THEORY:

Introduction (2-3) (7 - 15)

Cell injury & death (1-2) (8 - )
Shock (3-4)
Inflammation (2-3)
Neoplasia (3-4)
Malignancy of – Thyroid, Breast, Stomach, Kidney, Prostate, Ovary, Cervix,
Endometrial, Lung, Bone,
Soft tissue, Skin (12-15)
Haematology – Anaemia, Polycythemia, Leukemia , Aplastic anemia,
Lymphoma.(5-7)
Kidney- Glomerulonephritis, carcinoma, CKD (3-4)
Thyroid – Goiter, tumour (2-3)
Cardiac – MI, Rheumatic fever, Hypertension (3-4)
Infections – Abscess, Tuberculosis, HIV-AIDS, Amoebiasis, Malaria,
Meningitis, Septic shock, UTI (8-10)
Others / electives (4-6)


CELL INJURY & DEATH

CELL INJURY: A cell is injured of damaged, when it fails adapt to the exposed injurious or
damaging agent.

The injurious or damaging agent may be due to external as well as internal environmental
changes or may be stress.

Causes of Cell Injury:

 Oxygen deprivation (anoxia): It is a common cause of cell injury and cell death. Hypoxia
can be due to:

 A- inadequate oxygenation of the blood due to Cardio-respiratory failure

 B- Decreased oxygen-carrying capacity of the blood, as in anemias, carbon

monoxide poisoning and acute and after severe loss of blood

 Depending on the severity of the hypoxic state, cells may adapt, undergo injury,
or die.

 Physical agents:
- Mechanical trauma,
 - Burns,
- Deep cold,
- Sudden changes in atmospheric pressure,
- radiation, and electric shock.
 Chemical agents:
- Oxygen, in high concentrations
- Poisons, such as arsenic, cyanide, or mercuric salts
- Strong acids and alkalies
- Environmental and air pollutants: CO, Asbestos etc.
- Hypertonic glucose and salt
- Insecticides, herbicides, industrial and occupational hazards
- Alcohol and narcotic drugs and therapeutic drugs 1
 Infections agents: Bacteria, fungi, viruses and parasites.
 Immunologic reactions: Hypersensitivity and anaphylactic reactions and autoimmune
disorders
 Genetic defects: Due to deficiency of functional proteins such as enzyme defects in
inborn errors of metabolism or accumulation of damaged DNA or folded proteins.
 Nutritional imbalances: PEM, obesity, specific vitamin deficiencies etc.

MECHANISM OF CELL INJURY:

1. Depletion of ATP:

 Decreased sodium pump activity leading to increased intracellular sodium, calcium ions
and water causing cell and endoplasmic reticulum swelling.

 Increase anaerobic glycolysis à causing lactic acidosis à nuclear chromatin clumping.

 Detachment of ribosomes inhibiting protein production.

Figure: Functional and morphologic consequences of decreased intracellular ATP during

cell injury.
 2
2. Mitochondrial damage: Mitochondria are important targets for all types of injury, including
hypoxia and toxins.

Mitochondrial damage leads to exodus of cytochrome C and hydrogen ions into the cytoplasm,
which leads to initiation of apoptosis.

3. Increased intracellular calcium

 Loss of sodium pump and mitochondrial damage injury leads to elevation of

intracellular calcium ion levels causing activation of various enzymes like ATPase,
phospholipase, protease, endonuclease which leads degradation of cytoplasmic
organelles and nuclear material.

4. Accumulation of oxygen-derived free radicals (oxidative stress)

 Free radicals are accumulated due to imbalance between free radical producing and
free radical scavenger mechanisms

 The free radicals cause cell damage by lipid peroxidation of membranes, oxidation of
proteins and by producing lesions in DNA.

5. Defects in membrane permeability:

 In ischemic cells, membrane damage may be the result of ATP depletion and calcium-
modulated activation of phospholypases.

 It can also be damaged directly by certain bacterial toxins, viral proteins etc.

The biochemical mechanisms which contribute to membrane damage are:

 Mitochondrial dysfunction
  Cytoskeletal abnormalities

 Reactive oxygen species

 Lipid breakdown products 3

6. Damage to DNA and proteins

 Cells have mechanism that repair damage to DNA, but if this damage is too severe to be
corrected, the cell initiates a suicide program that results in death by apoptosis. A
similar reaction found in improperly folded proteins.

Earliest changes associated with cell injury are :

 decreased generation of cellular ATP,

 Intracellular lactic acidosis -- Nuclear clumping

 loss of cell membrane integrity – Hydropic swelling and other changes

 defects in protein synthesis, cytoskeletal damage – Ribosomes detatched from

endoplasmic reticulum

 DNA damage.

 Within limits, the cell can compensate for these derangements. 4

 If the injurious stimulus is removed the damage can be reversed.

 Persistent or excessive injury, however, causes cells to pass the threshold into
irreversible injury.
  Fig: Cellular and biochemical sites of damage in cell injury.

Earliest changes associated with cell injury are :

 decreased generation of cellular ATP,

 Intracellular lactic acidosis -- Nuclear clumping

 loss of cell membrane integrity – Hydropic swelling and other changes

 defects in protein synthesis, cytoskeletal damage – Ribosomes detatched from

endoplasmic reticulum

 DNA damage.

 Within limits, the cell can compensate for these derangements. 4

 If the injurious stimulus is removed the damage can be reversed.

 Persistent or excessive injury, however, causes cells to pass the threshold into
irreversible injury.

Reversible & Irreversible Cell Injury:

 If the damaging stimulus is mild or removed, functional and morphologic changes are
reversible.
  If the stimulus persists or is severe enough from the beginning, the cell reaches a point
of no return and suffers irreversible cell injury and ultimately cell death.

 Cell death, is the ultimate result of cell injury.

Morphological changes in Reversible injury:

1. Cell membrane bleb formation.

2. Swelling of endoplasmic reticulum and mitochondria.
3. Clumping of nuclear chromatin.

Morphologic forms of reversible cell injury are included under this heading:

1. Hydropic change (cloudy swelling, or vacuolar degeneration)

2. Fatty change

3. Hyaline change

4. Mucoid change

Morphological changes in Irreversible injury:

1. Large cell membrane blebs.

2. Swelling of endoplasmic reticulum and loss of ribosomes.
3. Rupture of lysosomes.
4. Swelling of mitochondria with formation of amorphous densities.
5. Myelin figures formed under cell membrane. 5
6. Nuclear condensation.

Characteristic changes Irreverisble injury are:

 Severe mitochondrial vacuolization,

 Extensive damage to plasma membranes,
 Swelling of lysosomes and
 The appearance large, amorphous densities in mitochondria. 6

CELL DEATH
Cell death is a state of irreversible injury.
It may occur in the living body as a local or focal change (i.e. autolysis, necrosis and apoptosis)
and the changes that follow it (i.e. gangrene and pathologic calcification), or result in end of the
life (somatic death).

Cell death of cells occurs in two ways:

Necrosis--(irreversible injury) changes produced by enzymatic digestion of dead cellular

elements

Apoptosis--vital process that helps eliminate unwanted cells--an internally programmed series
of events effected by dedicated gene products

Mechanisms of Cell Death:

Mechanisms of cell death caused by different agents may vary. However, certain biochemical
events are seen in the process of cell necrosis:

 ATP depletion
 Loss of calcium homeostasis and free cytosolic calcium
 Free radicals: superoxide anions, Hydroxyl radicals, hydrogen peroxide
 Defective membrane permeability
 Mitochondrial damage
 Cytoskeletal damage

NECROSIS
Definition: It is defined as the morphological changes takes place in a tissue after cell death, due
to degradative action of enzymes on irreversibly injured cell.

Morphological changes:

Cytoplasmic changes:

 Increased eosinophilia of cytoplasm.

 Vacuolation and moth-eaten appearance of cytoplasm.
 Calcification of cell membrane and intracellular structures.
 Formation of myelin figures.

Nuclear changes:

 Karyolysis: Fading of basophilia of nucleus.

  Pyknosis: Nuclear shrinkage due to condensation of chromatin.
 Karyorrhexis: Nuclear fragmentation.

** With the passage of time (a day or two), the nucleus in the necrotic cell totally
disappears.

Types of necrosis :

-Coagulative necrosis,

-Liquefactive necrosis,

- Casseous necrosis

-Fat necrosis

-Gangrenous necrosis and

-Fibrinoid necrosis 8

Coagulative necrosis: Characteristic of hypoxic death of cells in all tissues except the brain,
with preservation of the general tissue architecture.

 It is caused by denaturation of intracellular proteins.

 Affected tissue maintains firm consistency.
 Microscopically - The cellular outlines and architecture of necrosed tissue is
maintained.
 In most cases the necrotic cells are ultimately removed by inflammatory cells.
 Ex: Myocardial infarction, renal infarcts.

Liquefactive necrosis: It is a characteristic of focal bacterial or, occasionally, fungal infections.

 It is caused by enzymatic degradation of tissue.

 The tissue undergoing liquifactive necrosis results softening with destruction of

architecture and accumulation of semifluid pus.

 Microscopically - The cellular outlines of cells in tissue are completely lost.

 Liquefaction is also characteristic of ischaemic necrosis in the brain.

 Ex: Cerebral abscess, spinal cord abscess.

Caseous necrosis: Is a type of coagulative necrosis.

 It is seen in tuberculous infection and occurs due to both enzymatic degradation of

tissues and denaturation of cellular proteins.
 Tissue architecture is lost and replaced by soft, creamy cheese like material.
 Microscopically, there is amorphous granular debris seen.
 Ex: TB Lung, TB lymph node.

Fat necrosis: Is focal areas of fat destruction, due to release of activated pancreatic lipases into
the substance of the pancreas and the peritoneal cavity.

 It is seen in adipose tissue and is characterized by grey white chalky deposits in fatty
tissue.
 Free fatty acids accumulate and precipitate as calcium soaps (saponification).
 Microscopically, the digested fat loses its cellular outlines. There is often local
inflammation
 Ex: Enzymatic fat necrosis is seen in acute pancreatitis, Traumatic fat necrosis seen in
breast and buttocks following blunt trauma.

Gangrenous necrosis: Not a separate kind of necrosis at all, but a term for necrosis that is
advanced and visible grossly.

 It is a coagulative necrosis of tissue with superadded putrefaction by putrefactive

bacteria Ex: Clostridium species.

 Grossly – The organ is grayish black in colour and foul smelling

 Ex: Gangrene of fingers in diabetics, Intestinal gangrene.

** If there's mostly coagulation necrosis, call it as Dry gangrene.

If there's mostly liquefactive necrosis, called it as Wet gangrene.

Fibrinoid necrosis: Is a special form of necrosis usually seen in blood vessels.

 It occurs in the walls of blood vessels, secondary injury leading to insudation and
accumulation of plasma proteins giving an eosinophilic hyaline like deposition.
 Ex: Fibrinoid necrosis of blood vessels in immune and non immune vasculitis.
 APOPTOSIS
 Apoptosis is programmed cell death, means "falling off." Serves to eliminate unwanted
or potentially harmful cells and cells that have outlived their usefulness.

 It is a pathway of intracellular programmed cell death. In which cells destined to die, by

the activate of their own enzymes to degrade their nuclear DNA, nuclear proteins and
cytoplasmic proteins.

 The cell's plasma membrane remains intact, but its structure is altered and sends signal
to macrophages to phagocytose it.

 The dead cell is rapidly phagocytosed and cleared, therefore cell death in this pathway
does not elicit an inflammatory reaction in the host.

 Thus, apoptosis is fundamentally different from necrosis, which is characterized by loss

of membrane integrity, enzymatic digestion of cells, and frequently a host reaction.

 Apoptosis can be physiologic, adaptive, and rarely pathologic.

** Apoptosis and necrosis sometimes coexist.

Apoptosis in Physiologic Situations:

 The programmed destruction of cells during embryogenesis.

 Hormone-dependent involution in the adult, such as endometrial cell breakdown during

the menstrual cycle, the regression of the lactating breast after weaning, and prostatic
atrophy after castration.

 Cell deletion in proliferating cell populations.

Ex. Intestinal epithelia.

Apoptosis in Pathologic Conditions:

 Cell death produced by a variety of injurious stimuli eg. radiation and cytotoxic
anticancer drugs damage DNA.

 Cell injury in certain viral diseases, such as viral hepatitis.

  Pathological atrophy in parenchymal organs after duct obstruction, such as occurs in the
pancreas, parotid gland, and kidney.

 Cell death in tumors.

Morphology of Apoptosis:

 Cytoplasmic changes: Formation of cytoplasmic blebs (surface blebbing) and apoptotic

bodies, composed of cytoplasm and tightly packed organelles. (with or without nuclear
fragments.)

 Cell shrinkage ultimately

 Nuclear changes: Chromatin condensation: This is the most characteristic feature of

apoptosis. The chromatin aggregates peripherally, under the nuclear membrane.

 The nucleus itself may break up into fragments.

 Phagocytosis of apoptotic cells or cell bodies, usually by macrophages.

 Microscopic: In tissues stained with hematoxylin and eosin.

 Apoptosis involves single cells or small clusters of cells.

 The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm
with dense nuclear chromatin fragments.

There is no inflammation.
Figure 1-9 The sequential ultrastructural changes seen in necrosis (left) and apoptosis (right). In
apoptosis, the initial changes consist of nuclear chromatin condensation and fragmentation,
followed by cytoplasmic budding and phagocytosis of the extruded apoptotic bodies. Signs of
cytoplasmic blebs, and digestion and leakage of cellular components.

Differences between Necrosis and Apoptosis:

Feature Necrosis Apoptosis

Cell size Enlarged (swelling) Reduced (shrinkage)
Nucleus Pyknosis → karyorrhexis → Fragmentation nucleosome in to small
karyolysis fragments
Plasma membrane Disrupted Intact; altered structure, especially
orientation of lipids
Cellular contents Enzymatic digestion; may Intact; may be released in apoptotic bodies
leak out of cell
Adjacent Frequent No
inflammation
Physiologic / Invariably pathologic Often physiologic, means of eliminating
pathological role (culmination of irreversible unwanted cells; may be pathologic after
cell injury some forms of cell injury, especially DNA
damage

SHOCK:
Shock is a life-threatening clinical syndrome of cardiovascular collapse characterised by: ”
 an acute reduction of effective circulating blood volume
(hypotension); and
 an inadequate perfusion of cells and tissues (hypoperfusion).

If uncompensated, these mechanisms may lead to impaired cellular metabolism

and death.

Definition: shock” is a circulatory imbalance between oxygen supply and oxygen requirements
at the cellular level, and is also called as circulatory shock.

Classification and Etiology:

1. Hypovolaemic shock: This form of shock results from inadequate circulatory blood volume
by various etiologic factors that may be either from the loss of red cell mass and plasma due to
haemorrhage, or from the loss of plasma volume
alone.
Causes: i) Acute haemorrhage, ii) Dehydration from vomitings, diarrhoea
iii) Burns, iv) Excessive use of diuretics, v) Acute pancreatitis

2. Cardiogenic shock: Acute circulatory failure with sudden fall in cardiac output from acute
diseases of the heart without actual reduction of blood volume (normovolaemia) results in
cardiogenic shock.
Causes: i)Myocardial infarction, ii) Cardiomyopathies, iii) Rupture of the heart, ventricle or
papillary muscle, iv) Cardiac arrhythmia.s

3. Septic (Toxaemic) shock: Severe bacterial infections or septicaemia induce septic shock. It
may be the result of Gram-negative septicaemia (endotoxic shock) which is more common, or
less often from Gram-positive septicaemia (exotoxic shock).
Causes: i) Gram-negative septicaemia (endotoxic shock) e.g. Infection with E. coli, Proteus,
Klebsiella, Pseudomonas and Bacteroides
ii) Gram-positive septicaemia (exotoxic shock) e.g. Infection with streptococci,
pneumococci

4. Other types These include following types:

i) Traumatic shock Shock resulting from trauma is initially due to hypovolaemia, but even after
haemorrhage has been controlled.
Causes: a) Severe injuries, b) Surgery with marked blood loss and c) Obstetrical
trauma.

ii) Neurogenic shock: Neurogenic shock results from causes of interruption of sympathetic
vasomotor supply.
Causes: a) High cervical spinal cord injury, b) Accidental high spinal anaesthesia and c) Severe
head injury

iii) Hypoadrenal shock: Hypoadrenal shock occurs from unknown adrenal insufficiency in which
the patient fails to respond normally to the stress of trauma, surgery or illness.
Causes: a) Administration of high doses of glucocorticoids
b) Secondary adrenal insufficiency (e.g. in tuberculosis, metastatic disease, bilateral adrenal
haemorrhage, idiopathic adrenal atrophy)
 Pathophysiologic derangements of shock occur -- at cellular level
 The driving force of blood flow is blood pressure, .Arterial pressure depends on COP and
peripheral resistance, so – basis is inadequate COP

Stages of shock : three stages

 Initial – non progressive stage
 A progressive stage
 An irreversible stage

Stage I: Compensatory stage  Reflex mechanisms-activated  Perfusion of vital organs

maintained.
Neurohumoral mechanism to maintain COP and B.P
- baro-receptor refluxes
- Release of catecholamines
- Activate renin – angiotensin axis
- release of ADH
- Generalized sympathetic stimulation , results
 Tachycardia – increased cardiac rate
 Peripheral Vaso constriction
 Renal conservation of fluid
 Augmented myocardial contractility
Stage II : Progressive – decompensated stage.
if underlying cause is not corrected
- wide spread tissue hypoxia
- Intra cellular anaerobic glycolysis
- increased lactic acid – lactic acidosis
- Tissue pH is low
- It blunts the vaso motor response

So – Dilation of arterioles
Pooling of blood in micro – circulation
Decreases COP – tissue hypoxia
Aanoxic injury to endothelial cells – DIC
Vital organs affected – fail to function
Oliguria – urine out put is low - reduced renal blood flow
Reduced pulmonary perfusion – ARDS
Reduced cerebral flow – mental confusion
BAD TO WORSE

Stage III: Irreversible stage

 Wide spread cell injury
 leakage of lysosomal enzymes
 aggrevating effect on shock
 reduced COP – MOF
 Ischemia of bowel – intestinal flora enter into circulation - endotoxemia
 Complete renal shut down- acute tubular necrosis
 down ward clinical course – death

 At this stage – correction of primary cause do not stop the down ward trend
- Progressive fall in B.P
- Worsening metabolic acidosis
- Reduced flow to brain, heart and kidney - ischemic cell death
- Coma, renal failure – uremia
- Pulmonary edema – ARDS
- Multi - system failure

Various organs shows the following changes:

 Brain – hypoxic encephalopathy
 Heart – shock syndrome, due to Hemorrhages and Necrosis
 Kidney – Acute tubular Necrosis
 Lungs – shock lung – ARDS due to Diffuse alveolar damage
 Adrenals – Stress response
 GIT – hemorrhagic gastro – enteropathy
 Liver – fatty change & central necrosis
Clinical Features and Complications

The classical features of decompensated shock are characterized by depression of 4 vital

processes:
i) Very low blood pressure
ii) Subnormal temperature
iii) Feeble and irregular pulse
iv) Shallow and sighing respiration

In addition, the patients in shock have pale face, sunken eyes, weakness, cold and clammy skin.

Life-threatening complications in shock are due to hypoxic cell injury resulting in immuno-
inflammatory responses and activation of various cascades (clotting, complement, kinin).
These include the following*:
1. Acute respiratory distress syndrome (ARDS)
2. Disseminated intravascular coagulation (DIC)
3. Acute renal failure (ARF)
4. Multiple organ dysfunction syndrome (MODS)

With progression of the condition, the patient may develop stupor, coma and death.

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

INFLAMMATION
Definition: Inflammation is defined as the local response of living mammalian tissues to injury
from any agent.

It is a body defense reaction in order to eliminate or limit the spread of injurious agent,
followed by removal of the necrosed cells and tissues.

The causative agents:

1. Infective agents like bacteria, viruses and their toxins, fungi, parasites.
2. Immunological agents like cell-mediated and antigenantibody reactions.
3. Physical agents like heat, cold, radiation, mechanical trauma.
4. Chemical agents like organic and inorganic poisons.
5. Inert materials such as foreign bodies.

To the causative agent “inflammatory response” by the host is almost essential, these are
called “Signs of inflammation”.
SIGNS OF INFLAMMATION The Roman writer Celsus in 1st century A.D. named the famous 4
cardinal signs of inflammation as:
i) Rubor (redness);
ii)Ttumor (swelling);
iii) Calor (heat); and
iv) Dolor (pain).

To these, fifth sign, functio laesa (loss of function) was later added by Virchow.

Types of inflammation: Depending upon the defense capacity of the host and duration of
response, inflammation can be classified as acute and chronic.

A. Acute inflammation: is of short duration (lasting less than 2 weeks) and represents the early
body reaction, resolves quickly and is usually followed by healing.

B. Chronic inflammation: is of longer duration and occurs after delay, either after the causative
agent of acute inflammation persists for a long time.

ACUTE INFLAMMATION: The main features of acute inflammation are:

1. accumulation of fluid and plasma at the affected site;
2. intravascular activation of platelets; and
3. polymorphonuclear neutrophils as inflammatory cells.

For the purpose of discussion, it can be divided into following two events:
I. Vascular events, II. Cellular events.

I. Vascular events: are

 Hemodynamic changes (Changes in vascular flow and caliber)
 Changes in vascular permeability (vascular leakage)
 Leukocyte exudation

A. Hemodynamic changes:
1. Transient vasoconstriction: Transient and inconstant of arterioles.
2. Persistent progressive vasodilatation: First the arterioles, and then the capillaries.
3. Local hydrostatic pressure: Resulting in transudation of fluid into the
extracellular space. This is responsible for swelling at the local site of
acute inflammation.
4. Slowing or stasis of microcirculation: Follows which causes increased
concentration of red cells, and thus, raised blood viscosity..
The features of haemodynamic changes in inflammation are best demonstrated by the Lewis
experiment., known as triple response or red line response consisting of the following: i) Red
line ii) Flare iii) Wheal

These features, thus, elicit the classical signs of inflammation— redness, heat and swelling, to
which fourth feature, pain, has been added.

II. CELLULAR EVENTS

The cellular phase of inflammation consists of 2 processes:
1. exudation of leucocytes; and
2. phagocytosis.

Exudation of Leucocytes: The escape of leucocytes from the lumen of microvasculature to the
interstitial tissue is the most important feature of
inflammatory response.

The changes leading to

◦ 1. Margination, rolling, and adhesion
◦ 2. Diapedesis (transmigration across the endothelium)
◦ 3. Emigration toward a chemotactic stimulus
◦ 4. Phagocytosis
◦ Schematic illustration of pathogenesis of increased vascular
permeability in acute inflammation.

◦ Phagocytosis: Recognition and attachment

◦ Engulfment
◦ Killing or degradation
◦

◦ Killing or degradation: Oxygen dependent

In general, following mechanisms are involved in disposal of microorganisms:
 Myeloperoxidase dependent (the most important!)
Myeloperoxidase independent
Oxygen independent

MEDIATORS OF INFLAMMATION:

I. Cell-derived mediators
1. Vasoactive amines (Histamine, 5-hydroxytryptamine, neuropeptides)
2. Arachidonic acid metabolites (Eicosanoids)
i. Metabolites via cyclo-oxygenase pathway (prostaglandins,
thromboxane A2, prostacyclin, resolvins)
ii. Metabolites via lipo-oxygenase pathway (5-HETE, leukotrienes,
lipoxins)
3. Lysosomal components (from PMNs, macrophages)
4. Platelet activating factor
5. Cytokines (IL-1, IL-6, IL-8, IL-12, IIL-17, TNF-, TNF-, IFN-,
chemokines)
6. Free radicals (Oxygen metabolites, nitric oxide)

II. Plasma protein-derived mediators (plasma proteases) Products of:

1. The kinin system
2. The clotting system
3. The fibrinolytic system
4. The complement system

Chronic inflammation: is of longer duration and occurs after delay, either after the causative
agent of acute inflammation persists for a long time.

Chronic inflammation occurs following acute inflammation .

◦ Without prior acute inflammation

◦ Ex: TB, Viruses , Silica, Asbestos etc.

THE INFLAMMATORY CELLS: The cells participating in acute and chronic inflammation are
circulating leucocytes, plasma cells, tissue macrophages
and inflammatory giant cells.

Cells and mediators: Lymphocytes, plasma cells, and macrophages

◦ Proliferation of fibroblasts and small blood vessels
◦ Increased connective tissue
◦ Tissue destruction
◦
Mononuclear phagocytes (Macrophages/MOs/histiocytes):
 The macrophage is central to chronic inflammation
 ◦ Synonyms:
 Macrophages (MOs)
 Histiocytes
 Kupffer cells (etc.)

Functions of macrophages:

 Produce toxic, biologically active substances such as oxygen metabolites

 Cause influx of other cells such as other macrophages and lymphocytes

 Cause fibroblast proliferation and collagen deposition
 Phagocytosis

Chronic Granulomatous Inflammation:

 Def:--A type or pattern of chronic inflammation defined by the presence of granulomas
which are small, collections of modified "epithelioid " histiocytes/macrophages and
(Langhan's) giant cells surrounded by a rim of lymphocytes.

Sites of Granulomas:

 Foreign body
 Tuberculosis (TB)
 Fungal infections
 Sarcoidosis
 Schistosomiasis
 Leprosy
 NEOPLASIA

Neoplasia is: Defined as “ a mass of tissue formed as a result of abnormal,

excessive, uncoordinated, autonomous and purposeless
proliferation of cells even after cessation of stimulus for growth
which caused it“.

The branch of science dealing with the study of neoplasms or tumours is called oncology
(oncos=tumour, logos=study).

Neoplasms may be ‘benign’ when they are slow-growing and localised without causing much
difficulty to the host, or

‘malignant’ when they proliferate rapidly, spread throughout the body and may eventually
cause death of the host.

The common term used for all malignant tumours is cancer.

All tumours, benign as well as malignant, have 2 basic components:

”. ‘Parenchyma’ comprised by proliferating tumour cells; parenchyma determines the nature
and evolution of the tumour.
”. ‘Supportive stroma’ composed of fibrous connective tissue and blood vessels; it provides the
framework on which the parenchymal tumour cells grow.

The tumours derive their nomenclature on the basis of the parenchymal component comprising
them. The suffix ‘-oma’ is added to denote benign tumours.

Malignant tumours of epithelial origin are called carcinomas,

while malignant mesenchymal tumours are named sarcomas (sarcos = fleshy)

Nomenclature of Tumors:
Benign Tumors :
Epithelial Mesenchymal
Benign tumor arising from glandular • Benign connective tissue
structure is called adenoma tumors have prefix denoting
Benign tumor arising from epithelial the cell of origin
surface having papillary structure is E.g.: Fibroma
called papilloma Osteoma
E.g.: Squamous cell Papilloma Chondroma
Transitional cell papilloma Lipoma
Malignant tumors:
Epithelial Mesenchymal
Carcinoma Sarcoma
• Squamous cell carcinoma • Fibrosarcoma
• Adenocarcinoma • Osteosarcoma
• Transitional Cell Carcinoma • Rhabdomyosarcoma
• Leiomyosarcoma

 All benign tumors have suffix – omas attached to their cell of

origin
 Benign epithelial tumors are either papillomas or adenomas
 Benign connective tissue tumors have prefix denoting the cell
of origin
 Malignant epithelial tumors are carcinomas
 Malignant mesenchymal tumors are sarcomas

Special categories of tumours:

1. Mixed tumours When two types of tumours are combined in the same tumour.
Ex: i) Adenosquamous carcinoma, ii) Adenoacanthoma, iv) Collision tumour and v) Mixed
tumour of the salivary gland (or pleomorphic adenoma).
2. Teratomas These tumours are made up of a mixture of various tissue types arising from
totipotent cells derived from the three germ cell layers—ectoderm, mesoderm and endoderm.
3. Blastomas (Embryomas) Blastomas or embryomas are a group of malignant tumours which
arise from embryonal or partially differentiated cells which would normally form blastema of
the organs and tissue during embryogenesis.
4. Hamartoma Hamartoma is benign tumour which is made of mature but disorganised cells of
tissues indigenous to the particular organ e.g. hamartoma of the lung consists of mature
cartilage, mature smooth muscle and epithelium. Thus,
all mature differentiated tissue elements which comprise the bronchus are present in it but are
jumbled up as a mass.
CHARACTERISTICS OF TUMOURS:
Majority of neoplasms can be categorized into benign and malignant on the basis of certain
clinical features, biologic behaviour and morphological characteristics.

The characteristics of tumours are described under the following headings:

I. Rate of growth
II. Cancer phenotype and stem cells
III. Clinical and gross features
IV. Microscopic features
V. Local invasion (Direct spread)
VI. Metastasis (Distant spread).
Based on these characteristics, contrasting features of benign and malignant tumours are
summarized:
I. Rate of growth: The tumour cells generally proliferate more rapidly than the
normal cells. In general, benign tumours grow slowly and malignant tumours rapidly.
Ex: Leukaemias, Lymphomas, Lung cancers etc.
Cancer cells disobey the growth controlling.

II. Cancer phenotype and stem cells: Normally growing cells in an organ are related to the
neighbouring cells—they grow under normal growth controls,
perform their assigned function and there is a balance between the rate of cell proliferation
and the rate of cell death including cell suicide (i.e. apoptosis). signals in the body and thus
proliferate rapidly.
So, the cancer dells show: 1.proliferate rapidly, ii) Cancer cells escape death signals,
iii) Imbalance between cell proliferation and cell death in cancer causes excessive growth,
Imbalance between cell proliferation and cell death, iv perform little or no function, v) develop
newer mutations, vi) overrun their neighbouring tissue and invade locally. vii) Cancer cells have
establish distant metastasis

III. Clinical and gross features

Clinically, benign tumours are generally slow growing, and depending upon the location, may
remain asymptomatic (e.g. subcutaneous lipoma), or may produce serious symptoms (e.g.
meningioma in the nervous system).
On the other hand, malignant tumours grow rapidly, may ulcerate on the surface, invade locally
into deeper tissues, may spread to distant sites (metastasis), and also produce systemic
features such as weight loss, anorexia and anemia.
Gross appearance of benign and malignant tumours may be quite variable.
Benign tumours are generally spherical or ovoid in shape. They are encapsulated or well-
circumscribed, freely movable, more often firm and uniform.
Malignant tumours, on the other hand, are usually irregular in shape, poorly-circumscribed and
extend into the adjacent tissues. Secondary changes like haemorrhage, infarction and
ulceration are seen more often.

IV. Microscopic features:

The tumour cells may be arranged in a variety of patterns in different tumours as under:
The epithelial tumours generally consist of acini, sheets, columns or cords of epithelial tumour
cells that may be arranged in solid or papillary pattern.
The mesenchymal tumours have mesenchymal tumour cells arranged as interlacing bundles,
fasicles or whorls, lying separated from each other usually by the intercellular matrix, such as
hyaline material in leiomyoma
cartilaginous matrix in chondroma, osteoid in osteosarcom, reticulin network in soft tissue
sarcomas etc

V. Spread of tumours
a. Local invasion or direct spread: Most benign tumours form encapsulated or circumscribed
masses that expand and push aside the surrounding normal tissues.
Malignant tumours also enlarge by expansion, and some well-differentiated tumours may be
partially encapsulated. But malignant tumours are characteristically, distinguished from benign
tumours by invasion, infiltration and destruction of the surrounding tissue.

b. Metastasis or distant spread: Metastasis and invasiveness are the two most important
features to distinguish malignant from benigntumours:
Routes of Metastasis: Cancers may spread to distant sites by following pathways:
1. Lymphatic spread
2. Haematogenous spread
3. Spread along body cavities and natural passages
(Transcoelomic spread, along epithelium-lined surfaces, spread via cerebrospinal fluid,
implantation).

Based on these characteristics, contrasting features of benign and malignant tumours

MICROSCOPIC BENIGN MALIGNANT

Growth rate Slow Relatively rapid
Local invasion No Yes
Metastasis Never Frequent
Capsule Often well circumscribed Often poorly circumscribed
Necrosis Rare common
Differentiation Well differentiated Variable
Nuclear morphology Often Normal Usually hyperchromatic,
irregular outline, multiple
nucleoli and pleomorphic
Mitotic activity Low High

Characteristics of a malignant cell:

 1. Pleomorphism: variation in size and shape of cell and nuclei . Thus, cells within
the same tumor are not uniform, but range from large cells, many times larger than
their neighbors, to extremely small and primitive appearing.

 2.Abnormal nuclear morphology: Characteristically the nuclei contain abundant

chromatin and are dark staining (hyperchromatic). The nuclei are disproportionately
large for the cell, and the nuclear cytoplasmic ratio is increased .

 3. Nuclear-to-cytoplasm ratio: may approach, 1 : 1 instead of normal 1 : 4 or 1 : 6. The

nuclear shape is often irregular, and the chromatin is coarsely clumped and distributed
along the nuclear membrane. Large nucleoli are usually present in these nuclei .

 4 . Mitoses: Increased mitosis , reflects the higher proliferative activity of the

parenchymal cells. Malignant and undifferentiated tumors usually possess large
numbers of mitoses . More important feature malignancy are atypical, bizarre mitotic
figures, sometimes producing tripolar, quadripolar, or multipolar forms of mitosis .

 5. Loss of polarity: refers to Sheets or large masses of tumor cells grow in an anarchic,
disorganized fashion.
  6 . Other changes: Formation of tumor giant cells, some possessing only a single huge
polymorphic nucleus and others having two or more large, hyperchromatic nuclei .

Fig: Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma) with marked cellular
and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells

 7. Necrosis - Often the vascular stroma is scant, and in many anaplastic tumors, large
central areas undergo ischemic necrosis.

In brief:
 Cellular & Nuclear pleomorphism
 High nuclear – cytoplasmic ratio (normal 1:4-6; in cancer 1:1)
 Increased and often atypical mitosis
 Tumor giant cells
 Loss of polarity or organization of cells
 Loss of normal function (functional dedifferentiation) & Development of new function
(sometimes)

GRADING AND STAGING OF CANCER

‘Grading’ and ‘staging’ are the two systems.
Grading is defined as the gross and microscopic degree of differentiation of the tumour,
while staging means extent of spread of the tumour within the patient.

Thus, grading is histologic while staging is clinical.

Malignant tumours of various systems:

Thyroid tumours: Approximately 95% of all primary thyroid cancers are
carcinomas.

Carcinoma of the thyroid gland has 4 major morphologic types with distinctly different clinical
behaviour and variable prevalence. These are: Papillary, Follicular, Medullary and
Undifferentiated (anaplastic) carcinoma.

Papillary Thyroid Carcinoma: These are most cancers of Thyroid.

Age group: 20-50 yrs., male to female ratio 1:3

Pathogenesis: Risk factors are associated with:

 Iodine excess
 External radiation exposure to head and neck region.
 Genetic factors: It is 4-10 times more common in first degree relatives of patients with
papillary thyroid carcinoma
 Somatic mutations: RET proto-oncogene mutations on chromosome 10q11.2 are
common in papillary thyroid carcinoma

Gross morphology:
 They are solitary to multiple, pale, firm to hard, gritty lesions.
 They can be encapsulated or show infiltrative margins.
 Cut surface shows papillae.

Papillary carcinoma of the thyroid. Cut surface of the enlarged thyroid gland shows a
single nodule separated from the rest of thyroid parenchyma by incomplete fibrous
septa (arrow). The nodule is grey-white soft and shows grossly visible papillary pattern.
Microscopy:
 They are branching papillae seen lined by single or stratified layer of cuboidal or
columnar cells and a fibrovascular core.
 The lining neoplastic cells show crowding with overlapping of nucleus.
 The nuclei are clear in majority of them(ground glass appearance-Orphan-Annie eye)
with few showing eosinophilic pseudo inclusions and nuclear grooves.
 Calcospherites called as Psammoma bodies are seen in core papillae in > 50 % of cases.
 Capsular and lymphovascular invasion is classically seen.

Papillary carcinoma thyroid. Microscopy shows branching papillae having

flbrovascular stalk covered by a single layer of cuboidal cells having ground-
glass nuclei. Colloid-filled follicles and solid sheets of tumour cells are also
present.

Follicular carcinoma of Thyroid: It is second most common malignant tumour of thyroid and is
purely follicular with no papillary areas.
Age group: > 40 yrs., male to female ratio 11:3.
Nodular goiter predisposes it.

Pathogenesis:
 N – RAS mutation is seen in >50% of follicular thyroid carcinomas.
 PAX 8 – PPARγ 1 fusion gene due to translocation t (2, 3) is seen in 30-40% cases.
Gross morphology:
 The tumour is 3-6 cm encapsulated lesion with presence of capsular invasion.
 Cut surface is fleshy and solid.
Microscopy:
  The tumour shows variably sized follicles, which are distinct from surrounding thyroid
tissue.
 There is capsular invasion noted by the tumour follicles.

Follicular carcinoma, showing encapsulated tumour with invasion of a

capsular vessel. The follicles lined by tumour cells are of various sizes and
there is mild pleomorphism.

Medullary carcinoma of thyroid:

- 5-8 % of all thyroid cancers

- Most common on females except inherited cases.
- Sporadic in 80% of cases, familial in 20% of cases
- Tumour derived from parafollicular ‘C’ cells of thyroid.
- Tumour possess neuroendocrine features.
- Better prognosis in sporadic cases.

Anaplastic Carcinoma of Thyroid:

- Least common of all thyroid cancers.

- Mostly occurs in older patients.
- Invasion beyond capsule, blood vessel involvement and foci infarct, necrosis
common.
- A mutated ‘p53’ tumour suppressor is often demonstrated.
- Rapidly growing tumour in neck region invades esophagus, causes dysphagia or
trachea causes and vocal cord paralysis.
Malignant tumours of the Breast

Cancer of the breast is among the commonest of human cancers throughout the world. The
incidence of breast cancer is highest in
the perimenopausal age group and is uncommon before the age of 25 years.

Clinically, the breast cancer usually presents as a solitary, painless, palpable lump which is
detected quite often by self examination.
Higher the age, more are the chances of breast
lump turning out to be malignant.

Early diagnosis by mammography, xero-radiography and thermography.

Techniques like fine needle aspiration cytology (FNAC), stereotactic biopsy and frozen section
are immensely valuable to the surgeon for immediate pathological diagnosis.

Malignant tumours of the Breast:

• More often in left breast than right
• Bilateral in 4%
• Commonest in Upper outer quadrant
• Most arise from ductal epithelium

Risk factors
• Age ( Incidence increases with age)
• Family history
• Excessive exposure to estrogens
Early menarche,
Late menopause,
Nulliparity,
Post menopausal HRT,
OCP &
H/o endometrial cancer
 Pre existing breast diseases-
Atypical ductal hyperplasia
 Environmental factors- high dietary factors, Obesity, radiation, alcohol

General Features:
Cancer of the breast occurs more often in left breast than the right and is bilateral in about 4%
cases. Anatomically, upper outer quadrant is the site of tumour in half the breast cancers;
followed in frequency by central portion, and equally in the remaining both lower and the
upper inner
Quadrant.
Carcinoma of the breast arises from the ductal epithelium in 90% cases while the remaining
10% originate from the lobular epithelium.

The tumour cells remain confined within the ducts or lobules (noninvasive
carcinoma) before they invade the breast stroma (invasive carcinoma).
non-invasive carcinoma have been described—intraductal carcinoma and
lobular carcinoma in situ,

Fig: Topographic considerations in breast cancer.

Presentation:

 Most breast cancers present as painless breast lumps

 Mammography is most useful in detecting non palpable breast lesions
 Most are hard in consistency ( Scirrhous) & gritty to cut
 Advanced cases can have nipple retraction and may be attached to underlying chest
wall

Classification of Carcinoma of the Breast.

A. NON-INVASIVE (IN SITU) CARCINOMA

1. Intraductal carcinoma
2. Lobular carcinoma in situ

B. INVASIVE CARCINOMA
1. Infiltrating (invasive) duct carcinoma-NOS (not otherwise
specified)
2. Infiltrating (invasive) lobular carcinoma
3. Medullary carcinoma
4. Colloid (mucinous) carcinoma
5. Papillary carcinoma
6. Tubular carcinoma
7. Adenoid cystic (invasive cribriform) carcinoma
8. Secretory (juvenile) carcinoma
9. Inflammatory carcinoma
10. Carcinoma with metaplasia

B. PAGET’S DISEASE OF THE NIPPLE

A. NON-INVASIVE (IN SITU) BREAST CARCINOMA

In general, two types of non-invasive or in situ carcinoma— intraductal carcinoma and lobular
carcinoma in situ, are characterised histologically by presence of tumour cells within the ducts
or lobules respectively without evidence of invasion.

Intraductal Carcinoma
Carcinoma in situ confined within the larger mammary ducts is called intraductal carcinoma.
The tumour initially begins with atypical hyperplasia of ductal epithelium followed by filling of
the duct with tumour cells.

Clinically, it produces a palpable mass in 30-75% of cases and presence of nipple discharge in
about 30% patients.

Grossly, the tumour is irregular, 1-5 cm in diameter, hard cartilage-like mass that cuts with a
grating sound.

C/S: tumour is grey-white to yellowish with chalky streaks and

often extends irregularly into the surrounding fat.

Micro: i) Anaplastic tumour cells forming solid nests, cords, poorly-formed glandular structures
and some intraductal foci.
ii) Infiltration by these patterns of tumour cells into diffuse fibrous stroma and fat.
iii) Invasion into perivascular and perineural spaces as well as lymphatic and vascular invasion.

B. Infiltrating (Invasive) Lobular Carcinoma

Invasive lobular carcinoma comprises about 5% of all breast cancers. more frequently bilateral;
and within the same breast, it may have multicentric origin.

Micro:Tthere are 2 distinct features :

i). Pattern—A characteristic single file (Indian file) linear arrangement of stromal infiltration by
the tumour cells.
ii) Tumour cytology—Individual tumour cells resemble cells of in situ lobular carcinoma. They
are round and regular with very little pleomorphism and infrequent mitoses.
Medullary Carcinoma
Medullary carcinoma is a variant of ductal carcinoma and comprises about 1% of all breast
cancers.

MORPHOLOGIC FEATURES.
Grossly, the tumour is characterised by a large, well-circumscribed, rounded mass that is
typically soft and fleshy or brain-like and hence the alternative name of ‘encephaloid
carcinoma’. Cut section shows areas of haemorrhages and necrosis

Micro: Medullary carcinoma is characterised by 2 distinct features i) Tumour cells—Sheets of

large, pleomorphic tumour cells with abundant cytoplasm, large vesicular nuclei and many
bizarre and atypical mitoses are diffusely spread in the scanty stroma.
ii) Stroma—The loose connective tissue stroma is scanty and usually has a prominent lymphoid
infiltrate.

C. Paget’s disease:
 Eczematoid lesion of nipple associated with invasive or noninvasive ductal carcinoma of
the underlying breast
 Paget’s cells- large cells with hyperchromatic nuclei and perinuclear halo- lie singly or in
clusters in the epidermis.

Malignant Tumors of the Stomach

Carcinoma of the stomach comprises more than 90% of all gastric malignancies and is the
leading cause of cancer.

 Malignant tumours:
 Adenocarcinoma – most common malignant tumor of stomach (90-95%)
 Lymphoma (4%)
 Carcinoid tumour(3%)
 Malignant Stromal tumors (2%)

Adenocarcinoma :
 It is the most common malignant tumour of stomach.
 Age= 5th to 7th decade
 M:F = 2:1

Etiological factors:
 Environmental factors:
- Alcohol intake
 - Nitrites derived from nitrates in water
- Consumption of smoked food
- Starchy food, pickles
- Lacks of fruits
- Smoking
- Low economic status
- H. pylori infection (3 -6 times high risk of
development of gastric carcinoma.)

 Host factors:
- Partial gastrectomy
- Chronic gastritis
- Gastric adenomas
- Barret esophagus
 Genetic factors:
- Blood group A individuals.
- Family history
- Hereditary non-polyposis
- Colon carcinoma syndrome

 Pathogenesis: Allelic loss of several genes e.g. TGFβ, p53, BAX etc. leads to
tumorigenesis.

 Lauren classification: 2 sub types.

1. Intestinal type: Bulky tumors with malignant cells in diffuse
sheets and glandular pattern.
Age: 55 yrs. M:F= 2 : 1
2.Diffuse type: Malignant cells in diffuse sheets
Age: 58 yrs. M:F= 1 : 1

 Macroscopic: (Gross morphology):

Location: pylorus & antrum (50-60%), cardia (25%),
body & fundus (15%);
L. curvature (40%), G. curvature (15%)
Ulcer in the G. curvature is more likely to be malignant
Gross growth patterns:
 Excavated – (ulcerative)
 Flat or depressed
 Exophytic – (cauliflower like mass)
 Linitis plastica: Leather bottle appearance due to complete infiltration of stomach wall
by tumor.
Excavated Type Flat or depressed Type
Large area of stomach Wall is thickened by Infiltrating tumor -linitis plastica or leather
bottle stomach.

 Microscopic: 2 histological sub types.

 Intestinal type: Neoplastic glands with expanding growth pattern and cells having
mucin vacuoles.

 Diffuse type: Neoplastic cells in singles or small clusters and have large mucin vacuole
in cytoplasm pushing the nucleus to periphery (signet ring appearance -> arrow).
Complications of gastric carcinoma:

Most common complication is Haemorrhage. (In the form of haematemesis or melaena.),

Obstruction, Perforation and Jaundice.

 Frequently metastasises to supra-clavicular node (Virchow node), peri-umbilical area

(sister Mary Joseph nodule) and ovaries (Kruckenberg tumour)

 Prognosis is generally poor related to depth of invasion, nodal involvement and

presence of metastasis

 Hence early diagnosis is required to increase the survival rate.

 5 year survival:

 Early cancer (surgically treated) - 90-95%

 Advanced cancer - <15 %

Malignant tumors of the Kidney

Both benign and malignant tumours occur in the kidney, the latter being more common. These
may arise from renal tubules (adenoma, adenocarcinoma), embryonic tissue (mesoblastic
nephroma, Wilms’ tumour), mesenchymal tissue
(angiomyolipoma, medullary interstitial tumour) and from the epithelium of the renal pelvis
(urothelial carcinoma). Besides these tumours, the kidney may be the site of the secondary
tumours.
Classification of tumours:
 Benign:
 Renal papillary adenoma-from tubular epithelium
 Renal fibroma
 Angiomyolipoma - associated with tuberous sclerosis

 Oncocytoma - from intercalated cells of collecting duct
 MALIGNANT
 A. EPITHELIAL TUMOURS OF RENAL PARENCHYMA
Adenocarcinoma (hypernephroma, renal cell carcinoma)
 B. EPITHELIAL TUMOURS OF RENAL PELVIS
Transitional cell carcinoma
Others (squamous cell carcinoma, adenocarcinoma of renal pelvis,
undiff erentiated carcinoma of renal pelvis)
 C. EMBRYONAL TUMOURS
Wilms’ tumour (nephroblastoma)
 D. NON-EPITHELIAL TUMOURS
Sarcomas (rare)
 E. MISCELLANEOUS
 F. METASTATIC TUMOURS

MALIGNANT TUMOURS
 Th e two most common primary malignant tumours of the kidney are adenocarcinoma
and Wilms’ tumour. A third malignant renal tumour is urothelial carcinoma occurring
more commonly in the renal pelvis.
Renal Cell Carcinoma:
 Malignant tumors of renal tubular or ductal epithelial cells.
 Age: 6th -7th decade
 Etiology: Tobacco chewing
 Others-obesity, hypertension, unopposed estrogen therapy, asbestos , petroleum
products and heavy metals
 Chronic renal disease, acquired renal disease and tuberous sclerosis
 VHL syndrome, Hereditary clear cell carcinoma and Hereditary papillary carcinoma

Pathogenesis:
 95 % of Renal cell carcinomas are sporadic. 5% inherited
 Hereditary RCC occurs in three different syndromes:
1. Hereditary papillary RCC
2. Autosomal dominant clear cell RCC
3. Von Hippel-lindau Syndrome: consisting of
Hemangioblastoma of the cerebellum and retina and Renal cysts
Bilateral, often multiple renal cell carcinoma
Clinical features: Costovertebral pain, palpable mass and hematuria – classical
features seen only in 10% of cases.
 Paraneoplastic syndrome
 Hypercalcemia, hypertension, amyloidosis
 Polycythemia, eosinophilia, leukemoid reaction
 Hepatic dysfunction, cushing syndrome feminization or masculinization,
Most common metastasis seen in lung and bones.

 Macroscopic: The upper pole of the kidney shows a large and tan mass while rest of
the kidney has reniform contour.

 Sectioned surface shows irregular, circumscribed, yellowish mass with areas of

haemorrhages and necrosis. The residual kidney is compressed on one side and shows
obliterated calyces and renal pelvis.

Gross - usually arise from upper pole, spherical bright yellow masses with
hemorrhage and necrosis

Classification Of Renal Cell Carcinoma :

 1. Clear cell carcinoma - 70% to 80%
o 95% spordic,5% familial associated with VHL disease
o 98% of clear cell carcinoma have (3p-) which harbor VHL gene
 2. Papillary carcinoma - 10% to 15%
o Trisomy 7 in familial, trisomy 7, 16 and 17 and loss of y in male in sporadic
o In familial form - MET proto oncogene
 3. Chromophobe carcinoma - 5%
 o Arises from intercalated cells of collecting dusts and have excellent prognosis
 4. Collecting duct (Bellini duct) carcinoma - 1%
Microscopic picture of Clear cell carcinoma:
 Growth pattern varies from solid to trabecular or tubular.
 The tumour cells have rounded or polygonal shape and abundant clear or
granular cytoplasm.
 The tumours have delicate vasculature.
Papillary carcinoma - cuboidal or low columnar cells arranged in papillary fronds.
Interstitial foam cells are present in papillary core. Psammoma bodies may be present.
 Chromophobe carcinoma - pale eosinophilic cells with perinuclear halo in solid pattern
 Collecting duct carcinoma-irregular channels lined by atypical epithelium within a
prominent fibrotic stroma

Wilm’s tumor:
It is the most common childhood abdominal malignant tumor.
 It is usually unilateral, bilateral in 5-10% cases.
 Also known as “Nephroblastoma”.
 Age group affected: 2-5 years.
 Etiology: Wilm’s tumors are sporadic or occur in association with
 Denys-Drash syndrome.
 WAGR syndrome.
 Beckwith-Weidemann syndrome
Pathogenesis:
 Mutation in WTI tumor suppressor gene is associated with it
 Mutation in IGF2 gene leading to its overexpression is associated with it
Clinical features:
 Asymptomatic abdominal mass
 Abdominal pain
 Hematuria
 Hypertension
 Fever
 Urinary tract infection
 Varic0coele
Gross morphology:
 Tumor is large, solitary, well circumscribed; bilateral or multicentric in 5-10% cases.
 C/S – Tumor is soft, homogenous, grey tan in color with foci of necrosis, hemorrhage
and cyst formation.
Microscopic:
 Tumor is triphasic, biphasic or rarely monophasic.
 Triphasic tumor show three components:
- Basement component: Composed of small blue cells
- Epithelial component: Composed of abortive tubules and glomeruli.
- Stromal component: Composed of fibrocytes in sheets
  Heterogenous elements like neurogenic rests, smooth muscle, bone, cartilage etc. may
be seen.

Urothelial Carcinoma Of Renal Pelvis

 Only 5% to 10% of renal tumours originate from urothelium of pelvis
 Urothelial tumours range from benign papilloma to transitional carcinoma – histology
resemble bladder tumours
 Increased incidence of urothelial carcinoma of pelvis and bladder in patients with
analgesic nephropathy
 Bad prognosis - infiltration of wall of pelvis is common

Malignant Tumors of the Prostate

 Most common form of cancer in men >60 years , second leading cause of cancer death
 Adenocarcinoma is the most common type
Etiology:
 Advanced age
 More common in whites
 consumption of fat and exposure to polycyclic aromatic
 hydrocarbons. – higher incidence
 Flavonoids, antioxidants and selenium may reduce the risk.
 Hormone – androgen sensitive
Genetic:
 Cancer susceptibility gene in ch. 1q
 Loss of cancer suppressor genes localized to ch 8p, 10q, 13q and 16q
 >90% of prostate cancers show hypermethylation of GSTP1 gene on ch 11q
Pathogenesis:
 Androgens play a major role in its causation
 Amplification of androgen receptor gene increases sensitivity of prostatic epithelium to
testosterone and cause caricnogenesis
 Genetic damage to gene located on 1 q chromosome leads to increased risk of familial
prostatic carcinoma

Morphology:
 Most commonest CA prostate – adenocarcinoma of acinar variant
 Site of origin: 70% arise from peripheral zone of prostate, classically in posterior
location
 Grossly : It is invisible within the gland
 C/S firm and gritty
 Micro – composed of well defined glandular pattern
  Minimal pleomorphism and few mitotic figures
Microscopic: –
 Most frequently, the glands in well differentiated prostatic adenocarcinoma are small
or medium-sized, lined by a single layer of cuboidal or low columnar cells.
 Moderately- differentiated tumours have cribriform or fenestrated glandular
appearance.
 Poorlydifferentiated tumours have little or no glandular arrangement but instead show
solid or trabecular pattern.
 The tumour cells may be clear, dark and eosinophilic cells. Clear cells have foamy
cytoplasm, dark cells have homogeneous basophilic cytoplasm, and eosinophilic cells
have granular cytoplasm.
 The cells may show varying degree of anaplasia and nuclear atypia but is generally slight.

Prostatic Intra Epithelial Neoplasia (PIN)

 Benign glands having intra acinar proliferation and nuclear anaplasia
 Widely separated large branching glands with papillary infolding
Intact basement membrane and presence of basal layer.

Clinical features:
 Incidence increases with advancing age
 Clinically advanced tumors have urinary symptom
 Osteoblastic metastases
 PSA is serine protease , product of prostatic epithelium and secreted in semen
 Serum level of PSA > 4 ng /ml – abnormal
 PSA is organ specific , not cancer specific
 PSA – BPH, prostatitis, infarct, instrumentation and ejaculation
 20% to 40% of patients with organ confined prostate cancer have <4ng/ml
 PSA density, PSA velocity, age specific reference range and ratio of free and bound PSA
 Early detection – rectal examination, trans rectal USG and serum PSA
 Also used to assess response to therapy

Ovarian tumours:
 The ovary is third most common site of primary malignancy in the female genital tract,
preceded only by endometrial and cervical cancer. Both benign and malignant tumours
occur in the ovaries.
 6% of all cancers in females, half of deaths from cancers of FGT (late diagnosis).
 80% benign, 20 to 45 years.
 Malignant – 40 to 65 years.
 Pathogenesis: Nulliparity, family history & heritable mutations
 Gonadal dysgenesis in children.

 Structure of the ovary to illustrate origin of ovarian tumors.

 

Ovarian Neoplasms (WHO classification)

I. TUMOURS OF SURFACE EPITHELIUM (COMMON EPITHELIAL
 TUMOURS) (60-70%)
 A. Serous tumours
1. Serous cystadenoma
2. Borderline serous tumour
3. Serous cystadenocarcinoma

 B. Mucinous tumours
1. Mucinous cystadenoma
2. Borderline mucinous tumour
3. Mucinous cystadenocarcinoma
 C. Endometrioid tumours
 D. Clear cell (mesonephroid) tumours
 E. Brenner tumours
II. GERM CELL TUMOURS (15-20%)
 A. Teratomas
 1. Benign (mature, adult) teratoma
 • Benign cystic teratoma (dermoid cyst)
 • Benign solid teratoma
 2. Malignant (immature) teratoma
 3. Monodermal or specialised teratoma
 • Struma ovarii
 • Carcinoid tumour
 B. Dysgerminoma
 C. Endodermal sinus (yolk sac) tumour
  D. Choriocarcinoma
 E. Others (embryonal carcinoma, polyembryoma, mixed germ cell tumours)
III. SEX CORD-STROMAL TUMOURS (5-10%)
 A. Granulosa-theca cell tumours
 1. Granulosa cell tumour
 2. Thecoma
 3. Fibroma
 B. Sertoli-Leydig cell tumours (Androblastoma, arrhenoblastoma)
 C. Gynandroblastoma
IV. MISCELLANEOUS TUMOURS
 A. Lipid cell tumours
 B. Gonadoblastoma
V. METASTATIC TUMOURS (5%)
 A. Krukenberg tumour
 B. Others

Important malignant tumors of ovary:

I. TUMOURS OF SURFACE EPITHELIUM (COMMON EPITHELIAL

 TUMOURS) (60-70%)

 Serous cystadenocarcinoma:
 Multilayered malignant anaplastic epithelial cells arranged in solid sheets, cells show
loss of polarity. Definite evidence of stromal invasion seen.
 Papillae formations are more frequent in malignant variety and may be associated with
psammomabodies.
 Presence of psammoma bodies is not indicative of malignancy
Brenner Tumour
 Brenner tumours are uncommon and comprise about 2% of all ovarian tumours. They
are characteristically solid ovarian tumours. Less than 10% of Brenner tumours are
bilateral. Most Brenner tumours are benign. Rarely, borderline form is encountered
called proliferating Brenner tumour while the one with carci nomatous change is termed
malignant Brenner tumour.
 Histogenesis of the tumour is from coelomic epithe lium by metaplastic transformation
into transitional epithelium (urothelium).
 MORPHOLOGIC FEATURES
 Grossly, Brenner tumour is typically solid, yellow-grey, firm mass of variable size.
Occasionally, a few scattered tiny cysts may be present on cut section.
 Histologically, Brenner tumour consists of nests, masses and columns of epithelial cells,
scattered in fibrous stroma of the ovary. These epithelial cells resemble urothelial cells
which are ovoid in shape, having clear cytoplasm, vesicular nuclei with characteristic
nuclear groove called ‘coffee bean’ nuclei.
II. GERM CELL TUMOURS
 Ovarian germ cell tumours arising from germ cells which produce the female gametes
(i.e. ova) account for about 15-
 20% of all ovarian neoplasms. Nearly 95% of them are benign, the remainder are
malignant germ cell tumours.
Teratomas: Teratomas are tumours composed of different types of tissues derived from the
three germ cell layers—ectoderm, mesoderm and endoderm, in varying combi nations.
 Teratomas are divided into 3 types: mature (benign),
 immature (malignant), and monodermal or highly specialised teratomas.
MATURE (BENIGN) TERATOMA: Vast majority of ovarian teratomas are benign and cystic,
often termed clinically as dermoid cyst.
 Benign cystic teratomas are more frequent in young women during their active
reproductive life.
 The tumour is bilateral in 10% of cases.
 Mature teratoma may be solid and benign and has to be distinguished from immature
or malignant teratoma.
 IMMATURE (MALIGNANT) TERATOMA Immature
 or malignant teratomas of the ovary are rare and account
 for approximately 0.2% of all ovarian tumours. Th ey are
 predominantly solid tumours that contain immature or
 embryonal structures in contrast to the mature or adult
 structures of the benign teratomas. Th ey are more common in prepubertal adolescents
and young women under 20 years of age.
Dysgerminoma
 Dysgerminoma is an ovarian counterpart of seminoma of the testes (page 697).
Dysgerminomas comprise about 2% of all ovarian cancers. They occur most commonly
in 2nd to 3rd decades. About 10% of them are bilateral. About 10% of patients with
dysgerminoma have elevated hCG level in the plasma. All dysgerminomas are malignant
and are extremely radiosensitive.
Endodermal Sinus (Yolk Sac) Tumour:
 Endodermal sinus tumour or yolk sac tumour is the second most common germ cell
tumour occurring most frequently in children and young women. More often,
endodermal sinus tumour is found in combination with other germ cell tumours rather
than in pure form. The tumour is rich in alpha fetoprotein (AFP) and α-1-antitrypsin. The
tumour is usually unilateral but may metastasise to the other ovary. It is a highly
aggressive and rapidly growing tumour.
Choriocarcinoma
 Choriocarcinoma in females is of 2 types—gestational and non gestational. Gestational
choriocarcinoma of placental origin is more common and considered separately later
(page 742). Pure primary non-gestational chorio carcinoma of ovarian origin is rare
while its combination with other germ cell tumours is seen more often. The patients are
usually young girls under the age of 20 years.
III. SEX CORD-STROMAL TUMOURS (5-10%)
 Derived from ovarian stroma, which in turn is derived from sex cords of the embryonic
gonads

Granulosa-theca Cell Tumours:

 Ovarian tumours containing varying proportion of granulosa & theca cell differentiation.
 5% of ovarian neoplasms, any age 2/3rd in postmenopausal women.
 Unilateral, varying size, solid & cystic encapsulated mass, hormonally active are yellow
due to lipids.
 Pure thecomas are solid firm tumours
 The small, cuboidal to polygonal cells in cords, sheets or strands, occasionally gland like
structures filled with eosinophilic material (Call- Exner bodies) – diagnostic
 Thecoma - clusters or sheets of cuboidal to polygonal cells
 Luteinized granulosa-theca cell tumors are seen.
 Potential elaboration of large amounts of estrogen,
 Small but distinct hazard of malignancy in the granulosa forms. Theca cells are never
malignant
 Precocious puberty in young girls with functionally active tumours (J GCT)
 Adults- Endometrial hyperplasia, cystic disease of breast & endometrial carcinoma.
 Difficult to predict behavior, recurrences common with 10 year survival rate is 85%.
 Tumours with.
 Recent – Inhibin is raised in all these tumours, useful in diagnosis & in therapy
monitoring.
 Granulosa cell Tumour

V. METASTATIC TUMOURS:
 About 10% of ovarian cancers are secondary carcinomas. Metastasis may occur by
lymphatic or haematogenous route but direct extension from adjacent organs (e.g.
uterus, fallopian tube and sigmoid colon) too occurs frequently. of metastatic tumour.
Most common primary sites from where metastases to the ovaries are encountered are:
carcinomas of the breast, genital tract, gastrointestinal tract (e.g. stomach, colon
appendix, pancreas, biliary tract) and haematopoietic malignancies.
 Malignant tumors of Cervix

Malignant tumours are common in the cervix, that include cervical dysplasia and carci noma in
situ (cervical intraepithelial neoplasia, CIN), currently termed squamous intraepithelial lesions
(SIL).

Carcinoma of Cervix
Carcinoma of cervix is the commonest carcinoma of female genital tract
Risk factors – host & virus interaction
 Early age at first intercourse
 Multiple sex partners
 Increased parity
 A male partner with multiple previous sexual partners
 Presence of a cancer-associated HPV
 Persistent detection of HPV high concentration (viral load)
 Certain viral & HLA types
 Exposure to OCP 7 nicotine
 Genital infection (Chlamydia)
 Specific HPV types
 High risk- 16,18,31,33,35,39,45,51,52,56,58,59,68.
 Low risk- 6,11,42,44,53,54,62 & 66.
Vaccines of papilloma viruses - prevent infection and development of precancerous condition.

I. Cervical Intraepithelial Neoplasia:

 Mostly preceded by precancerous state, remain for as long as 20 years and shed
abnormal cells-detected cytologically.

CIN: Represent a continuum of morphologic change with indistinct boundaries

  Do not invariably progress to cancer and may spontaneously regress, with the
risk of persistence or progression to cancer increases with severity of the CIN
 Associated with HPV, high risk type.

Classification: Classified as Dysplasia/Carcinoma in situ – Mild to severe

 Cervical Intraepithelial Neoplasia
 Mild dysplasia-CIN I & Carcinoma in situ-CIN grade III
 Low grade CIN & High grade CIN

 CIN I Koilocytes CIN II

CIN III Squamous cell carcinoma

 Squamous Cell Carcinoma:
 Second decade to senility – 40-45 for invasive cancers, 30 years for precancerous lesions
Morphology ( Gross):
 Fungating (exophytic)
 Ulcerating
 Infiltrative
 Advanced lesions directly spread to peritoneum, urinary bladder, ureters, rectum &
vagina
 Local & distant regional lymph nodes
Distant metastases to liver, lungs, bone marrow and others

Microscopy:
 95% show large cells
 keratinizing (well differentiated)
 Non-keratinizing (moderately differentiated)
 5% are poorly differentiated
 small cell squamous or
 small cell undifferentiated (neuroendocrine / oat cell carcinomas)- frequently
associated with HPV-18
 Koilocytic change: Sq. ep. Cell that has undergone a a number of structural
changes, due to infection of cells by HPV.

Invasive carcinoma of the cervix common gross appear ance is of a fungating or

exophytic, caulifl ower-like tumour. Gross photograph on right shows replacement
of the cervix by irregular grey-white friable growth (arrow) extending into cervical
canal as well as distally into attached vaginal cuff .
 Invasive Carcinoma-staging:
 Stage 0- Carcinoma in situ (CIN III)
 Stage I- Carcinoma confined to cervix.
 Ia. Preclinical carcinoma, diagnosed only by microscopy
 Ia1. Stromal invasion no greater than 3mm & no wider than 7mm(so celled
microinvasive carcinoma)
 Ia2. maximum depth of invasion of stroma greater than 3mm & no greater than
5mm, either surface or glandular horizontal invasion no wider than 7mm.
 Ib. Histologically invasive carcinoma confined to cervix and greater than Ia2.
 Stage II. Carcinoma extends beyond the cervix but not onto the pelvic wall. Carcinoma
involves the vagina but not lower third
 Stage III. Carcinoma has extended onto pelvic wall. On rectal examination, there is no
cancer free space between the tumour and pelvic wall. Tumour involves the lower third
of vagina.
 Stage IV. Carcinoma has extended beyond the true pelvis or has involved the mucosa
of the bladder or rectum. Obvious metastatic dissemination.

Stage III. Carcinoma has extended onto Stage IV. Carcinoma has extended beyond
pelvic wall the true pelvis or has involved the mucosa
of the bladder or rectum

Invasive Carcinoma- Morphology

 25%- adenocarcinoma, adenosquamous & undifferentiated carcinomas
 Adenocarcinoma- arise from endocervical glands, preceded by intraepithelial glandular
neoplasm, one fifth as common as SCC
 Adenosquamous carcinoma- less favourable,
  Clear cell carcinoma –DES(Diethylstilbestrol) exposure as in vagina, relation to
papillomavirus uncertain.

Clinical course & Management:

 1. Periodic Papaniculaou smears – management is predicted based on the abnormality
( CIN/ ASCUS)
 2. Colposcopic examination & confirmation by histology for the former.
 HPV screening for the latter.
 Morphological criteria histologically with IHC for biomarkers like p161NK4, cyclin E & Ki-
67
 1. Cytological screening & management of papaniculaou smear abnormalities – HPV
 2. Histological diagnosis & removal of precancers
 3. Surgical removal of invasive cancers with adjunctive radiation & chemotherapy.
 4. Latest – HPV vaccine for prevention/treating existing diseases.

Carcinoma of Endometrium
 Carcinoma of the endometrium, commonly called uterine cancer, is the most common
pelvic malignancy in females, where cervical cancer continues to be the leading cancer
in women.
 It is primarily a disease of postmenopausal women, the peak incidence at onset being
6th to 7th decades of life and is uncommon below the age of 40 years.
 The most important presenting complaint is abnormal bleeding in postmenopausal
woman or excessive flow in the premenopausal years.

 Etiology: A few factors associated with increased frequency

 1. Chronic unopposed oestrogen excess
 2. Obesity
 3. Diabetes mellitus
 4. Hypertension
 5. Nulliparous state
 6. Heredity.

 Pathogenesis:
 Endometrial hyperplasia is the initial phase of the endometrial carcinoma, is supported
by mutated PTEN gene (located on chromosome 10) seen in 20% cases of complex
hyperplasia while it is seen in 40-80% cases of endometrioid carcinoma.
 Other gene mutations in these cases are hMLH, KRAS and catenin oncogenes.
 Papillary serous endometrial carcinoma is seen associated with mutation in p53 tumour
suppressor gene.
  Endometrial cancer is supported by higher incidence in hereditary non-polyposis colon
cancer (HNPCC) syndrome (having simultaneous cancers of the colon and endometrioid
adenocarcinoma)
 and in Cowden syndrome (having simultaneous cancers of
 the breast, thyroid, and endometrium).

 Gross morphology: Grossly, endometrial carcinoma may have 2 patterns— localized

polypoid tumour, or a diff use tumour; the latter being more common
 The tumour protrudes into the endometrial cavity as irregular, friable and grey-tan
mass.
 Tumours are multi focal with areas of hemorrhage and necrosis.

 Microscopy: Based on histological pattern endometrial carcinoma is of five major types:

 Endometroid adenocarcinoma(60-80%)
 Endometroid adenocarcinoma with squamous differentiation (5-8%)
 Serous adenocarcinoma(10-15%)
 Clear cell adenocarcinoma(3-5%)
 Secretory adenocarcinoma (1-2%)

Endometrial carcinoma. A, B, Diagrammatic representationof the common gross patterns—

localised polypoid growth and diff use growth.
C, The specimen of the uterus and cervix shows enlarged uterus and dilated uterine cavity
containing irregular, grey-white, friable growth arising from endometrial mucosa and invading
the underlying myometrium superfi cially.

Adenocarcinomas are three grades, well, moderately and poorly differentiated, based on the
degree of glandular differentiation.
 Serous carcinomas are always poorly differentiated and show very poor prognosis.
Staging
 Stage I. Confined to corpus uteri itself
 Stage II. Involved the corpus & cervix.
 Stage III. Extended outside the uterus, not outside the true pelvis.
 Stage IV. Extended outside the true pelvis or involved the bladder/rectal mucosa.
Further each stage can be sub grouped with regards to grading.(1-3).

Endometrial carcinoma – Clinical Course

 Irregular vaginal bleeding with excessive leucorrhea
 Pap smear- variable only serous can be detected.
 Curettage tissue is diagnostic.
 Treatment depends on the stage of the lesion
 Surgery, irradiation. 90% for grade1&2/stage I, 75% for grade3/stage I, 50% for stage II
& III.
 Uterine serous/clear cell lesions- extra uterine spread is common.
 50% alive after 3 years of diagnosis.

MALIGNANT TUMOURS OF LUNGS:

 A number of benign and malignant tumours occur in the lungs but the primary lung
cancer, commonly termed bronchogenic carcinoma, is the most common (95% of all
primary lung tumours). The lung is also the commonest site for metastasis from
carcinomas and sarcomas.

 Based on histological types, lung tumours classified in to

 I. EPITHELIAL TUMOURS
 II. SOFT TISSUE TUMOURS
 III. PLEURAL TUMOURS
 IV. MISCELLANEOUS TUMOURS
 V. SECONDARY TUMOURS

I. EPITHELIAL TUMOURS are mainly divided into

 A. Benign : 1. Papilloma, 2. Adenoma
 B. Dysplasia and carcinoma in situ
 C. Malignant
 Bronchogenic carcinoma
 1. Squamous cell (epidermoid) carcinoma
 2. Small cell carcinoma
 3. Adenocarcinoma
 4. Large cell carcinoma
 5. Adenosquamous carcinoma
 Other carcinomas
  1. Pulmonary neuroendocrine tumour (carcinoid tumour)
 2. Bronchial gland carcinomas
 i) Adenoid cystic carcinoma
 ii) Mucoepidermoid carcinoma
II. SOFT TISSUE TUMOURS
 (Fibroma, fibrosarcoma; leiomyoma, leiomyosarcoma; lipoma,
 chondroma, haemangioma, lymphangioma, granular cell
 myoblastoma)
III. PLEURAL TUMOURS
 A. Benign mesothelioma
 B. Malignant mesothelioma
IV. MISCELLANEOUS TUMOURS
 1. Carcinosarcoma
 2. Pulmonary blastoma
 3. Malignant melanoma
 4. Malignant lymphoma
V. SECONDARY TUMOURS

Bronchogenic carcinoma
 It is the most common cancer of the lungs which includes carcinomas arising from the
respiratory epithelium lining the bronchi, bronchioles and alveoli.
 Based on major histological pattern they are of four types:
 1. Squamous cell carcinoma.
 2. Adenocarcinoma.
 3. Large cell carcinoma.
 4. Small cell carcinoma
 5. Adenosquamous carcinoma

Etiology: Major risk factors causing lung carcinoma are:

 i) Radiation exposure: Long-term exposure to radon or
patients receiving thoracic radiation have increased risk of lung cancer.
 Tobacco smoking: Heavy cigarette smokers have 10-60 times higher risk.
 Cigar and pipe smokers have lesser risk. Carcinogens in smoke are benzopyrenes,
phenolderivatives carbon, polnium etc.
 Occupational exposure: Exposure to asbestos increases risk 5-10 times. Asbestos
workers who smoke have 90 times have higher risk.
 Atomic bomb survivors exposed to radiation have higher risk

Pathogenesis: 1.In Small cell carcinomas, mutations in c-MYC and RB genes occur.
 2. In Non-small cell carcinomas, mutations in RAS and p16 gene are noted
 3. Autocrine growth factors: Studies have shown that some initiator carcinogens
causing mutation, followed by action of tumour promoters. Ex: Nicotine acts as both
initiator as well as promoter carcinogen.
  4. Inherited predisposition : i) Patients of Li-Fraumeni syndrome who inherit p53
mutation may develop lung cancer.
 ii) Clinical cases of retinoblastoma having mutation in Rb
 gene are predisposed to develop lung cancer if they live up to
 adulthood.

Gross morphology:
 Bronchogenic carcinoma present as cauliflower like grey white hard mass with areas of
necrosis and hemorrhage.
 Extension into pleura seen in late stages.
 Lymphatic metastasis to trachea, bronchial and mediastinal lymph nodes noted
 Metastasis occur in liver brain and bone.
Microscopic:
 Squamous cell carcinoma:
 Occurs in smokers and is central in location.
 Tumour cells arranged in solid sheets and in small clusters with variable amount of
keratinization.
 Adenocarcinoma: seen in non smokers and women
 They are peripheral in location
 Tumour cells arranged in papillae, acini, solid patterns with variable amount of mucin.
 Large cell carcinoma:
 They are undifferentiated malignant tumours.
 Tumour cells are large with moderate cytoplasm and large nucleus with prominent
nucleoli.
 Small cell carcinoma:
 Highly malignant tumour, strongly associated with smoking Occurs in smokers and is
central in location.
 Tumour cells are round, oval and spindle shaped with scant cytoplasm. Ill defined cell
margins and nucleus with salt and pepper chromatin.

CLINICAL FEATURES:
 1. LOCAL SYMPTOMS: Most common local complaints are cough, chest pain, dyspnoea
and haemoptysis (A list of various causes of haemoptysis.;
 2. BRONCHIAL OBSTRUCTIVE SYMPTOMS: occlusion of a bronchus may result in
bronchopneumonia, lung abscess and bronchiectasis in the lung tissue distal to the site
of obstruction and symptoms like fever, productive cough, pleural effusion and weight
loss.
 3. SYMPTOMS DUE TO METASTASES: Distant spread may produce varying
features ,these include: superior vena caval syndrome, painful bony lesions, paralysis of
recurrent nerve and other neurologic manifestations resulting from brain metastases.

STAGING AND PROGNOSIS:

 TNM staging divides all lung cancers into the following 4 stages:
  Occult: Malignant cells in the broncho-pulmonary secretions but no evidence of primary
tumour or metastasis.
 Stage I: Tumour less than 3 cm, with or without ipsilateral nodal involvement, no distant
metastasis.
 Stage II: Tumour larger than 3 cm, with ipsilateral hilar lymph node involvement, no
distant metastasis.
 Stage III: Tumour of any size, involving adjacent structures, involving contralateral
lymph nodes or distant metastasis.
 In general, tumour size larger than 5 cm has worse prognosis.
 5-year survival rate with surgery combined with radiotherapy or chemotherapy in the
last 30 years has been doubled earlier rate of 9% to present rate of 15%.

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

MALIGNANT TUMOURS OF BONE:

 Bone and cartilage tumours, commonly called together as bone tumours, bone tumours
may be primary or metastatic.
 Classification of primary bone tumours based on both histogenesis and histological
criteria.
A. OSSEOUS TUMOURS
 I. Bone-forming (osteogenic, osteoblastic) tumours: Ex: Benign: Osteoid osteoma,
Osteoblastoma
Malignant: Osteosarcoma
 II. Cartilage-forming (chondrogenic) tumours:
 Ex: Benign: Enchondroma, Osteochondroma
Chondroblastoma, Chondromyxoid fibroma
Malignant: Chondrosarcoma
 III. Haematopoietic (marrow) tumours:
Ex: Malignant: Multiple myeloma, malignant lymphoma
 Unknown: Benign: Giant cell tumour(osteoclastoma)
 Malignant: Malignant giant cell tumour, Ewing’s
sarcoma, Adamantinoma of long bones

B. NON-OSSEOUS TUMOURS
 I. Vascular tumours: Benign: Haemangioma
Malignant: Haemangioendothelioma, Haemangiopericytoma Angiosarcoma
 II. Fibrogenic tumours: Benign: Non-ossifying fibroma Malignant: Fibrosarcoma
 III. Neurogenic tumours: Benign: Neurilemmoma and neurofibroma,
Malignant: Neurofibrosarcoma
IV. Lipogenic tumours: Benign: Lipoma
Malignant: Liposarcoma
V. Histiocytic tumours: Benign: Fibrous histiocytoma
Malignant: Malignant fibrous histiocytoma
  Anatomic locations of common primary bone and cartilage tumours.

Osteosarcoma:
 Also called Osteogenic sarcoma, most common primary malignant tumour of the bone.
The tumour is characterized by formation of osteoid or bone, or both, directly by
sarcoma cells.
 It comprises one fifth of all bone tumours.
 Most common primary malignant tumour of bone, exclusive of lymphoma and Multiple
myeloma.
 Age group: 10-20 yrs.
 Sex: M:F : : 2:1
Locations: The tumour arises from metaphysis of bone.
 60% are located around knee joint.
 Flat bones are involved in patients > 25 yrs. of age.
Pathogenesis: Two thirds of cases show mutations in retinoblastoma gene and many tumours
contain p53 gene mutation.
 Osteosarcoma of two types:
 Primary osteosarcoma: When there is no underlying bone pathology.
 Secondary osteosarcoma: when it develops in patients with Paget disease or post
exposure to radiation.
Clinicoradiological features: Clinically present as painful enlarging masses.
 X-ray findings: Codman triangle classically seen, which is formed due to elevation of
periosteum away from the matrix.
Gross morphology: They are bulky tumours, Which are gritty, grey white and contains areas
hemorrhages and cystic degeneration.

Microscopic features: Histologically tumour cells are pleomorphic and display osteoblastic
differentiation producing oven bone(malignant osteoid) which has coarse, lace like architecture.
 Histological sub types:
 Osteoblastic variant
 Chondroblastic variant
 Fibroblastic variant
 Telangiectatic variant
 Small cell variant
 Giant cell variant

Ewing’s sarcoma (ES)

 is an uncommon and highly malignant bone tumour composed of uniform small round
cells.
 Epidemiology: 5% of all bone tumours.
 Age group: 5-10 yrs.
 Sex: M: F :: 2 : 1
 These are second most common child hood bone sarcomas, after osteosarcoma.
Pathogenesis:
 It is thought to arise from primitive marrow elements or immature mesenchyme.
 Ewing’s sarcoma includes 3 variants:
 i) classic (skeletal) Ewing’s sarcoma;
 ii) soft tissue Ewing’s sarcoma; and
 iii) primitive neuroectodermal tumour (PNET).
 The three are linked together by a common neuroectodermal origin and by a common
cytogenetic translocation abnormality t(11; 22) (q24; q12).
Locations:
 Ewing’s sarcoma arises in the medullary canal of diaphysis or metaphysis.
 The common sites are shafts and metaphysis of long bones, particularly femur, tibia,
humerus and fibula, although some flat bones such as pelvis and scapula may also be
involved.
Clinical features:
 include pain, tenderness and swelling of the affected area accompanied by fever,
leucocytosis and elevated ESR.
 These signs and symptoms may lead to an erroneous clinical diagnosis of osteomyelitis.
However, X-ray examination reveals a predominantly osteolytic lesion with patchy
subperiosteal reactive bone formation producing characteristic ‘onion-skin’ radiographic
appearance.
Gross morphology:
 Ewing’s sarcoma is typically located in the medullary cavity and produces expansion of
the affected diaphysis (shaft) or metaphysis, often extending into the adjacent soft
tissues. The tumour tissue is characteristically grey-white, soft and friable.
Microscopic features:
 Ewing’s tumour shows the following histological characteristics:
 1. Pattern The tumour is divided by fibrous septa into irregular lobules of closely-packed
tumour cells. These tumour cells are characteristically arranged around capillaries
forming pseudorosettes.
 2. Tumour cells individual tumour cells, comprising the lobules are small and uniform
resembling lymphocytes and have ill-defined cytoplasmic outlines, scanty cytoplasm and
round nuclei having ‘salt and pepper’ chromatin and frequent mitoses.
Giant cell tumour:
 It is a locally aggressive potentially malignant tumour characterized by the presence of
“osteoclastic multi nucleated giant cells” randomly and uniformly distributed in the
background of proliferating mononuclear cells.
Epidemiology:
 Giant cell tumour occurs in patients between 20 and 40 years of age with no sex
predilection.
Locations:
 The tumour arises in the epiphysis of long bones close to the articular cartilage.
 Most common sites of involvement are lower end of femur and upper end of tibia (i.e.
about the knee), lower end of radius and upper end of fibula.
Clinical features:
 Presentation include pain, especially on weight-bearing and movement, noticeable
swelling and pathological fracture.
Radiologically,
 Giant cell tumour appears as a large, lobulated and osteolytic lesion at the end of an
expanded long bone with characteristic ‘soap bubble’ appearance.
Gross morphology:
 The tumour clearly circumscribed with light brown and soft cut surface. Numerous
hemorrhagic and necrotic areas may be seen. Aggressive tumours penetrate the bone
cortex into the surrounding soft tissue.
Microscopic features:
 The tumour is composed of sheets of uniform oval mononuclear cells with syncytial
growth pattern.
 There are numerous osteoclastic like giant cells seen with 50-100 nuclei.
 There is variable amount of mitoses seen.

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

Soft tissue tumours

Liposarcoma:
 Liposarcoma is one of the most common sarcomas of adulthood. It occurs mainly in
people in their 50s to60s in the deep soft tissues of the proximal extremities and
 in the retroperitoneum.
 Amplification of 12q13-q15 and t(12;16) are characteristic of well-differentiated and
myxoid liposarcomas, respectively.
 One of the key genes in the amplified region of chromosome 12q is MDM2, which you
will recall encodes a potent inhibitor of p53.
 Pleomorphic liposarcomas contain complex karyotypes without reproducible genetic
abnormalities.

Morphology:
 Liposarcomas are histologically divided into three morphologic subtypes:
 • Well-differentiated liposarcoma contains adipocytes with scattered atypical spindle
cells (Fig. 26-50A).
 • Myxoid liposarcoma contains abundant basophilic extracellular matrix, arborizing
capillaries and primitive cells at various stages of adipocyte differentiation reminiscent
of fetal fat (Fig. 26-50B).
 • Pleomorphic liposarcoma consists of sheets of anaplastic cells, bizarre nuclei and
variable amounts of immature adipocytes (lipoblasts).

Skeletal Muscle Tumors:

Rhabdomyosarcoma
 is a malignant mesenchymal tumor with skeletal muscle differentiation. Three subtypes
are recognized: alveolar (20%), embryonal (60%) and pleomorphic (20%).
 Rhabdomyosarcoma (alveolar and embryonal) is the most common soft tissue sarcoma
of childhood and adolescence, usually appearing before age 20. Pleomorphic
rhabdomyosarcoma is seen predominantly in adults.
 Rhabdomyosarcomas are aggressive neoplasms that are usually treated with surgery
and chemotherapy, with or without radiation therapy. The histologic type and location
of the tumor influence survival. The botryoid variant of embryonal rhabdomyosarcoma
has the best prognosis, while the pleomorphic subtype is often fatal.

Leiomyosarcoma:
 Leiomyosarcoma accounts for 10% to 20% of soft tissue sarcomas. They occur in adults
and afflict women more frequently than men.
 Most develop in the deep soft tissues of the extremities and retroperitoneum. A
particularly deadly form arises from the great vessels, especially the inferior vena cava.
 Leiomyosarcomas present as painless firm masses. Retro peritoneal tumors may be
large and bulky and cause abdominal symptoms.
 They consist of eosinophilic spindle cells with blunt-ended, hyperchromatic nuclei
arranged in interweaving fascicles.
  Ultrastructurally, the tumor cells contain bundles of thin filaments with dense bodies
and pinocytic vesicles, and individual cells are surrounded by basal lamina.
Immunohistochemically, they stain with antibodies to smooth muscle actin and desmin.
 Treatment depends on tumor size, location, and grade.Superficial or cutaneous
leiomyosarcomas are usually small and have a good prognosis, whereas those of the
retroperitoneum are large, cannot be entirely excised, and cause death by both local
extension and metastatic spread, especially to the lungs.

 Soft tissue Tumors of Uncertain Origin:

 Synovial sarcoma, (this name is a misnomer), as these tumors can present in locations
(chest wall, head and neck) that lack synovium and their morphologic features are
inconsistent with an origin from synoviocytes.
 Synovial sarcomas account for approximately 10% of all soft tissue sarcomas and rank as
the fourth most common sarcoma. Most occur in people in their 20s to 40s.
 Most synovial sarcomas show a characteristic chromosomal translocation t(x;18)
(p11;q11) producing SS18-SSX1, -SSX2, or -SSX4 fusion genes that encode chimeric
transcription factors.

Malignant tumors of the skin

 There are three major types of skin cancers:
 Basal cell carcinoma (BCC),
 Squamous cell carcinoma (SCC), and
 Melanoma.
 The first two skin cancers are grouped together as non-melanoma skin cancers. Other
unusual types of skin cancer include Merkel cell tumors and dermatofibrosarcoma
protruberans.

Classification: There are three main types of skin cancer:

Squamous-cell skin cancer (squamous-cell carcinoma), Basal-cell skin cancer (basal-cell
carcinoma) (BCC), (SCC) and Malignant melanoma.
squamous-cell Commonly presents as a red, crusted, or scaly patch or bump.
carcinoma Often a very rapidly growing tumor.

Basal-cell Note the pearly translucency to fleshy color, tiny blood vessels
carcinoma on the surface, and sometimes ulceration which can be characteristics.
The key term is translucency.

Malignant These are commonly asymmetrical in shape and/or pigment

melanoma Distribution , with an irregular border, color variation, and
 often greater than 6 mm diameter.
Squamous Cell Carcinoma:
 Squamous cell carcinoma is the second most common tumor arising on sun-exposed
sites in older people, exceeded only by basal cell carcinoma.
 These tumors have a higher incidence in men than in women. Invasive squamous cell
carcinomas are usually discovered while they are small and resectable.
 Less than 5% of these tumors metastasize to regional nodes; these lesions are generally
deeply invasive and involve the subcutis.
Pathogenesis:
 The most important cause of cutaneous squamous cell carcinoma is DNA damage
induced by exposure to UV light

 In Squamous cell carcinoma in situ, cells with atypical (enlarged and hyperchromatic)
nuclei involve all levels of the epidermis.
 Invasive squamous cell carcinoma shows variable degrees of differentiation, ranging
from tumors composed of polygonal cells arranged in orderly lobules and having
numerous large areas of keratinization, to neoplasms consisting of highly anaplastic cells
that exhibit only abortive, single-cell keratinization (dyskeratosis).
 The latter tumors may be so poorly differentiated that immunohistochemical stains for
keratins are needed to confirm the diagnosis

Gross description:
 Often hyperkeratotic scaly plaque
 May have induration, ulceration, hemorrhage.
Microscopic (histologic) description
 Carcinoma of keratinocytes that infiltrates the dermis
 An associated precursor lesion (actinic keratosis/ keratinocytic dysplasia / Squamous cell
carcinmoa) is often present
 Spectrum of histologic features; all share downward growth below level of adjacent or
overlying epidermis
 Grading based on degree of differentiation and keratinization
 Well differentiated: easily recognizable squamous epithelium, abundant
keratinization, intercellular bridges apparent, minimal pleomorphism, mitotic
figures basally located
 Moderately differentiated: focal keratinization; features between well and
poorly differentiated
 Poorly differentiated: no / minimal keratinization, marked nuclear atypia, may
be difficult to establish squamous differentiation
 Undifferentiated: no keratinization, immunohistochemistry is usually necessary
to confirm the diagnosis and to exclude melanoma or sarcoma

 Basal-cell carcinoma:
  cancer grows slowly and can damage the tissue around it but is unlikely to spread to
distant areas or result in death. It often appears as a painless raised area of skin that
may be shiny with small blood vessels running over it or may present as a raised area
with an ulcer.
 Pathogenesis:
 Risk factors include exposure to ultraviolet light having, lighter skin, radiation therapy,
long-term exposure to arseni and poor immune system immune function.
 Diagnosis often depends on skin examination, confirmed by tissue biopsy.

Micrograph of a basal cell basal carcinoma showing the characteristi histomorphologic

features (peripheral palisading, myxoid stroma, artefactual clefting).

Melanoma
 is the most deadly of all skin cancers and is strongly linked to acquired mutations caused
by exposure to UV radiation in sunlight.
 Melanoma is a relatively common neoplasm that can be cured if it is detected and
treated when it is in its earliest stages.
 The great preponderance of melanoma arises in the skin; other sites of origin include
the oral and anogenital mucosal surfaces (i.e., oropharynx, gastrointestinal and
genitourinary tracts), esophagus, meninges, and the uvea of the eye. The
 following comments apply to cutaneous melanomas.
 A, Typical lesions are irregular in contour and pigmentation. Macular areas correlate
with the radial growth phase, while raised areas correspond to nodular aggregates of
malignant cells in vertical growth phase.
 B, Radial growth phase, showing irregular nested and single-cell growth of melanoma
cells within the epidermis and an underlying inflammatory response within the dermis.
 C, Vertical growth phase, demonstrating nodular aggregates of infiltrating cells.
  D, High-power view of melanoma cells. The inset shows a sentinel lymph node with a
tiny cluster of melanoma cells (arrow) staining for the melanocytic marker HMB-45. Even
small numbers of malignant cells in a draining lymph node may confer a worse
prognosis.

 Basal-cell cancer grows slowly and can damage the tissue around it but is unlikely to
spread to distant areas or result in death. It often appears as a painless raised area of
skin that may be shiny with small blood vessels running over it or may present as a
raised area with an ulcer.
 Squamous-cell skin cancer is more likely to spread.[5] It usually presents as a hard lump
with a scaly top but may also form an ulcer
 Melanomas are the most aggressive. Signs include a mole that has changed in size,
shape, color, has irregular edges, has more than one color, is itchy or bleeds

Haematology – ANAEMIA
Anaemia:
• is defined as reduced haemoglobin concentration in blood below the lower limit (9.5
g/dl) of the normal range for the age and sex of the individual.
• Normal values:
• In adults: 13.0 – 17.0 g/dl for males
• 11.5 – 15.5 g/dl for females.
• Newborn infants (have higher haemoglobin level) : 15.0 – 18.0 g/dl
Classification of Anaemias:
• Numerous classifications have been proposed. The most acceptable one is
A. Based on Pathophysiology (aetiology)
• Anaemias are broadly classified into 3 categories:
1. Anaemia due to increased blood loss.
 a) Acute post-hemorrhagic anaemia
 b) Chronic blood loss

2. Anaemia due to failure of erythrocyte production.

 a) Cytoplasmic maturation defects
• 1. Deficient haem synthesis: Iron deficiency anaemia
• 2. Deficient globin synthesis: Thalassaemic syndromes
 b) Nuclear maturation defects
• Vitamin B12 and/or folic acid deficiency: Megaloblastic anaemia
 c) Defect in stem cell proliferation and differentiation
• 1. Aplastic anaemia
• 2. Pure red cell aplasia
  d) Anaemia of chronic disorders
 e) Bone marrow infiltration
 f ) Congenital anaemia

3. Anaemia due to increased destruction (Haemolytic anaemias):

 A. Extrinsic (extracorpuscular) red cell abnormalities.
 B. Intrinsic (intracorpuscular) red cell abnormalities.

B. Based on morphology
• I. Microcytic, hypochromic
• II. Normocytic, normochromic
• III. Macrocytic, normochromic
Iron deficiency anaemia:
• Most common type of nutritional in world caused by deficiency iron human body.
• The iron required for haemoglobin synthesis is derived from 2 primary sources—
• Ingestion of foods containing iron (e.g. leafy vegetables, beans, meats, liver etc) and
• Recycling of iron from senescent red cells
• Iron absorption: M – 1mg/day, F – 1.5 mg/day.
Etiology:
 Blood loss: Peptic ulcer, Gastric malignancies, Alcoholic gastritis, Salicylate ingestion,
Hookworm infestation, Hemorrhoids
 Inadequate dietary intake: Infants, Pregnancy, Adolescents, Poor diet due to low
economic status, Malabsorption, Tropical sprue, Post-gastrectomy, Atrophic gastritis,
Achlorohydria.
Clinical features:
Weakness, fatigue, lethargy, memory loss, irritability, deficient learning, Pica(perversion of
appetite leading to bizarre eating)
Peripheral blood smear findings:
 Decreased hemoglobin(mean Hb-8.4 gm/dl).
 Decreased MCV(55-74 fl), MCH(14-26 pg) and MCHC (22-31 g/dl).
 Increased red cell distribution width(RDW).
 Erythrocytes are microcytic and hypochromic with few target cells and elliptocytes.
 Leucocytes are normal or increased eosinophilia in hookworm infestation.
 Platelets are normal, increased or decreased.
 Reiculocyte percentage is decreased.
Bone marrow findings:
 Micronormoblastic erythroid hyperplasia.
Other investigations:
 Iron studies: Serum iron decreased(<30mg/dl).
 Total iron binding capacity – increased
 Transferrin saturation decreased (< 15%)
 Serum ferritin – decreased (< 12mg/L).
THALASSAEMIA:
It is an heterogenous group of inherited disorders caused by genetic mutation in α or β globin
genes, leading to deficient production of a α or β globin chains of hemoglobin A.
Classification of α – thalassaemia:
 Hydrops fetalis – No α chain synthesis; lethal in utero
 Hemoglobin H disease – Severe anemia resembling thalassemia intermedia.
 α – thalassaemia trait – Asymptomatic resembling thalassemia minor.
 silent carrier – No erythrocyte abnormality.
Classification of β – thalassaemia:
 Thalassemia major – Severe anemia occurs which requires blood transfusion.
 Thalassemia intermedia – Severe diseases which does not require blood transfusion.
 Thalassemia minor – Asymptomatic with mild or no anaemia.
Pathogenesis:
 Hemoglobin A composed of 2α and 2β globin chains coded by two α globin genes on
chromosome 16, one β globin gene on chromosome on 11.
 β – thalassaemia occur in mutations in β gene leading to deficient or absent β globin
protein synthesis.
 α – thalassaemia occur in mutations in α globin gene leading to impaired synthesis of α
globin protein.
Clinical features:
 Symptoms of anemia.
 Failure to thrive and gain weight.
 Diarrhea, fever and enlarged abdomen.
 Growth retardation, brown pigmentation of skin.
 Massive splenomegaly.
 Facial bone deformities, with frontal bossing of skull with hair on end appearance on X-
ray.
 Gall stones, gout and icterus due to hemolysis.
Peripheral blood smear findings:
 Hemoglobin low; 2 – 3 gm/dl in thalassemia major.
 Decreased – MCV. MCH and MCHC.
 Erythrocytes are microcytic and hypochromic with schistocytes, ovalocytes, target cells,
polychromatophils and nucleated erythrocytes seen.
 Leucocytes and platelets are normal.
 RDW – increased.
 Reticulocyte count – increased (<10%).
Bone marrow findings:
 Micronormoblastic erythroid hyperplasia with myeloid : erythroid ratio up to 1:10.
Other investigations:
 Iron studies:
- Serum iron – normal or increased.
- Total iron binding capacity normal or decreased.
- Transferrin saturation – increased.
 - Serum ferritin normal or increased.
 Hemoglobin electrophoresis – In thalassemia major, absence of Hb A with 90% Hb F and
low, normal or increased Hb A2.

SICKLE CELL ANAEMIA:

It is a type of hereditary hemoglobinopathy characterized by production of defective
hemoglobin(Hb S).
Etiopathogenesis:
 Hemoglobin is formed due to point mutation in at 6th position of β globin chain leading
to substitution of valine for glutamic acid.
 Underdeoxygenated state, HbS is aggregated and polymerized converting liquid cell
cytosol to viscid gel.
 On oxygenation, it depolymerizes but repeated deoxygenation makes it an irreversible
process.
 Irreversibly sickled cells are destroyed in spleen.
Clinical features:
 Symptoms appear at 6 months of age.
 Symptoms of moderate to severe chronic hemolytic anemia.
 Vasoocclusive crisis – due to blockade of microvasculature leading to infarction of
genitourinary tract, liver, lung, bone and spleen; dactylitis with chronic leg ulcers.
 Spleen is enlarged first followed by infarction and fibrosis leading to autosplenectomy
by 10 years of age
 Bacterial infection like pneumonia is commonly seen.
 Aplastic crisis – After early erythroid hyperplasia, the bone marrow undergo hypoplasia
followed by aplasia leading to infections and bleeding manifestatioins.
Peripheral blood smear findings:
 Hemoglobin – decreased (6-10%).
 Hematocrit – 18-30%.
 Reticulocyte count – increased(10-20%)
 Erythrocytes are normocytic and normochromic with presence of sickled cells and target
cells.
 Leucocytes are normal or decreased.
 Platelets are normal, increased or decreased.
 RDW – Increased.
Bone marrow findings:
 Marrow shows erythroid hyperplasia.
Other investigations:
 Hemoglobin electrophoresis – At Ph 8.5 on cellulose acetate, 85-90% HbS is detected
with rest being HbF and HbA2; HbA – absent.
 Sickling test – Blood is deoxygenated with sodium metabisulphite and examine under
the microscope on a glass slide with sealed cover slip after 30 minutes show sickle cells.


POLYCYTHEMIA:
  It is a myeloproliferative disorder characterized by unregulated proliferation of
erythroid elements in the bone marrow and an increase in erythroid concentration in
peripheral blood.
Classification:
 Polycythemia vera.
 Secondary polycythemia
Appropriate erythropoietin production.
- High attitude
- Chronic Obstructive Pulmonary Diseases.
- Pickwickian syndrome

Inappropriate erythropietin production

- Tumour
- Renal ischemia
 Familial erythropoiesis.
Clinical features:
 Age group: 40-60 years; peak 6th decade of life.
 Males affected more than females.
 Head ache, weakness, pruritis, weight loss and fatigue due increased erythrocyte mass.
 Gingival bleeding, menorrhagia, hemoptysis, gastro-intestinal bleeding
 Spleenomegaly and hepatomegaly
 In late stages: anemia symptoms, infection and bleeding occur due to bone marrow
failure.
Peripheral blood smear findings:
 Hemoglobin 18 gms%.
 Hematocrit 55-60%
 Erythrocyte count 6-10 millions/cumm.
 Erythrocytes are normocytic and normochromic in early stages with microcytic and
hypochromic cells in late stages due to iron deficiency.
 Leucocyte count is 12,000-20,000/cumm. With mild shift to left.
 Platelet count >4,00,000/cumm.
Bone marrow findings:
 Moderate to marked increase in bone marrow cellularity.
 Myeloid to erythroid ratio is normal.
 Eosinophilic precursors are increased.
 Megakaryocytes are increased in number.

APLASTIC ANAEMIA:
• Aplastic anaemia is defined as pancytopenia (i.e. simultaneous presence of anaemia,
leucopenia and thrombocytopenia) resulting from aplasia of the bone marrow.
• The underlying defect in all cases appears to be sufficient reduction in the number of
haematopoietic pluripotent stem cells which results in decreased or total absence of
these cells for division and differentiation.
Etiology:
 Acquired causes:
 Idiopathic
 Drugs – Chloramphenicol, phenylbutazone, gold, sulpha drugs, antihistamines,
phenytoin.
 Chemicals – Benzene, insecticides, hair dyes, Ccl4, arsenic , cancer chaemotherapeutic
drugs
 Ionizing radiation.
 Infections – Human parovirus, hepatitis, infectious mononucleosis, influenza, measles
etc.
 Pregnancy
 PNH
Congenital causes
 Fanconi anemia.
 Familial aplastic anemia.
 Diamond Blackfan Syndrome
Clinical features:
 Bleeding with skin hemorrhages.
 Symptoms of anemia.
 Infections leading to fever
 Peripheral blood findings:
 Hemoglobin <7g/dl.
 Erythrocytes are reduced in number with normocytic and normochromic appearance.
 Leucocytes are reduced in number neutropenia preceeds leucopenia. Lymphocyte and
monocyte counts are normal.
 Platelets are reduced in number.
Bone marrow findings:
 Bone marrow is hypocellular with >70% fat
 Bone marrow aspiration is different and often yields dry tap,

Leukemias
 Leukemia, is a group of blood cancers that usually begin in the bone marrow and result
in high numbers of abnormal blood cells. These blood cells are not fully developed and
are called blasts or leukemia cells.
 Symptoms may include bleeding and bruising, fatigue, fever, and an increased risk of
infections. These symptoms occur due to a lack of normal blood cells. Diagnosis is
typically made by blood tests or bone marrow biopsy.
 The exact cause of leukemia is unknown.
 A combination of genetic factors and environmental (non-inherited) factors are believed
to play a role.
 Risk factors include smoking, ionizing radiation, some chemicals (such as benzene), prior
chemotherapy, and Down syndrome.
  People with a family history of leukemia are also at higher risk.
 There are four main types of leukemia—acute lymphoblastic leukemia (ALL), acute
myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) and chronic myeloid
leukemia (CML)—as well as a number of less common types.
 Leukemias and lymphomas both belong to a broader group of tumors that affect the
blood, bone marrow, and lymphoid system, known as tumors of the hematopoietic and
lymphoid tissues.

Four major kinds of leukemia Cell types, Acute and Chronic Lymphocytic leukemia
Acute lymphoblastic leukemia (or "lymphoblastic") (ALL),
Chronic lymphocytic leukemia(CLL)
Myelogenous leukemia ("myeloid" or "nonlymphocytic")
Acute myelogenous leukemia (AML or myeloblastic)
Chronic myelogenous leukemia (CML).

Signs and symptoms:

• Common symptoms of chronic or acute leukemia
• The most common symptoms in children are easy bruising, pale skin, fever, and
an enlarged spleen or liver.
• Damage to the bone marrow, and displacing the normal bone marrow cells with higher
numbers of immature white blood cells, results in a lack of blood platelets, which are
important in the blood clotting process. This means people with leukemia may easily
become bruised, bleed excessively, or develop pinprick bleeds (petechiae).

• White blood cells, which are involved in fighting pathogens, may be suppressed or
dysfunctional.
• This could cause the person's immune system to be unable to fight off a simple infection
or to start attacking other body cells.
• Because leukemia prevents the immune system from working normally, some people
experience frequent infection, ranging from infected tonsils, sores in the mouth,
or diarrhea to life-threatening pneumonia or opportunistic infections.
• Finally, the red blood cell deficiency leads to anemia, which may
cause dyspnea and pallor.
Acute lymphoblastic leukemia (ALL)
• is the most common type of leukemia in young children. It also affects adults, especially
those 65 and older.
• Standard treatments involve chemotherapy and radiotherapy.
• Subtypes include precursor B acute lymphoblastic leukemia, precursor T acute
lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.
• While most cases of ALL occur in children, 80% of deaths from ALL occur in adults.
Chronic lymphocytic leukemia (CLL)
• most often affects adults over the age of 55. It sometimes occurs in younger adults, but
it almost never affects children.

• Two-thirds of affected people are men. The five-year survival rate is 85%. It is incurable,
but there are many effective treatments. One subtype is B-cell prolymphocytic
leukemia, a more aggressive disease.

Acute myelogenous leukemia (AML)

• occurs far more commonly in adults than in children, and more commonly in men than
women.
• It is treated with chemotherapy. The five-year survival rate is 20%. Subtypes of AML
include acute promyelocytic leukemia, acute myeloblastic leukemia, and acute
megakaryoblastic leukemia.
Chronic myelogenous leukemia (CML)
• occurs mainly in adults; a very small number of children also develop this disease. It is
treated with imatinib (Gleevec in United States, Glivec in Europe) or other drugs.
• The five-year survival rate is 90%. One subtype is chronic myelomonocytic leukemia.
Lymphomas
• is the name for a group of blood cancers that develop in the lymphatic system. Which is
part of the body's germ-fighting network.
• The lymphatic system includes the lymph nodes (lymph glands), spleen, thymus gland
and bone marrow.
• Lymphoma can affect all those areas as well as other organs throughout the body.
• Lymphoma, involves the lymphocytes or cells of the immune system.

• These cells typically have undergone genetic changes, which makes them cancerous.

• Lymphoma is characterized by enlarged lymph nodes usually without pain and fatigue,
fever, and weight loss are common symptoms to many types of lymphoma.

• Treatments include medications, radiation therapy, and bone marrow transplant.

Causes
• Lymphoma develops when the white blood cells, called lymphocytes, undergo a genetic
change and start multiplying rapidly
• This leads to accumulation of diseased lymphocytes in the body
• Some of the factors that influence this genetic change include:
• - Increasing age
• - Gender: Men are more at risk of lymphoma
• - Diseased or suppressed immune system
• - Certain infections such as HIV, Epstein- Barr virus, or Helicobacter pylori infections
• - Family history
Symptoms include:
• Painless enlargement of lymph nodes, particularly in the neck (cervical
lymphadenopathy), armpit, and groin
• Fatigue
• Fever and/or chills
• Night sweats
• Shortness of breath
• Loss of appetite
• Weight loss
• Persistent back or bone pain
• Headaches

Classification of lymphomas
• There are many types of lymphoma exist, but the main subtypes are:
• Hodgkin's lymphoma (formerly called Hodgkin's disease) (10%)
• Non-Hodgkin's lymphoma (90%).
 • Hodgkin lymphoma has characteristics that distinguish it from other diseases classified
as lymphoma, including the presence of Reed-Sternberg cells.

• Most of the non-Hodgkin lymphomas are

• B-cell lymphomas, and either grow quickly (high-grade) or slowly (low-
grade). There are over a dozen types of B-cell non-Hodgkin lymphomas.
The rest are T-cell lymphomas, named after a different cancerous white blood
cell, or lymphocyte.

Classification of Hodgkin lymphomas

Hodgkin Lymphoma classified into 5 Types:

• 1. Nodular Sclerosing Hodgkin Lymphoma (NSHL) This is the most common type of
Hodgkin lymphoma. In the developed countries, 60 to 80 percent of the ...
• 2. Mixed Cellularity Hodgkin Lymphoma (MCHL)
• 3. Lymphocyte Depleted Hodgkin Lymphoma (LDHL)
• 4. Lymphocyte-rich Classic Hodgkin Lymphoma (LRCHL)
 • 5. Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL)
How is lymphoma diagnosed?
• A biopsy typically is taken if a doctor suspects lymphoma. This involves removing cells
from an enlarged lymph node. A doctor known as a hematopathologist will examine the
cells to determine if lymphoma cells are present and what cell type they are.
• If the hematopathologist detects lymphoma cells, further testing can identify how far
the cancer has spread. These tests can include a chest X-ray, blood testing, or testing
nearby lymph nodes or tissues.
• Imaging scans, such as a computed tomography (CT) or magnetic resonance imaging
(MRI) scans may also identify additional tumors or enlarged lymph nodes.
Conditions related to Lymphomas
• Non-Hodgkin's LymphomaA cancer of the immune system that develops from abnormal
lymphocytes.
• Hodgkin's LymphomaA cancer of the immune system that develops from abnormal B-
cells.
• LeukaemiaA type of cancer which affects the production and function of blood cells.
• Swollen Lymph NodesLymph nodes become swollen in response to illness, infection, or
stress.
• Multiple Myeloma Cancer of mature plasma cells in the bone marrow.
• Chronic Lymphocytic Leukaemia A type of cancer that begins in the lymphocytes of
bone marrow and extends into the blood.
• Itching Irritation of the skin that is uncomfortable and results in scratching.
Classification: Based on WHO guidelines:
1. Hodgkin lymphoma:
- Nodular sclerosis
- Mixed cellularity
- Lymphocyte rich
- Lymphocyte depletion
- Lymphocyte predominance
2. Non-Hodgkin lymphoma:
B-cell lymphoma, T-cell lymphoma
B-cell lymphoma
 Chronic/Small lymphocytic lymphoma
 B-cell prolymphocytic lymphoma
 Splenic and nodal marginal zone lymphoma
 Extra nodal marginal zone lymphoma
 Mantle cell lymphoma
 Follicular lymphoma
 Marginal zone lymphoma
 Hairy cell leukemia
 Plasma cell myeloma
 Diffuse large B-cell lymphoma
 Burkitt’s lymphoma
T-cell lymphoma:

 - Precursor T-cell neoplasms

 - Peripheral T-cell and NK –cell neoplasms
 T-cell prolymphocytic lymphoma
 Large granular lymphocytic leukemia
 Mycosis fungoides/Sezary syndrome.
 Peripheral T-cell lymphoma
 Anaplastic large cell lymphoma
 Angioimmunoblastic T-cell lymphoma
 Enteropathy associated T-cell lymphoma
 Paniculitis like T-cell lymphoma
 Hepatosplenic γδ T-cell lymphoma
 Adult T-cell lymphoma
 NK cell lymphoma

Diseases of the kidneys

NEPHRITIC SYNDROME:

It is a classical syndrome characterized by:

Haematuria,
Proteinuria,
Decreased GFR(Glomerular Filtration Rate) resulting elevation of BUN(Blood Urea
Nitrogen), S. creatinine
Oliguria
Salt and water retention
Edema and
Hypertension

Pathogenesis:

 Glomerulonephritis caused by immunological mechanisms.

 Both antibody and cell mediated immunity play a role.
 3 mechanisms of antibody induced inflammation are:
 In situ immune complex formation.
 Deposition of circulating immune complexes.
 Anti-neutrophil cytoplasmic antibody.

Causes:
  Secondary causes:
 Diabetes mellitus
 SLE
 Amyloidosis
 Infections
 Drugs – Non steroid anti inflammatory drugs(NSAID), Pencillamine.
 Malignancies – carcinomas, lymphomas

Primary causes:

 The causes are in decreasing order of frequency:

 Crescentic glomerulonephritis(RPGN).
 Acute post-streptococcal glomerulonephritis(PSGN)
 Membranoproliferative glomerulonephritis(MPGN)
 Focal segmental glomerulosclerosis(FSGS)
 Membranous glomerulonephritis(MGN)

Crescentic glomerulonephritis(RPGN):

 It is a syndrome associated with severe glomerular injury characterized by presence of

crescents in most of the glomeruli.

Classification:

 Type I RPGN(Anti-GBM antibody type)

 Type II RPGN (Immune complex mediated)
 Type III RPGN(Pauci-immune)

How is lymphoma diagnosed?

• A biopsy typically is taken if a doctor suspects lymphoma. This involves removing cells
from an enlarged lymph node. A doctor known as a hematopathologist will examine the
cells to determine if lymphoma cells are present and what cell type they are.
• If the hematopathologist detects lymphoma cells, further testing can identify how far
the cancer has spread. These tests can include a chest X-ray, blood testing, or testing
nearby lymph nodes or tissues.
• Imaging scans, such as a computed tomography (CT) or magnetic resonance imaging
(MRI) scans may also identify additional tumors or enlarged lymph nodes.

Glomerulonephritis
Morphology:
 Grossly, kidneys are enlarged and pale with petichial hemorrhages on cortical surface.
  Microscopically, crescents are formed by proliferation of parietal cells and migration of
monocytes and macrophages in urinary space.
 Glomeruli show focal necrosis, diffuse or focal endothelial and mesangial proliferation.
Membranoproliferative glomerulonephritis(MPGN):
 It is a type of glomerulonephritis characterized by alterations in the basement
membrane, glomerular proliferation and infiltration by leucocytes.
 It is also called mesangioproliferative glomerulonephritis.
Classification:
 Primary or idiopathic MPGN
 There are two types based on ultrastructural features:
 Type I or Type II
 Microscopically, glomeruli are large and hypercellular.
 There is mesangial and capillary endothelial cell hypercellularity seen.
 Glomerular capillary wall shows tram track appearance.
Secondary MPGN:
 It arises in following conditions:
 Autoimmune diseases – SLE, hepatitis B, hepatitis C
 α1-antitrypsin deficiency.
 Cancers – CLL, Lymphoma.

Chronic Kidney Diseases (CKD)

 Chronic kidney disease (CKD) means, the kidneys are damaged and can’t filter blood the
way they should.
 The main risk factors for developing kidney disease are diabetes, high blood pressure,
heart disease, and a family history of kidney failure.
• Diseases and conditions that cause chronic kidney disease include:
• Type 1 or type 2 diabetes
• High blood pressure
• Glomerulonephritis (gloe-mer-u-low-nuh-FRY-tis), an inflammation of the kidney's
filtering units (glomeruli)
• Interstitial nephritis (in-tur-STISH-ul nuh-FRY-tis), an inflammation of the kidney's
tubules and surrounding structures
• Polycystic kidney disease
• Prolonged obstruction of the urinary tract, from conditions such as enlarged prostate,
kidney stones and some cancers
• Vesicoureteral (ves-ih-koe-yoo-REE-tur-ul) reflux, a condition that causes urine to back
up into your kidneys
• Recurrent kidney infection, also called pyelonephritis (pie-uh-low-nuh-FRY-tis)
Symptoms:
• Signs and symptoms of chronic kidney disease develop over time if kidney damage
progresses slowly. Signs and symptoms of kidney disease may include:
• Nausea, Vomiting
• Loss of appetite
 • Fatigue and weakness
• Sleep problems
• Swelling of feet and ankles
• Persistent itching
• Chest pain, if fluid builds up around the lining of the heart
• Shortness of breath, if fluid builds up in the lungs
• High blood pressure (hypertension) that's difficult to control
Complications
• Chronic kidney disease can affect almost every part of your body. Potential
complications may include:
• Fluid retention, which could lead to swelling in your arms and legs, high blood pressure,
or fluid in your lungs (pulmonary edema)
• A sudden rise in potassium levels in your blood (hyperkalemia), which could impair your
heart's ability to function and may be life-threatening
• Heart and blood vessel (cardiovascular) disease
• Weak bones and an increased risk of bone fractures
• Anemia

Diseases of the Thyroid

 GOITRE:
 It is the enlargement of thyroid gland, which reflects decreased production of
‘thyroxine’.
 Types: 1. Multinodular goitre
 2. Diffuse toxic goitre
 1. Multinodular goitre: It refers to irregular enlargement of thyroid gland with
formation of multiple nodules.
 Gross morphology:
 The thyroid gland is asymmetrically enlarged with formation of multiple nodules.
 C/s shows irregular large nodules filled with colloid and show degenerative changes like
fibrosis, haemorrhages and calcification.
Microscopy:
 There are variable sized thyroid follicles, filled with colloid and lined by flattened
follicular epithelial cells.
 Variable amount of calcification, fibrosis and haemorrhages are seen.

 2.Diffuse non-toxic goitre: Refers to diffuse enlargement of thyroid gland with no

nodule formation.
 F:M ratio is 8:1
 Age group: Adolscence and pregnancy.
Gross morphology:
 The thyroid gland is diffusely and symmetrically enlarged and weighs 100–150 gm.
Microscopy:
  There are two phases:
 Hyperplastic phase: In this phase, follicles are small, lined by tall columnar epithelium
with scanty colloid.
 Involution phase: In this phase, follicles are large lined by flattened epithelium and
filled with abundant colloid

Diseases of the Cardio-vsascular system(Hreart)

MYOCARDIAL INFARCTION:
Is defined as death of cardiac muscle secondary to ischemia.
• Acute MI accounts for 10-25% of all deaths. Due to the dominant etiologic role of
coronary atherosclerosis
• Age: Acute MI may virtually occur at all ages, though the incidence is higher in the
elderly. About 5% of heart attacks are under the age of 40 years.
• Sex: Males are at higher risk of developing acute MI as compared to females. Women
during reproductive period
ETIOPATHOGENESIS:
 Myocardial Infarction: i) Diminished coronary blood flow e.g. in coronary artery disease,
shock.
• ii) Hypertrophy of the heart without simultaneous increase of coronary blood flow e.g.
in hypertension, valvular heart disease.
• Iii) Rupture of an atherosclerotic plaque exposes the subendothelial collagen of
coronary blood vessel
• 2. Non-atherosclerotic causes: such as coronary vasospasm, arteritis, coronary ostial
stenosis, embolism, Thrombotic diseases, trauma and outside compression
•
MYOCARDIAL INFARCTION: Is defined as death of cardiac muscle secondary to ischemia.
Types of infarct:
 Transmural infarct:
 Involves entire thickness of muscle wall.
 Unifocal, solid.
 Occurs in distribution of specific coronary artery.
 Complications – shock, epicarditis, aneurysm.
 Subendocardial infarct:
 Involves inner one-third or half of ventricular wall
 Multifocal, patchy
 No epicarditis.
 No aneurysm formation.
 Coronary thrombosis is seen.
Location of infarction based on blood vessel involved:
 Left anterior descending branch of left coronary artery(40-50% cases)
 Anterior wall of left ventricle.
 Anterior part of interventricular septum.
 Apex of heart.
 Right coronary artery(30-40% cases)
 Posterior wall of left ventricle.
 Posterior part of interventricular septum
 Left circumflex coronary artery(15-20% cases)
 Lateral wall of left ventricle except apex of heart.
Gross morphological changes:
 First 24 hours – dark brown mottling seen.
 2-3 days - dark mottling with yellow tan centre.
 1-3 weeks – red grey depressed infarct with gelatinous appearance.
 More than 4 weeks – grey white scar formation from periphery to centre.
 5-8 weeks – complete grey white scarring.

Microscopic morphological changes:

 First 24 hrs - coagulative necrosis begins 4-12 hrs. after attack, myocyte
hypereosinophilia, nuclear pyknosis, neutrophilic infiltrate begins.
 2-3 days - accumulation of neutrophils at periphery of necrotic muscle fibres, muscle
fibres show reduced striation.
 5-7 days – neutrophils abate, macrophages and lymphocytes accumulate, fibroblasts lay
collagen from 5th day.
 1-3 wks – collagen deposits, inflammation recedes sprouted capillaries are well formed
 > 4 wks – dense fibrous tissue with less cellular scar.
Serological enzyme markers:
 Troponin T and I levels-
 Most sensitive marker; absent normally
 Increase 2-4 hrs. after infarct, peak at 48 hrs. and elevated till 7-CK-MB10 days.
 Creatine kinase-
 3 isoenzymes – CK-MM, MB and BB.
 CK-MB is most sensitive.
 Increases 2-4 hrs. after infarct, peak at 24 hrs. and normal in 72 hrs.
 C – reactive protein (CRP).
 > 3mg/l associated with high risk of CVS disease.
COMPLICATIONS:
 1. Arrhythmias: Arrhythmias (or abnormalities in the normal heart rhythm) are the
most common complication in acute MI.
 2. Congestive heart failure: About half the patients with MI develop CHF which may be
in the form of right ventricular failure, left ventricular failure or both. CHF.
 3. Cardiogenic shock About 10% of patients with acute MI develop cardiogenic shock
characterized by hypotension with systolic blood pressure of 80 mmHg or less for many
days. Shock may be accompanied by peripheral circulatory failure, oliguria and mental
confusion.
• 4. Mural thrombosis and thromboembolism: The incidence of thromboembolism from
intracardiac thrombi in the leg veins is 15-45% in cases of acute MI and is the major
cause of death in 12% cases.
• 5. Rupture: Rupture of the heart occurs in up to 5% cases of acute MI causing death.
 • 6. Cardiac aneurysm: Another 5% of patients of acute MI develop aneurysm, often of
the left ventricle.
• 7. Pericarditis: Sterile pericarditis appearing on about the second day is common over
transmural infarcts.
• 8. Post myocardial infarction syndrome About 3 to 4% of patients who suffered from
acute MI develop post myocardial infarction syndrome or Dressler’s syndrome
subsequently.

Rheumatic fever (RF):

• is a systemic, post-streptococcal, nonsuppurative inflammatory disease, principally
affecting the heart, joints, central nervous system, skin and subcutaneous tissues.
• The chronic stage of RF involves all the layers of the heart (pancarditis) causing major
cardiac sequelae referred to as rheumatic heart disease (RHD).
• In Rheumatic fever : Acute arthritis migrating from joint to joint, it is well known that it
is the heart rather than the joints which is first and major organ affected.
• William Boyd years ago gave the dictum ‘rheumatism licks the joint, but bites the whole
heart’.
Etiology:
• Age: The disease appears most commonly in children between the age of 5 to 15 years
when the streptococcal infection is most frequent and intense.
• Sex: Both the sexes are affected equally, though some investigators have noted a slight
female preponderance.
• Crowding: Crowding promotes interpersonal spread of the streptococcal infection.
• Dampness: Damp and crowded environment helps to spread the infection.
• Economic factor: High in low socio-economic group.
• Recurrent infection: Recurrent attacks of rheumatic fever
Pathological changes:
• Aschoff bodies: Aschoff bodies are inflammatory granulomatous lesions present in
cardiac and extracardiac areas.
• Pancarditis: Rheumatic fever causes, inflammation and aschoff body formation in all the
three layers of the heart called pancarditis.
• Verrucal or vegetations: Vegetations are multiple nodular or warty projections
occurring on the superior surface of valves.
Complications:
• Bacterial endocarditis: due to damage of rheumatic valve.
• Valve leaflets are fibrosed and hyalinised.
• Formation of mural thrombi.
• Congestive cardiac failure.
• Corpulmonale, due to pulmonary hypertension.
• Adhesive pericarditis, if inflammation spreads to pericardium.
Lab diagnosis of RHD:
• Anti Streptolysin O(ASO), increased in the early stages of rheumatic fever.
• Group A Streptococci can be isolated from throat culture.
• Acute phase reactants: ESR rises.
 • C-reactive protein positive.

HYPERTENSION:
• It is a complex system disease characterized by sustained elevation of systolic blood
pressure > 140 mmHg or diastolic blood pressure > 90 mm of Hg.
Classification:
• Based on etiology Hypertension is classified into 2 types:
• 1. Primary or essential hypertension: In which the cause of increase in blood pressure
is unknown. Essential hypertension constitutes about 80-95% patients of hypertension.
• Causes: 1. Genetic factors 2. Racial and environmental factors 3. Risk factors modifying
the course
• 2. Secondary hypertension: In which the increase in blood pressure is caused by
diseases of the kidneys, endocrines or some other organs. Secondary hypertension
comprises remaining 5-20% cases of hypertension
• Causes: 1. Renal: i) Renovascular ii) Renal parenchymal diseases
• 2. Endocrine: i) Adrenocortical hyperfunction ii) Hyperparathyroidism iii) Oral
contraceptives
• 3. CVS: Coarctation of Aorta, Increased cardiac output
• 4. Neurogenic: Increased intracranial tension, Stress, Psychogenic, Sleep apnea.
• Based on clinical severity hypertension is classified into:
• 1. Benign hypertension: is moderate elevation of blood pressure and the rise is slow
over the years. About 90-95% patients of hypertension have benign hypertension.
• 2. Malignant hypertension: is marked and sudden increase of blood pressure to
200/140 mmHg or more in a known case of hypertension or in a previously
normotensive individual;
• The patients develop papilloedema, retinal haemorrhages and hypertensive
encephalopathy. Less than 5% of hypertensive patients develop malignant hypertension
• The environmental factors which influence hypertension are:
 Heavy consumption of salt.
 Obesity.
 Smoking.
 Stress.

INFECTIONS
Causes:
• Abscesses are caused by , Bacterial infection is the most common cause, others are
injuries, parasites, or foreign substances.
• ** An abscess is a defensive reaction of the tissue to prevent the spread of infectious
materials to other parts of the body.
• Gross: Single or multiple, vary in size few millimetres to centimetres.
• Micro: abscess contains suppurative debris, composed of live and dead neutrophils,
fibrin and coagulative necrosis.
• Treatment: Incision and drainage
Tuberculosis
Tuberculosis (TB):
• is a chronic granulomatous infectious disease usually caused by
Mycobacterium tuberculosis.
• Tuberculosis generally affects the lungs, but can also affect other parts of the body.
• Tuberculosis is spread from one person to another through the air.
• The classic symptoms of active TB are a chronic cough with blood containing mucus,
fever, night sweats and weight loss.
Tuberculosis is a chronic communicable disease caused by
 Mycobacterium tuberculosis hominis – is the most common cause tuberculosis, in
human beings.
 Mycobacterium tuberculosis bovis – It occurs mainly in cows and spread to human
beings through the milk causing intestinal tuberculosis or tonsillar tuberculosis.
 Mycobacterium tuberculosis avium and Mycobacterium tuberculosis intracellulare
are non pathogenic in normal human beings, but affected in patients with AIDS.
MODE OF TRANSMISSION:
 Human beings acquire infection with tubercle bacilli by one of the following routes:
 1. Inhalation of organisms present in fresh cough droplets or in dried sputum from an
open case of pulmonary tuberculosis.
 2. Ingestion of the organisms leads to development of tonsillar or intestinal
tuberculosis. This mode of infection of human tubercle bacilli is from self-swallowing of
infected sputum of an open case of pulmonary tuberculosis, or ingestion of bovine
tubercle bacilli from milk of diseased cows.
 3. Inoculation of the organisms into the skin may rarely occur from infected
postmortem tissue.
 4. Transplacental route results in development of congenital tuberculosis in foetus from
infected mother and is a rare mode of transmission.
Spread of tuberculosis:
 The disease spreads in the body by various routes:
 1. Local spread: This takes place by macrophages carrying the bacilli into the
surrounding tissues.
 2. Lymphatic spread: Tuberculosis bacilli may pass into lymphoid follicles of pharynx,
bronchi, intestines or regional lymph nodes resulting in regional tuberculous
lymphadenitis.
 3. Haematogenous spread: Tuberculous bacillaemia because of the drainage of
lymphatics into the venous system or due to caseous material escaping through
ulcerated wall of a vein
 4. By the natural passages Infection may spread from:
 i) lung lesions into pleura (tuberculous pleurisy);
 ii) transbronchial spread into the adjacent lung segments;
 iii) tuberculous salpingitis into peritoneal cavity (tuberculous peritonitis);
 iv) infected sputum into larynx (tuberculous laryngitis);
 v) swallowing of infected sputum (ileocaecal tuberculosis); and
  vi) renal lesions into ureter and down to trigone of bladder.
TYPES OF TUBERCULOSIS

 Lung is the main organ affected in tuberculosis while amongst the extra-pulmonary
sites, lymph node involvement is most common.
 Depending upon the type of tissue response and age, the infection with tubercle bacilli
is of 2 main types: primary and secondary tuberculosis;
 A. Primary Tuberculosis: The infection of an individual who has not been previously
infected or immunised is called primary tuberculosis or Ghon’s complex or childhood
tuberculosis.
 Primary complex or Ghon’s complex in lungs consists of 3 Components :
 1. Pulmonary component.
 2. Lymphatic vessel component.
 3. Lymph node component.
 B. Secondary Tuberculosis: The infection of an individual who has been previously
infected or sensitised is called secondary, or post-primary or reinfection, or chronic
tuberculosis.


• The primary complex is composed of 3 components: Ghon’s focus, draining lymphatics,

and hilar lymph nodes.

Secondary infection may occur from :

• Endogenous source such as reactivation of dormant primary complex; or

• Exogenous source such as fresh dose of reinfection by the tubercle bacilli.
• Secondary tuberculosis occurs most commonly in lungs. Other sites and tissues which
can be involved are lymph nodes, tonsils, pharynx, larynx, small intestine and skin.

Gross morphology:
 • Primary tuberculosis:
 TB bacilli implant in the lower part of the upper lobe and upper part of the lower lobe
of the lung.
1 – 1.5 cm grey white focus of consolidation called Ghon focus.
 Ghon focus with hilar lymph node and lymphatic s is called Ghon complex.
 Ghon complex undergo calcification to form ‘Ranke complex.’

Secondary tuberculosis:

 1-2 cm lesion in the apex of lung.

 Lesion is well circumscribed, grey white with central caseation and peripheral fibrosis.

Microscopy:

 Formation of caseating and non caseating granulomas.

 Granulomas are surrounded by lymphocytes, fibroblasts and collagen.
 Granulomas are composed of epitheloid histiocytes and multinucleated Langhans type
of giant cells.

Clinical Features and Diagnosis of Tuberculosis

 1. Referable to lungs—such as productive cough (may be with haemoptysis), pleural

effusion, dyspnoea, orthopnoea etc. Chest X-ray may show typical apical changes like
pleural effusion, nodularity, and miliary or diffuse infiltrates in the lung parenchyma.
• 2. Systemic features—such as fever, night sweats, fatigue, loss of weight and appetite.
Long-standing and untreated cases of tuberculosis may develop systemic secondary
amyloidosis.

ZN Stain for AFB

 Caseating granuloma with giant cell in TB L.N.

 The diagnosis is made by the following tests:

 i) AFB microscopy of diagnostic specimen such as sputum, aspirated material.
ii) Mycobacterial culture (traditional method on L J medium for 4-8 weeks, newer rapid
method by HPLC of mycolic acid with result in 2-3 weeks).
 iii) Molecular methods such as PCR.
 iv) Complete haemogram (lymphocytosis and raised ESR).
 v) Radiographic procedures e.g. chest X-ray showing characteristic hilar nodules and
other parenchymal changes).
 vi) Mantoux skin test
 vii) Serologic tests based on detection of antibodies are not useful although these are
being advocated in some developing countries.
 viii) Fine needle aspiration cytology of an enlarged peripheral lymph node is quite
useful and easy way for confirmation of diagnosis and has largely replaced the biopsy
diagnosis of tuberculosis.
• Causes of death in pulmonary tuberculosis are usually pulmonary insufficiency,
pulmonary haemorrhage, sepsis due to disseminated miliary tuberculosis, cor
pulmonale or secondary amyloidosis.

HIV - ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS):

• AIDS is caused by an RNA (retrovirus) virus called human immunodeficiency virus (HIV),
and is characterized by immunosuppression, which leads to opportunistic infections and
other manifestations. There are 4 members of human retroviruses in 2 groups:
 • Transforming viruses: These are human T cell leukemia lymphoma virus (HTLV) I and II
and are implicated in leukemia and lymphoma.
• Cytopathic viruses: This group includes HIV–1 and HIV-2, causing two forms of AIDS.
Most common case of AIDS in the world including US is HIV-1, while HIV-2.

Etiology:

 AIDS caused by HIV, a retrovirus of lentivirus family

 HIV is of two types.
 HIV I – causes AIDS in USA, Europe and Africa.
 HIV II – causes AIDS in India.
 HIV infects humans by following routes.
- Sexual contact (75% of cases).
- Parenteral transmission.
- Perinatal transmission.
 High risk groups:
- Homosexual men.
- Bisexual men.
- Intravenous drug abusers.
- Hemophiliacs.
- Blood transfusion recipients.
- Health workers

Routes of transmission:

 1. Sexual transmission.
 2. Transmission via blood and blood products.
 3. Perinatal transmission.
 4. Occupational transmission.
 5. Transmission by other body fluids.

Pathogenesis:

• The pathogenesis of HIV infection is largely related to the depletion of CD4+ T cells
(helper T cells) resulting in profound immunosuppression
Pathogenesis of HIV AIDS:

Clinical manifestations: occur in 3 phases:

 Early acute infection: - occur 3-6 wks after infection.

- Non specific clinical symptoms.
- Persistent generalized lymphadenopathy.
- CD4 +T - cell count > 500 cells/µl.
 Middle chronic infection: - Occurs multiple years after infection.
- Symptoms due to impaired dell-mediated immunity
- CD4 +T - cell count 200 - 499 cells/µl.
  Final phase (progression to AIDS): - Opportunistic infection develop.
- Neurodegenerative disease.
- Development of secondary malignancies.
- CD4 +T - cell count > 200 cells/µl.

Opportunistic infections:

 Cryptosporidiosis.
 Pneumocystic carinii infection.
 Atypical mycobacterial infection.
 Nocardiosis.
 Esophageal or tracheal candidiasis.
 Cryptococcal meningitis.
 Coccidiomycosis.
 Histoplasmosis.
 Cytomegalovirus infection.
 Herpes simplex infection.
 Varicella-Zoster virus infection.
 Kaposi sarcoma.
 B-cell non-Hodgkin lymphoma
 Carcinoma cervix.
 Central nervous system lymphoma.

 AIDS associated with Kaposi’s sarcoma

 Tests for diagnosis of HIV/AIDS.
• 1. TESTS FOR ESTABLISHING HIV INFECTION
• i) Antibody tests:
• a) ELISA
• b) Western blot
• ii) Direct detection of HIV
• a) p24 antigen capture assay
• b) HIV RNA assay
• c) NA-PCR
• d) Culture of HIV
• 2. TESTS FOR DEFECTS IN IMMUNITY
• i) CD4+ T cell count: Fall
• ii) CD8+ cell count: Increased
 Tests for diagnosis of HIV/AIDS.
• iii) Ratio of CD4+ T cell/CD8+ T cell count: Reversed
• iv) Lymphopenia
• v) Hypergammaglobulinaemia
• vi) Increased α-2 microglobulin level
• vii) Platelet count: Thrombocytopenia
• 3. TESTS FOR DETECTION OF OPPORTUNISTIC INFECTION AND SECONDARY TUMOURS
• i) FNAC/exfoliative cytology
• ii) Biopsy
• Amoebiasis:
• is caused by Entamoeba histolytica, named for its lytic action on tissues. It is the most
important intestinal infection of man. The condition is particularly more common in
tropical and subtropical areas with poor sanitation.
• The parasite occurs in 2 forms:
• ”a trophozoite form which is active adult form seen in the tissues and diarrhoeal stools;
and
• ”a cystic form seen in formed stools but not in the tissues.
• Amoebic cysts having four nuclei can be identified in stools. The cysts are the infective
stage of the parasite and are found in contaminated water or food.
• The trophozoites are formed from the cystic stage in the intestine and colonise in the
caecum and large bowel.
• The trophozoites as well as cysts are passed in stools but the trophozoites fail to survive
outside or are destroyed by gastric secretions.
 •
• MORPHOLOGIC FEATURES The lesions of amoebiasis include amoebic colitis,
amoeboma, amoebic liver abscess and spread of lesions to other sites
• Diagnosis: by examination of stools.

• Cysts of Entamoeba histolytica(Amoebiasis)

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX

MALARIA
• Malaria is a protozoal disease caused by any one or combination of four species of
plasmodia:
• Plasmodium vivax,
• Plasmodium falciparum,
• Plasmodium ovale and
• Plasmodium malariae.
 • While Plasmodium falciparum causesthe dangerous fever malignant malaria, the
other three species produce benign form of illness. These parasites are transmitted by
bite of female Anopheles mosquito.
• The life cycle of plasmodia falciparum is complex and is differs from other forms of
plasmodial species in 4 respects:
• i) It does not have exo-erythrocytic stage.
• ii) Erythrocytes of any age are parasitised while other plasmodia parasitise juvenile red
cells.
• iii) One red cell may contain more than one parasite.
iv) The parasitised red cells are sticky causing obstruction of small blood vessels by thrombi, a
feature which is responsible for extraordinary virulence of P. falciparum.

• Major complications due to malaria :

• Falciparum malaria which may cause manifestations of cerebral malaria (coma),
• Hypoglycaemia,
• Renal impairment,
• Severe anaemia,
• Haemoglobinuria,
 • Jaundice,
• Pulmonary oedema, and
• Acidosis followed by congestive heart failure and hypotensive shock.

MENINGITIS

• Meningitis is inflammatory involvement of the meninges. Meningitis may involve the

dura called pachymeningitis, or the leptomeninges (pia-arachnoid) termed
leptomeningitis. , meningitis would mean leptomeningitis.
• Pachymeningitis is invariably an extension of the inflammation from chronic
suppurative otitis media or from fracture of the skull.
• An extradural abscess may form by suppuration between the bone and dura. Further
spread of infection may penetrate the dura and form a subdural abscess.
• Other effects of pachymeningitis are localised or generalised leptomeningitis and
cerebral abscess.
• Leptomeningitis, commonly called meningitis, is usually the result of infection but
infrequently chemical meningitis and carcinomatous meningitis by infiltration of the
subarachnoid space by cancer cells may occur.

• Meningitis is defined as inflammatory process of leptomeninges and CSF within the

subarachnoid space.
• Classification: Classified into two groups:
• 1. Acute meningitis:
 Acute pyogenic meningitis.
 Acute aseptic meningitis.
 2.Chronic meningitis:
 Chronic tuberculous meningitis
 Chronic spirochaetal meningitis
 Chronic cryptococcal meningitis
Acute Pyogenic Meningitis or acute purulent meningitis is acute infection of the pia-
arachnoid and of the CSF enclosed in the subarachnoid space. Since the subarachnoid
space is continuous around the brain, spinal cord and the optic nerves, infection spreads
immediately to whole of the cerebrospinal meninges as well as to the ventricles.

 The causative organisms vary with age of the patient:

 1. Escherichia coli infection is common in neonates with neural tube defects.
  2. Haemophilus influenzae is commonly responsible for infection in infants and
children.
 3. Neisseria meningitidis causes meningitis in adolescent and young adults and is
causative for epidemic meningitis.
 4. Streptococcus pneumoniae is causative for infection at extremes of age and
following trauma.

• The routes of infection in acute pyogenic meningitis are as follows:

• 1. Most commonly by the blood stream.
• 2. From an adjacent focus of infection.
• 3. By iatrogenic infection such as introduction of microorganisms at operation or during
lumbar puncture.

MORPHOLOGIC FEATURES :

• Grossly, pus accumulates in the subarachnoid space so that normally clear CSF
becomes turbid or frankly purulent. The turbid fluid is particularly seen in the sulci and
at the base of the brain where the space is wide.
• In fulminant cases, some degree of ventriculitis is also present having a fibrinous coating
on their walls and containing turbid CSF. In addition, purulent material may interfere
with CSF flow and result in obstructive hydrocephalus.

Microscopically:

• There is presence of numerous polymorphonuclear neutrophils in the subarachnoid

space as well as in the meninges, particularly around the blood Vessels.
• Gram-staining reveals varying number of causative bacteria.

CLINICAL FEATURES AND DIAGNOSIS

• Acute bacterial meningitis is a medical emergency. The immediate clinical

manifestations are fever, severe headache, vomiting, drowsiness, stupor, coma, and
occasionally, convulsions. The most important clinical sign is stiffness of the neck on
forward bending.

DIAGNOSIS:

• The diagnosis is confirmed by examining CSF as soon as possible.

• 1. Naked eye appearance of cloudy or frankly purulent CSF.
• 2. Elevated CSF pressure (above 180 mm water).
• 3. Polymorphonuclear neutrophilic leucocytosis in CSF (between 10-10,000/μl).
• 4. Raised CSF protein level (higher than 50 mg/dl).
 • 5. Decreased CSF sugar concentration (lower than 40 mg/dl).
• 6. Bacteriologic examination by Gram’s stain or by CSF culture reveals causative
organism.

Acute Lymphocytic (Viral, Aseptic) Meningitis:

• Acute lymphocytic meningitis is a viral or aseptic meningitis, especially common in

children and young adults.
• Among the etiologic agents are numerous viruses such as enteroviruses, mumps, ECHO
viruses, coxsackie virus, Epstein-Barr virus, herpes simplex virus-2, arthropode-borne
viruses and HIV. However, evidence of viral infection may not be demonstrable In about
a third of cases.

MORPHOLOGIC FEATURES

• Grossly, some cases show swelling of the brain while others show no distinctive change.
• Microscopically,
• There is mild lymphocytic infiltrate in the leptomeninges.

CLINICAL FEATURES AND DIAGNOSIS

• The clinical manifestations of viral meningitis are much the same as in.
• Symptoms: fever.
• However, viral meningitis has a benign and self-limiting clinical course of short duration
and is invariably followed by complete recovery without the life threatening
complications of bacterial meningitis.
• The CSF findings in viral meningitis are as under:
• 1. Naked eye appearance of clear or slightly turbid CSF.
• 2. CSF pressure increased (above 250 mm water).
• 3. Lymphocytosis in CSF (10-100 cells/μl).
• 4. CSF protein usually normal or mildly raised.
• 5. CSF sugar concentration usually normal.
• 6. CSF bacteriologically sterile.

Chronic (Tuberculous and Cryptococcal) MeningitisThere are two principal types of chronic
meningitis—one bacterial (tuberculous meningitis) and the other fungal (cryptococcal
meningitis). Both types cause chronic granulomatous reaction and may produce parenchymal
lesions.

• ”Tuberculous meningitis :
 • occurs in children and adults through haematogenous spread of infection from
tuberculosis elsewhere in the body, or it may simply be a manifestation of miliary
tuberculosis. Less commonly, the spread may occur directly from tuberculosis of a
vertebral body.
• ”Cryptococcal meningitis:
• develops particularly in debilitated or immunocompromised persons, usually as a result
of haematogenous dissemination from a pulmonary lesion.
• Cryptococcal meningitis is especially an important cause of meningitis in patients with
AIDS.

MORPHOLOGIC FEATURES

• Grossly, in tuberculous meningitis, the subarachnoid space contains thick exudate,

particularly abundant in the sulci and the base of the brain.
• Tubercles, 1-2 mm in diameter, may be visible, especially adjacent to the blood vessels.
The exudate in cryptococcal meningitis is scanty, translucent and gelatinous.
• Microscopically, tuberculous meningitis shows exudate of acute and chronic
inflammatory cells, and granulomas with or without caseation necrosis and giant cells.
Acid-fast bacilli may be demonstrated.
• Late cases show dense fibrous adhesions in the subarachnoid
• space and consequent hydrocephalus. Cryptococcal
• meningitis is characterised by infiltration by lymphocytes, plasma cells, an occasional
granuloma and abundant characteristic capsulated cryptococci.

CLINICAL FEATURES AND DIAGNOSIS:

• Tuberculous meningitis manifests clinically as headache, confusion, malaise and

vomiting.
• The clinical course in cryptococcal meningitis may, however, be fulminant and fatal in a
few weeks, or be indolent for months to years.

CLINICAL FEATURES AND DIAGNOSIS:

• The CSF findings in chronic meningitis are as under:

• 1. Naked eye appearance of a clear or slightly turbid CSF which may form fibrin web on
standing.
• 2. Raised CSF pressure (above 300 mm water).
• 3. Mononuclear leucocytosis consisting mostly of lymphocytes and some macrophages
(100-1000 cells/μl).
• 4. Raised protein content.
• 5. Lowered glucose concentration.
• 6. Tubercle bacilli may be found on microscopy of centrifuged deposits by ZN staining in
tuberculous meningitis. Pathognomonic capsulated cryptococci with a halo are
appreciated in India ink preparation of CSF in cases of cryptococcal meningitis, while the
capsule is better demonstrated by mucicarmine stain

Feature Normal Acute pyogenic Acute Chronic

(Bacterial) lymphocytic (Tuberculous)
meningitis (Viral) meningitis
meningitis
1. Naked eye Clear and Cloudy or Clear or slightly
Clear or slightly
appearance colourless frankly turbid turbid, forms
purulent fibrin coagulum
on standing
2. CSF pressure 60-150 mm Elevated Elevated Elevated
water (above 180 mm (above 250 mm (above 300 mm
water) water) water)
3. Cells/μl 0-4 10-10,000 10-100 100-1000
lymphocytes neutrophils lymphocytes lymphocytes

4. Proteins 15-45 mg/dl Markedly Mildly raised Raised

raised
5. Glucose 50-80 mg/dl Markedly Normal Reduced
reduced
6. Bacteriology Sterile Causative Sterile Tubercle bacilli
organisms present
present