temperature
that interfere with normal
- Defect in closure of the posterior vertebral Developmental disease - Painless weakness and wasting of
arch resulting in vertebral defect in caudal
folate metabolism the hands and arms
aspect
- Critical period = up to 6 - Flaccid muscle weakness
Types:
weeks after last - Horner Syndrome
1) Spina Bifida Occulta
menstrual period Tuberous Sclerosis Complex
- Dimple or patch of hair
(Bourneville’s Disease)
2) Spina Bifida with cystic protrusion
Genetics:
- Meningocele
- Mutations in TSC1 gene or TSC2
Screening: •Meningeal outpouching from spinal cord
gene
- Increase Maternal - Meningomyelocele
Pathogenesis:
Serum Alpha-Fetoprotein •Meninges and spinal cord herniate
- TSC1 and TSC2 bind together to
(MSAFP) during 2nd through the defect
form a complex that blocks kinase
trimester mTOR

Clinical Features:
- Mental retardation and seizures
- Angiofibromas on face
- Shagreen patches = leathery
thickening
- Ash-leaf = hypopigmented lesions
- Hamartomas, cardiac rhabdomyomas
and lymphangioleiomyomatosis
Angiofibromas
Shagreen patches

Ash-leaf
 Part 3

Morphology: Clinical Features:

- Mononuclear inflammation -  Initially meningeal manifestation
around blood vessels -  Flaccid paralysis of muscle due
(perivascular cuffing); may to spinal cord involvement
produce cavitation -  If diaphragm or respiratory
-  neuronophagia of the anterior muscles are involved, it becomes
horn cells of spinal cord life threatening

Pathogenesis: Poliomyelitis Epidural Hemorrhage

- Poliovirus invades CNS and - Spherical, unencapsulated RNA -Presence of blood between the skull
- Replicates in: virus causes an acute systemic viral bone and dura
1) Motor neurons of the spinal infection - Fracture of temporo-parietal bone
cord (spinal poliomyelitis) or Transmission: tears middle meningeal artery
2) Brain stem (bulbar poliomyelitis) -  Fecal-oral route (poor sanitation) - forms a hematoma, with smooth inner
Spinal cord: -  Virus binds to CD155, an contour (lens shaped on CT scans)
-  Damage to the anterior horn cells epithelial adhesion molecule Clinical Features:
-  produces' LMN signs - Viral replication occurs in mucosa - Lucid interval of several hours
-  flaccid muscle paralysis, muscle of pharynx (Tonsils), and gut - Onset of neurologic deterioration
atrophy, fasciculations, reduced (Peyer’s patches) - Increased ICP
muscle power, abnormal reflexes - spreads thru’ lymphatics, and - Tentorial brain herniation
eventually blood —> CNIII palsy

Spinal Cord Lesion CNS #1 Traumatic vascular injury

Etiology and Pathogenesis:

-  Autosomal recessive Werdnig-Hoffman disease Subdural Hematoma
-  Mutation in SMN1 gene -  rare, spinal muscle atrophy -Venous bleeding between the dura and the
- Leads to degeneration of the disease arachnoid membranes
anterior horn cells -Blood is seen to cover the brain due to
tearing of the bridging veins
Due to:
Clinical Features: - Blunt trauma
-  Type I (infantile): muscle - Ederly (atrophy of brain, Decrease in
weakness by 6 months of age brain volume allows excess traction on
-  severe progressive muscle bridging veins)
weakness & flaccid or reduced - Shaken Baby Syndrome
muscle tone Pathology:
-  “floppy baby” - Slow bleed
- Progressive neurologic signs
 Pathogenesis:
Mild cases Pathogenesis:
- Post-ischemic confusional state HTN:
- Followed by complete recovery - Causes accelerated atherosclerosis
- No irreversible tissue damage in larger arteries, and hyaline
- Hierarchy of severity: Pyramidal layer of the arteriolosclerosis in smaller arteries
Hippocampus(Sommer sector) > cerebellar Purkinje - Weakening of the wall of the blood
cells > Pyramidal cells in cortex vessels makes them vulnerable to
Severe cases CNS #2: rupture
Charcot-Bouchard microaneurysms:
-  widespread neuronal death occurs
-  irrespective of regional vulnerability
Cerebrovascular disease -  Associated with chronic hypertension
-  vegetative state in those who survive, others go into -  In penetrating branches of the middle
“brain death” cerebral artery (lenticulostriate
Introduction: branches).
- Border zone infarcts (watershed areas): between
- Abrupt onset of focal or global neurological - Rupture causes bleeding in the
anterior and middle cerebral artery produces a
symptoms putamen, thalamus, adjacent white
sickle shape band of necrosis over the cerebral
- Due to ischemia or hemorrhage matter, pons, and cerebellum
convexity
- Symptoms > 24 hrs = “stroke”
- Symptoms resolvee in 24 hrs = “TIA”
- Amaurosis fugax: transient monocular blindness due Intracerebral hemorrhage
to emboli from to central retinal artery of one eye - Due to Rupture of small Morphology:
Morphology: intraparenchymal vessels -  Common sites: putamen,
Gross: edema, poor demarcation Global cerebral ischemia - “ganglionic” hemorrhages = thalamus
between gray and white matter - Due to reduction of cerebral located in the basal ganglia and -  Old hemorrhages show cavitary
Microscopy: perfusion thalamus destruction of brain
1) Early changes (12-24 hrs): Causes: -  “lobar” hemorrhages = located in - Rimmed by brownish
- presence of red neurons - cardiac arrest the lobes of cerebral hemispheres discoloration
2) Subacute changes (24hr-2 wks): - hypovolemic shock Causes: -  Later, hemosiderin laden
- tissue necrosis - hypoglycemia 1) HTN (Most Important) macrophages appear
- granulation type reaction - carbon monoxide 2) Cerebral amyloid angiopathy
- gliosis poisoning (Alzheimer disease)
Classification

2) Hemorrhage
1) Ischemia
Pathogenesis:
- Berry aneurysm have structural
anomalities
- There is absence smooth muscle
and intimal elastic lamina
- This anomaly is mostly seen to
occur along branching points, near
major arterial branch points in
Focal cerebral ischemia Subarachnoid hemorrhage anterior circulation
- Reduction or complete cessation of blood flow to a localized - Rupture of sacular (berry) - May be linked to genetic factors
Morphology: aneurysm
area of the brain like:
Gross: - Bleed occur into the subarachnoid
- Due to arterial occlusion or low perfusion (ex: TIA and 1) autosomal polycystic kidney
- Hemorrhagic infarcts space
Stroke) disease (ADPKD)
- Pale infarcts Causes: 2) Ehlers-Danlos synd (type IV)
In both patterns: 1)Embolization 3) Marfan syndrome
-  By 10 days affected brain appear - Mural thrombi from heart Clinical Features: 4) Neurofibromatosis (NF-1)
gelatinous - Atrial fibrillation - “Worst headache of my life” - Predisposing factors: smoking,
-  10 days to 3 weeks tissue liquefies - Typically produces hemorrhagic infarct - Stiff Neck hypertension
-  Eventually a fluid filled cavity remains 2)Thrombotic occlusion - Vomiting
Micro: - Associated with atherosclerosis and plaque rupture - Period of unconsciousness
First 12 hours: - Commonly seen at the carotid bifurcation, origin of MCA, followed by extreme headache
- Red neurons and either ends of basilar artery - Lysis of the red blood cells and
48 hours: Morphology
- Produces a pale infarct subsequent conversion of
-  neutrophils at the infarct site (liquefactive Micro:
3) Lacunar infarct hemoglobin to bilirubin stains the
necrosis) - Smooth muscle and intimal elastic
- Affects the deep penetrating arteries and arterioles that spinal fluid yellow within 6–12
-  appearance of microglia lamina do not extend into the neck
supply the basal ganglia. ie lenticulostriate branches (internal hrs
2 to 3 weeks: of the aneurysm
capsule) - Xanthochromic spinal fluid
-  Myelin leaden macrophages - Associated with hypertension peaks in intensity at 48 h and lasts
-  Microglial reaction  hyaline arteriolosclerosis for 1–4 weeks, depending on the
After several months: - Leads to single, or multiple small cavitary infarcts called amount of subarachnoid blood
- Cavity surrounded by meshwork of glial fibers lacunes (lake-like)

Clinical Features:
- Hypertension
• Diffuse cerebral dysfunction
• Headaches
• Confusion
• Vomiting
• Seizures stain: Trichrome
• Coma
- Vascular dementia
• Multiple bilateral grey and white
matter infarcts
- Binswanger Disease
• Loss of large areas of sub-cortical
white matter involved with myelin and
axon loss
 globoid cells.Globoid cells are hisiocytes Morphology:
filled with galactocerebroside. Gross:
Part 1 - Lesions appear as ‘plaques’
Micro: note loss of white matter
Acute plaque
- Ongoing myelin breakdown
Clinical Features: - Macrophages containing lipid rich PAS positive debris
- Normal at birth, develop irritability, - Lymphocytes & monocytes around blood vessels
spasticity around 3 to 6 months (perivascular cuffing)
- Rapidly progressive, predominant - Preservation of the axons (important point)
motor signs such as weakness - Depletion of oligodendrocytes
- Usually die in two or three years. Inactive plaque
- Little or no myelin found Labs:
- Reduction in oligodendrocytes - Raised IgG in CSF
- Astrocyte proliferation, gliosis - Raised oligoclonal bands
Krabbe disease - Axons show depletion of myelin
- Autosomal recessive disorder
Pathogenesis:
- Deficiency of galactocerebroside β- Clinical features:
galactosidase (galactosylceramidase) Multiple sclerosis - Reduction in muscle power,
- is required for the catabolism of - Autoimmune demyelinating disorder spasticity
galactocerebroside —> ceramide and galactose -Incidence: 20 to 40 years old, Scotland, Women - Pins and needles, numbness, pain
- Absence leads to accumulation of Pathogenesis: - Vertigo, scanning speech
galactosylsphingosine, which is cytotoxic 1) Genetics: - Eye Findings (important):
- Brain shows loss of myelin and oligodendrocytes - Increase risk with those having HLA-DR2 1) Optic neuritis, visual blurring,
- Presence of ‘globoid ‘ cells in brain 2) Immune: 2) Internuclear opthalmoplegia
- TH1 and TH17 cells react against myelin antigen (characterized by MLF)
and secrete cytokines - Bladder dysfunction
Metachromatic leukodystrophy - TH1 secrete IFN-γ which activates macrophages
- Autosomal recessive - TH17 promote recruitment of leukocytes
Pathogenesis: Subacute Sclerosing
- Deficiency of lysosomal enzyme: arylsulfatase A Panencephalitis
- Cleaves sulfate from sulfate containing lipids - Rare progressive syndrome
(sulfatides) - Characterized by cognitive decline,
- Deficiency leads to accumulation of sulfatides Leukodystrophies spasticity of limbs, and seizures
(cerebroside sulfate) - Myelin may be absent or CNS #3 Pathogenesis:
- Which causes white matter injury decreased Demyelinating disorders - Seen months or years after early-age
Histology: acute infection with measles
- Macrophages contain membrane bound - Myelin degeneration and gliosis
vacuoles which shows crystalloid structures Microscopy: viral inclusions positive
- These show ‘metachromasia’ when stained with for measles
Toluidine blue Clinical Features: often fatal

Adrenoleukodystrophy
- X-linked recessive Central Pontine Myelinolysis Progressive Multifocal Leukoencephalopathy
Pathogenesis: - Symmetrical Loss of myelin in basis pontis - Encephalitis caused by JC polyoma virus
- Mutation in a ATP-binding cassette transporter family of and portion of the pontine tegmentum - Which preferentially infects oligodendrocytes
proteins: ABCD1 Pathogenesis: - Characterized by demyelination
- Cause inability to catabolize very long chain fatty acids - Follows 2 to 6 days after rapid correction of - Aeen exclusively in immunosuppressed patients
- Leading to elevated levels in serum hyponatremia (osmotic demyelination) Morphology:
- Causing progressive loss of myelin in CNS and Clinical Features: - Irregular, ill-defined white matter injury
peripheral nerves also adrenal insufficiency associated - Rapidly evolving quadriplegia - Lesions reveal demyelination
with adrenal atrophy - “Locked in” syndrome (only eye movement is Clinical Features:
Clinical Features: preserved) - visual loss, weakness, high mortality
- childhood type: muscle spasms, gait abnormality &
strabismus
7
 Part 2
caudate atrophy leads to enlarged
later ventricles

Neuritic plaque
Morphology:
- Brain is small, atrophy of caudate
Morphology:
Morphology: nucleus
Gross: Clinical Features:
Gross: - Secondary atrophy of globus
- Cortical atrophy Motor impairment: Bradykinesia,
- Pallor of substantia nigra and pallidus & dilation of the lateral Clinical:
- Widening of sulci Hypophonia, Sialorrhea, Resting
locus ceruleus ventricles - Manifests by 4th decade of life
- Compensatory ventricular enlargement (hydrocephalus ex vacuo) tremor, Cogwheel rigidity, Gait
Micro: Micro: - Involuntary jerky movements
Micro: disturbance
- Loss of pigmented neurons in - Severe loss of striatal neurons - Chorea, aggression, depression,
Neuritic plaques (senile plaques) Non-motor impairment:
Neurofibrillary tangle substantia nigra - Loss of medium spiny striatal suicidal, dementia
- Stain positive for Congo Red Depression, Anxiety, Cognitive
- Gliosis neurons
- Seen as extracellular material impairment, Sleep disturbances,
Neurofibrillary tangles: - Presence of Lewy body (fine
Restless legs, Rapid eye
- Twisted neurofilaments in neuronal cytoplasm filaments densely packed in the
movements
- Contains hyperphosphorylated tau protein (microtubule core composed of α-synuclein) Huntington disease
associated protein) - Autosomal dominant
- Best seen on silver stains - Degeneration of striatal neurons (GABAnergic neurons)
Cerebral amyloid angiopathy (CAA) Parkinson disease - Progressive movement disorder dementia
- Accumulation of Aβ amyloid in wall of cerebral arterioles - Loss of dopaminergic neurons from Pathogenesis:
Cerebral amyloid angiopathy (Congo Red)
- May lead to intracerebral hemorrhage substantia nigra - HTT located on chr 4 encodes for Huntingtin
Granulovacuolar degeneration: - Leading to hypokinetic movement - Expanded trinucleotide repeats (CAG)
- Clear intraneuronal cytoplasmic vacuolation disorder —> When the repeats expand, disease sets in earlier
Hirano bodies: - Diagnostic triad: Tremor, Rigidity, and (seen with spermatogenesis)
- Elongated, glassy, eosinophilic bodies found in hippocampal Bradykinesia —> Following generation the disease would manifest at
pyramidal cells Pathogenesis: an earlier age than the preceding
Loss of cholinergic neurons: 1) Degeneration of dopaminergic neurons in - The loss of medium spiny striatal neurons causes
- Nucleus basilis of Meynert the substantia nigra pars compacta, dysregulation of basal ganglion circuitry which
2) Reduced striatal dopamine and modulates motor output
3) Intracytoplasmic proteinaceous inclusions -  Leading to increased motor output, seen as
known as Lewy bodies choreoathetosis
Clinical features: Alzheimer’s disease
- This is related to neuronal loss (cerebral cortex)
- Memory impairment Sporadic: with aging; presence of
- Cognitive problems epsilon 4 allele which promotes Aβ
- Language problem (apraxia) generation Clinical Features:
Amyotrophic lateral sclerosis (motor neuron disease
- Loss of judgment, reason Early Forms: - Bilateral flaccid weakness of
- Aggression, loss of inhibition a)Familial: associated with presenilin 1 CNS #3 or Lou Gehrig’ s disease)
- Onset 40 to 60 years. upper limb and spastic weakness
- Altered sleep-wake cycle b)Down’s syndrome: chr 21houses the Degenerative disorders - Degenerative disease characterized by loss of upper of the lower limbs
- Bedridden Aβ - Involuntary contractions:
and lower motor neurons
Pathogenesis: fasciculation
- Leading to muscle atrophy (amyotrophy)
-β-secretase acts on APP leading to - Combined upper motor neuron
- The loss of cortical motor neurons results in thinning of
improper breakdown (cleavage) of it Friedreich ataxia
the corticospinal tracts that travel via the internal capsule and lower motor neuron deficits
- Leading to formation of an insoluble - Autosomal recessive
- Loss of fibers in the lateral columns and resulting - No oculomotor deficits
Aβ and formation of amyloid plaques - Affects cerebellum and spinal cord
fibrillary gliosis impart a particular firmness (lateral
Pathogenesis:
sclerosis)
- Expansion of unstable trinucleotide
Pathogenesis:
repeats (GAA) in Frataxin
- Mutation in gene encoding for copper-zinc
- This leads to undetectable or extremely
superoxide dismutase (SOD1)
low levels of Frataxin mRNA
- Possible mechanisms:
- Causing mitochondrial dysfunction,
1) Reduced capacity to detoxify free radicals that
affecting iron regulation
leads to neuronal death
- Iron accumulation leads to free radical
2) Mutated SOD1 is a misfolded protein therefore
Clinical Features: injury (apoptotic cell death)
triggers a misfolded protein response
- Gait ataxia (staggering) - Causing degeneration of dorsal root
- Nystagmus, dysarthria, pes ganglia & posterior column.
cavus, hammer toes, hypertrophic
cardiomyopathy
- Kyphoscoliosis in childhood Morphology:
- Spinal cord: loss of axons, gliosis
of posterior columns, degeneration
- Heart: frequently manifests as lesions in the dorsal
columns and
hypertrophic cardiomyopathy , and
spinocerbellar tracts
pericardial adhesion
Part 1
Necrosis, vascular proliferation, & cellularity. Note areas of necrosis, vascularity, & Tends to cross the midline.
Marked cellular & nuclear pleomorphism cellularity

Note ‘chicken-wire’ capillary pattern, “fried egg” cells

Pilocytic astrocytoma
Morphology:
Glioblastoma multiforme
Gross:
- Increased glial cellularity
- Cystic, may be well circumscribed
Anaplastic astrocytoma - Nuclear pleomorphism
Micro:
- Poorly defined, infiltrative - Vascular proliferation Note i) cellularity, ii) perivascular cuffing by
- Bipolar cells, with hair-like
- Pleomorphism, abnormal mitosis - Network of astrocytic tumor cells referred to as pseudorosettes.
processes, Rosenthal fibers,
- GFAP positive processes
eosinophilic granular bodies
-  GFAP positive
-  GFAPpositive
Clinical features:
- Raised ICT Anaplastic Oligodendroglioma
- Recurrence free intervals of more - Grade III malignancy
Infiltrating (diffuse)
than 20 yrs - Poor prognosis
- Accounts for 80% of adult brain tumors
-  4 tiered grading system
- Examples:
- Grade III: Anaplastic astrocytoma Non-infiltrating Clinical features:
2) Oligodendroglioma
- Grade IV: Glioblastoma Multiforme - Childhood tumor, seen in cerebellum, slow Morphology: - Headache,nausea,vomiting,or
-Low-grade glioma resembling
- Most are seen in the cerebral hemispheres growing - Solid or papillary (cauliflower- vertigo
oligodendrocytes
Genetics: -Grade I/IV (indicates low-grade, “considered like growths) - Secondary to increased ICP
- less infiltrative
- PDGF, PDGFR, sis proto-oncogene & benign”) - Cells show round to oval nuclei - From obstruction of CSF flow
- Mostly adults (40 to 60 yrs)
EGFR gene stimulate RAS and PI3K /AKT - Long dendritic processes through the fourth ventricle
- Seen in cerebral hemispheres, with
signaling pathway - Perivascular pseudo-rosette - Well-differentiated,slow growing
predilection for white matter
Clinical Course: - 5 year survival rate: 45 to 50%
Morphology:
- High grade astrocytoma have poor prognosis
- Well circumscribed
- Present Atypia, Mitosis, Endothelial Necrosis
- Gelatinous with cystic spaces
- Calcification (D/Dx: Meningioma - Location)
- Low proliferative index
Clinical Features: 3) Ependymoma
- Seizures, slow growing, long post-operative - Slow growing, composed of neoplastic
survival time ependymal cells
- Overall survival rate is good - Typically originates from the cells lining the
ventricles of the brain and the central canal of
the spinal cord
1) Astrocytoma - Chr 22q, which contains the
- Tumors which show astrocytic neurofibromatosis 2 (NF2) gene
differentiation - Ependymomas that can be completely
resected
- Partially resected ependymomas will recur
Gliomas
and require irradiation
Location:
- Close to vital pontine and medullary nuclei
CNS Tumor - Children: 4th ventricle
- Bimodal age frequency - Adults: spinal cord (myxopapillary)
- Children: medulloblastoma, pilocyctic
astrocytoma
- Adults: glioblastoma
Etiology:
- Radiation
- Familial: NF-1, NF-2,VHL, LiFraumeni, Trucot,
Cowden

CNS #4
 Part 2

Morphology:
Clinical features:
Gross:
- Slow growing monotonous appearance of the cells and their Note the cellularity, pleomorphism
- Rounded, encapsulated masses, has a dural
- Parasagittal aspect of brain convexity, perivascular location
base, compress underlying brain
dura over lateral convexity, wing of
- En plaque: tumor spreads thinly over dural
sphenoid, olfactory groove, sella turcica,
surface
foramen magnum
Micro:
- New onset of Seizures, visual changes,
Midline - Various histological types: syncytial, fibroblastic,
undifferentiated (primitive cells) mental status changes, hearing loss,
Homer Wright Rosettes transitional, psammomatous
muscle weakness
- Psammoma bodies may be seen
- Surgery is best option
- Low risk of recurrence

Morphology:
Meningiomas B- cell markers (CD20)
- Multiple, and deeply situated, well
- Benign tumors (majority) defined, but as discrete as metastases
- Arising from meningothelial cell of -  periventricular spread
arachnoid Micro:
- Commonly located along the falx, - Diffuse large B cell lymphoma
Morphology: cortical convexity, and sphenoid bone (DLBCL)
- Midline of cerebellum Risk factors: low dose radiation - B-cell markers are positive (CD20,
- May occlude CSF flow Molecular genetics: CD19)
- Often well-circumscribed - Association with NF-2 (Chromosome -  EBV markers positive, in setting of
Micro: 22q contains the NF2)
Primary CNS Lymphoma (PCNSL) immunosuppression
- Sheets of tumor cells
- Homer-Wright rosettes - Aggressive malignancy arising
- Seeding of the CSF is common exclusively in the CNS
Medulloblastoma - Often multifocal
- Embryonal malignant tumor, -  Epstein-Barr virus (EBV)

Clinical features:
poorly differentiated (grade IV) CNS #4 frequently plays an important role in
the pathogenesis of HIV-related
Diagnosis:
-  arise from granular cells CSF: shows elevated protein and
- Raised ICT, epilepsy, focal (cerebellum) PCNSL malignant cells
neurologic deficit, grade IV, Risk factors: Clinical features:
aggressive Craniopharyngioma - Congenital or acquired - Focal neurologic deficits
-  70% of patients have long-term - Hypothalamic suprasellar tumor immunodeficiencies - Visual disturbances
survival but usually at the cost of (occasionally intrasellar) - Neuropsychiatric
significant neurocognitive - Derived from vestigial remnants of - Seizures
impairment Rathke pouch - Raised ICT
- Slow growing benign tumors, most -  B symptoms: fever, weight loss, night
seen in 5 to 15 age group and sweats,
second age group 65 years and - Poor response to treatment
older
- Children present with growth
retardation (pituitary deficiency may
result)

Morphology:
- Small 3-4 cm diameter Clinical course:
- Encapsulated, solid, and cystic - Symptoms result from
pattern compression of adjacent structures,
- Encroach on optic chiasm/cranial -  Optoc chiasm: bitemporal
nerves hemianopia
Micro: - Diabetes insipidus
- Children: Adamantinomatous - Risk of recurrence associated with
(enamel, calcification) larger tumors
- Adults: Papillary
craniopharyngioma (rarely calcify)
- Cysts show cholesterol rich
suprasellar craniopharyngioma thick brownish-yellow fluid
 Part 3
Familial cases (40%): Sporadic cases 60%:
- Children are born with one - Children are born with 2 normal
defective (First hit: germ cellsf) copies of RB gene
and one normal copy of RB gene - These copies are lost thru’
normal copy is lost thru’ somatic somatic mutation occurring in one
note opacities in meninges. mutation in retinoblasts (second of the retinoblasts (both hits:
hit: somatic cells) somatic cells)
Metastatic tumors
Common tumors giving rise to
mets: types:
- Lung, Breast, Skin (melanomas),
Kidney, Gastrointestinal tract
Morphology Retinoblastoma Morphology:
- Sharply demarcated masses, Pathogenesis: - Undifferentiated & differentiated
junction of gray & white matter CNS #4 - Both normal alleles of the RB locus elements are seen
- Meningeal carcinomatosis: seen must be inactivated (2 hits) for - Undifferentiated: small round
with carcinoma of lung & breast retinoblastoma cells, rosettes…
Clinical course: - Flexner-Wintersteiner
- Present as mass lesions
sometimes may the presenting Clinical:
feature - Leukocoria (white pupillary reflex)
- Strabismus, ocular pain
- Tumor extension into brain
involving optic nerve
Pathology 1 Concept Maps
Block 4

Jandrely Lopez
Material from Dr. Roy’s Lectures
 Hemorrhagic cystitis:
Causes:
1) Patients receiving cyclophosphamide or ifosfamide
—> are metabolized to acrolein, which is a strong
chemical irritant that is excreted in the urine
2) Pelvic radiation (uterine, prostate, colon)
Morphology:
- Edema, hyperemia, mucosal ulceration Cystitis glandularis:
Clinical Features: - Associated with long standing cystitis,
- Frequency, lower abdominal pain, dysuria irritation
- Hematuria Pathogenesis:
- Risk of cancer 1) nests of urothelium (Brunn nests) grow
downward into lamina propria
2)Here, undergo transformation into
Exstrophy cuboidal/columnar epithelium
- Developmental failure of anterior leading to:
wall of abdomen and bladder —> Cystitis glandularis = cystic spaces
- Bladder then communicates filled with glands
directly through the defect or —> Cystitis cystica = cystic spaces filled
appears as an opened sac with clear fluid lined by flattened urothelium
Clinical Importance: Clinical Features
- Colonic glandular metaplasia - Asymptomatic mostly
Sinus = blind opening (no - Risk of adenocarcinoma - Risk of cancer
communication)
Fistula = open at both ends
Diverticulum= out-pounching Urachus
- Vestigial structure that connects Malakoplakia
bladder with allantois - Due to chronic inflammatory reaction i.e.
- Should becomes median umbilical bacterial infections like E. coli, Proteus
ligament if not leads to clinical - Higher association with immuno-
features compromised patients
Clinical Features: Urinary bladder Morphology:
- Sinus, fistula, diverticulum - Soft, yellow, slightly raised plaques
- Drainage from umbilicus, redness - Large, foamy macrophages, occasional
around umbilicus multi-nucleate giant cells
Clinical importance: - Michaelis-Gutmann bodies = laminated
risk of adenocarcinoma bladder mineralized concretions from calcium
depositions in enlarged lysosomes

Transitional cell carcinoma Bladder cancer

- Most frequent type Risks:
Gross: - Smoking, occupational exposure to carcinogens (beta Urine Cytology
- Elevated lesions, multiple naphtylamine used as dyes,rubber industry) Note: pleomorphism of cells
- Field defect: entire bladder lining - Parasitic infection: Schistosoma hematobium and nuclei, irregular nuclear
affected. This leads to Types: - Drugs: phenacetin, cyclophosphamide border, altered N/C ratio
multicenteric tumor formation. Pathogenesis: Labs:
- Papillary lesions contain finger-like - FGFR3 & H RAS mutations : noted in non-invasive low
papillae with central core of loose grade papillary carcinoma Bladder Biopsy
fibrovascular tissue - p53, and RB gene mutations: mostly high-grade tumors Note: marked dysplasia of
with muscle invasion the lining, however the BM
Clinical Features: is intact
- Painless hematuria
- Urgency, dysuria (irritative voiding)
- Pyelonephritis, hydronephrosis

Papillary type: Papillae lined by

transitional cells with a fibrovascular core
 Renal cell carcinoma
Causes: Clear cell carcinoma:
- Smoking - Tumor cells show clear cytoplasm
- Diet - Sporadic and Hereditary types are associated
Pathogenesis: with VHL gene (chr 3)
1) Sporadic = single tumor, upper pole, older, smoking Progression:
2) Hereditary = von Hippel Lindau syndrome: multiple, bilateral, 1) Causes increased IGF-1 (insulin like growth
younger factor)
Classification: 2) Leads to dysregulation of hypoxia inducible
1) Clear cell carcinoma (70 to 80%) factor (HIF)
2) Papillary carcinoma (10 to 15%) 3) HIF increases production of VEGF and
3) Chromophobe renal carcinoma (5%) PDGF
4) Collecting duct (Bellini duct) carcinoma (1%) 4) These then promote angiogenesis and
Clinical Features: growth of the tumor
- Triad: painless hematuria, costovertebral pain, palpable mass Gross:
- Invasion of Inferior Vena Cava - Show yellow solid areas with hemorrhage
- Left-sided varicocele due to obstruction of left testicular vein Micro:
- Para neoplastic syndrome: Clear cell: abundant clear cytoplasm
1) Erythropoietin —> polycythemia* contains glycogen and lipids
Angiomyolipoma 2) PTHrP —> hypercalcemia) well-differentiated
- Benign hamartoma seen 3) ACTH —> Cushing syndrome
bilaterally in adults with Tuberous
sclerosis
Morphology: Kidney:
- Composed of thick walled blood Bening: Malignant:
vessels, muscle fibers, and adipose Neoplasms
Clinical Features:
- May lead to spontaneous
retroperitoneal hemorrhage
Wilms tumor
- Pediatric age group, less than 10 years of age
- Arises from persistent embryonal renal cells (blastema)
Pathogenesis: 3 groups
1) WAGR syndrome (WT1): Wilms tumor, Aniridia, Genital anomalies,
and mental Retardation Morphology:
2) Denys-Drash syndrome: gonadal dysgenesis (male - Histogenesis: nephrogenic rests
pseudohermaphroditism) - Triphasic
3) Beckwith-Wiedemann syndrome:organomegaly, macroglossia, 1) Epithelial
hemihypertrophy, omphalocele, and abnormal large cells in the adrenal 2) Stromal
cortex (adrenal cytomegaly) 3) Blastemal
Clinical Features:
- Large abdominal mass
- Hematuria, pain in the abdomen
- Hypertension
- Good prognosis
 Benign Hyperplasia of Prostate
- main androgen in prostate: dihydrotestosterone
dense fibromuscular stromal & glandular proliferation. Morphology: (DHT)
Gross: - Testosterone is converted by the stromal cell
- Early stages: stromal proliferation enzyme type 2 5α-reductase to DHT
- Later: epithelial proliferation - DHT causes GF release
- Enlargement compresses Clinical features:
prostatic urethra - Obstructive symptoms: hesitancy, decreased
Micro: force and caliber of stream, sensation of
- Stromal: fibromuscular incomplete bladder emptying, double voiding
proliferation (urinating a second time within 2 hours of the
- Epithelial: glandular proliferation previous void), straining to urinate, and postvoid
dribbling
- Irritative symptoms: urgency, frequency, and
nocturia, infection
Tx:
- α1-antagonists: terazosin, tamsulosin, finastride
- Transurethral resection of prostate (TURP)

Prostatitis Carcinoma Prostate

Types: - Age (older), ethnicity (African-Americans)
1) Acute bacterial: - Diet: high-saturated fat diet, red meat, low processed
- Symptoms and signs of prostatitis usually with tomatoes may be protective (lycopenes)
positive urinary tract cultures - BRCA2: germline mutation (familial)
2) Chronic bacterial: Micro:
- Chronic or recurrent bacterial infection of the - Prostatic adenocarcinoma
prostate or urinary tract - Absence of outer basal layer
3) Chronic pelvic pain syndrome or chronic Prostate - Large nuclei, 1 to 2 nucleoli present
nonbacterial prostatitis: - Mitosis rare
- Pelvic discomfort greater than 3 months with or - Grading system: Gleason score
without pyuria and negative prostate or urinary tract Metastases:
cultures - Lymphatic (obturator LN, para-aortic LN
4) Asymptomatic inflammatory prostatitis: - Bone metastases (osteoblastic): lumbar spine
- The presence of pyuria in prostatic secretions or - Elevated Alkaline Phosphatase (associated with
tissue with an absence of clinical symptoms osteoblastic activity

Investigations:
Screening by biopsies:
- Digital rectal examination (DRE)
- Prostate needle biopsy done under guidance- trans adenocarcinoma on the left lower side of the
urethral ultrasound (TRUS) specimen and bilateral benign prostatic
- Use markers for basal cells = absence indicate hypertrophy toward the top
likelihood of malignancy
- Prostatic intraepithelial lesion (PIN) = early detection of
cancer
- Serial PSA levels is better to pick up cases
- Free PSA: decreased
Note: strongly PSA positive
- Prostate cancer there is increased total PSA with
malignancy
decrease in free PSA
Part 1

1) Bowen disease:
- > 35 years of age
Condyloma acuminatum - Solitary grey-white thickened
- Benign tumor, sexually transmitted plaque
- HPV 6 and 11 - Involves shaft of penis, and
Epispadias
- Warty growth from external genitalia and scrotum
-The urethra opens on the dorsum
anus - Squamous cell carcinoma in-
of the penis, with deficient corpus
Morphology: situ associated with HPV 16
spongiosum and loosely attached
Koilocytosis: Clear cytoplasm (swept), - May progress to invasive
corpora cavernosa
sharp cytoplasmic border & Nuclear squamous cell carcinoma
- Associated with bladder
abnormalities Micro:
exstrophy and other
Clinical course: - Carcinoma in situ
developmental defects.
- Lesions on coronal sulcus, and prepuce - Epidermal proliferation
- Tend to recur - Numerous mitosis atypical mitosis, 2) Bowenoid Papulosis
- Rarely progress to malignancy dysplastic Intro:
Hypospadias - Seen in sexually active younger
- External meatus opens on the age males
underside of penis (hooded penis) Gross:
- Results from failure of fusion of Multiple lesions rather than solitary
the urethral folds on the Micro:
undersurface of the genital tubercle Pre-malignant lesions of the penis - Carcinoma in situ
Classification:
Male Genital System - Linked to HPV 16
- Based on the position of the Clinical Importance:
meatus - Does not transform to invasive
- Perineal hypospadias- most carcinoma
severe form Carcinoma Penis
Treatment: surgical - Caused by Pre-malignant conditions.
3) Erythroplasia of Queyrat
Gross:
- Bright red, shiny patches, or
- Begins in glans/inner prepuce
plaques of mucosal sites, the glans,
- Papillary/flat lesions
and prepuce of the uncircumcised
Micro:
- Associated with: uncircumcised,
- Squamous cell carcinoma (95%).
poor hygiene, Herpes/HPV
—> Verrucous carcinoma:
red, velvety, well-demarcated lesion
- Well-differentiated variant of squamous cell
on glans/prepuce penis
carcinoma
Clinical Importance:
- Exophytic (going outward), locally invasive
- High risk of transforming into
- Good prognosis
invasive carcinoma
- Don’t give radiation
Clinical features:
- Painless lesion
- Obstruction and infection
- Inguinal lymph node involvement

Verrucous carcinoma: typically

involves the oral cavity, larynx,
genitalia, skin, and esophagus.
 Note: dense inflammation (pus)
within duct
Part 2

Acute:
- Due to bacterial infection in the urinary
tract
- Infection reaches thru’ vas deferens or
Torsion of testis Chronic:
lymphatics of the spermatic cord
- Twisting of spermatic cord - Lower pole of epididymis is involved
- Sexually transmitted (Chlamydia/
- Cuts off venous drainage but arteries remain - Retrograde infection from a
Gonorrhea)
patent Tubercular focus in seminal vesicle
- Pathogen: E. coli, Pseudomonas
- Leading to vascular engorgement - Presence of Tubercular granulomas
Clinical Features:
Types: 1) Neonatal 2) Adolescence (2/3 of all cases show previous TB)
- Dull pain in groin, fever
Morphology: Clinical Features:
- Testis and epididymis: swollen, red,
- ‘Hemorrhagic’ testicular infarction - Usually painless
painful
Clinical: - Whole epididymis feels firm and
- May be a complication of indwelling
- Sudden pain, without preceding injury craggy, beaded vas
catheter
- If treated within 6 hours, testis can be - Urine & semen examined repeatedly
salvaged for TB bacilli
- Cremasteric reflex is absent

Varicocele Epididymo-orchitis
- Abnormal dilatation, and tortousity of veins of
Pampiniform plexus
Pathogenesis:
- A result of incompetent valves in the
testicular vein, permitting transmission of Mumps Orchitis
hydrostatic venous pressure. - Males afflicted by mumps virus
Surgical anatomy: - Usually noted as the parotid
Male Genital System - Swelling is a warning sign
- Left-sided predominance (90%), because of
venous drainage of the left testes into the left Complication: testicular atrophy
renal vein, causing increased retrograde
venous pressure.
Clinical:
- ‘bag of worms’ on palpation Cryptorchidism Lymphogranuloma venereum
- May lead to infertility - Incomplete testicular descent - Sexually transmitted due to specific
Testicular descent Chlamydia trachomatis (L1, L2, L3)
1) First transabdominal phase: Morphology:
- Testis rests in the lower abdomen/pelvic brim - Mixed granulomatous and
- Controlled by müllerian inhibiting substance neutrophilic inflammatory response
2) Second inguinoscrotal phase: - Chlamydial inclusion seen within
- Testes decent through the inguinal canal and into cytoplasm of epithelial or inflammatory
the scrotum influenced by androgens cells
Morphology: - Regional lymphadenopathy
- Small, firm due to fibrosis —> sterility
Micro:
- Arrest in development of germ cells
marked hyalinization, increase in interstitial stroma
- Prominent Leydig cells
Clinical Features:
- Sterility, trauma (inguinal positioned testis)
- Inguinal hernia
- Increased risk of malignancy (germ cell tumor)
 Note: pleomorphism and giant cells

Part 3
Yolk sac tumor: Schiller-Duval
body, AFB postivity

Choriocarcinoma: cytotrophoblasts,
synctiotrophoblasts, hemorrhage

Embryonal carcinoma
- More aggressive than seminomas
Gross:
- smaller lesion, does not replace the entire
Spermatocytic seminoma testis Yolk sac (endodermal sinus) tumor
- Uncommon - poor demarcation, areas of hemorrhage/ - Most common in infants and
- Older male necrosis children up to 3 yrs
- Slow growing, no metastases - tumor extension to epididymis or cord seen Micro: Choriocarcinoma
Morphology: Micro: - Lace-like pattern formed by - Both, cytotrophoblasts &
- Soft, pale gray on gross - Undifferentiated cells predominate, giant cells cuboidal to flattened cells synctiotrophoblasts must be present
- Histology: medium-sized seen - Forms Schiller-Duval bodies - However, no villi identified
cells, smaller cells, & scattered Clinical Features: - Eosinophilic bodies that are α- Gross:
giant cells - Tend to be painful fetoprotein (AFP) positive - Tend to be small lesions (palpable)
- Prognosis not as good as seminoma - Presence of hemorrhage/necrosis
- On chemotherapy the tumor may show Micro:
differentiation into teratoma - Positive for β-Hcg
Seminoma Clinical features:
- Similar tumor in ovary: Dysgerminoma - structural similarity of β-Hcg to TSH,
- Homogenous, solid, gray-white FSH, and LH may produce
tumor, appears lobulated on cut hyperthyroidism or gynecomastia
section
Micro: Seminomatous tumors Non-seminomatous tumors
- ‘Fried egg appearance’ - Contains cells resembling primodial germ - Undifferentiated cells resembling Teratoma
- Some tumors may produce β-hCG cells embryonic stem cells - Derived from more than one germ
expression OCT3/4 and NANOG cell layer
Clinical Features: Morphology:
- Painless testicular mass - Large tumors, solid with cystic
- Metastases to retroperitoneal lymph areas
nodes - Collection of differentiated cells
- Excellent prognosis - In postpubertal male, all teratomas
- No transillumination are regarded as malignant
1) Germ Cell Tumors Clinical:
- Most common type - Good prognosis
- 15 to 34 yrs
- Caucasians
Risk Factors:
- Testicular dysgenesis syndrome (Klinefelter,
cryptorchidism, hypospadias)

Male Genital System:

Testicular Tumor

2) Sex Cord-Stromal Tumors

Leydig Cell Tumors

- Elaborate androgens
Sertoli Cell Tumor
- Gynecomastia may be a
- Hormonally silent
presenting feature
- Presents a testicular
Morphology:
mass
- Well circumscribed tumors
- Histological: benign
- Appears similar to Leydig cells
- Contain rod-shaped crystalloids
of Reinke
 Bullous Pemphigoid
- Auto-antibodies against hemidesmosomes
Pemphigus vulgaris
- Sub-epidermal blistering disease
- Caused by IgG autoantibodies against
Pathogenesis:
‘desmogleins’ Dermatitis Herpetiformis
- Antibodies against one of the
- Present Acantholysis = these cells are - Rare, chronic, sub epidermal blistering disease
hemidesmosome antigen (BPAG2)
detached and appear rounded - 90% have gluten sensitive enteropathy (Celiac
- Leading to neutrophil & eosinophil
- Level of blistering: Suprabasal disease)
chemotaxis
- The row of suprabasal cells are referred Pathogenesis:
- Proteolytic enzymes released by these
to as ‘tombstones’ - IgA antibodies (against gluten)
cells produce blisters
Immunofluorescence: net-like pattern of - Leads to complement activation
Immunoflourescence: linear deposition of
intercellular IgG - This brings neutrophils to papillary dermis
IgG/C3 = ribbon candy
Clinical Features: - Neutrophils destroy basement membrane
Clinical Features:
- Oral lesions are seen components: laminin & Type IV collagen
- Older people
- Positive Nikolsky sign Morphology:
- Eosinophilia in peripheral blood
- Corticosteroid therapy - Early lesions: papillary microabscesses
- Negative Nikolsky sign
- Later eosinophils also present
- Blister cavity contains neutrophils, eosinophils &
Pemphigus fibrin
- Autoimmune blistering disorder of Immunofluorescence: granular deposits of IgA
skin & mucus membrane Clinical features:
- Results in dissolution of - Ontensely pruritic lesions (papule / vesicle)
intracellular attachments - Symmetric distribution of lesions on elbows, knees,
(intraepidermal blister) buttocks, shoulders, and sacral areas

Inflammatory Blistering disease

Skin Path #1: Erythema Multiforme

Blisters Etiology:
Vesicle: 5.0 mm or less 1) Infections: herpes simplex, mycoplasma,
Bullae: more than 5.0 mm or more histoplasmosis, coccidiomycosis, typhoid, leprosy
Introduction: 2) Drugs: sulfonamides, penicillin, barbiturates, salicylates,
Acantholysis: loss of keratinocyte
to keratinocyte contact; once hydantoins, anti-malarial
separated, they become spherical 3) Malignancies: carcinomas, lymphomas
4) Collagen vascular dis: SLE
Morphology:
- >ultiform lesions, typical targetoid
Micro:
- Superficial perivascular lymphocytic infiltrate
- Dermal edema, lymphocytes along dermal-epidermal
junction
- Necrotic keratinocytes
 elongated rete ridges = camel foot Monroe’s microabscesses & Parakeratosis

Civatte bodies
Wickham striae
Part 1

Psoriasis
- Epidermal hyperplasia with elongation of rete ridges in a
regular manner
Pathogenesis:
Lichen Planus
Genetic:
- Pruritic, Purple, Polygonal, Planar, Papules, and Plaques
- HLA-C
- Wickham striae = network of fine white lines:
Immune
Acne vulgaris Pathogenesis:
- Sensitized populations of CD4+ TH1 & TH17 cells, & CD8+
- Self-limited disorder of the - Altered antigens at basal layer and epidermo-dermal junction
effector T cells enter skin, and accumulate in the epidermis
pilosebaceous unit - Draws in lymphocytic infiltrate
- Leading to secretion of cytokines and growth factors
Pathogenesis: - Cytokines released damages epidermal basal cells/basement
- Causing keratinocyte proliferation
1) Follicular epidermal hyperproliferation membrane (interface region)
Morphology:
(keratin), Morphology:
- Epidermal hyperplasia = acanthosis
2) Excess sebum production, Civatte bodies = apoptotic epidermal cells in basal layer
- Elongation of rete ridges
3) Inflammation, and - Band-like lymphocytic infiltrate
- Parakeratosis = keratinocytes with retained nuclei
4) presence and activity of rete ridges show “saw tooth” appearance
- Thinning of stratum granulosum
Propionibacterium acnes Clinical features: Seborrheic Keratosis “Church spikes”
- Monroe’s microabscesses in superficial epidermis
- Association with chronic hepatitis C Intro:
Treatment: PUVA (Psoralen, UV-A)
- Senile warts, seen in elderly
Pathogenesis:
Acute Eczematous Dermatitis
- Activating mutation in FGFR3
Pathogenesis:
- Association with Leser-Trélat
- T cell mediated inflammatory reactions (type IV)
sign (carcinoma stomach)
- Triggered by contact antigens (ex: uroshiol from
Morphology:
poison ivy)
- Sharply demarcated, gray-brown
Morphology:
to black lesions
- Red, papulovesicular, oozing, and crusted lesions
- Basaloid cells, valleys filled with
Micro:
keratin, keratin cysts (horn cysts)
- Spongiosis, superficial perivascular lymphocytic
infiltrate, papillary edema, and mast cell degranulation
Acanthosis Nigricans
- Thickened, hyperpigmented skin
Urticaria
lesion
- Wheal-and-flare reaction
Pathogenesis:
- Localized intracutaneous edema (wheal) is
surrounded by an area of redness (erythema) that is Skin #2 - Associated with gastrointestinal
adenocarcinomas
typically pruritic
Morphology:
Pathogenesis:
- Hyperplastic epidermis, with
- Mast cell degranulation
hyperkeratosis
- Results dermal microvascular hyperpermeability
Basal cell carcinoma
Predisposing factors: Actinic keratosis
Note: perivenular infiltrates - Fair skin, sun exposure - Lesion associated with sun damaged
Edema= dermal collagen not as firmly pack as normal - Xeroderma pigmentosum Squamous cell carcinoma skin
- Nevoid Basal Cell Carcinoma Predisposing factors: Pathogenesis:
Syndrome - Exposure to sunlight, fair skin - Progressive worsening dysplastic
Morphology: - Industrial carcinogens (benzene) change
Gross: - Chronic ulcers (Marjolin’s ulcer) - May result In skin cancer
- Pearly plaques, telangietatic - Ionizing radiation Morphology:
Micro: - Xeroderma pigmentosum - Typically tan brown, roughened lesions
- Arranged in nests, with cells in the Morphology: Clinical importance:
periphery forming ‘picket - ‘Keratin pearls’= seen in well - Premalignant lesion
fence’ (palisading) differentiated squamous cell carcinoma
Clinical features: Clinical features:
- “Invades rather than metastasize” - Early lesions appear as sharply defined,
- Patient morbidity due to local tissue red scaly plaques
destruction and disfigurement - Advanced lesions are nodular, ulcerated
- Lymph node metatases
 Note: pigmented cells at the dermo-epidermal Note: pigmented cells in both epidermis and
junction dermis

Note: pigmented & non pigmented cells within

dermis only

Part 2

Compound nevi: junctional nevi

growing into dermis

Junctional: aggregates or nests of Intradermal: only dermal present,

cells along dermo-epidermal the epidermal nests disappear
junction

Lentigo
- Benign localized hyperplasia of melanocytes Types:
Morphology:
- Linear, distribution of melanocytic hyperplasia
- Hyperpigmented basal cell layer Melanocytic nevi (pigmented
Clinical Features: nevus, mole)
- Differs from freckle Dysplastic nevi
—> freckles show increase in melanosomes, - Precursors to melanoma
but no increase in melanocytes Pathogenesis:
- Autosomal dominant
- Inherited loss of function mutations in CDKN2A
(remember: CDKN2A encodes p16/INK4A)
Vitiligo Morphology:
Pathogenesis: - Larger than usual type of nevi
- Autoimmune destruction of - Flat macules/raised plaques/pebbly surface with
melanocytes irregular borders
- Localized loss of pigmentation Skin #2: Micro:
Different from Albinism: Disorders of Pigmentation - Replace basal cells
- Albinism is characterized by - Lentiginous hyperplasia
deficiency of tyrosinase, therefore - Cytologic atypia
leading to absence of melanin Malignant melanoma
Risk factors:
- Sun exposure, light skin pigmentation,
- Tanning artificial lights
- Dysplastic nevi, family history
- Xeroderma pigmentosum
Clincopathologic subtypes: Pathogenesis:
1) Superficial spreading = most common - Majority are sporadic, due to UV radiation
2) Lentigo maligna = in situ with a prolonged - CDKN2A mutation = This encodes for three different
radial growth phase that may progress to tumor suppressors: p15/INK4b, p16/INK4a, p14/ARF
invasive Mutations that activate pro-growth signaling pathways:
3) Acral lentiginous = more often in an older 1) Aberrant increase in RAS and PI3K/AKT signaling
population, most common site is the sole, with 2) activation mutations in BRAF
the palm and subungual locations this is downstream of RAS
4) Nodular melanoma = rapid evolution, Mutations that activate telomerase:
lacks an radial growth phase - Mutations in promoter of TERT, the gene which Asymmetry
encodes for catalytic subunit of telomerase Border irregularity
Morphology: 2 patterns Color variegation
- Radial pattern = horizontal growth Diameter
- Vertical pattern = downward growth

Large polygonal cells (or spindle cells

in some cases) have very pleomorphic
nuclei which contain prominent
nucleoli.
 X linked Agammaglobulinemia
Severe combined Immunodeficiency (Bruton)
-Either X-linked recessive or Autosomal recessive - Failure of B cell precursors to
X-linked: develop into mature B cells
- Most common DiGeorge syndrome
- X linked recesive
- Mutation in the common gamma chain subunit - T-cell deficiency, from failure of
- Mutation in Bruton’s tyrosine
of cytokine receptors development of 3rd & 4th
kinase (Btk)
Autosomal recessive: pharyngeal pouches
Lab investigations:
- Adenosine deaminase (ADA) deficiency - Deletion of a gene in chr 22q11
- Poorly developed germinal
- Accumulation of deoxyadenosine, and deoxy ATP Morphology:
centers in lymph nodes/lymphoid
which are toxic to lymphocytes, especially of T- - Low number of T-cells
aggregates
cell lineage - Poor defense against fungal and
-Plasma cells are absent
Morphology: viral disease
- Thymus is small and devoid of lymphoid cells - Lymph nodes: T-cell areas
(paracortical) are depleted
- Spleen: periarteriolar sheaths Hyper IgM syndrome
show absence of T- cells - X linked recessive.
- Mutations in the gene encoding
CD40L located on Xq26
Chronic granulomatous disease - Affected patients make IgM
(CGD) antibodies but are deficient in their
- X linked defect ability to produce IgG, IgA, and IgE
Defects in Lymphocyte maturation
- Absence of NADPH, therefore antibodies.
phagocytic cells are unable to kill
micro organisms
Defects in lymphocyte activation
Immunopathology, Part 1 & function Common variable
immunodeficiency
Chediak-Higashi syndrome - Low levels of immunoglobulin
- AR - Normal or near normal numbers of
- LYST mutation = defective fusion B cells, however, are not able to
of phagosomes and lysosomes Ataxia telangiectasia Immunodeficiencies associated differentiate into plasma cells
- Neutropenia, contain giant - AR with systemic diseases
granules - Mutated gene on chr 11 which
- Abnormalities in melanocytes, encodes a protein called ATM
cells in nervous system - Leading to damage in DNA Wiskott Aldrich syndrome
- bleeding tendency: abnormal repair mechanism - X-linked recessive
platelets - The generation of antigen - Mutation in Wiskott Aldrich Syndrome
receptors may be abnormal Protein (WASP)
- Characterized by: thrombocytopenia,
eczema, recurrent infection
 glomerulus with prominent
neutrophil infiltration. Bright pink
material in glomeruli represent
fibrinoid necrosis.

Vascular pattern:
- Inflammation of vessels
Tubulointerstitial pattern:
(endothelitis), type II
- Extensive interstitial inflammation
or, sometimes with necrosis of
with infiltration of tubules, referred
vascular walls (type III)
to as tubulitis
Morphology: - Affected vessels have swollen
- Associated with focal tubular injury
Gross: endothelial cells, and at places the
- Occurs within minutes or hours after transplantation lymphocytes can be seen between
- Rapidly becomes cyanotic, mottled, and flaccid, and the endothelium and the vessel wall
may excrete a mere few drops of bloody urine
immunoglobulin and complement are deposited in the Patterns:
vessel wall, causing endothelial injury and fibrin-platelet Lymphocyte in the wall of a blood vessel.
Also note swollen endothelial cells
thrombi
Micro:
- Neutrophils seen around arterioles, glomeruli, and Acute rejection
peritubular capillaries - Caused by antidonor antibodies
- Glomeruli undergo thrombotic occlusion of the produced after transplantation
capillaries, and fibrinoid necrosis occurs in arterial - Causing injury by complement-
walls. dependent cytotoxicity, inflammation, and
antibody-dependent cell-mediated
cytotoxicity
- The initial target seems to be the graft
vasculature
Hyperacute rejection
- Occurs when preformed antidonor
antibodies are present in the
circulation of the recipient
Direct pathway
- Such antibodies may be present in
- T cells of the transplant recipient
a recipient who has previously Chronic rejection
recognize donor MHC molecules on
rejected a transplant - Develops insidiously Morpholgy:
the surface of APCs in the graft. - Primarily affects vascular components Micro:
- Antibodies are detected in the circulation but are not - Vascular changes
readily identified within the graft - Obliterative intimal fibrosis
Vascular changes include: (cortical arteries)
1) Intimal thickening with inflammation - Results in: Renal ischemia
Immunopathology, Part 1: 2) Glomerulopathy, with duplication of the basement Glomerular loss, Interstitial fibrosis,
Recognition of Graft Alloantigens
Rejection of Kidney grafts membrane, likely secondary to chronic endothelial Tubular atrophy, & small kidney
injury, and
3) Peritubular capillaritis with multilayering of
peritubular capillary basement membranes

Indirect pathway
- Recipient T cells recognize MHC
antigens of the graft donor after they are intimal fibrosis of blood vessels
presented by the recipient’s own APCs
- This process involves the uptake and
processing of MHC molecules from the
grafted organ by host APCs.