4

INDEX
GENERAL PATHOLOGY
CHAPTER:- Pg: no
1.Cell injury 05
2.Inflammation and Healing 14
3.Heamodynamic Disorders 23
4.Genetic & Pediatric Disorders 33
5.Immunology 147
6.Infectious And Parasitic Disease 47
7.Neoplasia 39

SYSTEMIC PATHOLOGY
CHAPTER:- Pg: no
1.RBC Disorders 55
2.Platelet Disorders 66
3.WBC Disorders 70
4.Lymphoid system 76
5.The Heart 79
6.Blood vessels And Lymphatics 89
7.The Respiratory System 93
8.Head and Neck 107
9.The Gastrointestinal System 109
10.Male Genital System 120
11. The Breast 128
12. Liver 135
13. Female Genital System 158
14. CNS 167
15.SKIN 186
16. Musculoskeletal system 191
17. Eye And Nose 201
18. Soft tissue tumour 203
19. Endochrinology 208
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CELL INJURY

1. HYPERTROPHY
2. HYPERPLASIA
3. ATROPHY
4. METAPLASIA
5. NECROSIS
6. GANGRENE
7. APOPTOSIS
8. PATHOLOGICAL CALCIFICATION
9. I/C ACCUMULATIONS-LIPOFUSCHIN
10.CELL INJURY
11.FATTY CHANGE
 6

1. HYPERTROPHY
- hypertrophy is an increase in size of cells resulting in increase in size of the organ
 CAUSES
- Hypertrophy may be physiologic or pathologic.
- In both cases, it is caused either by increased functional
Demand or by hormonal stimulation
A. Physiologic hypertrophy.
- Enormalarged size of the uterus
B- Pathologic hypertrophy.
- Examples of certain diseases associated with hypertrophy are as under:
1. Hypertrophy of cardiac muscle may occur in a number of cardiovascular diseases, LIKE:
i) Systemic hypertension
ii) Aortic valve disease (stenosis and insufficiency)
iii) Mitral insufficiency
2. Hypertrophy of smooth muscle e.g.
i) Cardiac achalasia (in oesophagus)
- ii) Pyloric stenosis (in stomach)
- iii) Intestinal strictures
 MORPHOLOGIC FEATURES.
- The affected organ is enormalarged and heavy. For example, a hypertrophied
heart
of a patient with systemic hypertension may weigh
700-800 g as compared to average normal adult weight of
350 g.
- There is enormalargement of muscle fibres as well as of
nuclei .
- At ultrastructural level, there is increased synthesis of DNA and RNA, increased
protein synthesis and increased number of organelles like mitochondria,
endoplasmic reticulum and myofibrils.

1- HYPERPLASIA
- Hyperplasia is an increase in number of cells
- Because of proliferation of differentiated cells and replacement by tissue stem cells
- Hyperplasia types include,
 7

a) physiological b) pathological :
- > Hormonal hyperplasia : proliferation of - proliferation of uterine epithelium after a normal
glandular epithelium of female breast menstrual period
at puberty proliferation of connective tissue cells in wound
- > compensatory hyperplasia : residual liver healing
tissue grows after removal of a part of
Liver

2- ATROPHY
- Shrinkage in size of cell by loss of cell substance is called atrophy. When sufficient no. of cells involved organ
become atrophied.
PATHOGENESIS:
 Causes 3 mechanism:
 Decreased protein synthesis
- Decreased workload
 Degradation of cellular protein
- Loss of innervations - By ubiquitin protease pathway
- Decreased blood supply  Increased autophagy
- Inadequate nutrition
- Loss of endocrine stimulation
- Ageing
 Eg; atrophy of brain due to ageing and decreased blood supply.
3- METAPLASIA
- Reversible change of one type of epithelial or mesenchymal adult cells to another adult cell type, usually in response
to abnormal stimuli and often reverts back to normal on removal of the stimulus.

Types 1. Epithelial 2. Mesenchymal

Epithelial Mesenchymal
 Squamous metaplasia  Osseous metaplasia --- formation of bone
 In bronchus (normally lined by pseudo stratified in fibrous tissue cartilage and myxoid tissue
columnar ciliated ) in chronic smoker - Monckebergs calcific sclerosis
 In uterine endocervix ( normally lined by simple - In soft tissues in myositis ossificans
columnar epithelium) in old age  Cartilaginous metaplasia --- in healing of
 In gall bladder (normal-simple coloumnar ) in acute fractures
cystitis and cholelithiasis
 In renal pelvis and urinary bladder
 Vit A deficiency leads to Squamous metaplasia in non-
bronchi, urinary tract.
 Columnar metaplasia
 intestinal metaplasia in healed gastric ulcer
 Barrets esophagus ( Squamous to coloumnar)
 Chronic bronchitis
 In cervical erosion

4- NECROSIS
 DEFINITION: Irreversible cell injury
 8

- A type of cell death with loss of membrane integrity and leakage of cellular contents culminating in dissolution of
cells, due to degradative action of enzymes on lethally injured cells
- Enzymes from lysosomes of dying cells/leucocytes
 MORPHOLOGY:
Cytoplasmic changes - Nuclear changes – fate of necrotic cells- get calcified
a. increased eosinophilia a. Karyolysis (basophilia of later
b. Abundant myelin figures chromatin fade)
c. Break down of plasma b. Pyknosis (nuclear shrinkage)
membrane and organellar c. karyorrhexis (fragmentation)
membranes
d. Leakage and enzymatic
digestion of cellular contents
Dilated mitochondria , disrupted
lysosomes

 PATTERNS OF TISSUE NECROSIS

COAGULATIVE LIQUEFACTIVE CASEOUS NECROSIS : FAT NECROSIS : FIBRINOID NECROSIS
NECROSOS : NECROSIS :
 Cheese like  Action of  Seen in
common, associated
seen in friable yellow pancreatic polyartearitisno
with ischaemic areas
bacterial/fungal white necrotic enzymes from dosa
 Tissue infection area acinar cells and  Antigen –
architecture is
 Inflammatory  Tissue ducts Antibody
preserved for
cells and architecture  Lipases spilt complex
several days completely lost triglycerides & deposition on
leucocytic
 Recruitment of enzymes  District release fatty blood vessels
leucocytes liquefy tissue inflammatory acids  Pink and
 Dead cells  Liquid viscous border –  Chalky white amorphous in
digested by mass present formation of areas H&E
lysosomal
 Seen in
granuloma  Microscopy –
enzymes of
hypoxic death  In tuberculous necrotic fat
leucocytes infection cells with
of cells in
 Seen in infracts central basophilic ca2+
of solid organ nervous deposits seen
except brain system in acute
pancreatitis

============================================================================================

6. GANGRENE
- Necrosis of tissue associated with superadded putrefaction, most often followingowing coagulative necrosis due to
ischemia.
- 2 types: (1)- dry gangrene (2)- wet gangrene

Dry gangrene Wet gangrene

 9

-Occur in limbs(begin distally) -Occur in naturally moist tissue(bowel,mouthetc)

-Due to arterial occlusion.(severe atherosclerosis, -Blockage of both venous and arterial
trauma etc) vessels(intussuception,hernia)
-Less rapid(contain little blood so bacteria finds it hard -rapid 9part stuffed with blood favour bacterial growth)
to grow) -appear moist,soft,swollen,rotten and dark
-Macroscopically appear dry,shrunken and black -absent
-Line of demarcation present -poor due to toxaemia.
-Prognosis better due to little septicemia

- Black colour due to liberation of hemolysed RBC which is acted by H2S produced by bacteria to form black iron
sulphide.

7- APOPTOSIS
 A pathway of cell death in which cells activate enzymes that degrade the cells own nuclear DNA and nucleic acid and
cytoplasmic proteins
 No inflammation because the dead cells and its fragments are rapidly cleansed before contents have leaked out.
Also no collateral tissue damage.

Apoptosis in biologic process:-

Physiologic processes Pathologic processes

1. Development of embryo 1. Cell death in chemotherapy
2. Endometrial shedding, regression of lactating 2. Cell death by cytotoxic T cell in immune
breast mechanisms
3. Replacement proliferation as in intestinal 3. Progressive depletion of CD4 + T cells in AIDS
epithelium 4. Cell death in viral infection
4. Involution of thymus in early age

 Morphology
 Involvement of single cell / small clusters of cells.
 Apoptotic cells are shrunken highly eosnophilic masses with almost normal organisms
 Nuclear chromatin is condensed under nuclear membrane (pyknosis)
 Cell membrane has blebs / projections, apoptotic bodies
No inflammatory reaction, phagocytosis by macrophages
 Mechanism
A. Initiators of apoptosis
- Withdrawal of normal cell survival signals
- Agents of cell injury ( heat , radiation, light )
B. Initial steps in apoptosis
- Intrinsic (mitochondrial)
Caspase activated by  release of cytochrome c from mitochondria
By balance between

Pro apoptotic members of Anti apoptotic

Bal proteins Bcl2, Bclx,Mcl
 10

(Bim,Bid,Bad)
Activate Bax, Bak
- Extrinsic pathway (cell death receptor initiated)
An important cell death, receptors TNF-R1 and Fas (CD95) on CD8 + Tcells
And its ligand (Fas L)

Fas + Fas L activates Fas associated death domain (FADD) in cytoplasm activates caspases

C. Final phase
Mitochondrial caspase 9 action on nuclei, chromatin clumping,
Death receptor pathway caspases 8 & 10 disruption of ER, mitochondrial
Others caspases 3 & 6 damage, disturbed cell membrane

D. Phagocytosis
- Phosphatidylserine and thrombospondin on inner surface appear on outer surface facilitating phagocytosis

8- PATHOLOGIC CALCIFICATION
-Abnormal deposition of calcium salts in tissues together with smaller amount of iron and magnesium and other
minerals.

Two distinct types

 Dystrophic – deposition in dead & degenerated tissues (normal ca metabolism)

 Metastatic – deposition in normal tissue (Derangement in ca metabolism)

 Etiopathogenesis
1. Dystrophic calcification 2. Calcification in degenerated tissue
-Deposition in dead tissue  Dense old scar and atheroma
 Eg: caseous necrosis in Tb undergoing calcification
 Liquefaction necrosis in c/c abscess  Monckebergs sclerosis
 Gamma gandy bodies in CVC spleen  Stroma of tumors
 Micro calcification in breast cancer  Psammoma bodies

 Pathogenensis
 Initially cell injury  membrane damage pl released phosphates ca phosphate ppt
Metastaic calcification
 Excessive mobilisatioon of calcium from bone. Eg; hyperparathyroidism
Bony destructive lesions, hypercalcemia, prolonged immobilsation
 Excessive absorption of calcium from gut
 DYSTROPHIC CALCIFICATION  METASTATIC CALCIFICATION
 Includes initiation and propagation both of which  causes:
may be extracellular and intracellular - Increased secretion of parathyroid hormone
ultimate end product : formation of crystalline calcium - Destruction of bone due to accelerated urnover,
phosphate. immobilisation
 Initiation in extracellular sites in membrane bound - Vit –D related disorders
vesicle ( 200nm) in normal cartilage and bone they are - Renal failure.
known as matrix vesicles.
Initial concentration of calcium in these vesicle is by its
 11

affinity for membrane phospholipids and phosphate

accumulate due to action of membrane bound
phosphatases.
 Initiation followingowed up by propagation.

 Morphology

Gross Microscopy
- White granules flet as gritty deposits (in both types) -Calcification – basophilic deposits (
- Distrophic calcification common in areas of caseous intracellular/extracellular)
necrosis in TB.
- Metastatic calcification – interstitial tissues of vessels ,
kidney, lungs and gi mucosa

9- INTRACELLULAR ACCUMULATIONS
Intracellular accumulations in abnormal amounts can occur within cytoplasm or within nucleus of the cell causing
reversible or irreversible cell injury.

- Accumulations of constituents of normal cell metabolism produced in excess

(accumulation of lipids, carbohydrates, proteins)
- Accumulation of abnormal substances (inborn errors of metabolism)
- Accumulation of pigments (endogenous / exogenous pigments)
 LIPOFUSCIN:
- wear and tear pigment
- insoluble, brownish, yellow granular intra cellular material
- accumulates mainormaly in heart, liver, brain
- it is a complex of lipid and proteins that derived from free radical catalysed peroxidation of poly unsaturated
lipids of subcellular membranes
- not injurious to cell
- marker of past free radical injury
- lipoprotein, brown pigment, when present in large amount imparts an appearance to tissue atrophy
- in electron microscopy- pigment appear as perinuclear electron dense granules
 PATHOGENESIS:
- In normal cells in aeging or in some disease the phospholipid end product of membrane damage mediated by
oxygen free radical fails to get eliminated and forms lipofuscin pigment.
10- MECHANISM OF CELL INJURY
 Causes: => Various mechanism are as following:
- Oxygen deprivation A-
- Depletion of ATP
- Chemical agents - Influx of calcium
- Infectious agents - Mitochondrial damage and dysfunction
- Genetic imbalances - Accumulation of Oxygen Derived free radical
- Immunological - Defects in Membrane Permeability
- Nutritional imbalances Damage to DNA and Protein.
- Ageing
- Physical Trauma
 12

Depletion of ATP

B- Mitochondrial damage and dysfunction

C- Influx Of Calcium
 13

D- Accumulation Of Oxygen Derived Free Radical

==================================================================================================

11. FATTY CHANGE:

-I/C accumulation of neutral fat within parenchymalcells

-SITES: liver, non-fatty tissues (heart, skeletalmuscle, kidneys)

-Fatty Liver

Liver -commonest site(it plays central role in fat

ETIOLOGY. PATHOGENESIS metabolism)

1. Conditions with excess fat:exceeding

thecapacity of the liver to metabolise it. STAINS:

i) Obesity (ii) DM iii) Congenital -Sudan dyes (Sudan III, IV,

Sudan black)
2. Liver cell damage:
- oil red O
i) Alcoholic liver disease (most
common)ii) Starvation

iii) C/C illness (e.g. tuberculosis)

iv) Hypoxia

v) Reye’s syndrome

MORPHOLOGIC FEATURES.

G: the liver-enlarged & tense, glistening capsule &rounded margins.

C/S: pale-yellow &greasy to touch

M:i) The vacuoles - small & aroundthe nucleus (microvesicular).

ii) The vacuolesbecome larger pushing the nucleus to the periphery ofthe cells (macrovesicular).

iii) At times, the hepatocytes laden with large lipidvacuoles may rupture and lipid vacuoles coalesce to form
fatty cysts (lipogranulomas).

iv) Infrequently, lipogranulomasmay appear consisting ofcollections of lymphocytes, macrophages, and some
multinucleatedgiant cells.
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Inflammation & HEALING

 15

1- INFLAMMATION:
- Reaction of blood vessels to injury and followingowing injury there will be vascular and cellular tissue response
- SIGNS- calor (increase in temperature of inflammed tissue), rubor (change in colour of the inflamed tissue- usually to
red), dolor (increase in pain), tumor(swelling of inflammed tissue) amd loss of function.
- TYPES- acute and chronic

=> VASCULAR AND CELLULAR EVENTS

I. VASCULAR EVENTS

Earliest change is alteration in microvasculature. Include hemodynamic changes and changes in vascular permeability

 Haemodynamic Changes –sequence is :-

1. Transient vasoconstriction of arterioles with mild inflammation .
2. Persistent progressive vasodilatation of arterioles >venules and capillaries (WARMTH AND REDNESS)
3. Progressive vasodilatation elevating thelocal hydrostatic pressure => transudation of fluid into the extracellular
space. (SWELLING)
4. Slowing or stasis of blood raising blood viscosity
5. Leucocytic migration /emigration through the endothelial cell space into extravascular space.

Triple response or red line response (LEWIS EXPERIMENT)

i) Red line due to local vasodilatation of capillaries and venules.
ii) Flare from vasodilatation of the adjacent arterioles.
iii) Wheal (oedema) due to transudation of fluid.

 Altered Vascular Permeability-

Transudate by the escape of fluid due to vasodilatation and consequent elevation in hydrostatic pressure. Exudate by
increased vascular permeability of microcirculation.

(Refer Starling’s Hypothesis)

MECHANISMS OF INCREASED VASCULAR PERMEABILITY -

II. CELLULAR EVENTS -2 processes:

1. exudation of leucocytes2. phagocytosis.

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Exudation of Leucocytes –

- A/C inflammation, PMNORMAL’s comprise the first line of body defense, followingowed later by monocytes and
macrophages.
- The changes leading to migration of leucocytes :-
1. CHANGES IN THE FORMED ELEMENTS OF BLOOD –
VD slowing or stasis of bloodstream changes in normal axial blood flow (the central stream of cells
widens and peripheral plasma zone becomes narrower because of loss of plasma by exudation –margination)
pavementing of neutrophils.

2. ROLLING AND ADHESION -

- neutrophils slowly roll over the endothelial cells lining the vessel wall (rolling phase)

transient bond between the leucocytes and endothelial cells becoming firmer (adhesion phase).

=>Molecules bringing about rolling and adhesion phases:

i) Selectinson surface of activated endothelial cells recognise specific carbohydrate on the surface of neutrophils.

 P-selectin(preformed and stored in endothelial cells and platelets) isinvolved in rolling.

 E-selectin(synthesised by cytokineactivated endothelial cells) rolling andadhesion
 L-selectin(expressed on the surface of lymphocytesand neutrophils) homing of circulatinglymphocytes to the
endothelial cells in lymph nodes.

ii) Integrinson the endothelial cell surface are activated and neutrophils are also stimulated. Forming firm adhesion
between leucocyte and endothelium.

iii) Immunoglobulin gene superfamily adhesion molecule (ICAM-1) and (VCAM-1) allow a tighteradhesion.(PECAM-1) or
CD31 may also be involved in leucocyte migration.

3. EMIGRATION -neutrophils lodged between the endothelial cells and basement membrane damage it by collagenases
and escape out into the extravascular space (emigration). Simulataneously escaping of RBC’s through gaps between the
endothelial cells (diapedesis). Diapedesis gives haemorrhagic appearance to the inflammatory exudate.

4. CHEMOTAXIS –is the chemotactic factor-mediated transmigration of leucocytes to interstitial space.

Chemokines for neutrophils :-

i) Leukotriene B4 (LT-B4), product of lipooxygenase pathway
of arachidonic acid metabolites
ii) Components of complement system (C5a and C3a)
iii) Cytokines (Interleukins, in particular IL-8)
iv) Soluble bacterial products (such as formylated peptides).

- Phagocytosis -process of engulfment of solidparticulate material by the cells (cell-eating).

- 2 main types of phagocytic cells:

i) PMNORMAL’s early in acute inflammatory response also called microphages.

ii) Circulating monocytes and fixed tissue mononuclear phagocytes (macrophages).

On reaching tissues spaces, produce several proteolytic enzymes—lysozyme, protease, collagenase, elastase, lipase,
proteinase and acid hydrolases. These enzymes degrade collagen and extracellular matrix.
 17

=> Phagocytosis involves:-

1. Recognition and attachment

2. Engulfment
3. Killing and degradation

1. RECOGNITION AND ATTACHMENT

Phagocytosis is initiated by the expression of surfacereceptors on macrophages

Microorganismsare coated with opsonins(IgGopsonin, Lectins and C3b) and opsoninthey get opsonised by bond
betweenbacteria and the cell membrane of phagocytic cell.

2. ENGULFMENT

opsonised particle on surface of phagocyte

formation ofcytoplasmic pseudopods around the particle by activation of actin filaments beneath cell wall

enveloping it in a phagocytic vacuole

membrane lined phagocytic vacuole or phagosome liesinternalised and free in the cell cytoplasm.

The phagosomefuses with one or more lysosomes of the cell and form biggervacuole called phagolysosome.

3. KILLING AND DEGRADATION

-phagocytes act as scavanger cells.

-The microorganisms afterbeing killed are destroyed by

hydrolytic enzymes. However, this mechanism fails to killand degrade some bacteria like tubercle bacilli.

Disposal of microorganisms can proceed by followingowingmechanisms:

A. Intracellular mechanisms: B. Extracellular mechanisms:

i) Oxidative bactericidal mechanism by oxygen free radicals i) Granules : obtained by degranulation of macrophages.
a) MPO-dependent ii) Immune mechanisms:
b) MPO-independent immune-mediated lysis of microbes takes place outside
ii) Oxidative bactericidal mechanism by lysosomal granules the cells by mechanisms of cytolysis, antibody-mediated
iii) Non-oxidative bactericidal mechanism lysisand by cell-mediated cytotoxicity.

 OUTCOMES-
resolution, healing , suppuration and chronic inflammation
2- WOUND HEALING:
Healing is the body response to injury in an attempt to restore normal structure and function by two ways:
 Healing by first intention (primary union)
 Healing by second intention (secondary union).
A) Healing by First Intention (Primary Union)
Initial haemorrhage - seals the wound against
dehydration and infection

Acute inflammatory response -within 24 hrs

(polymorphs) and 3rd day (macrophages)
 18

Mainormaly in a wound which has the

i) clean and uninfected; Epithelial changes - The basal cells of epidermis from
ii) surgically incised; both the cut margins start proliferating and migrating
iii) without much loss of cells and tissue; and towards incisional space separting it from dermis
iv) edges of wound are approximated by surgical sutures. forming a scab which is cast off. By 5th day, multilayered
followingowingcharacteristics: new epidermis

=> Healing by Second Intention (Secondary Union) Organisation-By 3rd day (fibroblasts). By 5th day
Take place in wound having the (collagen fibrils)
followingowingcharacteristics:
i) open with a large tissue defect, at times infected; Suture tracks-Each suture track is a separate wound with
ii) having extensive loss of cells and tissues; and same inciting phenomenon.
iii) the wound is not approximated by surgical sutures but is
left open.

1. Initial haemorrhage
2. Inflammatory phase.
3. Epithelial changes – whole viable tssue separated from necrotic material and clot by a scab which is casted off.
4. Granulation tissue - formed by proliferationof fibroblasts and neovascularisation.
5. Wound contraction –because of myofibroblasts
6. Presence of infection –hence wound debridement is required.
-Larger tissue defect compared to primary union. Hence healing from base + margin with ugly looking scar.

Complications of Wound Healing

1. Infection of wound
2. Implantation (epidermal) cyst
3. Pigmentation because of hemosiderin
4. Deficient scar formation.

3- CHEMICAL MEDIATORS OF INFLAMMATION:

 19

1. MOROHOLOGICAL PATTERNS AND OUTCOME OF A/C INFLAMMATION

Morphological patterns Outcomes
Psuedomembranous inflammation Resolution
Ulcer Healing
Suppuration (abscess formation) Suppuration
Cellulitis Chronic inflammation
Bacterial infection of the blood (septicemia,
bacteremia and pyaemia)

4- GRANULOMA: definition and evolution of tubercle

Definition- granuloma is anodule which histologically has the centre composed of granular caseation
necrosis,surrounded by epithelioid cells and Langhans’ giant cells and peripheral rim of lymphocytes bounded by
fibroblasts.
initial response of neutrophils

progressive infiltration by macrophages

(because C2aand C3b acting as opsonins
for attracting macrophages)

macrophages phagocytose the tubercle bacilli

Activated CD4+T cells develops delayed type The fate of a granuloma is variable:
hypersensitivity reaction  cold
 sinus tracts
Modified macrophages (epitheliod cells- cytoplasm  adjacent granulomas coalesce
pale and eosinophilic, nucleus elongated and vesicular)  dystrophic calcification

Epitheliod cells cluster as granuloma, cytokines

also play an important part

multinucleated giant cells/ langhans type (from s

ome macrophages)

hard tubercle

soft tubercle.

5- FRACTURE HEALING:
There are two types of union of fracture:

1.Primary union of fracture Secondary union

- Occurs when the ends of fracture are approximated Occurs when plaster casts are applied for immobilization
surgically
- Union takes place with formation of medullary callus
without periosteal callus
- Extensive bone necrosis and slow healing
 20

This occurs by:

A.PROCALLUS FORMATION
B.OSSEOUS CALLUS FORMATION
C.REMODELLING

A.PROCALUS FORMATION B.OSSEOUS CALLUS FORMATION C.REMODELLING

1. Hematoma fills the area *Procallus act as a scaffolding on *Osteoclastic removal and
surrounding fracture which osseous callus is formed . osteoblastic laying occur
*A loose network is formed *Woven bone is cleared by simultaneously
osteoclasts&calcified cartilage *External callus cleared ,intermediate
framework for subsequent disintegrates callus replaced by compact bone,bone
granulation tissue formation * In their place,new blood vessels marrow cavity develops in internal
2. Local inflammatory response occur &lamellar bone is formed callus
and clear away the fibrin concentrically around the blood
- RBC,inflammatory exudateand debris vessels
*Necrosed bone removed by
osteoclasts and macrophages
3.Ingrowth of granulation tissue
occurs
*Soft tissue callus joins the end of
fractured bone
4.Callus composed of woven bone
and cartilage begin in few days
*Over the granulation tissue osteiod
matrix and collagen is formed by the
cells of inner layer of periosteum

*Osteiod undergo calcification called

woven bone callus ,they unite to
bridge the gap between the ends of
fractured bone on either side.
*This state is called procallus
formation

=>Compliations

1. Fibrous union if immobilization is not done

2. Nonunion occur if soft tissue is interposed between fractured ends

3. Delayed union

6- CELL ADHESION MOLECULES

*In acute inflammation the marginatedneutrophills roll over the endothelial lining of vessel wall(rolling phase)& is
followingowed by transient bond between leucocytes and endothelial cells (adhesion phase).It is brought about by cell
adhesion molecules.
 21

A) Selectins B) Integrins C) Immunoglobulin gene

superfamily adhesion
molecules

- expressed on surface of activated - Belong to family of endothelial cell - They partake in cell to cell contact
endothelial cells surface proteins having through other CAM
- They are composed of lectin α(CD11)&β(CD18)subunit - They play important role in
- Function: - On forming loose adhesion between recognition &binding of
Recognize &bind to glycoproteins endothelial cells and leucocytes,their immunocompetent cells as under
&glycolipids on surface of neutrophils receptor on neutrophil get activated a.Intercellular adhesion molecules-1&
It is of 3 types: and they form firm adhesion vascular cell adhesion molecule -1
a.P Selectin-involved in rolling allows tighter adhesion between
b.E Selectin –associated with rolling leucocytes and endothelial surface
and adhesion
c.L Selectin –homing of circulating
lymphocytes to endothelial cells in
lymphnodes

7-GRANULATION TISSUE
The formation of granulation tissue is by 3 phases

1.Phase of inflammation

*Blood clots are formed at the site of injury followingowed by the exudation of plasma,neutrophills etc…

2.Phase of clearance

*The enzymes liberated by neutrophils,dead tissues&phagocytosis of macrophages clear away necrotic tissue and clots

3.Phase of ingrowth of granulation tissue

=>It include 2 main processes

a.Angiogenesis: b.Fibrinogenesis

- formation of new blood vessels at site of injury New blood vessels present in the matrix
Initial proliferation of endothelial cells are solid buds
Collagen fibrils begin to appear by 6thday .
later they develop lumen and carry blood
Myofibroblast bridges between collagen fibrils
more leaky that accounts for the edematous appearance
Of new granulation tissue As maturation proceeds,more collagen is
formed ,fibroblasts and new blood vessels
differentiate into muscular arterioles , decreases
thin walled venules&true capillaries This results in inactive looking scar and the
process is called cicatrisation
This process take place under the influence of vascular endothelial
growth factor,platelet derived growth factor ,transforming growth
factor-β,basic fibroblast growth factor &surface integrins
 22

8- ACUTE PHASE REACTANTS

- APR are proteins released in plasma in response to trauma and infection

- Function:Protect the normal cells from harmful effects of toxic molecules produced in inflammation and clear away
waste material

- They are synthesized in liver

=>Some of them are:

1.Certain cellular protection factors(α1 antitrypsin ,α± antitrypsin,α2-antiplasmin etc)

2.Coagulation proteins (fibrinogen ,plasminogen etc) produce factor to replace those
consumed
3.Transport proteins
9ceruloplasmin, haptoglobin.
4.Immune agents(CRP-oppossing agent for phagocytosis)
5.Stress proteins (heat shock proteins-HSP,ubiquitin)-They carry toxic waste to lysosomes
6.Antioxidants(ceruloplasmin)-They eliminate excess oxygen free radicals
 23

HEMODYNAMIC DISORDERS

1. SHOCK
2. EMBOLISM
3. THROMBOSIS
4. EDEMA
5. CVC
6. INFARCTION
7. DECOMPRESSION SICKNESS
 24

SHOCK:
Life-threatening clinical syndrome characterized by: (i) Hypotension

TYPES: (ii) Hypoperfusion

COMPLICATIONS
1. ARDS

2. DIC

3. ARF

4. MODS
 25

PATHOGENESIS OF CIRCULATORY SHOCK MANIFESTATIONS:

1.HYPOXIC ENCEPHALOPATHY:-brain have ischemic
damage. G: Ischemic necrosis(Anterior CA & Middle CA)

M: Cytoplasm of purkinje cells are

eosinophilic&pyknotic nuclei with rep. by gliosis

2.HEART IN SHOCK: 2 changes(i) Hmg& necrosis

(ii)Zonal lesions(opaque
transverse contraction bands in myocytes near
intercalated disc)

3.SHOCK LUNG: Mainly in septic shock.

G: heavy & wet.

M: ARDS changes(congestion,interstitial& alveolar

edema, alveolar hyaline membrane, thickening of
alveolar septa)

4.SHOCK KIDNEY: Irreversible renal injury. G:soft&

swollen; M: ATN seen

5.ADRENALS IN SHOCK

6.HEMORRHAGIC GASTROENTEROPATHY

(hypoperfusion of alimentary tract in shock result in

mucosal & mural infarcts)-non occlusive ischemic injury

7.LIVER IN SHOCK

PATHOGENESIS OF SEPTIC SHOCK

 26

STAGES OF SHOCK
=====================================================================================---

EMBOLISM:
Definition: Process of partial or complete obstruction of some part of CVS by any mass in circulation

Transported I/V mass detached from its site of origin – embolus

PULMONARY THROMBOEMBOLISM: FAT EMBOLISM:

-Fatal form of venous thromboembolism -Obstructionof arterioles & capillaries by fat globules

-Occlusion of pulm. Arterial tree by thromboemboli ETIOLOGY: 1) Trauma – to bones, soft tissues

ETIOLOGY:1) Originate from large veins of L.L 2) Non traumatic- Extensive burns, DM,
Fatty liver, pancreatitis, Sickle cell anemia,
2)Varicosities of supl veins of legs, pelvic vein
decompression sickness
PATHOGENESIS: -Detachment ->venous drainage->rt side of
PATHOGENESIS: 1) Mechanical theory (mobilization
heart. 1) If large-saddle embolus (in bifurcation of main P A)
of fat following trauma to soft tissues/bone
2) Multiple emboli
2) Emulsion instability theory (non-
3) Paradoxical emboli(from Lt ->Rt heart) traumatic cases- aggregation of plasma lipids due to
disturbance in fatty acids)
CONSEQUENCES:
3) Intravascular coagulation theory
(In stress, release of some factors activates DIC)

4) Toxic injury theory (small BV of

lungs are chemically injured by high plasma FFA levels
resulting in pulm edema)

CONSEQUENCES: 1) Pulmonary fat embolism

(Microscopy: ARDS)

2) systemic fat embolism

 27

AIR EMBOLISM: AMNIOTICFLUID EMBOLISM:

-It occurs when air is introduced into venous or arterial - Most serious, unpredictable& unpreventable
circulation cause of maternal mortality
- Imm. Postpartum &labour period: contents of
VENOUS AIR EMBOLISM: (i) Operation on head, neck
amniotic fluid enter Uterine V & reach Rt side of
(ii) Obstetrical operations heart
- Amniotic fluid is seen in : eplsquames,
(ii) Intravenous infusion of blood
vernixcaseosa, lanugo hair, bile from meconium
(iv) Angiography & mucus
- Gain entry either through tears in myometrium
Effects (VAE) depends on – Amount of air introduced
&endocervix / sinusoids by uterine contraction
- Rapidity of entry of smaller air vol.
MORPHOLOGIC FEATURES: hmg, congestion, edema,
- Position of the patient(head>trunk) ARDS changes, dilatation of Rt side of heart

- General condition of patient

Mechm: Entrapment of air bubbles in pulmonary arterial CLINICAL SYNDROME: - Sudden resp distress
trunk in right heart
- Dyspnoea, deep cyanosis
ARTERIAL AIR EMBOLISM: (i) Cardiothoracic Sx& trauma - Cardiovascular shock
- Convulsions
(ii) Paradoxical Air Embolism
- Coma
(iii) Arteriography - Unexpected death

Effects (AAE) depends on – Marble skin CAUSE OF DEATH: -Mechanical blockage of pulmcircn

-Air bubbles in retinal vessels -Anaphylactoidrxn to amniotic fluid

-Pallor of tongue - DIC due to thromboplastin

-Coronary/cerebral AE- sudden - Hemorrhagic manifestations

death
 28

==================================================================================================
CLINICAL EFFECTS:
DECOMPRESSION SICKNESS:
2 types:
-Specialisedform of gas embolism
(i)Acute type - a/c obstruction of small BV in joints &
-Synonyms: Caisson’s disease, diver’s palsy or aeroembolism
sk. Muscles
PATHOGENESIS: -The bends(doubles in bed-pain in jts)
-when decompress suddenly from higher atm. -The chokes(accumulation of bubbles in lungs-resp
Pressure to nllevel(divers) or nl pressure to low distress)
atm. pressure
-Cerebral effects(vertigo,coma,death)
-on descend, increased amt of atm gases(N2,O2&
CO2) dissolved in blood & tissues and on ascend, (ii)Chronic type
gases come out as minute bubbles (esp. in fatty
-Avascular necrosis of bone
tissues having affinity to N2)
-Neurologic symptoms(parasthesias& paraplegia
EFFECTS: dep on depth/altitude reached, duration
of exposure to altered pressure, rate of -Lung inv(dyspnea,cough,chest pain
ascend/descend, general condition
-Skin manifestation (itching, erythema, cyanosis,
)edema)
CVC:(CHRONIC VENOUS CONGESTION):
-Dilatation of veins & capillaries due to impaired venous drainage results in passive hyperemia
CVC LUNG: CVC LIVER:
-In LEFT heart failure(incpulm venous pressure -In RIGHT heart failure, occlusion of IVC & hepatic vein

G: Lungs-heavy & firm in consistency G: -Enlarged & tender liver wihtense capsule
C/S – brown colour(BROWN INDURATION -C/S- NUTMEG appearance(red & yellow mottled
surface corr. To congested centre of lobules & fatty
of lungs)-pigments & fibrosis
peripheral zone resp.)
M:- Alveolar septa widened( interstitial edema +
M:- Congestion changes more marked in centrilobular
dilated & congested capillaries)
zone (severe hypoxia)
-Mildly thickened septa (inc. in fibrous conn tissue)
-Central veins & adj. sinusoids distended & filled with
-Intra alveolar hmg(Rupture of dilated & congested blood
capillaries)
-Centrilobularhaemorrhagic necrosis
-HEART FAILURE CELLS:( breakdown of RBCs liberates -c/c case: centrilobularfibrosis ,regeneration of
hemosiderin pigment taken up by alv. Macrophages) hepatocytes – cardiac cirrhosis
 29

CVC SPLEEN:
-In RIGHT heart failure

G:-Early stage (mod enlarged)

-c/c stage: progressive enlrgment

M:
(i)Enlarged red pulp(capillarisation of sinusoids)

(ii)Hyperplasia of RE cells(splenic macrophages)

(iii)Fibrous thickening of capsule

(iv) Firmness of spleen seen in hepatic cirrhosis

(v)GAMNA GANDY BODIES-hmg overlying fibrous tissue –deposits of hemosiderin pigment + Ca salts

INFARCTION:
An area of ischemic necrosis caused by occlusion of either arterial supply other venous drainage
MORPHOLOGY:

-Infarcts are classified acc. to color & presence or absence of infarction

RED INFARCT WHITE INFARCT

Occurs in areas with Occurs in
1.Venous occlusion 1.Arterial occlusions
2.Loose,spongy tissues 2. In solid organs with end arterial
3.Tissues with dual circulation(lung circulation
& small intestine) 3.Tissue density limits the seepage
4.Sluggish venous outflow of blood from adjoining capillary
5.Reestablished flow to site of beds into necrotic area
previous arterial occlusion

-G: WEDGE shaped (occluded vessel at apex & periphery of organ as base)

M: ISCHEMIC COAGULATIVE NECROSIS;Except in brain( LIQUEFACTIVE NECROSIS)

-Neutophilspredom. ->macrophaghes& fibroblasts->scar tissues(may show

dystrophic calcification)

-In cerebral infarcts->Liq necrosis foll by gliosis i.e replacement by microglial cells
distended by fatty material

-Recent infarcts: poorly defined & slightly hmgic ; old infarcts: well def. & pale

-Time reqd for change into infarct – 4-12 hrs

==================================================================================================
 30
TYPES:
EDEMA: (1) Localized - limited to an organ or limb e.g. lymphatic edema, inflammatory
edema, allergic edema.
-defined as abnormal and excessive (2) Generalized (anasarca) – systemic edema. e.g. renal edema, cardiac edema,

accumulation of “free fluid” in the nutritional edema

interstitial tissue spaces and Edema fluid may be

(1)transudatewhich is more often the case, such as in edema of cardiac and renal
serous cavities disease; (2)exudatesuch as in inflammatory edema.

PATHOGENESIS:

1.Decreased plasma oncotic pressure:

A fall in protein level-> lowering of plasma oncotic pressure-> increased outward movement of fluid from the
capillary wall & decreased inward movement of fluid from the interstitial space->edema.

2.Increased capillary hydrostatic pressure:

Rise in the hydrostatic pressure at the venular end of the capillary which is normally low (average 12 mmHg) to a
level more than the plasma oncotic pressure results in minimal or no reabsorption of fluid at the venular end->
edema

3.Lymphatic obstruction:

Normally, the interstitial fluid in the tissue spaces escapes by way of lymphatics. Obstruction to outflow of these
channels causes localized oedema, known as lymphedema

4. Tissue factors (increased oncotic pressure of interstitial fluid, & decreased tissue tension)

5. Increased capillary permeability

6.Sodium& water retention

 31

============================================================================
THROMBOSIS:
-Process of formation of solid mass in circulation from the constituents of flowing blood; the mass itself is called a
thrombus
 32

TYPES: FATE:

1) Cardiac thrombi more common in the atrial 1. RESOLUTION

appendages, especially of the right atrium, and on
2. ORGANISATION
mitral and aortic valves called vegetations which may
be seen in infective endocarditis and non-bacterial 3. PROPOGATION
thrombotic endocarditis
2) Arterial thrombi & venous thrombi 4. THROMBOEMBOLISM
3)Capillary thrombi

PATHOPHYSIOLOGY:
- Injury to the blood vessel initiates haemostatic repair mechanism or thrombogenesis
- VIRCHOW’S TRIAD: endothelial injury, altered blood flow, and hypercoagulability of blood.
1)ENDOTHELIAL INJURY:
-Integrity of blood vessel wall-> maintaining normal blood flow
-It elaborates a few anti-thrombotic factors,
-It can release a few prothrombotic factors which have procoagulant properties
2)ROLE OF PLATELETS:
Platelet adhesion (platelets adhere to the exposed sub endothelial collagen)  platelet release reaction by whivh
platelet granules (alpha granules containing fibrinogen, fibronectin, PD-GF, platelet factor 4 etc and dense bodies
containing ADP, histamine, epinephrine etc) are released to anterior  platelet aggregation
3)ROLE OF COAGULATION SYSTEM:
-Conversion of the plasma fibrinogen into solid mass of fibrin.
-Intrinsic, extrinsic and common pathways are involved
4)ALTERATION OF BLOOD FLOW:
-Turbulence and stasis occurs
-Blood slows down->the blood cells ( platelets) marginate to the periphery and form a kind of pavement close to
endothelium (margination and pavementing).
-While stasis-higher release of oxygen from the blood, turbulence injure the endothelium -> deposition of platelets
and fibrin
5)HYPERCOAGULABILITY OF BLOOD:
-increase in coagulation factor,
- increase in platelet count
-decrease level of coagulation inhibitors
 33

GENETICS AND PEDIATRIC DISEASES

1.KARYOTYPING
2.DOWN’S SYNDROME
3.TURNER’S SYNDROME
4.KLINEFELTER’S
SYNDROME
5.GAUCHER’S DISEASE
6.MARFAN’S SYNDROME
7.COMMON PEDIATRIC
TUMOURS.
 34

1) KARYOTYPING
-Process by which a karyotype is obtained.
-Metaphase chromosomes are obtained for analysis and photomicrographed.
-Photographs of individual chromosome are then cut and arranged according to standard classification.
-The basis of classification includes length of chromosomes,placement of centromere and relative length of arms.
Steps for chromosome preparation
1. Collection of blood –from peripheral vein under sterilized condition in heparinised syringe.
2. Planting -sample collected transferred to culture vials.Vial contains –cuture medium,fetal calf
serum,phytohemagglutinin,antibiotics.
3. Incubation-culture vials put in incubator at 37 degree celcius for 3 days.
4. Harvesting-around 70 hrs add colchocine to culture vial;that arrest mitosis and metaphase.The contents of vial are
centrifuged (supernatant discharged)and pellet containing cells at bottom of tube treated with hypotnic solution.The
cells swell and chromatid separate.
5. Staining –commonormaly used is Giemsa banding(G banding).Also Q,R banding present.

2) DOWNS SYNDROME
INTRODUCTION -Trisomy 21
-4% translocation of the long arm of chromosome 21 to chromosome 22
or 14 (familial, and the translocated chromosome is inherited from one
of the parents, who typically is a carrier of a robertsonian translocation.)
PATHOGENESIS meiotic nondisjunction.
PREDISPOSING FACTORS -Maternal age women > 45 years
-No effect of paternal age
MOSAIC PATTERN -1% mosaic usually having a
mixture of 46- and 47-chromosome cells
CLINICAL FEATURES 1. Children are gentle and shy
2. Severe Mental retardation
3. Short stature
4. Hypotonia of muscles
5. Brachycephaly with flat occiput
6. Low set malformed ears
7. Epicanthic folds
8. Mongloid slanted eyes
9. Flat nose
10. Mouth open
11. Tongue protruding
12. Tongue furrowed
13. Palate high arched
14. Dentition delayed
15. Short and broad hands
16. Cardiovascular defects(the major cause of deaths in infancy and
early childhood):-
i)most commonormaly defects of the endocardial cushion, including
atrial septal defects,
Atrioventricular valve malformations, and
ventricular septal defects.
17. Atresia of the esophagus and small bowel.
RISK OF DEVELOPING -acute lymphoblastic leukemias and acute myeloid leukemias.
- Alzheimer disease (>40 years)
 35

-Abnormal immune responses that predispose them to serious

infections, particularly of the lungs, and to thyroid autoimmunity

3) TURNER SYNDROME
INTRODUCTION -45,X
-Primary Hypogonadism in phenotypic female.
PATHOGENESIS -Partial or complete monosomy of the short arm of the X
chromosome.

-Fetal ovaries develop normally early in embryogenesis,

but the absence of the second X chromosome leads to
an accelerated loss of oocytes, which is complete by age
2 years. In a sense, therefore, “menopause occurs before
menarche.”
MOSAIC PATTERN -43% mosaic
CLINICAL FEATURES 1. Growth retardation
2. Swelling of the nape of the neck due to
distended lymphatic channels in infancy-
webbing of the neck in older children.
3. Low posterior hairline
4. Cubitus valgus
5. Shield like chest with widely spaced nipples
6. High arched palate
7. Lymphedema of the hands and feet
8. Urinary system anomalies:-
i)horse shoe kidney,
ii)Renal hypoplasia or aplasia or
ii)duplication of ureters.

9. Cardiovascular anomalies (most common cause

of death in childhood):-
 36

i)bicuspid aortic valve

ii) coarctation pf aorta
iii)VSD
10. Genital system:-
i)streak like gonads(ovaries),
ii)no ovarian followingicles,
iii)uterus small.
iv)secondary sex characteristics don’t develop.
v)the genitalia remain infantile,
vi)breast development is minimal,
vii)little pubic hair appears.
viii)Most patients have primary amenorrhea.
ix) Normal mental status but subtle defects in
nonverbal, visual-spatial information processing
have been noted.

HISTOLOGY -ovaries are reduced to atrophic fibrous strands, devoid

of ova and follicles (streak ovaries).
RISK OF DEVELOPING Hypothyroidism
DIAGNOSIS Karyotyping

4) KLINEFELTER’S SYNDROME
INTRODUCTION -47,XXY
-Male hypogonadism
PATHOGENESIS -Non disjunction of sex chromosome during meiosis.
PREDISPOSING FACTORS -Advanced maternal age
-History of radiaition in either parents.
MOSAIC PATTERN -15% mosaic pattern
CLINICAL FEATURES 1. Hypogonadism
2. Increase in length between the soles and the pubic bone
3. Eunuchoid body habitus
4. Reduced facial, body, and pubic hair and gynecomastia
5. Testicular atrophy
6. Infertile (because of impaired spermatogenesis, azoospermia)
HISTOLOGY -hyalinization of tubules which appear as ghost like structure on tissue
sectioning.
-Leydig cells are prominent
RISK OF DEVELOPING -Breast cancer,
-extragonadal germ cell tiumors and
-autoimmune disease such as SLE.
==================================================================================================
5) GAUCHER’S DISEASE
-Autosomal recessive disease.
-due to mutation in the gene that encodes glucocerebrosidase which cleaves glucose from ceramide.
-lysosomal accumulation of glucocerebroside (ceramide-glucose), an intermediate in glycoplipid metabolism, in the
mononuclear phagocytic cells and their transformation into so called Gaucher cells
 37

and in neurons.
-Gaucher disease is not normaly caused by burden of storage material but also by the activation of the
macrophages.
-The main sources of glucocerebroside in phagocytic cells are the membrane glycolipids of old leucocytes
and erythrocytes, while the deposits in the neurons consist of gangliosides.
-High levels of macrophage-derived cytokines, ( interleukins(IL-1, IL-6) &TNF are found in affected tissues.

Clinically, 3 subtypes of Gaucher’s disease are identified based on neuronopathic involvement:

Type I (classic -accounts for 99% of cases of Gaucher disease.
form/adult form/ - characterized by clinical or radiographic bone involvement (osteopenia, focal
chronic lytic lesions, and osteonecrosis)
nonneuronopathic - hepatosplenomegaly
form) -absence of CNS involvement.
- spleen often enormalarges to massive proportions, filling the entire
abdomen.
-Gaucher cells are found in the liver, spleen, lymph nodes, and bone marrow.
Type II(acute progressive involvement of CNS
infantile
neuronopathic form)
Type III(juvenile -they emerge later and are milder
form/ chronic -features in between type I and type II i.e. they have systemic involvement like
neuronopathic form) in type I and progressive involvement of
the CNS as in type II.

CLINICAL FEATURES
-depends on clinical subtype.
-splenomegaly, hepatomegaly, lymphadenopathy, bone marrow and cerebral involvement,
-pancytopenia, or thrombocytopenia
-secondary to hypersplenism, bone pains and pathologic fractures.

MICROSCOPY
Gaucher cells Distended and enormalarged macrophages are called gaucher cells.
They are found in spleen, liver, bone marrow and lymph nodes and in the case
of neuronal involvement, in the Virchow-Robin space.
show erythrophagocytosis and are rich in acid phosphatise
Cytoplasm of these cells Abundant , granular, fibrillar
CRUMBLED TISSUE PAPER APPEARANCE
Nucleus Single
Occasionally 2-3 nuclei
Staining :- PAS, oil red O, Positive as accumulated material is glycolipid admixed with hemosiderin.
Prussian - blue
==================================================================================================
6) MARFAN’S SYNDROME
INTRODUCTION -A connective tissue disorder
-Autosomal dominant inheritance
PATHOLOGY - mutation affecting fibrillin.
- Fibrillin is encoded by the FBN1 gene, which maps to chromosomal locus 15q21
-mutations in the TGF-β type II receptor give rise to a related syndrome, called Marfan
syndrome type 2 (MFS2).
-Fibrillin is a glycoprotein secreted by fibroblasts and is the major component of
 38

microfibrils found in the extra cellular matrix. Microfibrils lay down tropoelastin which is
an integral component of elastic fibres.
-Microfibrils are abundant in:-
1. aorta
2. ligaments
3. ciliary zonules that support the ocular lens;
Therefore these tissues are prominently affected in Marfan syndrome.
ETIOLOGY -70% to 85% of cases are familial
-rest are sporadic, arising from de novo FBN1 mutations in the germ cells of parents.
SKELETAL -abnormally long legs, arms, and fingers (arachnodactyly)
ABNORMALITIES -a high-arched palate
(are the most -hyperextensibility of joints.
obvious feature of -kyphoscoliosis,
Marfan syndrome) -pectus excavatum or a pigeon-breast deformity
OCULAR CHANGE -bilateral dislocation,or subluxation of the lens secondary to weakness of its suspensory
ligaments (ectopia lentis).
CARDIOVASCULAR -Fragmentation of the elastic fibers in the tunica media of the aorta aneurysmal
SYSTEM dilation and aortic dissection .These changes, called cystic medionecrosis, are not specific
for Marfan syndrome.
-Loss of medial support causes dilation of the aortic valve ring, giving rise to aortic
incompetence.
-floppy valve syndrome giving rise to mitral valve prolapse and congestive cardiac failure.
-aortic rupture .
-Less commonormaly, cardiac failure is the terminal event
Clinical trials with drugs that inhibit TGF-β signaling such as angiotensin receptor blockers are ongoing, as these
have been shown to improve aortic and cardiac function in mouse models
==================================================================================================
7) COMMON PAEDIATRIC MALIGNANT TUMOURS
Cancers of infants and childhood differ from those of adults in following respects.
1. Site
2. Genetic basis
3. Regression
4. Histologic features
5. Management
NOTE:
1. Infants and children <4 years – common malignant tumors are various type of blastomas.
2. children age:5-9 years- hematopoetic malignancies.
3. age : 10-14 years(prepubertal age)- soft tissue and bony sarcomas.
SYSTEM AGE <4 YEARS AGE 5-9 YEARS AGE 10-14 YEARS
1.HEMATOPOETIC a/c leukemia a/c leukemia Hodgkins
lymphoma
2.BLASTOMA Neuroblastoma, Neuroblastoma, Hepatocellular carcinoma
Hepatoblastoma, Hepatocellular
Retinoblastoma, carcinoma
nephrobalstoma
3.SOFT TISSUE Rhabdomyosarcoma Soft tissue sarcoma Soft tissue sarcoma
4.BONY - Ewing’s sarcoma Osteogenic sarcoma
5.NEURAL CNS tumour CNS tumour -
6.OTHERS teratoma - Thyroid cancers
 39

NEOPLASM
1. NEOPLASIA
2. CARCINOGENESIS
3. METASTASIS
4. ANAPLASIA
5. ONCOGENES
6. TUMOUR SUPPRESSOR GENES
7. PARANEOPLASTIC SYNDROMES
8. IMMUNE SURVEILLANCE
9. TUMOUR MARKERS
10.TUMOUR ANTIGENS
 40

1) NEOPLASIA:
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

===========================================================================================
2) CARCINOGENESIS
-Carcinogenesis/ oncogenesis / tumorigenesis means mechanism of induction of tumours (pathogenesis of cancer)

- TYPES:
(i)CHEMICAL CARCINOGENESIS: Mechanism
1. CHEMICAL

2. PHYSICAL

3. BIOLOGICAL

Tests for Chemical Carcinogenicity

2 methods:-
1. EXPERIMENTAL INDUCTION –
(experimental animals)
2. TESTS FOR MUTAGENICITY (AMES’
TEST). -Mutagen-substance that can
permanently alter the genetic composition
of a cell.
-Ability of a chemical to induce mutation
in the mutant strain of Salmonella
typhimurium that cannot synthesise
histidine.
-Incubated with the potential carcinogen
to which liver homogenate is
added(procarcinogen to ultimate
carcinogen).
-Detected by no. of bacterial colonies.
 41

(iii) BIOLOGICAL CARCINOGENESIS:

(ii)PHYSICAL CARCINOGENESIS:

1. Radiation – UV + ionizing radiation

2. Non-radiation
MECHANISM of Radiation carcinogenesis

a) It may directly alter the cellular DNA.

b) It may dislodge ions from water and

other molecules of the cell and result in
formation of highly reactive free radicals
that may bring about the damage.
 42

3) METASTASIS:
Routes of Metastasis 2. HAEMATOGENOUS SPREAD -mainly 3. SPREAD ALONG BODY CAVITIES
sarcomas + liver, lungs, brain, bones, AND NATURAL PASSAGES
1. Lymphatic spread
kidney & adrenals
i) Transcoelomic spread
2. Haematogenous spread
-Systemic veins drain into vena cava from
ii) Spread along epithelium-lined
3. Spread along body cavities limbs, head, neck and pelvis &
surfaces –unusual
& natural passages metastasize to the lung
iii) Spread via cerebrospinal fluid.
1. LYMPHATIC SPREAD – -Portal veins drain blood from the bowel,
spleen and pancreas into the liver iv) Implantation –by surgeon’s
-Carcinomas by lymphatic route; scalpel and apposing lips
sarcomas by haematogenous route. -Arterial spread less because thick-walled
and contain elastic tissue which is
Involvement of lymph nodes by:- resistant to invasion (except through
i) Lymphatic permeation. pulmonary capillary bed)

ii) Lymphatic emboli -enter the lymph GROSS:-

node at its convex surface and are Multiple, rounded nodules throughout
lodged in the subcapsular sinus where organ
they start growing
MICROSCOPICALLY :-
Also by 1.Regional nodal metastasis
Resemble the primary tumor
2.Sinus histiocytosis.
Same primary tumor at different
3.Skip metastasis. metastatic sites may show varying of
4.Retrograde metastases differentiation
--

4) ANAPLASIA:
-Lack of differentiation
 43

5) ONCOGENES

====================================================================
6) TUMOUR SUPPRESSOR GENES:

=========================================================================================
7) IMMUNE SURVEILLANCE
-Tumour cells recognized by - The different classes of tumor Ags  products of mutated
the immune system as non- proto-oncogenes, tumor suppressor genes,overexpressed
self & destroyed. expressed proteins, tumor Ags produced by oncogenic viruses,
oncofetal Ags,altered glycolipids and glycoproteins.
- Antitumor activity by CMI.
Tumour Ags presented on the - In immunocompetent patients(increased risk for cancer devpt),
cell surface by MHC class I tumors avoid the immune system by several mechanisms(
molecules and recognized by selective outgrowth of Ag-negative variants, loss or reduced
CD8+ CTLs. expression of histocompatibility Ags
 44

8) PARANEOPLASTIC SYNDROMES

=================================================================================================

9) TUMOUR MARKERS
 45

10) TUMOUR ANTIGENS

- Tumour specific Ags(TSAs)

-Tumour Associated Ags(TAAs)

-Oncoproteins from mutated oncogenes

-Protein pdts of Tumour suppressor genes

-Overexpressed cellular proteins

-Tumour Ags from viral oncoproteins

-Tumour Ags from randomly mutated genes

-Oncofetal Ags

-Abnl cell surface molecules

==================================================================================================

11) PREMALIGNANT LESIONS

Benign and malignant tumours as also a number of tumour like lesions and premalignant lesions are
encountered in the oral soft tissues
 46

12) GRADING & STAGING OF CANCER

GRADING: STAGING:

Grading is defined as the gross and microscopic Staging means extent of spread of the tumour within the
degree of differentiation of the tumour(histological) patient (clinical).

-Cancers graded grossly & microscopically. -Mostly for malignant tumors

-Gross -features like exophytic or fungating are less -Assessed by 3 ways—by clinical examination, by
malignant than infiltrating tumours. investigations, and by pathologic examination of the tissue
-Grading based on two features: the degree of removed.
anaplasia & the rate of growth. -2 staging methods: TNM & AJC staging.
-TNM staging:
- Broders’ grading : -T for primary tumour, N for regional nodal involvement,
i) Grade I: Well-differentiated (<25% anaplastic cells). and M for distant metastases
ii) Grade II: Moderately-differentiated (25-50% ) i)T0 to T4: In situ lesion to largest and most extensive
iii) Grade III: Moderately-differentiated (50-75%) primary tumour.
iv)Grade IV: Poorly-differentiated or anaplastic (>75%) ii)N0 to N3: No nodal involvement to widespread LN
involvement.
-Criteria for histologic grading : iii)M0 to M2: No metastasis to disseminated
 Flow cytometry for mitotic cell counts haematogenous metastases.
 Cell proliferation markers by -AJC staging:
immunohistochemistry American Joint Committee divides into stage 0 to IV, and
 By applying image morphometry for cancer cell takes into account all the 3 components of the preceding
& nuclear parameters. method.

==================================================================================================
 47

INFECTIONS:
1. TB
2. LEPROSY
3. IMN
4. TORCH
5. SYPHILIS
6. MALARIA
7. CANDIDIASIS
8. AMOEBIASIS
9. MYCETOMA
 48

1) TUBERCULOSIS
- Tuberculosis is a serious chronic pulmonary and systemic disease.
- Caused by Mycobacterium tuberculosis.
- source of transmission: Humans with active tuberculosis (mycobacteria present in the sputum)
 Pathogenesis

The outcome of infection in a previously unexposed, immune-competent person depends on the development of anti-
mycobacterial T cell mediated immunity.

 PULMONARY TUBERCULOSIS
- Infection of those who have not been previously infected or immunized is called primary tuberculosis or Ghon’s
complex. Lesion produced in the tissue of portal of entry with foci in the draining lymph node.

MORPHOLOGY

Grossly: Histologically :
- as sensitization develops , a 1 to 1.5 cm area of grey white - Marked granulomatous
inflammation with consolidation emerges known as Ghon’s inflammatory reaction that forms
focus . caseating& non caseating
- The centre of this focus undergoes casseous necrosis. Tubercle tubercles.
bacilli either free or within phagocytes , drain to the regional - It is onormaly when multiple
nodes which also often caseate. granulomas are usually enclosed
- This combination of parenchymal lung lesion and nodal within a fibroblastic rim
involvement is referred to as the Ghon complex. punctuated by lymphocytes and
95% cases – CMI controls the infection. Hence Ghon complex epitheloid cells with slipper
undergoes progressive fibrosis, often followingowed by radiologically shaped nucleus.
detectable calcification.
 49

 Secondary tuberculosis or post-primary or Features :In congenital rubella –

 reinfection or chronic tuberculosis - ocular defects
- cardiac defects
- Infection of an individual who has been previously
- CNS manifestations
- infected or sensitized.
- sensory neural deafness
- Infection occur from (1)reactivation of dormant - thrombocytopenia
- primary complex(endogenous) - hepatosplenomegaly.

(2) fresh dose of reinfection by tubercle bacilli (exogenous)

Lesion begin as 1-2 cm apical area of consolidation of lung which develop a small area of central caseation necrosis &
peripheral fibrosis.

Diagnosis :
[1]AFB microscopy –sputum,aspirated material
[2] mycobactial culture-LJ medium (4-8 weeks),HPLC
[ 3] PCR
[4] hemogram
[5]radiographic procedures
[6]mantoux skin test
[7]serologic test
[8]fine needle aspiration cytology

2) LEPROSY
(HANSEN’S disease) : c/c granulomatous disease caused by Mycobacterium leprae

RIDLEY & JOPLING classification:

TT- Tuberculoid polar LEPROMIN TEST:

BT-Borderline tuberculoid - Not a diagnostic test but for classifying leprosy on the basis of immune
response. On intradermal injection of lepromin
BB-Mid Borderline
1)FERNANDEZ Reaction- early indurated area (within 24-48 hrs=+ve)
BL-Borderline lepromatous
2)MITSUDA Reaction - delayed granulomatous lesion after 3-4 wks.
LL-Lepromatous polar
The test indicate that CMI is greatly suppressed in LL while TT- good
response.

REACTIONAL LEPROSY

A) TYPE 1 (Reversal Reaction) : polar forms has no change bt borderline groups are unstable.

1. Upgrading reaction: BLTuberculoid type

2. Downgrading reaction: BTLepromatous type

B) TYPE 2 (Erythema NodosumLeprosum) :occurs in LL patients after treatment & is marked by tender
cutaneous nodules, fever ,iridocyclitis and lymph node involvement.
 50

==================================================================================================

3) IMN:
- Infectious mononucleosis (IM) or glandular fever is a benign, self-limiting lymphoproliferative disease .
- Caused by: Epstein-Barr virus (EBV)
- Age: childhood to old age but the classical acute infection is more common in teenagers and young adults.
- Mode of tranmission: By person-to-person contact such as by kissing with transfer of virally-contaminated saliva.
Pathogenesis
 51

Characterised by:
virus in contaminated saliva
- fever
- generalised lymphadenopathy
invades and replicates within epithelial
- hepatosplenomegaly
cells of the salivary gland
- sore throat
- appearance in blood of atypical ‘mononucleosis
enters B cells in the lymphoid tissues
cells’
which possess receptors for EBV.
Laboratory Findings
The infection spreads throughout the 1. HAEMATOLOGIC FINDINGS. Major abnormalities
body via bloodstreamor by infected B cells. in blood are as under:
i) TLC: moderate rise (10,000-20,000/μl) .
Viraemia and death of infected B cells cause ii) DLC: There is an absolute lymphocytosis. (relative
an acute febrile illness neutropenia).
iii) Atypical T cells: The diagnosis of IM is the
appearance of specific humoral antibodies which presence of at least 10-12% atypical T cells (or
peak about 2 weeks after the infection and persist mononucleosis
throughout life. The appearance of antibodies marks cells) .
the iv) CD 4+ and CD8+ T cell counts. Reversal of
disappearance of virus from the blood. CD4+/CD8+ T cell ratio. There is marked decrease in
CD4+ T cells while there is substantial rise in CD8+ T cells.
v) Platelets. thrombocytopenia .
Though the viral agent has disappeared from the 2. SEROLOGIC DIAGNOSIS. The second characteristic
blood, laboratory finding is the demonstration of antibodies in
the EBV-infected B cells continue to be present in the the serum of infected patient. These are as under:
circulation. i) Test for heterophile antibodies. Heterophile antibody
test (Paul-Bunnell test) is used for making the diagnosis
of IM. In this test, patient’s serum is absorbed with guinea
EBV-infected B cells undergo pig kidney. Serum dilutions are prepared which are used
polyclonal activation and proliferation.. for agglutination of red cells of sheep, horse or cow and
are reported as heterophile titer of test serum. A high
proliferation of these cells is responsible for serum titer of 40 or more times is diagnostic of acute IM
generalised lymphadenopathy and infection in symptomatic case in the first week.
hepatosplenomegaly ii) EBV-specific antibody tests. Specific antibodies against
the viral capsid and nucleus of EBV can be demonstrated
sore throat in IMN may be caused by either necrosis in patients who are negative for heterophile antibody test:
of iii) EBV antigen detection. Detection of EBV DNA or
B cells or due to viral replication within the salivary proteins can be done in blood or CSF by PCR method.
epithelial 3. LIVER FUNCTION TESTS.
cells in early stage. These include elevated serum levels of transaminases
Besides the involvement of EBV in the pathogenesis (SGOT and SGPT), rise in serum alkaline phosphatase and
of mild elevation of serum bilirubin.
IM, its role in neoplastic transformation in
nasopharyngeal
Clinical Features
1. During prodromal period (first 3-5 days), the
symptoms
are mild such as malaise, myalgia, headache and
fatigue.

2. Frank clinical features (next 7-21 days) commonly

 52

are fever, sore throat and bilateral cervical

lymphadenopathy.
 Less commonormaly, splenomegaly ,
hepatomegaly
, transient erythematous maculo-papular eruption
on the trunk and extremities, and neurologic
manifestations
are found.
 Pneumonia and cardiac involvement are
infrequent.
 One of the complications of IM is proneness
for
splenic rupture due to splenitis.

==========================================
===================================
[T]- Toxoplasma

[O]- Others 4) TORCH COMPLEX:

[R]- Rubella - Development of common complex of symptoms in infants due
to infection with different microorganism that include
[C]- Cytomegalovirus
Causes-infection during intra uterine life ,perinatally ,damage to
[H]- Herpes Simplex virus infant.
Others – Hepatitis B , Coxsackie virus B , Mumps - Transmitted transplacentally , but herpes &cytomegalo
, Polio virus virus are common venereally acquired infections.
- Prevention & immunization – best modes of therapy.
5) SYPHILIS:
-Causative organism:Treponemapallidum ( a spirochete)
-Mode of transmission: sexual, transplacental (congenital syphilis) .
-Pathogenesis: proliferative endarteritis of small vessels &surrounding plasma rich infiltrate.

Mainly 3 stages : primary ,secondary, tertiary

Primary: - Secondary:- Tertiary:-

gross : Gross : Gross:
- chancre formation - mucocutaneous - In aorta aortitis, aneurysms, regurgitations
penis/scrotum in males lesions - General paresis, tabesdorsalis ,CSF
,vulva/cervix in female (infections) anomalies
- Lesion is slightly elevated firm, - Red brown - Also affects bone , liver , testis
red, papule macules ,less than - Syphilitic gumma –single or multiple white
- Erosion causes clean based 5mm diameter grey ,rubbery resemble tumour like masses
shallow ulcer Sites affected: skin, bone, joints,
- Enormalarged regional lymph subcutaneous tissue
node

Histology: Histology:
- chancre- infiltration by plasma Histology: - coagulative necrosis ,cell infiltration by
cells, macrophages - same as primary leukocytes ,plasma cells , Rarely treponemes
 53

,lymphocytes & proliferation of chancre

endarteritis Palmar rash
,condylomalata,
lymphadenopathy also
present.

Congenital syphilis:-
hutchinsons triad (interstitial keratitis ,8 th cranial nerve deafness, hutchinsons teeth ), periostitis, gummas in
liver, pneumonia alba, optic atrophy, bullous eruptions , saddle nose deformity.
-Diagnosis- serological tests

Non treponemal antibody tests → RPR, VDRL

Anti treponemal antibody tests→ FTA – absorption test

T.pallidum enzyme assay

6) MALARIA: (BLACKWATER FEVER)

- Malaria caused by any of the 4 species of plasmodium.

- P.falciparum,P.ovale,P.malariae,P.vivax.

- P.falciparum produce tertian malaria.The other two produces relatively benign disease.malaria transmitted by female
anopheles mosquito& humans are the natural host.

- P.falciparum infection produce complications such as cerebral malaria &black water fever.In cerebral malaria rapidly
progressive convulsions leads to coma &death later.

- It punctuated at any time by blackwaterfever.Massive intravascular hemolysis hemoglobinemia

,hemoglobinuria& jaundice.

=>Life cycle

mosquito gameto
bite gony

mosqui
to bite
Gametocytes
human
s

sporoz
schizont oites
s in RBC enter
into
human
body
enter reache
into s
RBC(er liver(ex
ythrocy merozo oerythr
tic ites ocytic
cycle) release cycle
d
 54

7) CANDIDIASIS:
- Opportunistic fungal infection. Caused by Candida albicans.
- Predisposing factors: impaired immunity, prolonged use of oral contraceptives, antibiotic therapy, corticosteroid
therapy, obesity, diabetes mellitus, pregnancy.
 Pathologic changes
- Produce superficial infection of skin &mucous membrane.
- Oral thrush, candidal vaginitis, cutaneous candidiasis, Systemic candidiasis.

8) AMOEBIASIS:
- Causative organism: Entamoebahistolytica– protozoan family
- Route:Feco-oral transmission
- infective form – cyst
- Causes : Dysentery & lung abcess

Life cycle
E.histolytica resistant to gastric acid → cysts pass through stomach → colonize epithelial surface of colon → release
trophozoites → encystations in colon → cyst in fecal matter

Sites of involvement – caecum , ascending colon, rectum, sigmoid colon

Pathogenesis of dysentery Pathogenesis of liver abscess

Amoebae attach colonic epithelium Amoebae penetrate splanchnic vessels
↓ ↓
Induce apoptosis Embolise to liver & abscess
↓ Abscess rarely forms in lungs, heart, kidney & brain
Invade crypts & burrow laterally into lamina propria
↓
Cell infiltrationFlask shaped ulcer
- Clinical presentation – abdominal pain, weight loss, bloody diarrhea, mega-colon
- Drugs – metronidazole, chloroquine

9) MYCETOMA
Chronic suppurative infection involving a limb ,shoulder or other tissus.Characterised by sinuses.Caused by
actinomyces.
Pathologic changes

After infection affected site swollen lesion extend deeply into subcutaneous tissue&bones

purulent material drain through sinuses granulomatous reaction

 55

..haematology..

- Classification of anaemia - AML

- Megaloblastic anaemia - ALL
- Iron deficiency Anaemia - CML
- Sideroblastic anaemia - Leukemoid reaction
- Thalassemia - Agranulocytosis
- Haemolytic anaemia - Myelodysplastic
- Immunohemolytic anaemia syndrome
- Hereditary spherocytosis - Polycythaemia Vera
- Sickle cell anaemia - Hodgkins Lymphoma
- PNH - Multiple Myeloma
- MAHA - Aplastic anaemia
- ITP
- TTP Haemophilia
- v WD
- DIC
- Haemolytic disease of new-
born
- Blood Transfusion reaction
 56

Classification of anaemia

===========================================

MEGALOBLASTIC ANEMIA

- Disorders caused by impaired DNA synthesis.

- Characterized by abnormality in hematopoietic precursor in the bone marrow in which maturation of nucleus is
delayed relative to the maturation of cytoplasm.

BLOOD PICTURE AND RED CELL INDICES BIOCHEMICAL BASIS -

BLOOD FINDINGS =>Hemoglobin- below normal, Reticulocyte count- low to normal , Leucopenia with hypersegmented
neutrophils , Platelets reduced in severely anemic.

BONE MARROW FINDINGS => Marrow cellularity- hypercellular with decreased M/E ratio , Erythropoiesis- characteristic
megaloblastic erythropoeisis.
 57


 ETIOLOGIC CLASSIFICATION OF MEGALOBLASTIC ANEMIA

 BIOCHEMICAL FINDINGS
- Rise in serum unconjugated bilirubin and LDH
- Serum iron and ferritin- normal or elevated
 SPECIAL TESTS FOR CAUSE OF SPECIFIC DEFICIENCY
- Tests for vit B12 deficiency-Microbiological assay using vit B12 dependent microorganisms
- Radioassay
- Schilling test
- Serum enzyme levels(methyl malonic acid, homocysteine, etc.)

===================

MICROCYTIC HYPOCHROMIC ANEMIA:-

 58

1)IRON DEFICIENCY ANEMIA

Commonest nutritional problem

2)SIDEROBLASTIC ANEMIA:.
Nucleated erythroid precursors in bone marrow show characteristic ‘ringed sideroblast’

TYPES :
1.Hereditary sideroblastic anemia –X
linked disorder.Defective enzyme activity
of ALA synthetase.

2.Acquired sideroblastic anemia

-Primary (possibly due to reduced activity
of the enzyme ALA synthetase)
-Secondary:Drugs,chemicals,toxins
Myelofibrosis,
polycythemia vera
Acute leukemia
Miscellaneous

Rx: Pyridoxine(200 mg/day for 2-3 months) LAB FINDINGS:

-Moderate to severe anemia

-MCV,MCH,MCHC decreased

-Blood pic:hypochromic anemia

-Ser. Ferritin, iron raised;

-Iron deposition in tissues increased

 59

3) ANEMIA OF CHRONIC DISORDERS:

LAB FINDINGS:
-Hb : <8g/dl
-Blood pic:
normocytic,normochromic anemia
-Absolute values: MCHC low
-Reticulocyte count: low

4) THALESSEMIAreduced synthesis of 1 or more globin chains

PATHOGENESIS: LAB DIAGNOSIS:

β Thalassemia – chain of HbA are encoded by a 1.Hematological findings
single β globin gene located on chromosome 16 i. Anemia
(1)β0 –Noβ globin chain are prodced. ii. Microcytic hypochromic anemia-
(2)β+-Reduced β globin synthesis peripheral smear finding
α Thalassemia :Deletion of genes iii. MCV,MCH,MCHC reduced
iv. Reticulocytosis
MORPHOLOGY:
(1)Peripheral smear finding – microcytic v. Serum bilirubin raised
hyperchromic anemia.Target cells are often seen (unconjugated)
,Normoblast-defective erythropoiesis. vi. WBC count raised
(2)Skeletal deformities -impair bone vii. Platelet count reduced
growth,expanded bone (malocclusion jaw)
(3)Splenomegaly 2.Osmotic fragility-increased resistance to
(4)Hepatomegaly saline,decreasd osmotic fragility
(5)Lymphadenopathy 3.Hb electrophoresis –detect HbF,HbA2 ,absence or
(6)Degrre of cachexia and growth retardation variable amount of Hba
(7)Hemosiderosis 4.Bone marrow aspirate –normoblastic erythroid
hyperplasia smaller than normal in size.

Rx:
1.Correct anemia
2.Splenectomy
3.BM transplantation
4.Chelation therapy to prevent Fe overload
 60

5) HEMOLYTIC ANEMIA:
Due to increase in red cell destruction
INVESTIGATIONS:
I.Test for increased RBC breakdown:
1.Ser. BR – Unconjugated-Raised
2.Urine UBG – Raised, no BRuria
3. Faecal Stercobilinogen-Raised
4.Ser.haptoglobulin –reduced/absent
5. Plasma LDH – raised
II.Test of increased RBC prodn:
1.Reticulocyte count – raised
2.BM- erythroid hyperplasia with increased Fe stores
3.X-ray bones – expansion of marrow spacs
III. Test of damage to RBCs:
1.Osmotic fragility – increased/decreased
2.Autohemolysis test
3.electrophoresis (abnormal Hb)
4. Estimation of HbA2 & HbF
5.Coomb’s antiglobulin test
6.Tests for sickling & screening test for G6PD deficiency &
other enzymes
 61

6)IMMUNOHEMOLYTIC
ANEMIA: 1. WARM Antibody AIHA:
C/F: -c/c anemia
-Splenomegaly
TYPES: -Occasional hyperBRemia
1.AIHA(AutoImmune ) Lab investigation:
Warm Antibody AIHA -Mild to moderate c/c anemia
(AutoAntiBody reactive at 370C) -Reticulocytosis
Cold Antibody AIHA -Prominent spherocytosis(PS)
(AutoAntiBody react at 40C) - +ve indirect Coomb’s test
2.Drug Induced IHA
(Methyl dopa, penicillin, quinidine) 2.COLD Antibody AIHA:
3.Isoimmunehemolytic anemia Pathogenesis: 2 conditions reactive at 40C:
(AntiBody acquired by blood 1)Cold agglutinin disease: IgM Antibody against I
transfusion, pregnancies & HDN) Antigen in RBC at 40C.Etiology-Mycobacterium Tb
2)Paroxysmal Cold Hemoglobinuria(PNH): IgG Antibody against P
blood group Ag-increase on cold.
C/F: 1. c/c anemia
2. Raynaud’s phenomenon
3. Cyanosis affecting cold exposed regions(tips of nose, ears,
fingers)
4. Hemoglobinemia & Hemoglobinuria
Lab Investigations: 1. Low reticulocyte count(young cells affected
more)
2.Spherocytosis less marked
3.+ve Direct Coomb’s test
4. Cold Antibody titre high at 4oC and low at
o
37 C

7)HEREDITARY SPHEROCYTOSIS:
-Hereditary hemolytic anemia of Autosomal Dominant type
 62

PATHOGENESIS: C/F: 1.Anemia mild to moderate

2. Splenomegaly
Defect in proteins which 3. Jaundice(rise in indirect BR)
anchor lipid bilayer to 4. Pigment gallstones(increased bile
underlying cytoskeleton production)
1.Spectrin deficiency LAB INVESTIGATIONS:
2.Ankyrin abnormality
RBCs with unstable membrane 1.Anemia-mild to moderate
but with normal volume, 2. Reticulocytosis(5-20%)
released in circulationlose 3. Blood film-microspherocytes
membraneformation of 4.MCV normall /decreased; MCHC increased
MICROSPHEROCYTESpassage 5. Osmotic fragility increased
thru 6. Autohemolysis test increased
spleenHYPERSHEROIDAL 7. DCT –ve (different from acquired
RBCs(non flexible-loose spherocytosis of AIHA)
membrane further)

8) SICKLE CELL ANEMIA:

- Qualitative disorder of hemoglobinopathies
- In 3 forms: 1. As heterozygous state(AS-sickle cell trait)
2. As homozygous state(SS – sickle cell anemia)
3. As double heterozygous state (SS/SD)
PATHOGENESIS: C/F:1.anemia-severe
1.Basic molecular leison: single point 2.vaso-occclusive phenomenon
mutation- substitution of Val by Glu at a .Microinfarcts(abdomen, chest,back,joints)
6th position of beta HB chain b. Macroinfarcts( spleen,BM,kidneys)
2. Mechanism of sickling : 3. Constitutional symptoms
deoxygenation – RBC containing HbS (decreased growth and development & increase
change to sickle shaped cells infections)
3. reversible- irreversible sickling LAB FINDINGS:
4. factors determining rate of sickling- 1.Anemia
-presence of non- HbS 2. Blood film-sickle cell, target cell & Howell Jolly
-I/C conc. of HbS bodies)
-acidosis, dehydration & 3.+ve sickling test
deoxygenation 4. electrophoresis shows HbS
 63

9) PAROXYSMAL NOCTURNAL HEMOGLOBINURIA(PNH):

Defective synthesis of RBC membrane protein
c/c intravascular hemolysis

PATHOGENESIS: C/F & LAB FINDINGS:

-mutation of PIG-A (phosphatidyl 1. Hemolytic anemia

inositol glycan) gene for 2. Pancytopenia
biosynthesis of GPI(glycosyl 3. Intermittent clinical
phophatidyl inositol) Haemoglobinuria
-result in deficicency of anchor 4. Hemosiderosis
proteins, 5. Venous thrombosis
-lack of 2 proteins- 6. Demonstration in vitro by
1.decay accelerating factor (DAF) HAM’S TEST(inordinate
2.membrane inhibitor of reactive sensitivity of RBCs to
lysis(MIRL) complement
sensitizes RBC’s to lytic effect of
complement

10) MICROANGIOPATHIC HEMOLYTIC ANEMIA(MAHA):

-small vessels become partially obstructed or narrowed.

CAUSE:
1) External impact
2) Cardiac hemolysis( prosthetic valves)
3) Fibrin deposit in microvasculature
MICROSCOPY:
Schistocytes, burr cell, helmet cells, triangle cells
 64

11) APLASTIC ANEMIA:

It is pancytopenia.

1.Primary congenital (Fanconis’ anemia)

Acquired(immunologically mediated)
2.secondary drugs eg:Methotrexate,Busulphan

Toxic chemicals

Infections eg: AIDS, EBV

In association with SLE etc.

Clinical features
1.Anemia and its symptoms like weakness and fatigue.
2.Hemorrhagic from various sites due to thrombocytopenia.
3.Infections of mouth and throat.

Laboratory findings
1.RBC :Hb levels moderately reduced,normocytic normochromic
anemia,reticulocyte count reduced.
2.WBC:absolute granulocyte count decreased with relative lymphocytosis.
3.PLATELET:thrombocytopenia
Bone marrow examination
Bone marrow aspiration yields “dry tap.”
Trephine biopsy –patchy cellular areas along with fat

Rx:
A.GENERAL MEASURES:
1. Identification & elimination
2.Supportive care
B.SPECIFIC Rx:
1.Marrow stimulating agents
2.Immunosuppressive therapy
3.BM transplantation
 65

PLATELET DISORDERS:
1) ITP:(Immune Thrombocytopenic Purpura):
- Immunologic destruction of platelets
-normal/ increased megakaryocytes in BM

PATHOGENESIS: C/F:
Dep. On duration-a/c & c/c -Petechial Haemorrhage, easy
bruising & mucosal bleeding
1)A/C ITP:-in children recovering from viral disease or URTI - Hepatomegaly &
- Sudden onset & severe thrombocytopenia splenomegaly(c/c)
- Recovery : few weeks to 6 months LAB FINDINGS:
- Mechanism: formation of immune complexes 1. platelet count reduced
containing Ag & production of antibody against 2. Blood film : large
viral antigenscross react with plateletsimmunologic platelets(few)
destruction 3. BM : increased no. of
2)C/C ITP:-In adults(women of reproductive age 20-40 yrs) megakaryocytes
- Formation of anti-platelet autoAntibody(IgG humoral 4. Anti platelet IgG Antibody
Antibody) syn. By spleen demo in serum
- Antibody directed against target Ags on platelets Gp(IIb- 5. Platelet survival studies :
IIIa & Gp Ib-IX complex decreased platelets life span
- destruction of platelets similar to AIHA

2) TTP((Thrombotic Thrombocytopenic Purpura):

-TTP &HUS(Hemolytic Uremic Syndrome) – Group of thrombotic microangiopathies
- Characterised by triad: 1) Thrombocytopenia 2) MAHA 3) Hyaline fibrin microthrombi
- Occur in young adults (fulminant & lethal disorders)
 66

PATHOGENESIS: C/F:
-Unormalike DIC, activation of -MAHA & thrombocytopenia
clotting system not involved -Fever, transient neurologic deficits, renal
-Initiated by endothelial injury failure
following by release of vWF from LAB FINDINGS:
endothelial cells lead to 1. –ve Coomb’s test
formation of microthrombi 2.Leucocytosis(with leukemoid reaction)
-Trigger for endothelial damage: 3. BM examination: normal/ increased
pregnancy, metastatic Carcinoma, megakaryocytes+myeloid hyperplasia
high dose chemotherapy, HIV 4. Biopsy examination(microthrombi in
infection, mitomycin C arterioles, capillaries & venules)

BLEEDING DISORDERS
1)HEMOPHILIA A ( Classic Hemophilia):
-Deficiency/reduced activity of factor VII(anti hemophilic factor)
- X-linked disorder
-Manifest in males; females are carriers

PATHOGENESIS: C/F:
-90%- quantitative reduction; 10%- normal/iincreased -Bleeding from injury for hours to days
level(F VIII) with reduced activity) -Recurrent painful hemarthroses & hematomas
- F VIII synthesis: hepatic parenchymal cells -Spontaneousaneous intracranial haemorrhage &
Function: activation of F 10 in intrinsic pathway oropharyngeal bleed
-During circulation: F VIII-vWF complex formation LAB FINDINGS:
-Hence, all these reduced 1.CT : prolonged
Rx: 2.PT : Normal
-F VIII replacement therapy(F VIII concentrates/plasma 3.APTT : prolonged
cryoprecipitate) 4.Specific F VIII assay – lowered activity

HEMOPHILIA B (CHRISTMAS DISEASE):

-Inherited deficiency of F IX(plasma thromboplastin factor)
-C/F & pathogenesis : Same as Hemophilia A
-Rx: infusion of FFP/plasma enriched with F IX

2) Von Willebrand’s Disease(VWD):

-quantitative or qualitative defect in vWF

PATHOGENESIS: C/F:
-vWF larger fraction in vWF-F VIII complex -Spontaneous bleeding from mucous membranes &
-Both circulate as a single unit but, excessive bleeding from wounds
vWF differs from F VIII in the following -3 types: TYPE I: MC; mild to moderate decrease in
1.Gene for vWF – chr 12(AD trait); F VIII- X chr(X-linked) plasma vWF
2.Synthesis: vWF - endothelial cells,megakaryocytes TYPE II:less common; normal platelet’s fn-
 67

F VIII- liver defective

3.Function:vWF – adhesion of platelets to subendothelial TYPE III: Rare; most severe form
collagen LAB FINDINGS:1.BT-prolonged;normal platelets
F VIII- activation of F X in Intrinsic pathway count
2. Reduced vWF & F VIII activity

3) DIC(Disseminated Intrvascular Coagulation):

-Synonyms: defibrination syndrome / consumption coagulopathy
-Is a complex thrombo-haemorrhagic disease occurring as a secondary complication in some systemic disease

ETIOLOGY: PATHOGENESIS:
1.Massive tissue injury 1.Acivation of coagulation
2.Infections 2.Thrombotic phase
3.Widespread endothelial damage 3.Consumption phase
4.Miscellaneous 4.Secondary fibrinolysis
C/F: LAB FINDINGS:
2 main features: 1.Bleeding 1.Platelets count-low
2. Organ damage 2.Blood film – MAHA(schistocytes & fragmented RBCs)
3.MAHA & thrombosis(less common) 3.PT,aPTT & TT – prolonged
4.Plasma fibrinogen-low
5.FDPs reduced

CHARACTERISTIC FEATURES OF COMMON BLEEDING DISORDERS

 68

4) HDN(Hemolytic Disease of Newborn)

-results from passage of IgG antibodies from maternal circulation across placenta

not circulation of foetal red cell

-CAUSES:

(1)Previous abortions (2)previous blood transfusions can also sensitise mother (3) pregnancy.

PATHOGENESIS:

-HDN can occur from incompatibility of ABO /Rh blood group system COURSE & PROGNOSIS:
1)Due to Rh incompatibility: -Rh-ve mother sensitized to Rh+ve blood -range from death to
-Rh+ve fetus by passage of Rh+ve RBCs minimal hemolysis to MR
across placenta into circulation of Rh-ve
mother Rx:
2)Due to ABO incompatibility:-In infants born to O grp mothers possess anti-Rh Ig
Anti-A or anti-B Antibody
-Less severe; naturally occurring Antibody(anti-A/B)
Of IgM type do not cross placenta; but immune
Type crosses(Ig G class)

CLINICAL FEATURES:

-Severe form: HDN due to Rh incompatibility results in IUD from hydrops fetalis
-Moderate form: severe anemia & jaundice(Unconjugated hyperBilirubenemia)
-Mild form :severe anemia+/- jaundice
LAB FINDINGS:

1.Cord blood shows anemia, reticulocytosis, raised ser.BR, +ve direct Coomb’s test
2.Mother’s blood is Rh-D –ve with high plasma titre of anti-D

===========================================================================
5) BLOOD TRANSFUSION REACTIONS:
-2 types: Immune & non-immune
IMMUNE TRANSFUSION REACTION: NON-IMMUNE TRANSFUSION REACTION:
1)Hemolytic transfusion Rxn: immsdiately/delayed; I/V or 1)Circulatory overload
 69

E/V 2)Massive transfusion

2)Transfusion-related a/c lung injury (TRALI): 3)Transmission of infection
-transfusion of donor plasma cont. high levels 4)Air embolism
Of anti-HLA Antibody bind to WBCs of recipient 5)Thrombophlebitis
-These WBCs aggregate in micro circulation;release 6)Transfusion hemosiderosis
mediatorsa/c pulmonary edema & signs and
symptoms of
respiratory failure
3)Other allergic reactions
 70

WBC DISORDERS:
1. AML(Acute Myeloid Leukemia)

PERIPHERAL SMEAR FINDING:

1. Anemia- severe, progressive,
normochromic

2. Thrombocytopenia- M3 ass with DIC

3. WBC - >1 lakh/mm3 (mostly blast cells)

BM EXAMINATION:

1. Cellularity – Hypercellular(sometimes dry

tap)

2. Leukemic cells- increased blast cells

3. Erythropoeisis- Reduced erythropoeitic

cells; dyserythropoeisis, megaloblastic cells &
ring sideroblasts present

4. Megakaryocytes – reduced/absent

5. Immunophenotyping – CD13 & CD33

antigens

CYTOCHEMISTRY:
-Myeloperoxidase & Sudan black

-PAS (M6) &NSE(M4 & M5)

2)ALL(Acute Lymphoid Leukemia)

 71

SPECIAL STAINS:
PAS & Acid phosphatase

BLOOD PICTURE: (Anemia & thrombocytopenia)

===============================================================================================

4) CML(Chronic Myeloid Leukemia):

MOLECULAR ABNORMALITY: CLINICAL FEATURES:

Reciprocal translocation b/w -Usually in 3rd-4thdecades of life
chr 9 &22 in t(9;22) – involves 1. Anemia (weakness, pallor, dyspnoea, tachycardia)
fusion of BCR gene on chr
22q11 with ABL on chr 9q34 2. Hypermetabolism symptoms (weight loss, lassitude, anorexia)

Also associated with changes 3. Splenomegaly

in p53, Rb gene, RAS oncogene, 4. Bleeding tendencies, visual disturbances, Juvenile CML(Lymph
MYC oncogene Node enlargement more prominent)
 72

BLOOD PICTURE: BM EXAMINATION:

1. Anemia (moderate degree) 1. Cellularity : Hypercellular with decreased fat
spaces
2. WBCs – Marked leucocytosis (> 2 lakhs/mm3)
2. Myeloid cells: Increased M:E ratio
NATURAL HISTORY of CML is of 3 phases:
3. Erythropoiesis:normoblastic, but reduction
(i) Chronic phase: Excessive proliferation
present
of myeloid cells+ basophils( upto 10%)
(ii) Accelerated phase: Incresing anemia, 4. Megakaryocytes: Conspicuos but smaller
Blast count(10-20%), basophils than normal
(20%/more) & platelet count falling CYTOCHEMISTRY:
below 1lakh/microlitre
(iii) Blast crisis(Blastic phase): -Reduced scores of NAP(Neutrophil Alkaline
blood/marrow blats>20% Phosphatase)

3.Platelets: normal or raised

5) LEUKEMOID REACTION
CAUSES
DEFINITION:
Reactive proliferation of leucocytes in
peripheral blood resembling leukemia in
a subject who doesn’t have leukemia.

2 TYPES:

Myeloid

Lymphoid

MYELOID LEUKEMOID REACTION LYMPHOID LEUKEMOID REACTION

Infections- pneumonia, TB, meningitis, Infections-IMN, CMV, measles, mumps, rubella,
diphtheria, sepsis, plague etc chickenpox,syphilis,brucellosis
Intoxications- eclampsia,Hg poisoning Malignancy –CLL,certain carcinomas
Malignancies –multiple myeloma, myelofibrosis,
hodgkin’s disease etc
Severe burns,hemorrhges,hemolysis
 73

6) AGRANULOCYTOSIS:

DEFINITION: MORPHOLOGY:
Reduction in number of granulocytes in blood is
a) Marrow hypercellularity –
called neutropenia , when severe,
agranulocytosis. due to neutrophil destruction
b) ↓ number of granulocytic
PATHOGENESIS: precursors- neutropenia.
c) Normal erythropoesis and
 ↓ granulocyte production megakaryopoesis.
a) Marrow failure as in aplastic anemia
b) Replacement of marrow by tumour
CLINICAL FEATURES:
c) Cancer chemotherapy
d) By certain drugs-less commonly Initial – malaise,chills,fever,fatiguability
-ulcerating and necrotizing lesions of
 ↑ granulocyte destruction gingival,floor of mouth,pharynx etc
a) Immune mediated injury
b) Bacterial , fungal or rickettsial
infections
c) Splenomegaly.

7) MYELODYSPLASTIC SYNDROME:
 74

DEFINITION: CLINICAL FEATRUES

-Group of closely related clonal disoreders having -Different cytopenias result in anemia , infections,
abnormal development of different marrow haemorrhages
elements(dysmyelopoesis) resulting in ineffective -Fever, weight loss
blood cell formation -Hepatomegaly and splenomegaly

-Characterised by celluar marrow and 1 or more LAB DIAGNOSIS

cytopenias A.BLOOD FINDINGS:
Cytopenia affecting two or all (pancytopenia)
PATHOPHYSIOLOGY:-
1. Anemia- macrocytosis; anisocytosis; dimorphic
 Primary MDS-idiopathic (most common)
blood picture in RARS
 Secondary MDS-following cancer
2. Thrombocytopenia with large agranular
chemotherapy ,radiation exposure
platelets
,pesticides etc.
3. WBC count normal, increased or decreased.
 Cytogenic abnormalities-monosomy 5 or
Neutrophils are hypogranulated and
7,deletion 5q,7q,20q etc.
hyposegmented
 Molecular abnormalities-mutation N-RAS
oncogene,p53 antioncogenes B.BONE MARROW:
Normal to hypercellular
1. Dyserythropoesis-ringed sideroblasts,
megaloblast seen
2. Hypogranular or hyposegmented myeloid
precursors
3. Megakaryocytes- small with abnormal nuclei.

CLASSIFICATION:
FAB CLASSIFICATION OF MDS(marrow blasts <30%)
1.Refractory anemia. RA -Blood blasts <1%
-marrow blast <5%
-anemia with reticulocytopenia
2.Refractory anemia with RARS -Blood blasts<1%,
ringed sideroblasts. -Marrow blasts <5%,
-Ring sideroblasts >15%
3.Refractory anemia with RAEB -Blood blasts 5%
excess blasts. -Marrow blasts 5-20%
-Cytopenia of 2 or more cells
4.Refractory anemia with RAEB-t -blood blasts 5%
excess blasts in transformation. -marrow blasts 21-30%
-Cytopenia of 2 or more cells
-Auer rods present
5.Chronic myelomonocytic CMML -Absolute monocytosis
leukemia. - increase in marrow monocyte
precursors

WHO CLASSIFICATION OF MDS(marrow blasts <20%)- 8 categories

 75

1.Refractory anemia
2.Refractory anemia with ring sideroblasts
3 .Refractory cytopenia with multinergic dysplasia(RCMD)
4. RCMD with ring sideroblasts
5. RAED –L
6.RAEB-2
7.MDS unclassified
8.MDS with isolated del 5q

8) POLYCYTHEMIA VERA:

 DEFINITION:
Excessive proliferation of erythryoid, granulocytic  LABFINDINGS:
and megakaryocytic elements (panmyelosis). a) Raised Hb concentration
b) Erythrocytosis
 Primary or idiopathic polycythemia only.
c) Hematocrit(>55% in males , >45% in
females)
 PATHOGENESIS:
d) Mild to moderate leucocytosis
JAK 2 mutation:valine →phenylalanine
e) Thrombocytosis.
substituition at residue 617
Reduce dependence of hematopoietic cells on
growth factors.Mainly absolute increase in red  BONE MARROW:
cell Hypercellular with increased myeloid and erythroid
myeloid megakaryocytes.
 MORPHOLOGY
a) Enlarged liver and spleen.  CYTOGENETIC ABNORMALITIES:
b) Infarction commonly in heart 20q, trisomy 8 and 9p(30% PV)
spleen and kidney.

CLINICAL COURSE:
a) Headache, Vertigo ,tinnitus
b) increased risk of
thrombosis(atherosclerosis)
c) Increased risk of hemorrhages(due to
increased blood volume and platelet
dysfunction)
d) Splenomegaly
e) Pruritis(due to histamine release)
 76

LYMPHOBLAST MYELOBLAST MEGALOBLAST

RS CELLS:
9) HODGKIN’S LYMPHOMA:
Morphologic variants of RS cells:
-Hodgkin’s disease (HD) primarily arises within the lymph
nodes& inv. the extranodal sites secondarily. 1.Classic RS cell –
- Bimodal peaks:one in young adults(15 and 35 yrs) -large cell+ bilobed nucleus (mirror image).
& other peak: after 5th decade of life. - Each lobe of nucleus -prominent, eosinophilic,
-SEX: young adult males>females. inclusion like nucleolus with a clear halo(owl-eye
appearance).
-Cytoplasm- amphophilic.
2. Lacunar type RS cell
- smaller,
-has lacuna(artefactual shrinkage of cytoplasm).
-In nodular sclerosis variety HD
3. Polyploid type (popcorn / lymphocytic-
histiocytic i) RS cells
- seen in lymphocyte predominancetype HD.
- Cell- larger+lobulatednucleus (shape of popcorn)
4. Pleomorphic RS cells
- seen in lymphocyte depletion type.
- pleomorphic and atypical nuclei.
 77

10)MULTIPLE MYELOMA:
Clinical features
Bone pain, infections, renal failure, anemia, bleeding, hyper
-Multifocal malignant proliferation viscosity syndromes, neurologic symptoms, hypercalcemia.
of plasma cells derived from single
Diagnosis (CRITERIAS)
clone of cells.
1)Major--Bone marrow plasmacytosis
-Osseous as well as extra osseous
manifestation. --Tissue biopsy ( plasmacytoma)

-Primarily in elderly (5th-6th decade)- --M spike in s.electrophoresis or >1g of BJP in 24 hrs urine
males. 2)Minor :–plasmacytosis in marrow (10-30%)
--Lytic bone lesions,signs of end organ damage
 78
Translocation btw IgHC locus & oncogene, causes Dysregulation of oncogenes to cause proliferation
surface adhesion molecules bind myeloma cells to BM stromal cells

Adhesion mediated signaling proliferation of IL-6, TNFα, MIP-1α, receptor activator of

nuclear factor-KB (RANK)

Affected cell cycle adversely via cyclin-D & p21

IL-6 –central in proliferation of cells via cyclin D & p21. Other cytokines activate osteoclast
activating factor

BM cell
Adhesion mediated signaling

Cytokine production
IL-1, MIP-1α, RANK, TNFα IL-6

Osteoclast activating factor cyclin p21

Bone destruction abnormal proliferation

Bence Jones proteins:

Most frequent M protein produced in Igh (60%) followed by Iga (20-25%). Rest 15% plasma cells produce
only К or λ light chains. Due to LMW excreted in urine & called B.J proteins.

Investigations
-CBC –Hb decreased

-ESR – increased

-RFT – S.cr, urea increased

-S.calcium increased

-B.J proteins in urine (precipitate @ 40-60 degree c, disappear at 100 degree c, reappear on cooling)
 79

..HEART..
- Myocardial Infarction
- RHD
- Infective Endocarditis
- Myocarditis
 80

HEART
INTRODUCTION TO CVS
The cardiovascular system consists of the heart, blood vessels and lymphatics . Although heart and blood vessels are
considered separately as a math of convenience it is evident that functionally the system is a unit. The heart is essential
a pump provided with valves and powered by muscular walls. Any disruption of the hearts- myocardium, valves,
conduction system and coronary vascular can adversely affect pumping efficacy thus leading to morbidity and mortality.
The major cardiac diseases include congenital malformation, IHD, hypertensive heart disease , disease of cardiac valves
and primary myocardial disorders.

Among vascular pathology the most clinically significant lesions involve arteries which are mainly degenerative and
inflammatory disease. Arterial disease may

1. Weaken the vessel wall with resulting aneurysm or rupture.

2. Narrow the lumen causing ischemia
3. Damage the endothelium with thrombosis as a result.

Venous pathologies mainly include thrombhophlebitis, venous thrombosis and varicose vein.

1) Myocardial infarction
- Necrosis of heart muscle as a result of ischemia
- Frequency increase with age and increase risk factors
 Pathogenesis
 Vast majority caused by a/c coronary artery thrombosis
 Disruption of atherosclerotic plaques
 Vasospasm, mucosal thromboembolism, valve vegetations
Above two includes transmural infarction
 Severe diffuse coronary atherosclerosis
 Disorder of small arterioles
Above two included in sub endocardial infarction
 Myocardial response to ischemia
 Decrease ATP, lactic acidosis, loss of compatibility, cell swelling, myofibrillar relaxation
 Reperfusion can also lead to injury
 Shinned myocardium
 Arrhythmias
 Irreversible injury
 Main patterns
 Transmural – full thicknesss of muscles STEMI in ECG
 Subendocardial – limited to inner 1/3rd , NSTEMI- decrease blood flow then reperfusion
 Microscopic infarcts – due to small vessel occlusion
--no ECG changes.
 81

 MORPHOLOGY
 82
 Diagnosis
 Complications
1. Clinical features
 Contractile dysfunction (  Pain
left ventricular failure)  Indigestion
 Arrhythmias  Shock
 Myocardial rupture  Oliguria
 a/c pulmonary oedema
 Aneurism
2. ECG changes
 Dilatation  ST elevation
 Thrombosis  T inversipon
 Heart failure  Deep Q
 Papillary muscle 3. Serum cardiac markers
 CK-MB – rises within 2-4 hours, peaks at 24-48 hours and
dysfunction
returns tso normal in 72 hours
 Right ventricular failure  Troponins - detectable within 2-4 hours peaks in 48 hours
 Pericarditis & remains elevated for 7-10 days
 Myoglobin – first rises and falls , then return to normal
within 24 hours because of rapid excreation
 LDH – rise after 24 hours, peak in 3-6 days, normal in 14
days

2) RHEUMATIC HEART DISEASE

 Acute immune mediated multi system disease which primarily involves the heart, joints ,CNS ,skin and
subcutaneous tissues.
 It is the cardiac manifestations of RF
 Associated with all parts of hearts but valvular inflammation and scarring produces the most important clinical
feature
 PATHOGENESIS

 It is a delayed inflammatory response to pharyngeal infection with group A streptococcus.

 Antibodies develop against streptococcal antigens but cross against with cardiac myosin and sarcodermal
membrane protein.
 MORPHOLOGY
 Characterised by exudative inflammatory lesion of all three layers and resulting in pancarditis.
 Myocardium:
 83

 Shows pathognomic ASCHOFF BODY- these are collections of lymphocytic (T cells) scattered
plasma cells and plump activated macrophages ANTISCHKOW CELLS, zone of fibrinoid necrosis.
 Evolution of aschoff bodies – 3 stages

1.Early (exudative /generative) 2.Intermediate(proliferation/granulomatous) 3.Late (healing/ fibrous ) stage

stage stage
 Occur at 4th week of  occur in about 4-13 weeks of illness  Occur in 12-16 weeks
illness  Proliferation of T cells, plasma cells after illness
 Oedema of connective & characteristic cardiac  The nodule become
tissue histiocytes(anitschkow cells) of the oval or fusiform shape.
margin of lesion.  Aschoff body become
↑ in acid  Anitschkow cells -abundant less cellular and
mucopolysaccharides in cytoplasm + central nuclei collagenous tissue
ground substance +chromatin condensed to form a increased.
slender , wavy ribbon(caterpillar  Later it is replaced by
separation collagen fibres cells) some of the modified cardiac fibro collagenous scar.
by accumulating ground histiocytes become multinucleate
substances . cells and are called aschoff cells

fragmentation and
disintegration of collagen
fibres fibrinoid
degneraion
- Aschoff bodies are classically located in interstitial connective tissue of myocardium specially in perivascular location
 Endocardium
 Rheumatic endocarditis produces verrucous lesion,which heal with fibrous thickening and adhesion of valve
commisures,leaflets amd chordate tendinae resulting in varying degrees of stenosis and regurgitation.
 Regurgitant streams produces irreruglar thickening of the left atrium called MacCallum plaques.
 Degree of involvement of valve. Mitral valve (most common) aortic valve tricuspid valve (rare)
pulomonary valve(almost never)

 Pericardium
 Serofibrinous pericarditis produces classical bread and butter appearance.

Note:
Aschoff bodies can be found in any of 3 layers of heart.

 Clinical manifestations:
 Sorethroat
 Polyarthritis major manifestation
Classical presentation of acute migratory or fleeting polyarthritis (most commonormaly large
joints of extrermities) . As pain and swelling subsides in one joint ,other tends to get involved.
 Carditis
Myocarditis :Tachycardia ,arrhythmia,CHF, cardiomegaly.
Endocarditis: 1) Apical, systolic murmur of mitral regurgitation.
2) Apical mid diastolic murmur (carey coombs murmur) due to nodules on mitral valve
leaflets.
3)Basal early diastolic murmur of aortic regurgitation
 84

Pericarditis:Pericardial pain, pericardial friction rub.

 Subcutaneous nodules:- Small,painormaless,nodules over extensor surface and bony prominence.
 Erythema marginatum:- Erythematous macules with a clear center and serpinginous margins most
commonormaly seen on the trunk and proximal parts of extremities.
 Chorea(sydenham’s chorea; chorea minor, saint vitus dance):- Purposeless involuntary movements associated
with muscle weaknessemotional instability,tics and psychotic featuers.

 Daignosis of a/c of rheumatic fever

Major manifestations Minor manifestations

1. Carditis 1. fever
2. Migratory polyarthritis 2. arthralgia
3. Subcutaneous nodules 3. previous RHD /RF
4. Erythema marginatum 4. raised ESR
5. Chorea 5. positive CRP
6. prolonged P-R interval

Supporting evidence of streptococcal infection

1. recent scarlet fever

2. positive throat culture for group A streptococcus
3. increased streptococcal antibodies.

Two major manifestations/ one major =2 minor manifestation along with one supporting evidence indicate RF

3) INFECTIVE ENDOCARDITIS
Infection of valvular and mural endocardium caused by different microorganisms and is characterised by typical infected
and friable vegetations.

 Depending on its severity- 2 types

Acute Subacute
1) Destructive, necrotizing and ulcerative 1) Caused by less destructive and less virulent
invasions by highly virulent bacteria. microorganisms
2) Usually affect normal valve 2) usually affect previously diseased heart
3) Death within day to weeks in 50%
patient

PREDISPOSING FACTORS
 Conditions initiating transient bacteremia and septicaemia
 Periodontal infection
 Genitourinary tract infections
 Infection of GIT,UTI
 Tonsillectomy , adenoidectomy , bronchoscopy and surgery on respiratory mucosa.
 85

 Underlying heart disease

CAUSATIVE AGENTS
 RHD
 Staphylococcus aureus
 CHD(congenital heart disease)
 Streptococcus viridance
 Impaired host defence  Streptococcus epidermidis
 Immunodeficiency  HACEK group(hemophilus , actinobacillus,
 DM lardobacterium,eikinella)
 Neutropenia
 MORPHOLOGY
 Gross: Microscopy:
 -Valves of left 3 zones are formed
heart ie mitral 1. Outer layer or cap :
and aortic are eosinophilic
affected most material( fibrin and
frequently. platelet)
 -Vegetations 2. Basophilic zones:
involve atrial bacterial colonies
surface of AV 3. Deeper zone: non
valve and specific
ventricular inflammatory
surface of
semilunar valve.
 -Few mm to cm ,
grey or multiple
and friable.
 -a/c bacterial
endocarditis
vegetations are
bulkier than
suba/c bacterial
endocarditis .

 PATHOGENESIS:

Bacteria causing bacterial endocarditis enters the blood stream 

implanted on cardiac valve on mural – endocardium by their surface
adhesion molecular which mediate their adherence to injured endocardium CLINICAL FEATURES
 Conditions producing hemodynamics stress on the valve are liable to  Fever with chill ,
cause damage to endothelium, favouring the formation of platelet- fibrin weakness , malaise
thrombi  thrombi get infected. and weight loss.

=> COMPLICATION AND SEQUALE

A) Cardiac complication:
Valvular stenosis or insufficiency
Perforation ,rupture , aneurysm formation
Abcess in valve ring
Suppurative pericarditis.

b)Extra cardiac complications

 86

- EMBOLISM

 Left side of heart systemic circulation emboli reach kidney,spleen,brain leading to the development of
infarct, abcess, mycotic aneurysm and necrotizing glomerulonephritis.
 Right side of heart pulmonary abcess.

OTHER MANIFESTATIONS

 Osler’s nodes- painful nodules seen in pulps of fingers due to immune complex deposition.
 Roth’s spots – circular retinal heammorhages with pale centers.
 Jane way spots on palms and soles – due to septic emboli of skin.
 Painful spelnomegaly.
 Subunghal splinter haemorrhages due to emboli damage to cutaneous capillaries.

CAUSES OF DEATH

 Cardiac failure.
 Embolism to various organism.
 Renal failure’rupture of mycotic aneurysm in vital organs.

Diagnosis is confirmed by positive blood culture and echocardiographic findings.

4) ASCHOFF BODIES
- Myocardial inflammatory lesion pathognomonic of rheumatic fever
- Collection of lymphocyte ,plasma cells and plumb activated macrophages called Anitschkow cells, occasionally
punctuating zone of fibrinoid necrosis
Anitschkow cells- cells with abundant cytoplasm and central nuclei and chromatin condensed to form a slender ,wavy
ribbon (caterpillar ribbon)
Aschoff bodies can be found in any 3 layers of heart –pericardium, myocardium and endocardium during rheumatic
fever – pancarditis

 Evolution of aschoff bodies

Pericardium exhibits a fibrinous exudates –proliferation of cells (lymphocytes ,plasma cells ,) at margin of lesion

Fibrinoid necrosis and fibrin deposition in aschoff bodies forming vegetation (1-2mm) (verrucae formation)

5) MAC CALLUM PATCHES

- Irregular thickening in the endocardium, most commonormaly in left atrium
- Produced by the regurgitation jets ,in valves narrowed by vegetations, which injure endocardium
- Seen in vegetative valve disease like rheumatic heart disease
6) MYOCARDITIS
Inflammation of heart muscle and can occur at any age, where infectious agents or inflammatory processes primarily
target the myocardium
 87

Main types are

Viral myocarditis: mainly caused by coxasackie A and B and other enteroviruses, CMV, HIV, influenza virus
Pathogenesis
1. Cytolytic injury
2. Immune response against infected cells
3. Reaction triggered by virus against cross reacting protein like myosin chains

=> Non infective myocarditis: lesions associated with systemic diseases of immune origin like SLE, polymyositis
-drug hypersensitivity also trigger reactions that injure myocardium
-idiopathic or Fiedler’s myocarditis is rapidly progressive and cause sudden severe cardiac failure or sudden death
without any inflammatory changes in endocardium or pericardium and occurs without any apparent cause.

 MORPHOLOGY
 GROSS  MICROSCOPY
- In a/c-heart appears normal - Active myocarditis characterised by edema ,interstitial infiltrates and myocyte
or dilated injury-lymphocyte infiltrates diffuse-most common
- In advanced stage –flabby - Hypersensitivity –infiltrates composed of lymphocyte,macrophage and
and often mottled with pale eosinophils
and haemorrhagic areas - Giant cell myocarditis – wide spread inflammatory infiltrates containing
multinuclear giant cells- end spectrum of lymphocyte myocarditis
- In chagas myocarditis –trypanosomes parasitized mofibers accompanied by an
inflammatory infiltrate of neutrophil,lymphocyte ,macrophages and occasional
eosinophil

 CLINICAL FEATURES
Asymptomatic and patients recover without any sequlae
Severe –dyspnoea, palpitation, pain, fever, CHF, arrhythmia
88
 89

..blood vessels..

1. Atherosclerosis
2. Aneurysm
3. Arteritis
4. Capillary hemangioma
5. Cavernous hemangioma
6. Wegernersgranulomatosis
 90

1) ATHEROSCLEROSIS

Atherosclerosis is one of the three patterns of arteriosclerosis, which literally means hardening of arteries.

Risk factors-

Constitutional-genetic abnormalities, family history, age and male gendeer

Modifiable-hyperlipidemia, hypertension, cigarette smoking, diabetes mellitus,

inflammation(raised CRP),

Hyperhomocystenemia, metabolic syndrome, lipoprotein a

Pathogenesis-

Chronic inflammation+response to injury, healing

Steps involved are-
ENDOTHELIAL INJURY

ACCUMULATION OF LIPOPROTEINS
AHA(American Heart Asociation) Classification:-
MONOCYTE ADHESION TO ENDOTHELIUM Type 0-No intimal thickening
Type I-initial lesions, foam cells
PLATELET ADHESION Type II-fatty streaks
Type III-preatheroma, raised fatty streaks
FACTOR RELEASE FROM INFLAMMATORY CELLS Type IV-atheroma
Type Va-fibroatheroma, Vb-calcified plaque, Vc- fibrotic
SMOOTH MUSCLEPROLIFERATION, EXTRACELLULAR plaque
MATRIX PRODUCTION AND T CELL RECRUITMENT Type VIb-wide hemorrhage VIc- thrombosis

LIPID ACCUMULATION
Morphology-

1. Fatty streaks- raised lipid filled foamy macrophages

2. Atherosclerotic plaque- cause intimal thickening with lipid accumulation and fibrosis (which microscopically has
the components:-smooth muscles, macrophages, T cells; extracellular matrix; intracellular and extracellular lipid)

Consequences-

Plaques are prone to rupture, hemorrhage, atheroembolism and aneurysm formation.

2) ANEURYSMS

- Aneurysm are congenital or acquired permanent dilatations of blood vessel occurring due to weakening or
destruction of vessel wall
Etiology

Congenital, atherosclerosis, hypertension

Pathogenesis
 91

1. Inadequate or abnormal connective tissue synthesis

Defective synthesis of fibrillin-marfan syndrome
Defective type 3 collagen- Ehler danormalos syndrome
2. Excessive connective degradation
Increased MMP expression-ECM degradation in arterial wall
Decreased TIMP expression-ECM degradation
3.loss of smooth muscle or change in the smooth muscle cell synthesis phenotypes

TYPES

1. Based on shape

2. compsition of wall
True aneurysm-all layers involved
False aneurysm –have fibrous wall occurring after trauma

3. pathogenic mechanism
Atherosclerotic aneurysm ,dissecting aneurysm
Syphilitic aneurysm
Mycotic aneurysm
Berry aneurysm

 DISSECTING ANEURYSM
Aneurysm in which blood enters the separated /dissected wall of
vessel and spreads for a varying distance , longitudinally.

 Pathogenesis
- Intimal tear occur due to hypertension ,
- Heritable or connective tissue disorders- blood under systemic pressure dissect through media along laminar
planes .
 Histology
- Focal separation of fibromuscular and elastic tissue of the media
- Numerous cystic spaces in the media containing basophilic ground substance
- Fragmentation of elastic tissue
- Increased fibrosis in the media
3) WEGENER’S GRANULOMATOSIS

A necrotizing vasculitis charaterised by triad of symptoms:

1) granulomas of lung and URT

2) Vasculitis of small to medium sized vessels
3) Glomerulonephritis
- Limited form localized to respiratory tract
 92

- Widespread form to eye, skin, heart resembling polyarteritis nodosa.

- Considered as a hypersensitivity reaction to inhaled antigens.
- PR3-ANCA,s present in 95% cases.
- ANCA level falls dramatically after treatment. Rising titres suggestive of relapse
 MORPHOLOGY:-
1) Upper respiratory lesions vary from granulomatous sinusitis to ulcerative lesions of nose, palate and pharynx.
2) Lung findings vary from parenchymal infiltrates to diffuse granulomatous nodules.
3) Multifocal necrotizing granulomatous vasculitis with fibroblasts in the surrounding.Multiple granulomas
coalesce to form visible nodule with central cavitation.
4) Destruction of blood vessels producing hemorrhage and hemoptysis.
5) Lesions undergo fibrosis and organization.
6) RENAL LESIONS- focal glomerulonephritis and crescentic glomerulonephritis
 CLINICAL FEATURES;-

40 YR old man presenting with pneumonitis with nodues and cavitary lesion(95%), chronic sinusitis(90%), mucosal
ulceration of nasopharynx(75%), renal lesions(80%).

Hematuria, proteinuria, rash, myalgia, articular involvement, neuritis, fever

TREATMENT: - steroid, cyclophosphamide, TNF inhibitors, Rifuximab

4) CAVERNOUS HAEMANGIOMA.

1. single or multiple, MICROSCOPY

2. discrete or diffuse,
3. red to blue, 1. Composed of thin-walled cavernous vascular
4. soft and spongy masses. spaces,filled with blood.
5. 1 to 2 cm in diameter. 2. The vascular spaces -lined by flattened
6. most common in the skin endothelial cells
(especially of the face and neck); 3. Scanty connective tissue stroma .
7. other sites
mucosa of the oral cavity,
stomach
small intestine,
internal visceral organs like the
liver and spleen.

Cavernous haemangiomas rarely involute spontaneously.

 93

.. respiratory system..

1. Atelectasis
2. ARDS
3. Emphysema
4. Bronchiectasis
5. Bronchial Asthma
6. Bronchogenic carcinoma
7. Pneumoconiosis
8. Chronic Bronchitis
9. Lung Abscess
10. Pneumonia
 94

1) ATELECTASIS
Incomplete expansion of lung/part of lung NEW BORN- weak respiratory action
Age: infants / new born Incomplete expansion of lung

Still born- total atelectasis Clinical attacks

CAUSES MORPHOLOGY
a. Prematurity GROSS-lungs are small, dark blue, fleshy, non crepitant .
b. Cerebral birth injury MICROSCOPY- alveolar spaces- small with thick intra-alveolar septum
c. CNS malformation -have proteinaceous fluid with few epithelial, squamous cells and
d. Intrauterine hypoxia meconium

2) ARDS
Clinical syndrome caused by diffuse alveolar capillary and epithelial damage –respiratory insufficiency,
cyanosis severe arterial hypoxemia refractory to oxygen therapy.

TYPES AND PATHOGENESIS

1. NEONATAL ARDS-Initiated by hypoxia 2- ADULT ARDS- Due to some alveolar injury
Neonatal hypoxia Acute alveolar injury in adults

Alveolar surfactant
Proinflammatory cytokines ) Fibrogenic cytokines
Increased surface tension (IL8,IL1,TNF,MIF ( TGF-α , PDGF)

Atelectiasis Entry of PMNs fibroblastic proliferation

And collagen formation
Hypoventilation Release of proteolytic
Substances ( proteases, paf,
Pulmonary hypoperfusion oxidants, leukotrienes)

Alveolar capillary
Ischaemic damage exudation of plasma membrane injury
protien
Fibrinogen Vascular permiability

Fibrin Hyaline membrane

Hyaline membrane

Consequences : death , resolution

MORPHOLOGY
GROSS-Lungs are normal in size, they are stiff, congested, heavy and airless .so they sink in water.
MICRO
1. They are collapsed alveoli and dilated alveoli
2. Necrosis of alveolar epithelium –eosinophillic hyaline membrane lining alveoli, alveolar duct
 95

3. Interstitial and intra alveolar oedema, congestion and intra alveolar haemorrhage
4. In organising stage, there is interstitial fibrosis obliterating alveolar spaces.
===============================================================================================

3) EMPHYSEMA
Defined as combination of permanent
dilation of air spaces distal to the terminal
bronchioles and destruction of walls of
dilated air spaces.

Etiology
1. Tobacco soke
2. Air pollutants
3. Less significant factors include:
-occupational exposure
-infections
-familial and genetic influences

Types of emphysema

 Centri-  Central or proximal part of acinus involved

acinar /  Occurs in smokers and coal miners
centri-  Upper lobes of lungs involved
lobar  Affected lobules surrounded by a rim of normal lung
parenchyma
 Severe cases distal to ascini also involved

 Pan  All portions of acinus are affected

acinar /  Lower zone of lungs involved
pan  Lungs inflamed and over inflated
lobular

 Para  Distal part of acinus involved

septal/  Localized among pleura and perilobular septa
distal  Upper part > lower zone affected
acinar
 Para  Usually seen surrounding scars
cicatrical  asymptomatic
/
irregular

 Mixed (  Usually seen surrounding scars

Unclassifi  Due to severe involvement of lung
ed )  Centri-acinar in upper lobe + pan-acinar in lower lobe + para-
septal in sub-pleural zone.
 96

Pathogenesis
a) Protease – antiprotease hypothesis

α-1-antitrypsin inhibits proteases (elastase) derived from neutrophils hence inhibits digestion of
lung parenchyma.
exposure to the etiologic factors inflammation
with accumulation of inflammatory cells and release
of elastases cytokines and oxidants elastin
degradation in the absence of anti- elasatase activity.

b) TGF-β gene polymorphism mesenchymal

response to TGF-β followingowing elastin
injury decreases parenchymal damage
emphysema.
 Gross: lungs are voluminous and pale
- Mild cases :- air spaces can be seen
- Advanced cases : - sub pleural bullae and c) Matrix metallo-proteases (MMP-9 & 12)
blebs
polymorphism and elevated levels also have
=> Microscopy : -
- dilation of air spaces pathogenic role in emphysema.
- destruction of septal walls of acinus Morphology
involved
-Bullae and blubs -show fibrosis and c/c
inflammation of walls.
4) BROCHIECTASIS
-Abnormal and irreversible dilatation of bronchi and bronchioles.
-Secondary to inflammatory weakening of muscle and supporting elastic tissue.
-Cause of inflammation necrotising skin infection.

NEVER AS PRIMARY DISEASE, ALWAYS SECONDARY TO INFECTION / OBSTRUCTION

CAUSES
- Bronchial obstruction(tumour , foreign body)
- congenital condition(cystic fibrosis, immunodeficient) PATHOGENESIS
- necrotising / suppurative pneumonia(staph aureus, klebsiella)
OBSTRUCTION
MORPHOLOGY
-mainormaly – distal bronchi and bronchioles beyond segmental bronchi Normal clearance much hampered
-region- lower lobe
Secondary infection
Gross
Chronic infection over time
-diffuse/ segmental involvement
-bilateral lower lobe involved. Damage to bronchial wall
-pleura- fibrotic, adherent to chest wall.
Cylindrical Weakening+ dilation of bronchi and
bronchioles
 97

DILATED AIRWAY CLASSIFICATION Fusiform

Saccular
Varicose

Cut section
-honey comb appearance
-bronchi dilated with thickened wall
-intervening lung fibrotic

Microscopy
-bronchial epithlieum normal(ulceratediseasequamous metaplasia)
-bronchial wall infiltration of neutrophil /lymphocyte
Destruction of normal muscle and elastic tissue
-lung parenchyma fibrous+ interstitial pneumonia

5)BRONCHIAL ASTHMA POLLEN/ ANY ALLERGEN

-Chronic disorder of conducting airway.
Th2 cells
-caused by immunological reaction which is marked by episodic
bronchoconstriction . Produce IL-4
- Due to increased airway sensitivity to variety of stimuli
Stimulate IgE production by B-cells
- resulting in inflammation of bronchial wall and increased
secretions IgE attach to the mast cell

TYPES IL-5 + granular contents are released

PATHOGENESIS
Eosinophil recruitment
 Atopic asthma - IgE mediated
 Non- Atopic asthma –trigger  respiratory infection by
Activation causing release of granules and
virus
mediators
 Drug induced – aspirin
 Occupational asthma- fumes, organic and chemical dust
Early late
, gases
Phase phase

 Morphology: Broncho inflamation

- Gross: Constriction, with activation of
Increased mucous eosinophil, T- cells,
 Lungs are over-extended.
Production, neutrophil +
 Cut surface: occlusion of bronchi and bronchioles by Vasodilation epithelial cells to
Vicid mucous plugs Produce chemokines
- Microscopy: Also this repeated inflammation lead to
 Mucous plug: normal/degenerated respiratory structural changes in the bronchial wall
epithelium forming twisted spirals called which include – bronchial smooth muscle
CURSCHMANN’S SPIRALS. hypertrophy, increased vascularity,
deposition of subepithelial collagen.
 Sputum contains : eosinophils, diamond shaped from
eosinophils called the CHARCOT LEYDEN CRYSTALS.  Molecular pathogenesis:
 Bronchial wall shows thickened basement membrane, sub- - Long arm of chromosome 5 ((5q)
mucosal oedema , inflammatory infiltrate: lymphocyte and - 20q  ADAM33.
plasma cells.
 98

6) BRONCHOGENIC CARCINOMA
Cancer of lung from: CAUSES: a) Smoking
a) Alveoli b) Atmospheric pollution
c) Occupational(asbestosis)
b) Bronchi
d) Dietary(vit A deficiency)
c) Bronchioles e) Secondary causes(Tb. Chronic fibrosis)
PATHOGENESIS

ACTIVATION OF GROWTH INACTIVATION OF AUTOCRINE GROWTH GENETIC

PROMOTING ONCOGENES TUMOUR SUPPRESOR FACTORS PREDISPOSITION
-K-RAS GENES
-Tyrosine kinase domain of
EFGR -p53 -Initiator Mutation -Li-Fraumani syndrome-
-BRAF -RB -Promoter Progression p53 mutation
-MYC -Others-p16,RASSF1A Eg :nicotine, hormones as part -Retinoblastoma-Rb
-Over expression of BCl-2 of paraneoplastic syndromes. mutation
-Cytochrome p450
mutation
MORPHOLOGY:

Gross:

HILAR PERIPHERAL
-Region: main bronchus -Region: small peripheral bronchioles
-Begins like small rough area -SINGLE NODULE /MULTIPLE

Enormalarges and thickens bronchial mucosa Produces pneumonia

like consolidation.
Nodules formed

Join to form friable spherical mass

Microscopy:

5 main subtypes: 1) Squamous cell carcinoma, 2) Adenocarcinoma, 3)Small cell carcinoma, 4) Large cell carcinoma 5)
Combined
 99

SQUAMOUS CELL TYPE ADENOCARCINOMA SMALL CELL LARGE CELL COMBINED

-centrally in major -more peripherllay -centrally located -more common in -adeno squamous
bronchi located-mainormaly in mass men carcinoma
-quickly spread to hilar women _ non-smokers -early involvement -highly malignant -show evidence of
lymph node but systemic -grow slowly but of hilar and tumour kerstinisation and
spread occurs later metastatise at an early mediastinal lymph -lack the glandular
-sq cell type stage node cytological differentiation
-aslo called -hair neurosecretory fearures of small
Metaplasia/dysplasia SCARCARCINOMA granules which cell carcinoma
produces ectopic -no glandular/
Ca.in situ. hormones. squamous
-+ve for neuro differentiation
endochrine granules
chromogranin.
MICROSCOPY ( REFER PAGE: -----)

SPREAD

DIRECT -bronchus ,pleural cavity ,pericardium

,myocardium, vessels of heart ,brachial plexus,
sympathetic chain.
LYMPHATIC -hilar lymph nodes(mainormaly)
-other lymph node mediastinalv, cortical,
supraclavicular, para aortic.
BLOOD -mainormaly liver ,brain, bones
-others adrenals ,pancreas, kidney.

STAGING-TNM STAGING

1-OCCULT malignant cells in bronchpulmonary secretions. But no evidence of primary tumour/metastasis.

2-STAGE-1 tumour <3 cm with/without ipsilateral nodal involvement, NO DISTANT METASTASES.

3-STAGE-3 tumour of any size, involving adjacent structure, involving contralateral lymp node/ distant metastases.

7) PNEUMOCONIOSIS
- Non–neoplastic lung reaction to inhalation of mineral dust depending on the size, shape, solubility & reactivity of
particles. PARTICLE SIZE :- 1-5 µm
- Also called occupational lung disease
1- Coal workers pneumoconiosis
Activation of alveolar macrophage by release of various mediators like free radicals, chemotactic factors,
febrogenic cytokines etc.

 Morphology
 Pulmonary anthracosis  Inhaled carbon pigment is engulfed by
alveolar or interstitial macrophages, which
accumulate in the connective tissues along
the lymphatics
 100

 Simple coal workers  Grossly :- small black focal lesions called coal
pneumoconiosis macules ( usually in upper lobe)
 Histology :-
- Coal macules composed of dust laden
macrophages
- Increase in collagen network
- Centrilobular emphysema can occur
 Progressive massive fibrosis  Gross :-
- Coal macules & nodules
- Multiple, intensely blackened scars
larger than 2cm
 Histology :-
- Dense collagen & carbon pigment
deposition

Clinical features

- Chronic cough with jet black sputum - Radiological appearance similar to TB

B) Silicosis
Pathogenesis

- Silica dust is febrogenic.

Morphology:
Inhaled silica particles taken up by
 Grossly :
macrophages
- tiny, barely palpable, discrete silicotic nodules
 Histology:
Activation & release of mediators.
- Concentrically arranged hyalinized collagen fibers’
( IL-1, TNF, fibronectin, febrogenic cytokines )
surrounding an amorphous center, which is further
enclosed by few lymphocytes & plasma cells.

Clinical features -Dyspnoea

Complications – Pulmonary tuberculosis, Rheumatoid arthritis, Cor pulmonale

C) Asbestosis
Pathogenesis

Asbestos Amphibole

Serpentine

Inhaled asbestos fibrosis are

phagocytosed by alveolar macrophages

 101

Release of chemo attractants for

neutrophills and macrophages

Formation of asbestos bodies &intestinal fibrosis

Clinical features

- Dyspnoea
- Productive cough

Morphology

 sbestosis  Grossly :- affected lungs are smaller and firm

with cartilage like thickening of pleura
=>Histology:- -Intestinal fibrosis
-Asbestosis body—asbestos fibers coated with
glycoprotein &haemosiderin& appear beaded or dumb
bell shaped.

 Pleural disease - Pleural effusion

- Visceral pleural fibrosis
- Pleural plaques- well circumscribed plaque of dense
collagen on parietal pleura

 Tumors  Asbestos fibres are carcinogenic

BronchogenicMalignant mesothelioma
carcinoma

8) CHRONIC BRONCHITIS
- Persistent productive cough for atleast 3 consecutive months in atleast 2 consecutive years.
- Common in smokers
- Frequently associated with emphysema.
-  PATHOGENESIS

Environmental irritants

Hypertrophy of mucosal Glands inflammation + infiltration

in trachea and main bronchi of CD8+ lymphocytes,
+ macrophage and neutro-
Increase in mucin secreting phil. But no eosinophil.
Goblet cells
 102

 CAUSES MORPHOLOGY
- GROSS:
 Smoking
 Atmospheric pollution  Bronchial wall: thickened, hyperemic, oedematous.
-SO2, NO, particulate,  Lumen of bronchioles and bronchi contain
fumes mucous plugs.
 Occupation - MICROSCOPY:
-workers in cotton mills  Enormalargement of mucous secreting glands
etc are exposed to  Metaplasia of goblet cells, mucous plugging,
organic and inorganic
inflammation , fibrosis.
gases
 REID INDEX:
 Microbial infection
- Ratio between thickness of the submucosal gland in the cartilage containing
large airway to that of bronchial wall.
9) LUNG ABSCESS
- Defined as localised area of lung tissue with suppuration resulting in the formation of lung cavities.
- 2 types primary lung abscess: develops in
otherwise normal lung.
-
commonest cause: aspiration of infective
material

Secondary lung abscess: due to

complication of some other disease.
 ETIOPATHOGENESIS

 Common microbes: streptococcus, staphylococcus, gram negative organism.

 Aspiration of infective foreign material
 Pre-existing bacterial infection: like bronchopneumonia, TB, mycotic infection.
 Bronchial obstruction: abscess form distal to obstructed bronchus
 Septic embolism: Infected emboli reach in lungs and form multiple abscess
 Miscellaneous: amoebic abscess, trauma to lungs, direct extension from a suppurative focus
 MORPHOLOGY
 GROSS  MICROSCOPY:
- Size: range from few mm to 5-6 cm in - Destruction of lung parenchyma
diameter - Suppurative exudate in lung cavity
- Number depends upon the mode of - a/c inflammation
development
- a/c lung abscess is surrounded by a/c c/c inflammation ( lymphocyte, plasma cell,
pneumonia and has partly defined engorged macrophage)
walls
- late stage: abscess become chronic and fibroblastic proliferation
form fibrous cap (resulting in febrogenic wall)
 103

10) Pneumonia
- Acute inflammation of lung parenchyma distal to the terminal bronchiole
 Stages of pneumonia:

Laennec’s classification to 4 stages

1) Stage of congestion
2) Stage of red hepatisation
3) Stage of grey hepatisation
4) Stage of consolidation

 PATHOGENESIS:
1. Stage of congestion (initial phase)
- initial acute inflammatory response
- lasts for 1-2 days
Grossly : affected lobe is enormalarged, heavy, darkened & congested
Histology : - Dilation & congestion of alveolar capillaries
- Air spaces with pale eosnophilic fluid
- Intra-alveolar fluid with few red cells & neutrophills
- Alveolar fluid has numerous bacteria ( gram stain )

2. Red hepatisation ( early consolidation)

- Hepatisation cut section liver like consistency
- Lasts for 2-4 days
Grossly : Red, firm, consolidated
Cut surface dry, red pink, granular with liver like consistency
Histology : - edema fluid replaced by strands of fibrin
- cellular exudates of neutrophills & extravasations of red cells
( ingested bacteria present )
3. Grey hepatisation ( late consolidation )
- Lasts for 4-8 days
Grossly : - firm and heavy
- Cut surface has liver like consistency, dry, granular, grey
- Change in color from red to grey begins in hilum & spreads towards
Periphery
Histology : - Fibrin strands are dense & more numerous
- Cellular exudates of neutrophills decrease, red cells decrease,
macrophages begin to appear
- Less organisms
4. Resolution
-Begins by 8-9th day
- Antibiotic therapy induced resolution about 3rd day
Grossly : - The solid fibrinous constituent formed by enzymatic reaction
- Normal aeration in affected lobe restored
Cut surface : Grey red or dirty brown with frothy, yellow creamy fluid
Histology : - Macrophages are the predominant cells. Some show engulfed
neutrophills& debris
- Granular & fragmented strands of fibrin in alveolar space
 104

- Progressive removal of fluid content & cellular exudates from air

Spaces.

Fig; Pathogenesis of three common forms of pneumoconiosis.

A, Coal-workers’ pneumoconiosis. The macrophages phagocytose large amount of coal dust particles which are then passed into the interstitial tissue
of the lung and aggregate around respiratory bronchiole and cause focal dust emphysema.
B, Silicosis. The tiny silica particles are toxic to macrophages. The dead macrophages release fibrogenic factor and eventually result in silicotic nodule.
C, Asbestosis. Asbestos fibres initiate lot of interstitial fibrosis and also form asbestos bodies.

WHO Classification of Lung Tumours.

I. EPITHELIAL TUMOURS
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
i) Oat cell carcinoma
ii) Intermediate cell carcinoma
iii) Combined oat cell carcinoma
3. Adenocarcinoma
i) Acinar adenocarcinoma
ii) Papillary adenocarcinoma
iii) Bronchiolo-alveolar carcinoma
iv) Solid carcinoma with mucus formation
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
 105

2. Pulmonary blastoma
3. Malignant melanoma
4. Malignant lymphoma
V. SECONDARY TUMOURS

Important pictures of bronchogenic carcinoma

squamous cell type adeno carcinoma

small cell carcinoma

 106

…GASTROINTESTINAL SYSTEM…

1) Pleomorphic Adenoma 8) 8) Peptic Ulcer

2) Warthins Tumour 9) Crohns disease and
3) Leukoplakia Ulcerative colitis
4) Hairy Leukoplakia 10) Colorectal Polyp
5) Eythroplakia 11) Barret’s Oesophagus
6) Gastric Carcinoma 12) Intussusception
7) Colorectal Carcinoma 13) Appendicitis
 107

INTRODUCTION TO GIT
Gastrointestinal tract is a hollow tube extending from the oral cavity to the anus that consist of anatomically distinct
segments including the oesophagus ,stomach , small intestine, colon, rectum and anus. It serves two main functions-
assimilation of nutrients and elimination of waste.

11) Diseases of gastrointestinal tract are a major causes of morbidity and mortality. GI diseases develop as a result
of abnormalities within or outside of the gut and range in severity from those that produce mild symptoms to
those with intractable symptoms and adverse outcomes. Diseases maybe localized to a single organ or exhibit
involvement at a number of sites.
SALIVARY GLANDS
SALIVARY GLAND TUMOURS
A.BENIGN
1.Adenomas
i. Pleomorphic adenoma [mixed tumour-50%]
ii.monomorphic adenoma
a]Warthin’s tumour{papilary cystadenoma
lymphomatosum,adenolymphoma-8%}
b]Oxyphil adenoma{Oncocytomas-1%}
c]Other types{myoepithelioma ,basal cell
adenoma,
clear cell adenoma}[uncommon]
2.Mesenchymal tumours[rare]
B.MALIGNANT
1. Mucoepidermoid carcinoma{15%}
2.malignant mixed tumour
a]carcinoma in pleomorphic adenoma{3-5%}
b]carcinosarcoma{rare}
c]metastasising mixed salivary tumour{rare}
3.Adenoid cystic carcinoma{cylindroma -5%}
4.Acinic cell carcinoma{5%}
5.Adenocarcinoma{10%}
6.Epidermoid carcinoma{1%}
7.Undifferentiated carcinoma{<1%}
8.Miscellaneous{2%}

1- PLEOMORPHIC ADENOMA
- Benign tumour of salivary gland.

- Painormaless ,slow growing , mobile discrete masses representing 60% of tumours in the parotid.

-Also called mixed tumour as it contains both epithelial and mesenchymal components.

-Epithelial components include a mixture of myxoid, hyaline, chondroid, and osseous tissue.

 PATHOGENESIS:-Overexpression of PLAG1.
MORPHOLOGY:

 GROSS  MICROSCOPY
- rounded, well demarcated ,encapsulated, masses, - Most striking histologic feature – heterogenicity.
 108

rarely exceeding 6cm in the greatest dimension. Epithelial elements- arranged in the form of tubules,
ducts, irregular tubules, strands or even sheets dispersed
-Cut surface – grey- white, bluish translucent area. within a mesenchymal like background of loose myxoid
tissue containing islands of chondriod.
No epithelial dysplasia or mitotic activity.
 TREATMENT:- Surgical excision.
 PROGNOSIS:
- Chances of recurrence : 25% after simple enucleation.
- Recurrence occurs because of the appendages into surroundings.
 Carcinoma ex pleomorphic adenoma/malignant mixed tumour-
- Type- adenocarcinoma or undifferentiated carcinoma.
- Incidence increases with time from 2 % of tumours present for <5 years to almost 10 years for those present for
more than 15 years.
 Complication: mortality rates of 30-50% at 5 years.

2)WARTHINS TUMOR/ PAPPILARY CYSTADENOMA LYMPHOMATOSUM

- 2nd most common benign tumour of salivary gland
- Exclusively of parotid gland.
- Male>female affected.
- Smokers have 8 times the risk than non-smokers.
 Morphology

Grossly, Microscopically,
- Round to oval encapsulated mass. 1) epithelial parenchyma, composed of glandular or
- C/S shows pale grey surface with narrow cleft like papillary pattern lined by double layer of neoplastic cells-
spaces filled with serous or mucinous secretions. upper layer of palisading columnar cells & lower layer of
cuboidal cells
2) lymphoid stoma often with germinal centres.
Recurrence rate is usually 2% after resection.

3)LEUKOPLAKIA
- A precancerous lesion of oral cavity.
- These are white patches which can neither be scrapped off nor be characterised as any other disease.
- Male > Female
- .Use of tobacco is a common cause.
 MICROSCOPY:
- A spectrum of epithelial changes ranging from hyperkeratosis to marked dysplasia sometimes merging with
carcinoma in-situ seen.

4)HAIRY LEUKOPLAKIA
- These are oral manifestation of systemic disease (HIV).
- Caused by EBV in immunocompromised patients.
- These are white confluent patches of fluffy hyperkeratotic thickening on lateral border of tongue which cannot be
scrapped off.
- Microscopic features include a) hyperkeratosis and b) acanthosis.

5)BARRETT’S OESOPHAGUS
 109

- Stratified squamous epithelium of lower oesophagus replaced by columnar epithelium.

- Etiology: Gastrooesophageal reflux
- Premalignant condition
- Barret’s epithelium Dysplasia Carcinoma in situ Oesophageal adenocarcinoma
- Morphological features
-Endoscopically : Red and velvety
-Barret’s ulcer—Hiatus hernia ,peptic ulcer at SCJ
- Microscopically
-Replacement of squamous epithelium by metaplastic columnar cells along with goblet cells and paneth
cells(intestinal metaplasia)
-Long segment≥3cm of oesophagus involved
-Short segment< 3cm

6)GASTRIC CARCINOMA
- Comprise more than 90% all gastric malignancies
- Highest incidence is between 4th to 6th decades of life
- Men>women
- Common sites – lesser curvature, pyloric antrum

Etiology
H.pylori infection  Dietary factors racial genetic geographical
3-6 fold susceptibily - Irritating food - blood group A
- Preservatives - family history
- Salt intake - E-cadherin
- smoked food - gene mutation

Premalignant lesions – adenomatous polyp, c/c gastric ulcer  Order of frequency

 Classification

Carcinoma

Early gastric carcinoma advanced gastric carcinoma

Carcinoma insitu Confined to mucosal layers

- Advanced gastric carcinoma penetrates muscularis or beyond

- 5 major types of advanced gastric carcinoma
 Ulcerative cancer
 Fungating (polypoid)
 Scirrhous carcinoma (lintis plastica)
 Colloid carcinoma
 Ulcer cancer
 Early gastric carcinoma – limited to mucosa & submucosa
- Histology – glandular adenocarcinoma
 110

- Grossly – 3 patterns – polypoid, superficial, ulcerated .

 Advanced gastric carcinoma

- Ulcerative carcinoma – most common. infiltrating, ulcerative growth, tumours appear as a flat, infiltrating &
ulcerative growth with necrotic base. Raised margins
- Fungating (polypoid) carcinoma – 2nd most common. Cauliflower growth projecting into the lumen. More seen in
fundus
- Scirrhous carcinoma (lintis plastica) – stomach wall thickened, leather-bottle appearance, localised or diffuse
involvement, lumen reduced, there will be no ulcers, rugae will be prominent
- Colloid (mucoid) carcinoma – masses having gelatinous appearance due to secretion of large quantity of mucous
- Ulcer cancer – cancer arising in case of chronic gastric ulcer

On the basis of extent of invasion, gastric carcinomas are classified into 2 groups

1. Expanding (intestinal type) – carcinoma grows laterally by an invasive margin. Tumour cells forms cohesive
clusters
2. Infiltrating (diffuse type) – poorly defined invasive border. Tumour cells are loose & invade singly or in small
groups
 Routes of spread
1. Direct spread 2. Lymphatic spread 3. Hematogenous
- Most commonTranscoelomic dissemination to - Esp in scirrhous carcinoma spread
peritoneal cavity Lymphnodes along lesser To liver, brain, bones,
- Krukenberg tumours (overian mass) &greater curvature kidneys & adrenals
- Submucosal spread may continue upwards into - Virchow nodes – left
those of esophahus, while spread downwards into supraclavicular lymph node
duodenum Troisier’s sign
- Invades lesser &greater omentum, pancreas, liver,
diaphragm, common bile duct, spleen, transverse
colon
 Clinical features
- Persistent abdominal pain
- gastric distension
- vomiting, loss of weight, anorexia, anaemia, malaise, weakness
 Complication –haemorrhage (melaena), haematemesis, obstruction, perforation, jaundice

Morphology – gross –
 111

7)PEPTIC ULCER
- Definition : areas of degeneration & necrosis of GI mucosa exposed to acid peptic secretion.
- Common site :duodenum & stomach ( 4:1)
- Types : acute and chronic
 Acute peptic ulcer (Stress) :
- common site –stomach
- Etiology :severe stress 1)psychological

2)physiological – shock , septicemia ,trauma,ICT ,drug intake, local irritants

 Morphology :
Pathogenesis :
 Gross:  Microscopic :
1.Ischemic hypoxic injury to mucosal
- multiple ulcers. - shallow
cells
- Oral / circular <1 cm - do not invade muscular layer .
2.Depletion of gatric mucosal barrier ,
- Some inflammatory reaction can be
by attack of acid peptic secretion.
seen in margins
- healed by complete
re-epithelialisation without leaving
scar.

 Complications :
hemorrhage& perforation.

Chronic peptic ulcer ( gastric& duodenal ulcer )

- Most frequent in middle aged adults

- Duodenal – 5 th decade
 112

- Common in males
 Etiology : disturbance in normal protective mucosal barrier acid pepsin , resulting in digeston of mucosa. Main 2
factors : H.pylori gastritis and NSAIDS induced injury.acid pepsin detetion , gastritis ,local irritant ,spicy food ,dietary
factors ,psychological factors ,genetic blood group {O} hormonal factors.
 Pathogenesis
 Duodenal ulcer =>Gastric ulcer
1. Hypersecretion of gastric acid. 1. hyperacidity due to increased serum gastrin.
2. Rapid emptying of stomach – exposed to 2. damaging influence of gastritis , bile reflux , cigarette
aggressive action of gastric acid. smoke.
3. Helicobacter gastritis. 3. Derrangement of gastric mucosal barrier.

I. Enzymatic actions of urease , protease,

catalase which breaks gastric mucosal
defects.
II. Host factors

 Morphological features :gastric ulcer – common site lesser curvature at pyloric antrum.
Duodenal ulcer-common site is first part of duodenum.
 Gross
- Round to oval punched out lesions.
- Benign :flat margin , mucosal folds converging towards ulcer.
- Malignant – larger , bowl shaped , indurated & elevated mucosa at margin.
 Microscopy :4 layers within outside .
- Granulation tissue zone – inflammatory infiltrate and proliferating capillaries.
- Zone of cicatrisation : dense fibrocollagenous scar tissue .
 Complication :-
- obstruction ,hemorrhage , perforation ,malignant transition.

clinical features gastric ulcer duodenal ulcer

pain within 2 hrs after food Relieved by food
Vomiting Relieves pain Rare .heart burn and water
brash present
Hematemesis&malena 60:40 40:60
Appetite Good . afraid to eat Very good
Diet Milk,egg All
weight Loss of weight Weight gain
Deep tenderness Mid line of epigastrium Right hypochondrium

 CURLING ULCER
Extensive burns in posterior aspect of first part of duodenum .It is an acute peptic ulceration.
 CUSHING’S ULCER
It is an intra cranial lesion developed from hyper acidity followingowing excessive vagal
stimulation.
 113

8)CARCINOID TUMOUR (ARGENTAFFINOMA)

- Tumour arising from endocrine cells belonging to APUD cells (argentaffin cells , kulchitsky cells, heterochromatin
cells) APUDoma.

Argentaffin type Tumour cells have argentaffin granules(silver stain)

Argyrophil type Argyrophil granules stain after adding reducing agent

 3 Types
1) Mid gut carcinoid-terminal ileum &appendix most common,argentaffin positive
2) Hind gut carcinoid-Rectum and colon ,arygrophil type
3) Foregut carcinoid-Stomach,duodenum,esophagus agyrophil type
- 2 common sites-Appendix and terminal ileum
1) Appendiceal carcinoid- 3rd and 4th decade no sex dielection, solitary, locally malignant
2) Ileal carcinoids- 7th decade of life, female more, multiple metastasis

 MORPHOLOGY
 Grossly  Histologically
- Small button like, submucosal Tumour cells arranged in solid nests ,cords ,tubercles solid masses of
elevation on cross section bright monotonous ,small cells with pallisading of the peripheral cells
yellow Tumour cells have uniform nucleus and poorly defined cytoplasm

9)Meckels Diverticulum
Most common congenital anomaly in the GIT in 2% of the population

- Out pouching containing all the layers of the intestinal wall in their normal orientation.
- Lined by intestinal type of epithelium.
- Contains islands of gastric mucosa and ectopic pancreatic tissue.

Site: Anterior mesenteric border of the ileum about 1m above the ileocaecal valve.

Embryonic origin: Incomplete obliteration of vitellointestinal duct.

Complication : Perforation , haemorrhage and divertialitis.

10)COLO RECTAL POLYP

Polyp is defined as any growth or mass protruding from the mucous membrane into the lumen.

2 groups : 1) Non neoplastic 2) Neoplastic

 NON-NEOPLATIC POLYP

 Hyperplastic polyp - Most common

- Epithelial hyperplasia at base of crypts
- Cystic metaplasia
- Symptomless
- No malignant potential
 Morphology:
Gross: Multiple sessile, smooth surfaced ( size<0.5 cm)
 114

Microscopy: Long and cystically dilated glands lined by normal

epithelium.

 Hemartomatous polyp - Abnormal mixture of the tissue indigenous to the part.

 Peutz Jegher’s polyps and polyposis:
-autosomal dominant
-hamartomatous intestinal polyp + melanotic pigmentation of the lip,
mouth and genital.
- gross: variable size , multiple pedunculated , site: small intestine.
- micro: Tree like branching of the muscularis mucosa , hyperplasia and
cystic change of gland, lining epithelium is normal.

 Juvenile polyp
- Mainormaly in children <5 yrs
- Gross: spherical, smooth surfaced , about 2 cm in diameter,
pedunculated.
- Microscopy: cystically dilated glands lined by normal mucous secreting
epithelium.
- If ulceration of surface occurs inflammatory cells are seen.

 Inflammatory polyp / - Re-epithelisation of the undermined ulcer and overhanging margins in

pseudo polyp IBD.
- No malignant potential
- Gross: Multiple cylindrical overgrowths of the mucosa
- Microscopy: centre- inflammatory cells, connective tissue core, cystically
dilated glands.
 Lymphoid polyp - Reactive hyperplasia of lymphoid tissue in rectum and terminal ileum-
rectal tonsil
- Gross: multiple tiny elevated lesion.
- Micro: prominent lymphoid followingicle with germinal centre lined by
epithelium that may be inflamed.

 NEOPLASTIC POLYP :
Colorectal adenoma with malignant potential.
3 types

- Most common neoplastic type .

- Asymptomatic or may manifest by rectal bleeding
- Gross: single /multiple, sessile/pedunculated, vary in size.
- Micro: branching tubules embedded in lamina propria. Cells are large
intestinal type ( diminished mucous secreting capacity , large nuclei,
increased mitotic activity , cytological atypia)

 Villous adenoma - Less common than tubular adenoma.

- Symptomatic rectal bleeding , diarrhoea
- Gross: round to oval , exophytic , sessile , 1-10 cm or more in
diameter
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- Micro: slender , finger like projection arising from the muscularis

mucosa.
- Papillae = fibromascular stromal core covered by epithelium varies
from brnign to anaplastic cells.
 Tubulovillous Intermediate form of pattern between villous and tubular adenoma.
adenoma - Gross: sessile or pedunculated, 0.5 – 5 cm

 Familial polyposis syndrome:

- A group of disorder with multiple polyposis of coli
- Autosomal dominant
 Familial polyposis coli - More than 100 neoplastic polyps ( adenomas) on the mucosal
surface of colon
- Autosomal dominant
- ADC gene mutation
- High malignant potential
- Colorectal cancer develop in 100% of cases by age of 50 yrs
- Morph: refer tubular adenoma.
 Gardener syndrome - Combination of familial oliposis coli and certain extra colonic lesion
- Multiple osteomas
- Sabaeceous cyst
- Connective tissue tumour
 Turcot syndrome - Combination of familial polyposis coli and malignant neoplasm
 Juvenile polyposis
syndrome

12) COLORECTAL CARCINOMA

- Most common malignancy of GI tract.
- Incidence increase with age(average-60 yrs).
- Cancer in the rectum is more common in males than females(2:1).

=>Etiopathogenesis

1.Geographic variations.

2.Dietary factors.

-low intake of vegetables fibres diet.

-consumption of refined carbohydrate is excessive.

3.Adenocarcinoma sequence

- Incidence of adenomas directly proportionate to prevalence of colorectal cancer.

- Familial polyposis syndrome malignancy.

Morphologic &molecular changes in adenocarcinoma sequence Fig.no

4.Genetic :mutation in microsatellite instability pathway.

Fig no.
 116

Morphology

Distribution of primary colorectal cancer

Fig.no

Macroscopy

Right sided growth: -polypoid,exophytic masses.

-extend along one wall of large caliber caecum&ascending colon,rarely produces obstruction.

Left sided growth:-annular lesion ,produce “Napkin ring”constrictions, luminal narrowing&obstruction. Microscopy
:Right sided & left sided colonic adenocarcinoma are similar.Tumors composed of columnar cells resembles dysplastic
epithelium formed in adenomas.

Histology grades –well differentiated,moderately differentiated &poorly differentiated.poorly differentiated forms few
glands.others produce mucin that accumulates in the intestinal wall- poor prognosis

13) ACUTE APPENDICITIS

- Inflammation of appendix
- Age group : young adults , adolscents ,more chance in males than females
 Pathogenesis:- ↑ intra luminal pressure- venous outflow compromise
 Causes: stool, masses ,fecolith , gall stone, worm mass, luminal content stasis

There is bacterial growth ,inflammation, ischemia ,neutrophilic infiltration of lumen & muscular wall.

 Morphology:
- GROSS:
-dull, granular ,erythematous surface, focal superficial ulcerations

- Histology:

-neutrophilic infiltration of muscular propria (figure no :18.39) harsh mohan

=>Complications :peritonitis, appendix abcess , adhesions ,portal pyelophlebitis , mucocele

=>Cinical features : periumbilical pain, fever , nausea ,↑ WBC count ,pain in macburney point

TUBERCULOUS ULCER TYPHOID ULCER AMOEBIC ULCER

GROSS Intestinal lesions are In intestinal lesions, Early lesion appear as
common than lymph terminal ileum is small area of elevation
node lesions in affected most, also on the mucosal surface.
secondary pulmonary jejunum and colon. In advanced stages,
tuberculosis. Peyer’s patches show flask shaped ulcers
Lesions begin in peyer’s ulcer with their long having narrow neck and
patches later fuse to axes along the bowel. broad base is seen.
form large ulcers Base of ulcer is black More conspicuous in
transverse to axis of due to sloughed caecum, rectum and
bowel. mucosa. flexures.
Inflammatory edema
and cellular
proliferation.
MICROSCOPY Mucosa and submucosa Hyperemia, edema and Ulcerated area shows
 117

show ulceration and cellular proliferation inflammatory reaction

muscularis may be consisting of phagocytic consisiting of
replaced by variable histiocytes, lymphocytes, plasma
degree of fibrosis. lymphocytes and cells, macrophages and
Tuberculous peritonitis plasma cells. eosinophils.
may be observed. Neutrophils are absent Trophozoites of
from cellular infiltrates entamoeba seen in
reflected in inflammatory exudates
neutropenia. and are concentrated at
margins of lesions.
GENARAL In advanced cases, Lesion intestine as well Infection by entamoeba
CONSIDERATIONS transverse fibrous as in other organ histolytica mainormaly
strictures and intestinal affects large intestine.
obstruction may be Ingested cyst wall is
seen dissolved in small
intestine where the
liberated amoeba
passes to the large
intestine.
They invade the mucosa
and reaches the
submucosa to form
flask shaped ulcers
COMLICATIONS Perforation or ulcer Amoebic liver abscess
Hemorrhage Amoebic hepatitis
Perforation
Hemorrhage

14) Colorectal carcinoma

- most common malignant tumor of GIT, common in age group more than 60 with male predominance
 pathogenesis
- involves combination of molecular events ie, adenocarcinoma is heterogenous
- includes genetic & epigenetic abnormalities
- two distinct genetic pathways are,
A) APC /B-catenin pathway , Involves Loss of tumor suppressor APC
- Classic adenocarcinoma sequence  mainormaly responsible for sporadic colon tumor. It involves mutation of
APC tumor suppressor in neoplastic process
- Both copies of APC gene should be inactivated for adenoma to develop
- Normally , APC is key negative regulator of B catenin, a component of WNT signaling pathway. It promotes
degradation of B catenin
- When mutation occurs  loss of APC gene product occurs and B catenin accumulates which is translocated
to nucleous activation of transcription genes proliferation
Other additional mutations like,
 Point mutations in K-RA Swhich promote growth and prevent apoptosis
 Mutation in other tumor suppressor genes suchas SMAD @ and SMAD 4 have effects on TGF-B
signaling(normally inhibits cell cycle) mutation causes uninhibited cell growth
 Mutation of p53- due to chromosomal deletion
 118

B) Microsatellite instability pathway in thi,s mutations lead to defective DNA mis match repair mechanism.
The significant DNA repair genes mutated are TGF-B receptor genes( which normally inhibits cell proliferation) leads
to uncontrolled proliferation, BAX gene ( which normally causes apoptosis) leads to loss of apoptosis & dysregulated
growth.

 Morphology
a) Gross
 Right side colonic growth  are large,
cauliflower like soft & friable masses
projecting into the lumen
 Left side colonic growth>have napkin- ring
configuration ie they encircle the bowel wall
circumferentially with increased fibrous
tissue forming annular ring & have
ulceration on surface with elevated margin

(These differences in right and left colonic growths are probably due to the liquid nature of the contents in
theascending colon leaving space for luminal growth on right side, while the contents in left colon are more
solidpermitting the spread of growth into the bowel wall)

b) Microscopy
 Similar on both sides
 95% are adenocarcinomas of varying grades of differentiation out of which approx. 10% are mucin-
secreating colloid carcinomas. 5% have uncommon patterns like undifferentiated CA, signet-ring cell
CA and adenosquamous CA
 Composed of tall coloumnar cells resemble the dysplastic epithelium in adenoma
 Invasive component of these tumor elicits strong stromal Desmoplastic response  characteristic
consistency

 Spread
1. Direct spread  most common, circumferentially as well as directly to depth of bowel wall to serosa,
pericolic fat and sometimes to peritoneal cavity.
2. Lymphatic spread  common, initially sentinel lymph nodes and then to other groups of LN like preaortic,
internal iliac & sacral LN
3. Haematogenous  occurs lately & involves spread to liver, lungs, brain, bones & ovary.
 Clinical features
occult bleeding (malena), change in bowel habits ( more in left sided growth), loss of weight( cachexia), loss
of appetite (anorexia), anemia, weakness
 Complications
Obstruction, hemorrhages, and less often perforation & secondary infection
 Diagnostic tools
1. Stool test – for occult blood
2. Per rectal examination
3. Proctoscopy
4. Radiographic contrast studies CT
5. Tumor markers carcino embryonic antigen- elevation in metastatic colorectal cancers
 It has onormaly prognostic significance
 Prognosis  depends on extent of bowel involvement, presence/absence of metastasis, histologic grades of
tumor, location of tumor
 Staging
 119

- Dukes ABC staging, Aster-coller staging

- TNM staging
1. T1N0M0 cancer confined to mucosa onormaly
2. T2N0M0  cancer intends to submucosa
3. T3N0M0  cancer extends to muscularis with or without serosa
4. TxN1M0 cancer intends muscularis + regional lymph nodes
5. TxN1M0 cancer intends serosa + regional lymph nodes
6. TxNxM1 cancer with distant metastasis
 120

Male genital system

1. Testicular tumour- classification

2. Seminoma
3. BPH
4. Ca prostate
5. Schiller duval body
 121

MALE GENITAL SYSTEM

Major anatomic subdivisions of the MGS- penis, scrotum and its contents, and the prostate- will be considered
individually. Although there is some overlap, diseases tend initially or predominantly to affect any one of these
structures. An exception to this anatomic consideration is the grouping of venereal diseases.

Testicular tumors

- 1% of all cancer death

- They have bimodal age distribution
a) A peak during infancy
b) Another during late adolescence & early adulthood

CLASSIFICATION
 122

Histogenesis :-

 Developmental disorders

Disorders such as cryptocredism , gonadal dysgenesis, and androgen insensitivity syndrome are high risk factors for
development of testicular cell tumour.

 Molecular genetic factors

1. Hyper diploidity
2. In most of the tumour an iso-chromosome of short arm of chromosome 12 ( 12p)
3. Deletion of long arm of chromosome 12 (12q)
4. Telomerase activity
5. Other mutation include p53, cyclin E & FAS gene
 CIS/ITGCN: carcinoma in-situ termed inter tubule germ cell metaplasia
 “3 HIT” process: germ cells in seminiferous tubules undergo activation ( firs hit ) before undergoing malignant
transformation confine to seminiferous tubules ( second hit) and eventually onto invasive stage by same epigenetic
phenomenon (3rd hit)

Clinical feature and diagnosis

CclCLINICAL FEATURE SPREAD:

1.Gonadal enlargement By both lymphatic and hematogenous routes.
2.dragging sensation in the testis.
Lymphatic spread: to retroperitoneal para aortic lymphnodes,
Metastatic involvement:-
mediastinal lymph nodes and supraclavicular lymphnodes.
secondary symptoms: -
pain, lymphadenopathy, hemoptysis and Hematogenous spread: occur in lungs, liver, brain and bones.
urinary obstruction.
 123

TUMOUR MARKERS: PROGNOSIS:

Two important markers:- For selecting post-orchitectomy treatment and for
-human chorionic gonadoroin{hCG} monitoring prognosis, 3 clinical stages are defined
(synthesised by placental syncytio-trophoblast)
-α fetoprotein(AFP) Stage1-tumour confined to the testis
(synthesised by the foetal liver cells, yolk sac and Stage 2-distant spread confined to retroperitoneal
foetal gut) lymph nodes below the diaphragm
In addition;
-carcinoembryonic (CEA), Stage 3-distant metastasis beyond the
-human placental lactogen(HPL), retroperitoneal lymph nodes
-placental alkaline phosphatise,
-testosterone,estrogen&LH

1) SEMINOMA
-commonest malignant tumour of the testis -corresponds to dysgerminoma in the female.
-2 main types:- CLASSIC SEMINOMA SPERMATOCYTIC SEMINOMA
Peak incidence – 4th decade of life Older patients-6th decade of life
10% pure seminoma- elevated hCG levels in Bilateral in 10% of patients
serum

MORPHOLOGY- GROSS
CLASSIC SEMINOMA SPERMATOCYTIC SEMINOMA
Homogenous, Larger, softer and more yellowish
and gelatinous than the classic seminoma.

Larger tumours:-replaces the entire testis

Smaller tumours:-circumscribed mass in the testis

2) Benign Prostatic Hypertrophy

- Non neoplastic tumour like enormalargement of prostate  Etiology:-
- Also called Benign nodular hyperplasia(BNH) or benign enormalargement of - Racial
- Inflammation
prostate(BEP)
- Arteriosclerosis
- Common above the age of 50 yrs.
 124

 Endocrinology:-
- With advancing age => decline in the level of androgen + rise of oestrogen in the males.

periurethral inner prostate ( primarily involved in BEP) responds to the rising level of oestrogen ,whereas the
outer prostate which is mainormaly involved in the carcinoma is responsive to androgen .There is synergestic
stimulation of prostate by both hormones.
 Morphological features
 Gross: HISTOLOGY:
- The enormalarged prostate is nodular smooth and - There is hyperplasia of all three tissue elements in
firm and weighs 2.4 times its normal weight on cut varying proportion
section appearance .varies depending upon  Glandular,Fibrous,Muscular
whether the hyperplasia is predominantly of the  GLANDULAR : Identified by exaggerated intra
glandular or fibromuscular tissue. acinar papillary infoldings with delicate
- In primary glandular BEP the tissue is yellow- fibrovascular cores. The lining epithelium is two
pink,soft,honeycombed and milky fluid exudates layered. The inner tall columnar mucus secretary
- In fibromuscular BEP the cut surface is with poorly defined borders and the outer
firm,homogenous and does not exudates milky cuboidal to flattened epithelium with basal
fluid. nuclei
- The hyperplastic nodule forms a mass mainormaly  Fibromuscular hyperplasia when present is
in the inner periurethral prostatic gland so that the dominent component appears as aggregates of spindle
surrounding prostatic tissue forms a false capsule. cells forming an appearance close to fibromyoma of the
uterus
It also has lymphocytic aggregates ,small areas of
infarction ,corpora amylaceae &foci of squamous
metaplasia

CLINICAL FEATURES

Cerebral obstruction &secondary effects on bladder (hypertrophy, cystitis),ureter (hydroureter) and kidney
(hydronephrosis). The presenting features include frequency change ,difficulty in micturition , pain, haematuria ,acute
retention of urine requiring immediate catheterisation .

3) CARCINOMA PROSTATE
- Second most common cancer in males
- Age group-above 50

 CLASSIFICATION
FOUR TYPES

Latent carcinoma- Occult carcinoma-no

Incidental symptoms of Ca Clinical carcinoma-
small carcinoma which carcinoma prostate but shows detected by rectal examination
remains asymptomatic evidence of and other investigations and
Four types; confirmed by taking biopsy of
metastases on
examination and prostate.
investigation
 125

 ETIOLOGY
1. Endocrinologic factors Androgens play a role in development of Ca prostate
eg.orchiectomy causes arrest of metastatic Ca
prostate,administration of estrogen causes regression,rare in
eunuchs and in patients with Klinfelters syndrome.

2. Racial and geographic factors uncommon in Japanese and Chinese,

high in Americans(especially African Americans)

3. Environmental factors high dietary fat,polycyclic aromatic hydrocarbons increases the

risk.
flavonoids antioxidants and selenium reduces the risk.

4. Nodular hyperplasia precursor for development of Ca prostate.

5. Heredity high risk among first degree relatives,men with prostatic cancer
susceptibility gene,BRCA2

 MORPHOLOGY
GROSS
Prostate enormalarged,normal or small firm and fibrous
Carcinoma mostly located in the peripheral zone, especially posterior lobe
C/s is homogenous containing irregular yellowish masses
MICROSCOPY
4 histologic types

Adenocarcinoma(most Architectural disturbances :-loss of intra acinar papillary convolutions. Acini either
common type) closely packed or haphazardly distributed
Stroma-little or no fibromuscular stroma
-replaced by tumor cells.
Gland pattern
i)well differentiated tumor
:-small medium sized glands lined by single layer of cuboidal or low columnar cells
:-Moderately differentiated tumor
:-cribriform or fenestrated glands

ii)Poorly differentiated
:-no glands,show solid or cribriform appearance

Tumor cells may be

:- clear(with foamy cytoplasm),
:-dark(homogenous and basophilic cytoplasm)or
:-eosinophilic(granular cytoplasm)cells

Invasion-intra prostatic peri neural spaces frequently invaded

Transitional cell carcinoma
 126

Squamous cell carcinoma

Undifferentiated
carcinoma

 SPREAD CLINICAL FEATURES

Direct spread to the prostatic capsule. 1. urinary obstruction with dysuria,
Later can extend into bladder 2. frequency,
neck,seminal vesicles,trigone and urethral 3. retention of urine,
openings. 4. hematuria,
5. back pain etc
Metastases -via lymphatic route to sacral,iliac and
paraaortic nodes
Hematogenous to pelvis,lumbar spine(osteoblastic
spread osseous metastasis)and to
lungs,kidney,breasts and brain.

 TNM STAGING

STAGE DESCRIPTION
T1a Non-palpable≤5% resected tissue involved
T1b Non-palpable>5% resected tissue involved
T1c Non-palpable,detected due to elevated PSA
T2a Palpable,≤50% of one lobe
T2b Palpable,>50% of one lobe
T2c Palpable, involves both lobes
T3a Palpable,unilateral extracapsular involvement
T3b Palpable, bilateral extracapsular involvement
T3c Tumour invades seminal vesicle
M1 Distant metastasis

=> DIAGNOSIS
-Cytologic , biochemical, radiologic, ultrasonoigraphic and pathologic methods.
-Definite diagnosis is made ny histopathologic examination of transrectal ultrasound (TRUS)- guided core needle biopsy.
-2 serum tumour markers are used for diagnosis and monitoring prognosis of prostatic carcinoma.

TUMOR MARKERS
Prostatic acid :-phosphatase secreted by prostatic epithelium.
Elevated:- in prostatic cancer which have extended beyond the capsule or have metastasised
:-present in normal prostatic tissues

Prostate specific Detected by immunohistochemical method in the malignant prostatic epithelium and in
antigen serum.
Value >10 is diagnostic of prostatic carcinoma.
 TREATMENT
- Surgery- transurethral resection, radical prostatectomy , transurethral US guided laser induced prostatectomy.
- Radiotherapy
 127

- Hormonal therapy- deprive the tumour cells of growth promoting influence of testosterone.
-achieved by bilateral orchiectomy followingowed by administration of estrogen.

4) PREMALIGNANT LESION OF THE MALE EXTERNAL GENITALIA

BOWEN’S DISEASE BOWENOID
(Associated with internal visceral cancers) PAPULOSIS
LOCATION 1.on the shaft of the penis 1.the penile shaft
2.the scrotum 2.adjacent genital
3. the sun exposed areas of the skin. skin
GROSS solitary , Solitary or multiple,
circumscribed plaque lesion with ulceration shiny ,
red-brown popular
lesions

HISTOLOGICALLY epithelium shows:- orderly maturation of

hyperplasia, epithelial cells in
hyperkaeratosis, hyperplastic
parakeratossi and epidermis with
scaterres bizarre dyskeratotic cells. scatteres
hyperchromatic
nuclei and dysplastic
cells.
 128

The breast

1. Fibroadenoma
2. Carcinoma Breaast
 129

1) Fibroadenoma
- Benign tumour of fibrous and epithelial elements of breast.
- Age: 15-300 years ( reproductive age group)\
- Clinically: solitary , discrete freely mobile nodule within the breast
 MORPHOLOGY  MICROSCOPY
- Small, solitary, well encapsulated, spherical - Mainormaly fibrous tissue
mass - Arrage b/w fibrous overgrowth and ducts may produce
- Cut surface: firm, grey white, myxoid, may show two type of pattern:
slit like spaces due to the compressed ducts 1- INTRACANALICULAR : Stroma compress the ducts
- Size: 15cm diameter ( GIANT FIBROADENOMA) reducee to slit like spaces lined by ductal
epithelium
2- PARACANALICULAR: Encircling mass of fibrous tissue
around the dilated ducts
- VARIANTS: Tubular adenoma, Lactating adenoma, Juvenile adenoma.
2) FIBROCYSTIC CHANGE
- Produces vague lumpy breast.
- Age: 3rd to 5th decade of life ( decline seen after the menopauseshows role of estrogen in pathogenesis)

- Two types: Characteristics:

 NON PROLIFERATIVE - Cystic dilation of terminal ducts
 PROLIFERATIVE - In inter and intralobular fibrous tissue.
- Variable degree of epithelial proliferation

TYPES NON-PROLIFERATIVE FIBROCYSTIC PROLIFERATIVE FIBROCYSTIC CHANGE

CHANGE
FEATURES - Common Two types:
-1- Epithelial hyperplasia
- Formation of cyst of varying size
-2-Sclerosing adenosis
- Increase in fibrous stroma
EPITHELIAL HYPERPLASIA SCLEROSING ADENOSIS
GROSS -
rarely solitary, present as multifocal - Not distinct - Coexist with other
and bilateral - Dominated by fibrous component of
- size: 5-6 cm in diameter and cystic change fibrocystic disease
- Blue dome cyst: Large round cyst, - May form a had mass
translucent with bluish colour
- On opening cyst has serous to
haemorrhagic fluid.
MICROSCOPY Mainormaly 2 features - ductal hyperplasiaof - Proliferation of
- CYST FORMATION: three types: ductules and acini.
-lining epithelium: flat/atrophic 1- mild hyperplasia
-apocrine metaplasia 2-moderate and florid
-epithelial hyperplasia. hyperplasia
- FIBROSIS: 3-atypical ductal
- increased firous stroma around hyperplasia
the cyst and variable degree of stromal 4- atypical lobar
 130
Early diagnosis
Triple technique
 palpation
 mammography
 FNAC
Other Techniques include stereotactic biopsy and frozen

lymphocytic infiltrate hyperplasia.

3) BREAST CARCINOMA
- Incidence higher in perimenopausal women
- presents as a solitary,painormaless, palpable lump (detected quite often by self examination)

 Risk factors
 Geography
 Age -Increases after age 30
 Family historyFirst-degree relative with breast cancer
 Menstrual history-Age at menarche &menopause
 Pregnancy
 Benign breast disease
 Other Possible Factors
Exogenous estrogens,Oral contraceptives,Obesity,High-fat diet,Alcohol consumption,Cigarette smoking)
=>PATHOGENESIS Gene expression profiling can separate breast cancer intofour molecular
(1) genetic changes, subtypes:
- overexpression of the HER2/NEU (1) luminal A (estrogen receptor–positive, HER2/NEU-negative);
proto-oncogene, (2) luminal B (estrogenreceptor–positive, HER2/NEU overexpressing);
- Amplification of RAS and MYC genes (3) HER2/NEU positive (HER2/NEU over expressing, estrogen receptor–
- Mutations of tumor suppressor genes negative);
RB and TP53 (4) basal-like (estrogen receptor–negativeand HER2/NEU-negative).

Roughly one third of women with hereditary breast cancer have mutations in BRCA1 or BRCA2
Hormonal Influences.
- Endogenous estrogen excess, or more accurately, hormonal imbalance, clearly has a significant role.

 CLASSIFICATION
A. Noninvasive
1. Ductal carcinoma in situ (DCIS)- tumour
cellswithin the ducts
2. Lobular carcinoma in situ (LCIS)- tumour
cellswithin the lobules
B. Invasive (infiltrating)
1. Invasive ductal carcinoma (“not otherwise
specified”),
2. Invasive lobular carcinoma
3. Medullary carcinoma
 131

4. Colloid carcinoma (mucinous carcinoma)

5. Tubular carcinoma
6. Other types

A. NON-INVASIVE (IN SITU) BREAST CARCINOMA

1. Intraductal Carcinoma 2- Lobular Carcinoma in Situ
- confined within the larger mammary ducts -LCIS has a uniform appearance.
- initially begins with atypical hyperplasia of ductal epithelium -LCIS is both a marker of an increased risk of
followingowed by filling of the duct with tumour cells. carcinoma in bothbreasts and a direct precursor of
- palpable mass and presence of nippledischarge some cancers.
=> MORPHOLOGIC FEATURES MORPHOLOGIC FEATURES.
Grossly: Grossly, no visible tumour is identified.
- vary from a small poorly-defined focus to 3-5 cm diameter Histologically,in situ lobular carcinoma is
mass. characterized by filling up of terminal ducts and
- On cut section, the involved area shows cystically ductules or acini by rather uniform cells which are
dilated ducts containing cheesy necrotic material loosely cohesive and have small, rounded nuclei
Histologically: with indistinct cytoplasmic margins
the proliferating tumour cells within the ductal lumina may
have 4 types of
i) Solid pattern
ii) Comedo pattern
iii) Papillary pattern
iv) Cribriform pattern

Paget disease of the nipple is caused by the extension of DCIS up

the lactiferous ducts and into the contiguous skin of the nipple,
producing a unilateral crusting exudate over the
nipple and areolar skin. In almost all cases, an underlying
carcinoma is present, and approximately 50% of the time this
carcinoma is invasive. Prognosis is based on the underlying
carcinoma and is not affected by the presence of Paget disease.

INVASIVE BREAST CARCINOMA

 Infiltrating (Invasive) Duct Carcinoma-NOS
-Is the most common histologic pattern accounting for 70% cases of breast cancer
-Clinically,majority of infiltrating duct carcinomas have a hard consistency due to dense collagenous stroma
(scirrhouscarcinoma).
-often in the upper outer quadrant.
-Retraction of the nipple.
=>MORPHOLOGIC FEATURES.
Grossly:
irregular, 1-5 cm in diameter,
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hard cartilage-like mass that cuts with a grating sound.

The sectioned surface of the tumour is grey-white to yellowish with chalky streaks andoften extends irregularly into
the surrounding fat
Histologically:
A variety ofhistologic features commonormaly present are as under
i) Anaplastic tumour cells forming solid nests, cords, poorly-formed glandular structures and some intraductal foci.
ii) Infiltration by these patterns of tumour cells intodiffuse fibrous stroma and fat.
iii) Invasion into perivascular and perineural spaces as well as lymphatic and vascular invasion
 Infiltrating (Invasive) Lobular Carcinoma
-5% of all breast cancers.
-more frequently bilateral; and within the same breast, it may have multicentric origin.
=>MORPHOLOGIC FEATURES.
Grossly:
well-defined scirrhous mass to a poorlydefined area of induration that may remain undetected by inspection as well
as palpation.
Histologically, there are 2 distinct features
i) Pattern—A characteristic single file (Indian file) linear arrangement of stromal infiltration by the tumour cellswith very
little tendency to gland formation is seen.Infiltrating cells may be arranged concentrically around ducts in a target-like
pattern.
ii) Tumour cytology—Individual tumour cells resemblecells of in situ lobular carcinoma. They are round and regular with
very little pleomorphism and infrequent mitoses. Some tumours may show signet-ring cells distended with cytoplasmic
mucin.

 Medullary Carcinoma
- is a variant of ductal carcinoma and comprises about 1% of all breast cancers.
- The tumour has a significantly better prognosis than the usual infiltrating duct carcinoma.
MORPHOLOGIC FEATURES.
Grossly,
a large, well-circumscribed, rounded mass that is typically soft and fleshy or brain-like ( ‘encephaloid carcinoma’)
.Cut section shows areas of haemorrhages and necrosis
Histologically,
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.
 Colloid (Mucinous) Carcinoma
-uncommon pattern of breast cancer occurring
-more frequently in older women
-is slow-growing.
-Colloid carcinoma has better prognosis than the usual infiltrating duct carcinoma.
MORPHOLOGIC FEATURES.
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Grossly, the tumour is usually a soft and gelatinous mass with well-demarcated borders.
Histologically, colloid carcinoma contains large amount of extracellular epithelial mucin and acini filled with mucin.
Cuboidal to tall columnar tumour cells, some showing mucus vacuolation, are seen floating in large lakes of mucin
Other Morphologic Forms
1. TUBULAR CARCINOMA
2. ADENOID CYSTIC CARCINOMA
3. SECRETORY (JUVENILE) CARCINOMA
4. INFLAMMATORY CARCINOMA.
5. METAPLASTIC CARCINOMA.

 GRADING, STAGING AND PROGNOSIS

Histologic grading and clinical staging of breast cancer determines the management and clinical course in these patients.

T Tumor invasion and size. In situ carcinomas -excellent prognosis (5-year survival rate >90%),
as do invasive carcinomas less than 2 cm in size(5-year survival rate of
87%).
N Extent of lymph node involvement. no axillary node involvementthe 5-year survival rate is close to 80%.
Survival is inversely related to the number of involved lymph nodes
involved and is less than 50% with 16 or more involved nodes.

Note:-
1.Sentinel node biopsy is currently the mainstay for staging the axilla.
Sentinel node identified by using dye or a radioactive tracer.
Once identifiedsentinel nodes removedexamined microscopically.
Negative node:-sentinel lymph node that is free from carcinoma
predictive of absence of metastatic carcinoma in the remaining lymph
nodes.
Positive node:-indication for a complete axillary dissection, which is
used to stage the patient’s disease.
M Distant metastases. hematogenous spread rarely curable,
chemotherapy may prolong survival (the 5-year survival rate is ~15%).

PROGNOSIS
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Better prognosis. Poor prognosis

Histologic grade Well-differentiated carcinomas poorly differentiated carcinomas
Note: Note: Moderately differentiated
carcinomas initially have a good prognosis,
but survival at 20 years approaches that for
poorly differentiated carcinomas.
Histologic type of carcinoma Specialized types of breast carcinoma No special type (ductal carcinomas).
(tubular, medullary, and mucinous). Note: A major exception is inflammatory
carcinoma, which hasa poor prognosis
Presence or absence of Presence of hormone receptors. Lower rates of response (25% to 45%) are
estrogen or progesterone They predict the response to therapy. The seen if onormaly estrogen receptor is
receptors highest rate of response (80%) to present. If both are absent, very few
antiestrogen therapy (oophorectomy or patients (less than 10%) respond
tamoxifen) is seen in women whose tumor
cells express both estrogen and
progesterone receptors.
Overexpression of - Overexpression is associated with a
HER2/NEU caused by gene poorer prognosis.
amplification and can be
determined by
immunohistochemistry
byfluorescence in situ
hybridization.
Note:- clinical importance of
evaluating HER2/NEU lies in
predicting response to
trastuzumab (Herceptin), a
monoclonal antibody.
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LIVER
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1. VIRAL HEPATITIS
1. Hepatitis viruses
a. Clinical presentation
i. Asymptomatic
11. Malaise and weakness
lll. Nausea and anorexia
1V. Jaundice
v. Urine may be dark
b. Lab: markedly elevated alanine aminotransferase (ALT) and aspartate aminotransferase
(AST)
c. Diagnosis: serology

2. Acute viral hepatitis

a. Definition: signs and symptoms <6 months
b. Caused by : of the hepatitis viruses
c. Micro
i. Lobular disarray
11. Hepatocyte swelling (balloon cells)
Ill. Apoptotic hepatocytes (Councilman's bodies)
iv. Lymphocytes in portal tracts and in the lobule
v. Hepatocyte regeneration
VI. Cholestasis

3. Chronic viral hepatitis

a. Definition: signs and symptoms >6 months
b. Caused by hepatitis virus B, C, and D
c. Micro
1. Chronic persistent hepatitis: inflammation confined to portal tracts
2- Chronic active hepatitis: Inflammation spills into the parenchyma, causing an
interface hepatitis (piecemeal necrosis of limiting plate)
lll. Hepatitis B often has "ground glass" hepatocytes (cytoplasmic HBsAg)
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2. ALCOHOLIC LIVER DISEASE

1. Fatty change (steatosis)
a. Reversible with abstinence
b. Gross: enlarged, yellow, greasy liver
c. Micro
1. Centrilobular macrovesicular steatosis (reversible)
11. Eventual fibrosis around the central vein (irreversible)
2. Alcoholic hepatitis
a. Acute illness usually following a heavy drinking binge
b. Clinically variable
1. No symptoms
11. RUQ pain, hepatomegaly, jaundice, malaise, and anorexia
lll. Fulminant liver failure
c. Micro
1. Hepatocyte swelling (ballooning) and necrosis
11. Mallory bodies (cytokeratin intermediate filaments)
iii. Neutrophils
IV. Fatty change
v. Eventual fibrosis around the central vein
d. Prognosis
i. Each episode has a 20% risk of death
ii. Repeated episodes increase the risk of developing cirrhosis
3. Alcoholic cirrhosis
a. Develops in 15% of alcoholics
b. Micronodular cirrhosis
c. Most common disease requiring liver transplantation in adults

3. METABOLIC LIVER DISEASE

1. Wilson disease (hepatolenticular degeneration)
a. Definition: genetic disorder of copper metabolism resulting in accumulation of
toxic levels of copper in various organs
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b. Genetics
1. Autosomal recessive (chromosome 13)
ii. WD gene (ATP7B) codes for a hepatocyte canalicular copper-transporting
ATPase
c. Mechanism: decrease biliary excretion of copper
d. Presents in childhood or adolescence with liver disease
e. Distribution of disease
i. Liver: fatty change, chronic hepatitis, and micronodular cirrhosis
11. Cornea: Kayser-Fleischer rings (copper deposition in Descemet's membrane)
111. Brain: neurological and psychiatric manifestations, movement disorder

f. Diagnosis
I. Decreased serum ceruloplasmin levels
ii. Increased tissue copper levels (liver biopsy)
iii Increased urinary copper excretion
g. Treatment
I. Copper chelators (D-penicillamine)
ii. Liver transplantation is curative
2. Hemochromatosis
a. Definition: increased levels of iron, leading to tissue injury
b. Hereditary (primary)
I. Recessive disorder (HFE gene on chromosome 6p)
ii. The most common mutation of the HFE gene is the C282Y mutation.
iii. Mechanism: increased small-intestine absorption of iron
c. Secondary (example: transfusions for chronic anemias)
d. Epidemiology
I. Males:females = 5:1
2. Common in people of Northern European descent
e. Distribution of disease
i. Liver: micronodular cirrhosis and HCC (200 times the normal risk ration
[RR))
ii. Pancreas: diabetes mellitus
iii. Skin: hyperpigmentation ("bronzing")
iv. Heart: congestive heart failure and cardiac arrhythmias
v. Gonads: hypogonadism
f. Diagnosis
i. Markedly elevated serum iron and ferritin
ii. Prussian blue stain and increased tissue iron levels (liver biopsy)
g. Treatment: phlebotomy

3. a-I-Antitrypsin deficiency
a. Definition: autosomal recessive disorder characterized by production of defective
a-I-antitrypsin (aI-AT), which accumulates in hepatocytes and causes liver damage
and low serum levels of aI-AT
b. Genetics
i. aI-AT is produced by the Pi gene (chromosome 14)
ii. More then 75 gene variants described
PiM: the normal, most common form (90%)
Most other variants also produce normal aI-AT levels
PiS deficiency variant: mildly reduced levels
PiZ deficiency variant: markedly reduced levels
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iii. Homozygous PiZZ have severe reductions (15% of normal) in enzyme levels
c. Distribution of disease
I. Liver: micronodular cirrhosis and an increased risk of HCC
2. Lungs: panacinar emphysema

d. Micro: PASpositive, eosinophilic cytoplasmic globules within hepatocytes

e. Treatment
1. Prevention of emphysema: no smoking!
2. Liver transplantation is curative
4. Reye syndrome
a. Rare, potentially fatal disease
b. Occurs in young children with viral illness (varicella or influenza) treated with aspirill
c. Mechanism: unknown; mitochondrial injury and dysfunction play an important
role
d. Distribution of disease
1. Liver: fatty change (microvesicular steatosis)
ii. Brain: cerebral edema/encephalopathy
e. Prognosis
1. Complete recovery (75%)
2. Coma, permanent neurologic deficits, and death
f. Treatment: supportive
4. HEMODYNAMIC LIVER DISEASE
1. Budd-Chiari syndrome (hepatic vein thrombosis)
a. Definition: occlusion of the hepatic vein by a thrombus, often resulting in death
b. Etiology
1. Polycythemia vera
11. Pregnancy
iii. Oral contraceptives
IV. Paroxysmal nocturnal hemoglobinuria
v. Hepatocellular carcinoma
VI. Idiopathic
c. Clinical: abdominal pain, hepatomegaly, ascites, and death
d. Micro: centrilobular congestion and necrosis

2. Chronic passive congestion of the liver

a. Definition: "backup of blood" into the liver, usually due to right-sided heart failure
b. Gross: nutmeg pattern of alternating dark (congested central areas) and light (portal
tract areas) liver parenchyma
c. Micro: centrilobular congestion
d. Complications
1. Centrilobular necrosis: ischemic necrosis of centrilobular hepatocytes
2. Long-standing congestion ~ centrilobular fibrosis ~ cardiac cirrhosis

5.INFLAMMATION OF THE PANCREAS

1. Acute hemorrhagic pancreatitis
a. Etiology
i. Gallstones
ii. Alcohol
lll. Hypercalcemia
IV. Drugs
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v. Shock
VI. Infections
vii. Trauma
viii. Scorpion stings
b. Mechanism: Pancreatic acinar cell injury results in activation of pancreatic enzymes and enzymatic
destruction of the pancreatic parenchyma

c. Clinical presentation
i. Stabbing epigastric abdominal pain radiating to the back
ii. Shock
iii. Hypocalcemia
d. Lab: elevation of serum amylase and lipase
e. Gross
1. Focal pancreatic hemorrhage and liquefication
2. Chalky, white-yellow fat necrosis of adjacent adipose tissue
f. Micro
i. Liquefactive necrosis of pancreatic parenchyma
ii. Acute inflammation
iii. Enzymatic fat necrosis
IV. Necrosis of blood vessels causes hemorrhage
g. Complications
i. May develop acute respiratory distress syndrome (ARDS) or disseminated
intravascular coagulation (DIC)
ii. Pseudocyst
iii. Pancreatic calcifications
h. Prognosis: Severe cases have a 30% mortality rate

2. Chronic pancreatitis
a. Middle-age male alcoholics
b. Definition: chronic inflammation, atrophy, and fibrosis of the pancreas secondary
to repeated bouts of pancreatitis
c. Gross: firm, white, fibrotic pancreas
d. Micro:
i. Extensive fibrosis and parenchymal atrophy
ii. Chronic inflammation
e. Presentation
i. Abdominal pain
ii. Pancreatic insufficiency and malabsorption
iii. Pancreatic calcifications
iv. Pseudocyst
v. Diabetes (late complication)

PRIMARY BILIARY CIRRHOSIS

Etiology –
1. endocrine origin( more common in females)
2. Familial incidence
3. elevated cholesterol (xanthoma and xanthelasma). Hepatomegaly and CLD.
4. autoimmune evidence-
 increased incidence of associated autoimmune diseases
(e.g. scleroderma, Sjögren’s syndrome, CREST syndrome and autoimmune thyroiditis),
 circulating anti-mitochondrial antibody of IgG class, increased IgM and immune complexes
 142

5. Lab investigations -increased ALP, conjugated bilirubin and autoantibodies

6. Chronic destructive and cholangitis of intrahepatic bile ducts
JAUNDICE

 It refers to yellow pigmentation of skin &sclera by bilirubin.

 It occurs when retention of bilirubin leads to seems level above 2 mg /dl
 Hepatic and intra and extra hepatic obstruction of bile flow are the most common cause of jaundice involving the
accumulation of conjugated bilirubin.
 Hemolytic anemia are the most common cause of jaundice involving accumulation of unconjugated bilirubin.
 Cholestasis and the impairment of bile flow resulting in the retention of bilirubin ,bile acids and cholesterol.
 Serum alkaline phosphatase usually elevated in cholestatic condition.

Main cause of jaundice

Unconjugated hyperbilirubinemia
(1)Excess production of bilirubin –Hemolytic anemia
Infective erythropoiesis syndrome
(2)Reduced hepatic uptake -viral or drug induced hepatitis
Cirrhosis
(3)Impaired bilirubin conjugation –physiologic jaundice of newborn
Conjugated hyperbilirubinemia
(1)Decreased hepatocellular excretion -Dubin Johnson syndrome
Viral hepatitis
(2)Impaired intra or extra hepatic bile flow-Primary biliary cirrhosis
-Primary sclerosing cholangitis
 Pathogenesis

Normally rate of systemic bilirubin production=rate of hepatic uptake,conjugation and biliary excretion.

Jaundice occurs when equilibrium is lost.

Different mechanism are ther e in the cause of jaundice ,especially hepatitis.When both unconjugated and conjugated
bilirubin may be produced excess.

Immaturity of hepatic machinery cause neonatal jaundice.

Inborn error causing error of metabolism ,Gilbert syndrome and Dubin Johnson syndrome.

GALL STONES(CHOLELITHIASIS)

- 2 Main types –Cholesterol stones

- Pigment stones

=> Pathogenesis

- Bile formation is the only significant pathway for eliminationof excess cholesterol.

- Cholesterol rendered water soluble by aggregation with bile salt and lecithin.

- Cholesterol gall stone formation hypomobility of gall bladder.

- Mucin hypersecretion
 143

-Pigment stones more likely in the presence of unconjugated bilirubin in the biliary tree.

=> Morphology

1.Cholesterol stones –pure stones –pale yellow,increasing proportions of calcium carbonate,phosphates and bilirubin
impacts gray white. Shape –ovoid and firm,occur singly,most are radiolucent
2.Pigment stones-black stones –sterile gall bladder bile

Brown stones-infected intra hepatic or extra hepatic ducts

50% to 75% black stones are radio opaque.
Brwn stones which contains calcium soaps are radiolucent.
Clinical features
Mostly remain asymptomatic.
Some have right upper quadrant or epigastric region biliary pain.
Complications
Empyema ,Perforations ,Fistulas,Inflammations of biliary tree,Obstructive cholestasis,Pancreatitis,Gall stone
ileus
Fig. no
10. Mallory bodies
 Eosinophilic
 Intracytoplasmic inclusions
 Seen in perinuclear location within swollen and ballooned hepatocytes
 Reprelent –aggregates of cytoskeletal intermediate filament.
 Stain used-Massons trichome and chromephobe aniline blue.
 Seen in –Alcoholic hepatitis,Primary biliary cirrhosis,Indian childhood cirrhosis,Cholestatic
syndrome,Wilsons disease,Hepatocellular Carcinoma.

NON-ALCOHOLIC FATTY LIVER DISEASE

Presented as steatosis steatohepatitis cirrhosis

Pathogenesis

Metabolic syndrome Insulin resistance Type II DM obesity

Impaired oxidation of fatty acid

dyslipidemia HTN

Apoptosis liver damage +inflammation

 144

Clinically: elevation of serum transaminases.

Mostly asymptomatic and diagnosed by biochemical tests. Sometimes presented with fever, malaise, right upper
quadrant discomfort or more severe symptoms of c/c liver diseases.

CIRRHOSIS
1. Definition: end-stage liver disease characterized by disruption of the liver architecture
by bands of fibrosis that divide the liver into nodules of regenerating liver parenchyma
2. Etiology
a. Alcohol
b. Viral hepatitis
c. Biliary tract disease
d. Hemochromatosis
e. Cryptogenic/idiopathic
f. Wilson disease
g. l-l-antitrypsin deficiency
3. Gross
a. Micronodular: nodules <3 mm
b. Macronodular: nodules >3 mm
c. Mixed micronodular and macronodular
d. At the end stage, most diseases result in a mixed pattern, and the etiology may not
be distinguished based on the appearance
4. Mechanism: Fibrosis is produced by the Ito cell (hepatic stellate cells) (Refer diagram )
5. Consequences
a. Portal hypertension
I. Ascites
ii. Splenomegaly/hypersplenism
iii. Esophageal varices
IV. Hemorrhoids
v. Caput medusae
b. Decreased detoxification
i. Hepatic encephalopathy
11. Spider angiomata
111. Palmar erythema
1V. Gynecomastia
 c. Decreased synthesis
 i. Hypoalbuminemia
 ii. Decreased clotting factors
 d. Hepatorenal syndrome
 145

CLASSIFICATION OF LIVER CIRRHOSIS

A.MORPHOLOGIC
I. Micronodular(nodules less than 3mm)
II. Macronodular(nodules more than 3mm)
III. Mixed
B.ETIOLOGIC
1.Alcoholic cirrhosis(most common,60-70%)
2.Post necrotic cirrhosis(10%)
3.Biliary cirrhosis(5-10%)
4.Pigment cirrhosis in haemochromatosis(5%)
5.Cirrhosis in Wilson’s disease
6.Cirrhosis in α-1-antitrypsin deficiency
7.Cardiac cirrhosis
8.Indian Childhood Cirrhosis(ICC)
9.Cirrhosis in autoimmune hepatitis
10.Cirrhosis in non-alcoholicsteatohepatitis
11.Miscellaneous forms of cirrhosis(Metabolic,infections,GI,infiltrative) diseases
12.Cryptogenic cirrhosis

HEPATOCELLULAR CARCINOMA (HEPATOMA)

- Common malignant tumor of liver

- Male: female ratio is 4:1
- Peak incidence in 5th -6th decades
 Etiopathogenesis-
1. Relation to HBV incidence-
Incidence of HBsAg positivity and presence of anti-HBc
higher in patients with hepatocellular carcinoma
Evidence of integration of HBV-DNA genome in the genome
 146

of tumor cells of HCC

2. Relation to HCV infection
Patient with anti-HCV and anti-HBC antibodies have higher
incidence of developing HCC
3. Relation to cirrhosis- all cirrhosis are related but more
commonly micronodular post necrotic cirrhosis
4. Relation to alcohol- Alcohol co- carcinogen
5. Mycotoxins
6. Chemical carcinogens
7. Miscellaneous factors
Hemochromatosis, à-1 antitrypsin deficiency
Immunosuppressive therapy for long time
Viral hepatits, smoking, schistosomiasis, chlonorchiasis

 Molecular pathogenesis-
 Inactivation p53 tumor suppressor gene by
HBV
 Binding of X protein from X gene of HBV to p53
 Mutation of oncogenes like KRAS
 Mutation in receptors for growth factor
 Activation of WNT and AKT pathway

 Morphology-
3 types of growth
 EXPANDING-forms single, brown, large mass, often in the right liver lobe with central necrosis, hemorrhages
 MULTIFOCAL-multifoca l, multiple mass, 3-5cm diameter, scattered throughout liver
 INFILTRATING-diffusely infiltrating tumor mass
 Microscopy-
- Showing trabecular growth pattern
- Tumor cells invade and grow along blood cell
- Histologic patterns-

 Trabecular/ sinusoidal
Clinical features-
pattern
 Hepatomegaly
 Pseudoglandular/ acinar  Right upper quadrant pain and tenderness
pattern  Jaundice
 Compact pattern  Fever
 Cirrhosis pattern  Hemorrhagic varices
- Cytologic features-  Immunohistochemically tumor cells stains positively AFP, EMA,
 Resemble hepatocytes keratin
having vascular nuclei and prominent nucleoli
 Granular eosinophilic cytoplasm, but gradually becomes basophilic
 Other features- pleomorphism, bizarre giant cell formation, tumor cells with clear cytoplasm, spindle shaped
cells, presence of bile within dilated canaliculi, intracytoplasmic mallory’s hyaline
 Variant- fibrolamellar carcinoma

 Spread- Intrahepatic and extra hepatic spread

 147

IMMUNOLOGY
 148

A. AUTOIMMUNE DISEASES

1. Systemic lupus erythematosis (SLE)

a. Definition: chronic systemic autoimmune disease characterized by loss of self-tolerance
and production of autoantibodies
b. Epidemiology
i. Females » Males (M:F= 1:9)
ii. Peak incidence: age iQ-45
iii, African American> Caucasian
c. Autoantibodies
i. Antinuclear antibody (ANA) (>95%)
ii. Anti-dsDNA (40-60%)
iii. Anti-Sm (20-30%)
iv. Antihistone antibodies
d. Mechanism of injury: type II and III hypersensitivity reactions
e. Distribution of disease
1. Hematologic
Hemolytic anemia
Thrombocytopenia
Neutropenia
Lymphopenia
2. Arthritis: polyarthralgia and synovitis without joint deformity
3. Skin
Malar "butterfly" rash
Maculopapular rash
Ulcerations and bullae formation
4. WHO classification of kidney manifestations
Class I: normal
Class II: mesangiallupus nephritis
Class III: focal proliferative glomerulonephritis
Class IV: diffuse proliferative glomerulonephritis (most common and severe)
Class V: membranous glomerulonephritis
5. Heart: Libman-Sacks endocarditis (nonbacterial verrucous endocarditis)
6. Serosal surfaces: pericarditis, pleuritis, and pleural effusions
7. CNS: focal neurologic symptoms, seizures, and psychosis.

f. Treatment: steroids and immunosuppressive agents

g. Prognosis
I. Chronic, unpredictable course with remissions and relapses
II. Ten-year survival: 85%
III. Death is frequently due to renal failure and infections

2. Sjogren syndrome (Sicca syndrome)

a. Definition: an autoimmune disease characterized by destruction of the lacrimal
and salivary glands resulting in the inability to produce saliva and tears
b. Clinical features
I. Females> males; age range: 30 to 50
ii. Keratoconjuctivitis sicca (dry eyes) and corneal ulcers
iii. Xerostomia (dry mouth)
IV. Mikulicz syndrome: enlargement of the salivary and lacrimal glands
 149

c. Often associated with rheumatoid arthritis and other autoimmune diseases

d. Anti-ribonucleoprotein antibodies
I. SS-A (Ro)
ii. SS-B (La)
e. Complication: increased risk of developing lymphoma
3. Scleroderma (progressive systemic sclerosis)
a. Definition: autoimmune disease characterized by fibroblast stimulation and deposition
of collagen in the skin andinternal organs
b. Females> males; age range: 20 to 55
c. Pathogenesis: activation of fibroblasts by eytokines interleukin 1 (IL-I), plateletderived
growth factor (PDGF), and/or fibroblast growth factor (FGF) leads to fibrosis
d. Diffuse scleroderma
I. Anti-DNA topoisomerase I antibodies (ScI-lO) (70%)
II. Widespread skin involvement
iii. Early involvement of the visceral organs
Esophagus-dysphagia
GI tract-malabsorption
Pulmonary fibrosis-dyspnea on exertion
Cardiac fibrosis-arrhythmias
Kidney fibrosis-renal insufficiency
e. Localized scleroderma (CREST syndrome)
I. Anti-centrornere antibodies
II. Skin involvement of the face and hands
Ill. Late involvement of visceral organs
IV. Relatively benign clinical course

B. PRIMARY IMMUNE DEFICIENCY SYNDROMES

1. X-linked agammaglobulinemia of Bruton
a. Definition: inherited immunodeficiency characterized by a developmental failure to produce mature B
cells and plasma cells, resulting in agammablobulinemia
b. Genetics: mutation of B-cell Bruton tyrosine kinase (btk)
c. Clinical findings
I. Male infants
II. Recurrent infections beginning at 6 months of life
iii. Common infections: pharyngitis, otitis media, bronchitis, and pneumonia
IV. Organisms: H. Influenza, S. pneumococcus, and S. aureus
2. Common variable immunodeficiency
a. Definition: group of disorders characterized by a B-cell maturation defect and hypogammaglobulinemia
b. Clinical findings
I. Both sexes are affected
II. Onset is in childhood
Ill. Recurrent bacterial infections
IV. Increased susceptibility to Giardia lamblia
c. Complications
I. Increased frequency of developing autoimmune diseases
II. Increased risk of lymphoma and gastric cancer
3. DiGeorge syndrome
a. Definition: embryologic failure to develop the 3rd and 4th pharyngeal pouches ,resulting in the absence
of the parathyroid glands and thymus
b. Clinical findings
i. Hypocalcemia and tetany
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II. T-cell deficiency

III. Recurrent infections with viral and fungal organisms
4. Severe combined immunodeficiency (SCID)
a. Definition: combined deficiency of cell-mediated and humoral immunity often caused by a stem-cell
defect
b. Modes of inheritance
i. X-linked (mutation of the chemokine receptor)
ii. Autosomal recessive (deficiency of adenosine deaminase)
c. Clinical features
i. Recurrent infections with bacteria, fungi, viruses, and protozoa
II. Susceptible to candida, cytomegalovirus (CMV), and Pneumocystis carinii
Infection
iii, Have adverse reactions to live virus immunizations
d. Treatment
I. Bone marrow transplant
ii. Gene therapy (experimental)
e. Prognosis: without treatment most infants die of infection within a year

5. Wiskott-Aldrich syndrome
a. Genetics
I. X-linked recessive inheritance
ii. Mutation in the gene for Wiskott-Aldrich syndrome protein (WASP)
b. Clinical triad
I. Recurrent infections
ii. Severe thrombocytopenia
iii. Eczema
c. Treatment: bone marrow transplant
d. Complications
I. Increased risk of lymphoma
ii. Death due to infection or hemorrhage
C. SECONDARY IMMUNE DEFICIENCY SYNDROMES
1. Systemic diseases
a. Diabetes mellitus
b. Collagen vascular disease (e.g., SLE)
c. Alcohol abuse
2. Renal transplantation
a. Patients are immunocompromised due to the immunosuppressive drugs required
to prevent rejection of the transplanted organ
b. Hyperacute rejection
I. Mediated by preformed antibodies
ii. Occurs immediately after transplantation
iii. Micro: neutrophilic vasculitis with thrombosis
c. Acute rejection
I. Occurs weeks or months after organ transplantation
ii. Abrupt onset of oliguria and azotemia
iii. Micro: neutrophilic vasculitis and interstitial lymphocytes
iv. Treated with increased doses of immunosuppressive drugs
d. Chronic rejection
I. Occurs months or years after organ transplantation
ii. Gradual onset of oliguria, hypertension (HTN), and azotemia
iii. Micro: intimal fibrosis of vessels and interstitial lymphocytes
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iv. Poor response to treatment

3. Acquired immunodeficiency syndrome (AIDS)
a. Definition: HIV positive and CD4 count <200 cells/pl. or mv positive and an AIDSdefining
disease
b. Epidemiology
I. Males> females
ii. Occurs in all ages and ethnic groups
Ill. All areas of the country are affected

c. Transmission of HIV
I. Sexual contact
-Homosexuals
-Increasing rate of heterosexual transmission
-Cofactors: herpes and syphilis
ii. Parenteral transmission
-Intravenous drug abuse (IVDA)
-Hemophiliacs
-Blood transfusions
-Accidental needle sticks in hospital workers
lll. Vertical transmission
d. Human immunodeficiency virus (HN)
I. Enveloped RNA retrovirus
ii. Reverse transcriptase
iii. HN infects CD4-positive cells
CD4+ T-cell lymphocytes
Macrophages
Lymph node follicular dendritic cells
Langerhans cells
iv. Binding of CD4 by gp 120
v. Entry into cell by fusion requires gp41 and coreceptors
• CCR5 (~-chemokine receptor 5)
• CXCR4 (a-chemokine receptor)
e. Diagnosis
I. HN antibody ELISA test
ii. Western blot confirmation
f. Monitoring
i. CD4 count
ii. HN-1 RNA viral load by PCR
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g. Treatment
I. Combination antiretroviral treatment
ii. Reverse transcriptase inhibitors

iii. Protease inhibitors

iv. Prophylaxis for opportunistic infections based on CD4 count
h. Acute phase
I. Initial infection
ii. Viremia with a reduction in CD4 count
iii. Mononucleosis-like viral symptoms and adenopathy
iv. Seroconversion
I. Latent phase
I. Asymptomatic or persistent generalized lymphadenopathy
ii. Continued viral replication in reservoir sites
iii. Low level of virus in the blood
IV. Minor opportunistic infections
. Oral thrush (Candidiasis)
. Herpes zoster
v. Average duration of latent phase: 10 years
j. Progression to AIDS
I. Reduction of CD4 count to <200 cells/ul,
ii. Reemergence of viremia
iii. AIDS-defining diseases occur
IV. Death
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k. Hairy leukoplakia: Epstein-Barr virus (EBV)-associated

l. Kaposi sarcoma
1. Common in homosexual males
ii. Associated with human herpes virus 8 (HHV8)
iii. Common sites: skin, GI tract, lymph nodes, and lungs
m. Non-Hodgkin lymphoma
i. Tend to be high-grade B-celllymphomas
ii. Extranodal CNS lymphomas are common
n. Cervical cancer
o. HIV wasting syndrome
p. AIDS nephropathy
q. AIDS dementia complex

Amyloidosis
A. DEFINITION
A group of diseases characterized by the deposition of an extracellular protein that has specific
properties
B. COMMON FEATURES OF AMYLOID
1. Individual subunits form ~-pleated sheets
2. Micro
a. Amorphous eosinophilic deposits of amyloid are seen on the H&E stain
b. The deposits stain red with the Congo red stain
c. Apple green birefringence of the amyloid is seen on the Congo red stain under
polarized light
C. COMPOSITION OF AMYLOID
1. A fibrillary protein that varies with each disease
2. Amyloid P (AP) component
3. Glycosaminoglycans (heparan sulfate)
D. SYSTEMIC TYPES OF AMYLOID
I
1. Primary amyloidosis
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a. Type of amyloid: Al,

b. Fibrillary protein: kappa or lambda light chains
c. Plasma cell disorders (multiple myeloma, B-celllymphomas, etc.)
2. Reactive systemic amyloidosis (secondary amyloidosis)
a. Type of amyloid: AA
b. Fibrillary protein: serum amyloid A (SAA)
c. SAA is an acute phase reactant produced by the liver
d. SAA is elevated with ongoing inflammation and neoplasia
e. Rheumatoid arthritis (RA), system lupus erythematosus (SLE), TB, bronchiectasis,
osteomyelitis, Crohn disease, cancer, etc.
3. Familial Mediterranean fever
a. Type of amyloid: AA
b. Fibrillary protein: serum amyloid A (SAA)

c. Autosomal recessive disease

d. Recurrent inflammation, fever, and neutrophil dysfunction
4. Hemodialysis-associated amyloidosis
a. Type of amyloid: A~2M
b. Fibrillary protein = ~2-microglobulin
c. May cause carpal tunnel syndrome and joint disease
E. lOCALIZED TYPES OF AMYLOID
1. Senile cerebral amyloidosis (Alzheimer disease)
a. Type of amyloid: A~
b. Fibrillary protein: ~-amyloid precursor protein (~APP)
c. Found in Alzhiemer plaques and in cerebral vessels
d. The gene for ~APP is located on chromosome 21
2. Senile cardiac amyloidosis
a. Type of amyloid: ATTR
b. Fibrillary protein: transthyretin
c. Men> 70 years old
d. May cause heart failure
3. Endocrine type
a. Medullary carcinoma of the thyroid (procalcitonin)
b. Adult-onset diabetes (amylin)
c. Pancreatic islet cell tumors (amylin)
F. CLINICAL FEATURES
l. Distribution of disease in systemic forms
a. Kidney
I. Most commonly involved organ
ii. Nephrotic syndrome
iii. Progressive renal failure
b. Heart
I. Restrictive cardiomyopathy
ii. Low voltage EKG
iii. Cardiac arrhythmias and CHF
c. Hepatosplenomegaly
d. Gastrointestinal tract
i. Tongue enlargement
ii. Malabsorption
ORGANS GROSS MICROSCOPY
1. KIDNEY Normal/ enlarged/ contracted Deposits in:
 155

due to ischemic narrowing of -glomeruli: initially in

vascular lumina basement membrane luminal
narrowingincrease in
permeabilityNEPHROTIC
SYNDROME
-Tubules: basement
membrane intertubular
connective tissuedegenerative
changes
2. SPLEEN -SAGO spleen : splenomegaly not -SAGO spleen : deposits begins in
marked; arterioles of white pulpreplace
C/S- translucent pale and waxy follicles
nodules resemble sago grains
-LARDACEOUS spleen: Marked -LARDACEOUS spleen: deposits
splenomegaly; in walls of splenic sinus & small
C/S – map like areas of amyloid arteries & in connective tissues
of red pulp
3. LIVER Enlarged, pale, waxy & firm -deposits in space of
Dissehepatocytesliver
shrinks
**Hepatic function remains
normal
4. HEART Enlarged,pale,translucent,waxy. Deposits in coronaries, branches,
-Epicardium, endocardium & -in primary amyloidosisRING
valves shows tiny nodular FIBRES(around myocardial fibres)
deposits or raised plaques of -localised typeLeft atrium &
amyloid interatrial septum

2. Diagnosis:
I. Biopsy of the rectal mucosa, gingiva, or the abdominal fat pad
ii. Congo red stain shows apple green birefringence under polarized light
3. Prognosis: the prognosis of systemic amyloidosis is poor

Transplant rejection
 Rejection – a phenomenon involving both cell and antibody mediated reaction
 For any tissue transplant without immunological reaction matched MHC locus antigen between donor
& recipient needed
Mechanism
- cell mediated immune reaction
cytotoxic T cells and hypersensitivity reaction initiated by T helper cells attack
antigen & destroy it.
- Humeral immune reaction
Include preformed circulating antibody
Eg; blood transfusion, previous pregnancy
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Types of rejection reaction

1. Hyper acute rejection
- Occur within minutes of placing transplant
- Mediated by humoral antibody against donor Ab
2. Acute rejection
- Within few days to few months
- mediated by cellular or humoral mechanism
3. Chronic rejection
- follow acute attacks of acute rejection or develop over months or years immunologic or
ischemic mechanism
Morphology

 Hyperacute rejection
Grossly : swollen , edematous, purple, hemorrhagic, cyanotic
Histology : - Characteristic of arthus reaction present
- Numerous neutrophills around dilated & obstructed capillaries
- Necrosis of much of the transplanted organ
 Acute cellular rejection
Histology : extensive infiltration in interstitium by lymphocyte, few plasma cells ,
monocytes & few polymorphs.
 Acute humoral rejection
- Occur due to poor response to immunosuppressive therapy.
- Consists mostly of B lymphocytes
 Chronic rejection
Histology : intimal fibrosis, interstitial fibrosis & tubular atrophy

Graft vs host reaction

 Occur when immunologically competent T cells are transplanted into recipients who are
immunologically compromised.
 It occurs mostly involving minor histocompatibility mismatch
 May also occur after transplantation of solid organs rich in lymphoid cells or after transfusion non
irradiated blood

Mechanism
T cells in donor perceive receptor as foreign
Activates CD4 + CD8 T cells
Inflammation & killing of host cells
Acute graft vs host disease

- cause epithelial cell necrosis Liver

- 3 important target organs Skin
 157

Gut
Bile duct destruction = Jaundice
Gut mucosal ulceration = Bloody diarrhea
Cutanious involvement = Generalized rashes
Chronic Graft vs host reaction

- follow acute or chronic insidiously

- skin lesions resembling systemic sclerosis
- manifestations mimicking other auto immune disorders
- graft vs host reaction minimized by HLA matching
- graft vs host reaction minimized by depleting donor T cells before marrow transplant
- but incidence of graft rejection & recurrence of leukemia increases
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FEMALE GENITAL SYSTEM

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FEMALE GENITAL SYSTEM

INTRODUCTION OF FEMALE GENITAL SYSTEM

Female genital system consists of a pair of ovaries , fallopian tubes,corpus uteri, cervix uteri and endometrium, vagina
and vulva. Various inflammatory and neoplastic changes may occur in any of the organs.

CARCINOMA ENDOMETRIUM
- Most common invasive carcinoma of FGS
- Classified ito type I and type II
 Pathogenesis-
 Type I- 80% of cases, are usually well differentiated and mimic endometrial glads, so called “endometrioid
carcinoma”. Arise from hyperplastic endometrium. Assocaited with obesity, diabetes, hypertension, infertility
and unopposed estrogenic stimulation.
 Mutations- PTEN mutations, increased signaling through PI3K/AKT pathway, KRAS activating mutation, loss of
function in ARID1A, p53
- Tumor is indolent and spreads in lymphatics
 Type II- seen more commonly in older women as compared with the risk group in type I.
 Seen to arise from atrophic endometrium. They are poorly differentiated tumors. Most common subtype is
serous carcinoma. Others are clear cell and malignant mixed mullerian.
 Mutations –p53(90%), aneuploidy, PIK3CA, FBXW7(regulator and cyclin E, MYC), CHD4(regulator of chromatin),
PPP2RIA(PP2A)

They begin as a surface epithelial neoplasm and then invades. They are aggressive and have a lymphatic and peritoneal
spread.

Malignant mixed mullerian tumors- endometrial carcinoma with malignant mesenchymal component “carcinosarcoma”.
Mutations are same as in type II endometrial carcinoma

 Morphology-
Localized polypoid tumor
 Endometrioid carcinoma- diffusely infiltrating
the endometrial lining, glandular growth
pattern Staging of endometrial carcinoma
 Serous carcinoma- large bulky deeply invasive  Stage I- confined to uterus
tumors, cells show malignant features  Stage II- involves corpus and cervix
 MMMT- bulky and polypoid, may protrude  Stage III- extends outside uterus but not
through the uterus and consists of carcinoid, true pelvis
adenoid and mesenchymal components  Stage IV- extends outside true pelvis or
involves rectum or bladder
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PREMALIGNANT LESION AND CARCINOMA IN-SITU

Premalignant lesions are a group of conditions which predispose to the subsequent development of cancer.

These conditions are characterized by morphological changes in the cells as increased N/C ratio, pleomorphism of cells
and nuclei, increased mitotic activity and poor differentiation.

 Dysplasia and carcinoma in- situ (intraepithelial neoplasia)

- Cytological atypia confined to epithelial layers above the basement membrane witjout invading the basement
membrane is called as carcinoma in-situ or intraepithelial neoplasia
- Common sites-uterine cervix, bronchus, bowen’s disease of skin, solar keratosis, oral leukoplakia, Barrett’s
oesophagus
- Carcinoma in-situ may be single, small and multifocal
- CIS may regress and return to normal or may develop into invasive cancer
e.g.- in some cervical, sequential transformation from squamous metaplasia to epithelial dysplasia to carcinoma
in- situ and eventually to invasive cancer
 Some benign tumors
- Some may become invasive
- Multiple adenomas of large intestine have slight incidence of adenocarcinoma
- Neurofibromatosis may develop into sarcoma
- Pleomorphic adenoma may sometime develop carcinoma
 Miscellaneous conditions
Certain inflammatory and hyperplastic condition are prone to development of cancer
e.g.- HPV induced chronic cervicitis has high incidence of developing cervical cancer
Liver cirrhosis may progress to hepatocellular carcinoma
H-pylori gastritis predispose to development of gastric cancer
Chronic bronchitis in heavy smokers may develop cancer of bronchus
SCC from an old burn scar

ADENOMYOSIS
 Refers to the growth of basal layer of endometrium down to the myometrium
 endometrial gland, stroma are found deep in the myometrium interposed between the muscle bundles.
 it induces reactive hypertrophy of myometrium, resulting in enlarged globular uterus often with a thickened uterine
wall.
 they don’t undergo cyclic bleeding
 marked adenomyosis may produce menorrhagia, dysmenorrhea ,pelvic pain before menstruation.
 161

CAUSE: metaplasia or estrogenic stimulation due to endocrine dysfunction of ovary.

MORPHOLOGY: Microscopy:
Gross: a) Benign endometrial glands +stroma deep within the
a) Uterus slightly or markedly enlarged. muscular layer.
b) Cut section- diffuse thickeness of uterine wall b) Minimum distance between endometrial glands
with presence of coarsely trabecular ill defines within the myometrium and the basal endometrium
areas of haemorrhages should be one low power microscopic field (2-3 mm)
for diagnosis.

ENDOMETRIOSIS
 DEFINITION:
- Presence of endometrial glands and stroma in a location outside the endometrium.
- Seen in women of reproductive years and in nearly half of women with infertility.

It often involve pelvic structures(ovaries,pouch of douglas,uterine ligaments,tubes and rectovaginal septum.

 PATHOGENESIS:  MORPHOLOGY:
a) Regurgitation theory: menstrual backflow through the a) Endometrium is functioning and undergo cyclic
fallopian tubes leads to implantation. bleeding
b) Metapalstic theory: endometrial differentiation of b) Blood collects in these aberrant foci,hence appear
coelomic epithelium as the source. grossly as red brown nodules or implants.
c) Vascular or lymphatic dissemination theory has been c) Individual lesions coalesce to form larger masses.
invoked to explain extrapelvic or intranodal implants. d) When ovaries are involved, the lesion may form
Endometrial tissue exhibits increased levels of inflammatory large blood filled cyst that form brown(chocolate)
mediators ,particularly PGE2 and increased estrogen cyst.
production due to high aromatase activity of stromal cells.

Teratomas
- Tumour of ovary
- composed of different types of tissues derived from the three germ cell layers—ectoderm, mesoderm and
endoderm, in different combinations
- Tumours arise from a single germ cell (ovum) after its first meiotic division.
3 types:
- mature (benign),
- immature (malignant), and
- monodermal or highly specialised teratomas
MATURE (BENIGN) TERATOMA. dermoid IMMATURE (MALIGNANT) MONODERMAL
cyst. TERATOMA. (SPECIALISED) TERATOMA.

- majority of ovarian teratomas rare -0.2% of all ovarian tumours. rare

benign and cystic solid tumours 2 important examples—
predominantly ectodermal elements contain immature or struma ovarii and
- more frequent in young women embryonal structures carcinoid tumour.
during their active reproductive life. They are more common
- The tumour is bilateral in 10% of in prepubertal adolescents and young
cases. women under 20 years
 162

of age.

Gross Gross Struma ovarii.

- unilocular cyst, - unilateral solid mass teratoma composed
- lined by the skin exclusively
(hence called dermoid). - cut section of thyroid tissue.
variegated appearance areas of  Gross:-
C/S:- haemorrhages, necrosis, tiny cysts and follicular adenoma of the
- the cyst filled with paste-like heterogeneous admixture of various thyroid.
sebaceous secretions and tissue elements. Rarely, struma ovarii
desquamated keratin admixed with may be hyperfunctioning
masses of hair. and produce
- The cyst wall is thin and opaque hyperthyroidism.
grey-white.
- Generally, in one area of the cyst
wall, a solid prominence is seen
(Rokitansky’s protuberance) where
tissue elements
such as tooth, bone, cartilage and various
other odd tissues
are present. Less often, the cyst may
contain mucoid material.
 Microscopically,  Microscopically  Carcinoid tumour.
teratoma arising
- Lining by stratified squamous - composed of immature tissues from argentaffin cells of
epithelium adnexal structures such containing hair, pultaceous material intestinal epithelium in the
as sebaceous glands, sweat glands and bony tissue having an embryonic teratoma.
and hair follicles (Fig. 24.27). appearance. hyperfunction and
- ectodermal, produce 5-HT and
endodermal,mesodermal elements - Immature tissue consequent carcinoid
are present elements may differentiate towards syndrome.
- other tissue components cartilage, bone,
found in teratomas are bronchus, glandular structures, neural tissue etc, Struma-carcinoid is a rare
intestinal epithelium, and are distributed combination of struma
cartilage, bone, tooth, smooth muscle, in spindle-shaped myxoid or ovarii and ovarian carcinoid.
neural tissue, undifferentiated sarcoma
salivary gland, retina, pancreas and cell.
thyroid tissue.  grading and determining : the
Thu kaleidoscopic patterns. prognosis of immature teratoma is
Less than 1% of patients with a dermoid the relative amount of immature
cyst neural tissue. Immature neural
malignant transformation of one of the tissue can undergo maturation
tissue components, even at the site of metastases
most commonly squamous cell over a period of years. Immature
carcinoma. teratoma may contain areas of
other germ cell tumours such as
endodermal sinus tumour,
embryonal carcinoma and
choriocarcinoma.
 163

- Grade I tumours: having

relatively mature elements and
confined to the ovary have a good
prognosis,
- Grade III immature teratomas:
having metastases ability
extremely
Have poor prognosis.

KRUKENBERG TUMOR
- About 20%clinically malignant ovarian tumors are secondaries.
- 2 types of secondaries – first where growth corresponds with the primary growth in histology and second is
krukenberg tumor.
- KRUKENBERG is diagnosed if it follows the following pattern:-
- Almost always bilateral.
- Smooth, slightly bossed surface, freely movable in the pelvis.
- No adhesion to surrounding viscera and no capsular infiltration.
- Tumour retains the shape of ovary
- 70% are secondaries from stomach, 15% large bowel, 6% breast
- Krukenberg outstrip the primary tumor in size, tumor is freely movable, tumor almost certainly arises by retrograde
lymphatic spread.
- In CA stomach carcinoma cells passes through superior gastric lymphatic glands, which also receives lymphatics
from ovary.
- HISTOLOGY:-
- Cellular and myxomatous stroma amongst which are signet ring cells.

Cervical carcinoma
a. Epidemiology
1. Third most common malignant tumor of the lower
female genital tract in
United States
11. Peak incidence in the 40s
b. Risk factors
1. Early age of first intercourse
11. Multiple sexual partners
111. Multiple pregnancies
lV. Oral contraceptive use
v. Smoking
V1. STDs
vii. Immunosuppresion
c. HPV
i. High-risk types 16, 18,31, and 33
ii. Viral oncogenes E6 (binds to p53) and E7 (binds to Rb)
d. Precursor lesion: cervical intraepithelial neoplasia (eIN)
1. Increasing in incidence
11. Occurs commonly at the squamocolumnar junction (transformation zone)
lll. Progression
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-CIN I (mild dysplasia)

-CIN II (moderate dysplasia)
-CIN III (severe dysplasia)
-CIS (carcinoma in situ)
-Invasive squamous-cell carcinoma
e. Clinical presentation
1. Asymptomatic
11. Postcoital vaginal bleeding
iii. Dyspareunia
IV. Malodorous discharge
f. Diagnosis
i. Papanicolaou (Pap) smear: early detection
ii. Colposcopy with biopsy

Leiomyoma (fibroids)
a. Most common tnmor of the female genital tract
b. Benign smooth muscle tumor of the myometrium
c. High incidence in African Americans
d. Responsive to estrogen
e. Gross
1. Well circumscribed, rubbery, white-tan masses
ii. Whorl-like trabeculated appearance on cut section
lll. Commonly multiple
f. Locations: subserosal, intramural, and submucosal
g. Clinical presentation
i. Menorrhagia
11. Abdominal mass
Ill. Pelvic pain, back pain, or suprapubic discomfort
IV. Infertility
h. Malignant variant: leiomyosarcoma
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GESTATIONAL TROPHOBLASTIC DISEASE

1. Hydatidiform mole (molar pregnancy)
a. Definition: tumor of placental trophoblastic tissue
1. Complete mole: results from fertilization of an ovum that lost all its chromosomal material
- All chromosomal material is derived from sperm
-90% of the time, the molar karyotype is 46,XX
-10% of the time, the molar karyotype includes a Y chromosome
-The embryo does not develop
ii. Partial mole: results from fertilization of an ovum that has not lost its chromosomal material by two
sperms, one 23,X and one 23,Y
-This results in a triploid cell 69, XXY (23,X [maternal] + 23X [one sperm]
+23Y [the other sperm])
-The embryo may develop for a few weeks
b. Incidence
1. United States: 1 per 1,000 pregnancies
11. Asia> United States
lll. Increased risk in women ages <15 and >40
c. Clinical presentation
1. Excessive uterine enlargement -7 "size greater than dates"
ii. Vaginal bleeding
iii. Passage of edematous, grapelike soft tissue
iv. Elevated beta-human chorionic gonadotropin (~-HCG)
d. Micro
1. Edematous chorionic villi
11. Trophoblast proliferation
lll. Fetal tissue (only in partial mole)
e. Diagnosis: ultrasound
f. Treatment: endometrial curettage and follow ~-HCG levels

Classification of ovarian tumour

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 167

CENTRAL NERVOUS SYSTEM

 168

CSF FINDINGS IN TB, PYOGENIC AND VIRAL MENINGITIS.

( refer pathology record)

PRION DISEASE

 Transmitted by altered form of a normal cellular protein

 They can be sporadic, transmitted or inherited
 Includes – crutzfeldt- Jacob d/s
- animal d/s such as scarpi ( in sheep), bivine spongiform encephalopathy ( In
Cattle-mad cow d/s)

Pathogenesis
 Agent : abnormal form of a cellular protein
 This protein called prion protein (PrP) undergoes a conformational change from normal shape to abnormal
form called PrPsc ( has high content of β sheets), which are resistant to proteolysis
( robbins fig; 22-21)
 PrPsc molecule interact with PrP induce them to adopt PrPsc conformation
 PrPc may also change its conformations spontaniously sporadic cases of prions
 Accumulation of PrPsc in neural tissue seems to be the casus of cell injury

Creutzfeldt – Jacob d/s – spongiform encephalopathy

- Majority of cases occur sporadically

- Familial predisposition with AD inheritance reported in 5-15% cases
- Clinically characterized by rapidly progressive dementia with prominent association of myoclonus
 MORPHOLOGY
 Gross :  Microscopy
- changes are too rapid to Spongiforn change : ie, small round vacoulation in neuronal cells
become notable - Changes mainly seen in cortex and other grey matter areas
- benign atrophy seen in long - Neuronal loss of glial cell proliferation results with out any
standing cases inflammation or grey matter involvement

ASTROCYTOMA
-Most common type of glioma Site:
-Peak at 6th decade - cerebral hemisphere
- spinal cord(occasionally)
 Diagnosis: H&E morphology, immunohistochemistry with GFAP
(pilocytic astrocytoma-optic
 Molecular abnormality nerve,cerebellum,brain stem)
Low grade-over expression of PDGF-α,mutation of p53
 169

High grade-mutation of Rb gene,p53

 Morphology
- 3 progressive histological grade- fibrillary, gemistocytic & protoplasmic

GRADE 1/diffuse GRADE 2 GRADE 3 GRADE 4

astrocytoma /well /anaplastic /glioblastoma multiforme
differentiated/fibrillary astrocytoma
Low grade tumour with Poorly defined, greyish All features of Origin - embryonal cells like but
good prognosis white, distorts anaplasia neoplastic transformation of mature
May be underlying tissue +proliferation of astrocytes
1) juvenile pilocytic Histologically 3 types - vascular Gross:
astrocytoma fibrillary, protoplasmic, endothelium - Varriegated appearance,brain
2) Pleomorphic gemistocytic tissue infiltration by tumour
xanthroastocytoma Histology:
- Highly anaplastic
cells,pseudopallisading,microvas
cular proliferation

Brain abscess
- bacterial infection

 Spread:

- direct implantation of organism

- local extension from adjacent foci

- hematogenous

 Predisposing condition:

- acute bacterial endicarditis ->emboli -> abscess

- cyanotic congenital heart disease->right to left shunt=>loss of pulmonary filtration of organism.

- chromic pulmonary infection

 Biochemical profile:

CSF white count increased , Protein level increased and Glucose level normal.

Complication: Abscess rupture-> ventriculitis, meningitis,venous sinus thrombosis

Treatment:

- Earlier intervention needed

- Surgery
- Antibiotics
-  Morphology:
 170

Gross: Microscopy: necrotic centre, surrounded by edema and

discrete lesion.Central liquefactive necrosis generation tissue, exuberant vascularization, fibrous capsule
surrounded by fibrous capsule. (zone of reactive gliosis)

SCHWANNOMAS (NEURILEMMMOMAS)
- Benign Tumors of the peripheral nerve,
- Arises from cranial and spinal nerve roots (acoustic neuroma/schwannoma, intraspinal neuromas)

In peripheral nerves, occurs as solitary nodule on any sheathed sensory, motor and autonomic nerve.

Multiple schwannoma uncommon

 Morphology-

GROSS: Microscopy-
An encapsulated, solid, sometimes Tumor composed of fibrocellular bundles in whored pattern
cystic tumor that produces eccentric There are areas of denser compact cellularity (Antoni A areas) and
enlargement of the nerve root from alternating with loose acellular areas (Antoni B areas)
which they arise Antoni A areas show palisaded nuclei called verocay bodies.
Express S-100 protein
Areas of degeneration present.

MENINGIOMA
Arise from the cap cell layer of arachnoid.
Site- front half of head including lateral cerebral convexity,falx cerebri,olfactory groove
Age- 2nd to 6th decade of life
Solitary(if associated with neurofibromatosis 2 ,is multiple)
Cytogenic abnormality: Deletion of chromosome 22q(NFII gene,Merlin protein)

Morphology

Gross: Histology
- well circumscribed Microscopically 5 sub type
- solid 1) meningiotheliomatous(syncitial)meningioma
- spherical mass Solid mass of polygonal cell with poorly defined cell membrane
- size varies(1-10cm) Round central nucleus ,highly granular cytoplasm
- Firm attachment with dura matter 2) Fibrous/fibroblastic
- Indents surface of brain-no invasion Spinfdle shaped tumour cells in interlacing bundles
3) Transitional/mixed
Cut surface-firm and fibrous,shows foci of
Combination of cells with fibroblastic and syncitial whorled
calcification
pattern around central blood vessel.
Psammoma bodies in some whorls.
Xanthomatous &myxomatous degeneration may be seen.
4) Angioblastic meningioma
 171

2 patterns high rate of recurrence

a) Hemangioblastic
b) Hemangiopericytic
5) Anaplastic or malignant
Rare ,invasion of brain and spinal cord,extraneural metstasis
mainly to lung

CLASSIFICATION OF INTRACRANIAL TUMOURS

I.TUMOURS OF NEUROGLIA(GLIOMAS)
1.Astrocytoma
2.Oligodendroglioma
3.Ependymoma
4.Choroid plexus papilloma
II.TUMOURS OF NEURONS
1.Neuroblastoma
2.Ganglioneuroblastoma
3.Ganglioneuroma
III.TUMOURS OF NEURONS AND NEUROGLIA
1.Ganglioglioma
IV.POORLY- DIFFERENTIATED AND EMBRYONAL TUMOURS
1.Medulloblastoma
2.Neuroblastoma
3PNET
V.TUMOURS OF MENINGES
1.Meningioma
2.Meningeal sarcoma
VI. NERVE SHEATH TUMOURS
1.Schwannoma(neurilemmoma)
2.Neurofibroma
3.Malignant nerve sheath tumour
VII.OTHER PRIMARY INTRAPARENCYMAL TUMOURS
1.Haemangioblastoma
2.Primary CNS lymphoma
3.Germ cell tumours
VIII.MISCELLANEOUS TUMOURS
1.Malignant melanoma
2.Craniopharyngioma
3.Pineal cel tumours
4.Pituitary tumours
IX.TUMOUR-LIKE LESIONS
(Epidermal cyst,dermoid cyst,colloid cyst)
X. METASTATIC TUMOURS
 172

RENAL SYSTEM
 173

RENAL SYSTEM
1.CHRONIC GLOMERULONEPHRITIS

- End stage of many glomerular diseases

- Causes progressive and irreversible impairment of renal function resulting in chronic renal failure.

=> CAUSES
MORPHOLOGY Rapidly progressive glomerulonephritis.
Gross Membranous GN.
 kidneys are small and symmetrically Membranoproliferative GN.
contracted. Focal segmental glomerulosclerosis.
 Surfaces are red brown and diffusely IgA nephropathy.
granular. A/c post streptococcal GN.
 Cut section shows narrow and atrophic Idiopathic.
cortex.
1)RAPIDLY PROGRESSIVE GN:
Microscopy
( RPGN, Crescentic GN, extra capillary GN)
 Glomeruli reduced in number and show
hyalinised tuffs. - Characterized by formation of crescents ( Crescentic
 Advanced scarring of glomeruli to GN) outside the glomerular capillaries ( extra capillary Gn)
complete sclerosis. - Crescents are formed from proliferation of parietal
 Marked interstitial fibrosis with epithelial cells lining bowman’s capsule with contribution from
lymphocytic infiltrates in the fibrotic
interstitium.
vesicle epithelial cells and invading mono nuclear cells
 Tubular atrophy and loss tubular cells - Stimulus for crescent formation: presence of fibrin in
show hyaline droplets ad lumina capsular space.
contain eosinophlic homogenous casts.
 Arterial and arteriolar sclerosis
following hypertension

Etiopathogenesis and distinguishing features of 3 main

categories of a RPGN ( Harshmohan table 20.10)

Clinical features
- Similar to a/c GN, presenting as a/c renal failure
- Pts of good pasture syndrome present as a/c renal failure/
associated intra pulmonary hemorrhage producing recurrent hemoptysis
- Prognosis – poor for all types of RPGN

Morphological features Light:

Gross: --kidneys area I. Glomeruli
enlarged, pale white with Pathognomonic crescent on the inside of Bowman’s
smooth outer surface capsule
--cut surface have pale - They are collection of pale white staining polygonal cells
cortex and congested medulla - Crescents obliterate bowman’s space compress glomerular tuft
- Fibrin deposition invariably present alongside crescents
 174

- Increased cellularity due to proliferation of endothelial cells and

mesangial cells and leukocyte infiltration
- Fibrin thrombi frequently present
II. Tubules
- Hyaline dropelets
- Tubular lumen may contain casts, rbc, and fibrin
III. Interstitium
- Edematous
- Show early fibrosis
- Inflammatory cells( lymphocyte, plasma cells)
IV. v/s
- arteries and arterioles have no change
Electron mc: vary according to type of RPGN
Post infectious RPGN is electron dense suepithelial
granular deposit similar to those seen in a/c GN

2)FOCAL SEGMENTAL GLOMERULAR SCLEROSIS: PATHOGENESIS:

 Injury to podocyte may occur due
- Sclerosis affecting segments of some Glomeruli
to:
- 10% of nephrotic syndrome - Circulating cytokines
- 50% of patient develop renal failure - Inherent injury – due to
- Not respond to corticosteroids mutation to glomeruli
- Incidence of hematuria & HTN more  These leads to podocyte epithelium
- Non selective proteinuria detachment from basement
membrane  Increased passage of
Sec causes : HIV, IgA neohropathy, sickle cell anemia, Heroin proteins to filtrate 
abuse, mal adaptation to nephron loss o Stimulate hyalinosis and
sclerosis of capillary wall

o Complete occlusion of
Electron microscopy  podocytes shows effacement of foot
vessels
process
FSGS progresses to MORPHOLOGY:
1. Global sclerosis - Focal and segmental sclerosis
Obliteration of vessels
2. Tubular atrophy
- In immunoflurescence  IgM and
3. Interstitial fibrosis compliment deposition
- The affected Glomeruli exhibit
Morphological variant – collapsing glomerulopathy
Increase of mesangial matrix
Obliterated capillary lumina
Deposition of hyaline masses
Lipid droplets

3)IgA NEUROPATHY:
 175

(Berger’s disease, IgA glomerulonephritis)

Most common, characterised by aggregates of IgA,

deposited principally in mesangium. PATHOGENESIS:
MORPHOLOGIC FEAURES: 1. Entrapment of Ig A immune complexes
in mesangium.
By light microscopy- focal proliferative GN, focal 2. Presence of C3 and properdin but
segmental glomerlosclerosis, absence of early components of
membranoproliferative GN and rarely RPGN. complement which point
Electron microscopy- finely granular electron- towardsactivation of alternate
dense deposits are seen in mesangium. complement pathway.
Immunofluroscence microscopy- diagnosis by 3. Due to close association between
measngial deposits of IgA. mucosal infection,it is suggested that Ig A
deposited in the mesangium could bedue
to increased mucosal secretion of IgA
4. HLA-B35 association has been reported.
Idiopathic 5. Genetically determined abnormality of
immune system producing circulating IgA
Part of henoch-Schonlein purpura
in increased amounts.
Association with chronic inflammation in
various body septum.(eg: chronic liver disease , IBD, leprosy, etc)

CLINICAL FEATURES:
Common in children and young adults.
Characterised by recurrent bouts of hematuria and precipaitated by mucosal infections

NEPHROTIC SYNDROME
CAUSES
- persistent and heavy proteinuria + 1. PRIMARY GLOMERULONEPHRITIS
hypoalbuminemia => causing decreased plasma - Minimal change disease(in children
common)
oncotic pressure.
- Membranous GN( common in adults)
Features are: - Membranoproliferative GN
- Focal segmented glomerulosclerosis
1. Heavy proteinuria - loss of protein of more - Focal and diffuse proliferative GN
than 3 gm/24 hours. Excess protein is filtered - Ig A nephropathy
out exceeding the capacity of tubules for
reabsorption and therefore appear in urine, 2. SYSTEMIC DISEASE
- Diabetes mellitus
feature of protein loss is its selectivity.
- Amylodosis
2. Hypoalbumnemia : due to urinary loss of - SLE
albumin and due to increased catabolism and
inadequate hepatic synthesis of albumin.
 176

Concentration of other protein in plasma such as immunoglobulin, clotting factors and antithrombin
may fall and lead to complications.
3. Edema- due to fall in colloid osmotic pressure consequently upon hypoalbuminemia. Sodium and
water retention also contribute.
4. Hperlipidemia- it is hypothesised that liver faced with stress of massive protein synthesis in reponse to
heavy urinary protein loss causes increased synthesis of lipoproteins.
5. Lipidemia- following hyperlipidemia due to excessive leakness of glomerular filtration barrier.
6. Hypercoagulabilty – due to increased urinary loss of antithrombin III, hyperfibrinogenemia, decreased
fibrinolysis,etc, patient develops spontaneous arterial or venous thrombosis.

HYDRONEPHROSIS
- Dilation of renal pelvis and calyxes due to partial or indermittent obstruction to the outflow of urine.
- Main causes- one or both pelviuretric sphincter are incompetent.
- Causes:
- intraluminal
-intramural
-extramural

- 2 types- unilateral and bilateral.

 Unilateral hydronephrosis:
Occurs due to ureteral obstruction at level of pelviuretric junction (PUJ)

 Bilateral hydroneprosis:
Occurs due to urethral obstruction mainly, or when above causes involves both sides can be longitudinal or
acquired.
Gross: Microscopy:
Moderately to markedly enlarged kidney . - Wall of hydronephrostic sac is
2 stages: thickened due to fibrous
- Extrarenal hydronephrosis. scarring and c/c inflammatory
- Intrarenal hydronephrosis
infiltrate.
- Extrarenal hydronephrosis:-
- Atrophy of tubules and
characterised by dilation of renal pelvis
medially in form of sac. Glomeruli.
- Interstitial fibrosis.
Progressive dilatation of pelvis and calyx.

Dilatation extends deep into renal cortex INTERNAL

HYDRONEPHROSIS

external surface assumes lobulated appearance

PYELONEPHRITIS
Tubulointerstitial nephritis affecting interstitium and tubules – caused by bacterial infection - renal pelvis mainly
involved.
 177

2 types – acute and chronic.

 Acute pyelonephritis
Acute suppurative inflammation of kidney –caused by pyogenic bacteria- staphylococcus, E coli etc

 PATHOGENESIS:
2 routes of entry into kidney - blood stream and lower urinary tract.

MORPHOLOGY:
Gross:
Enlarged and swollen kidney.
Cut surface show small,yellow white abscesses.

Microscopy:
Inflammation involving interstitium and destruction of tubules.
neutrophils in interstitial tissue.

COMPLICATIONS:

Papillary necrosis , pylonephrosis , perinephric abscess.

 Chronic pyelonephritis:
Chronic tuberculo-interstitial disease due to repeated interstitial inflammation and scarring- deformity of pelvicalyceal
system.
2 types:
- chronic obstructive pyelonephritis
- Reflux nephropathy
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MORPHOLOGY:
Gross:
a) Small and contracted kidney
b) Surface irregularly scarred
c) U shaped depressions on cortical surface- dilatation of calyces and pelvis
MICROSCOPY:
a) Interstitial fibrosis and inflammatory infiltrate of lymphocytes, plasma cells and neutrophils
b) dilatation of tubules with eosinophilic colloid casts
c) dilated renal pelvis and calyces
d) hyaline arteriosclerosis.

Chronic obstructive pyelonephritis:

Urinary tract obstruction- backflow of urine- infection of pappilae- diffuse uneven scarring and thickened capsule.

Reflux nephropathy:
Vesicouretric reflux cause infectionof peripheral papillae and scars at poles of kidney.

DIABETIC NEPHROPATHY
 An important compication of diabetes
 Death can occur due to renal failure

4 types of lesions Diabetic glomerulosclerosis(glomerular lesions)

Vascular lesions
Diabetic pyelonephritis
Tubular lesions

 PATHOGENESIS OF GLOMERULOSCLEROSIS

Diabetes hyperglycemia glomerular hypertension renal hyperperfusoin deposition of proteins in mesangium

glomerulosclerosis renal failure

=>MORPHOLOGY
1.DIABETIC GLOMERULOSCLEROSIS (diag)

2.VASCUlAR LESION
 Renal atherosclerosis(atheroma) and arteriosclerosis
 Hyaline areteriosclerosis in afferent and efferent arterioles
 Causes renal ischemia leading to tubular atrophy and interstitial fibrosis and results in small contracted kidney

3. DAIBETIC PYELLONEPHRITIS
 Chronic pyelonephritis is more common in diabetes
 Papillary necrosis(necrotising papillitis ) is an important complication in acute pyelonephritis

4. TUBULAR LESION (ARMANI EBSTEIN LESIONS)

 In untreated diabetes who have high blood dugar levels the epithelial cells of PCT develop extensive glycogen
deposits appearing as vacuoles.
 179

MINIMAL CHANGE DISEASE

- Or lipoid nephrosis or foot process disease or nil deposit disease
- Nephritic syndrome with no apparent change in glomeruli by light microscopy(minimal)
 Etiology-idiopathic/associated with systemic diseases like Hodgkin’s disease, HIV infection/ drugs like
NSAID,interferons,rifampicin.
 MORPHOLOGY:

Grossly- By Light microscopy:

- kidneys are of normal size and shape - glomeruli – normal except for slight in mesangail matrix(minimal
change disease)
- Tubules- presence of fine lipid vacualtions and hyaline droplets in
PCT
Interstitium- edemaous
- Vessels- no change
- By electron microscopy- no deposit in GBM but diffuse of foot
process of visceral epithelial cells or podocytes.(foot process
disease)
- By immunomicroscopy- no deposit of compliments

 CLINICALLY- fully developed nephrotic syndrome with massive and highly selective proteinuria , no hypertension
and preceded by URTI , actopic allergy, immunization

In children <16 years(peak at 6-8 years)

In children characterised by selective proteinuria

In adults non selective proteinuria.Therefore, exclusive membrane permeability defect.

Respond to steroid therapy.

WILM’S TUMOUR(NEPHROBLASTOMA)
- Its an Embryonic tumour derived from primitive renal epithelial and mesenchymal components.
- Most common abdominal malignant tumour of young children , seen most commonly between 1-6 years of age with
equal sex incidence.

=> ETIOLOGY AND PATHOGENESIS

- Defect in chromosome 11p 13 abdominal growth of metanephric blastema (without

differentiation ) into normal tubules and Glomeruli
- Seen in monozygotic twins and positive family history
- Congenital anomalies especially of genitourinary tract
- Seen in few other malignancies – higher incidence of Wilms tumour. These include
osteosarcoma, botyroid sarcoma, retinoblastoma, neuroblastoma
 MORPHOLOGY

Gross: -Large, spheriodal, replace most of the kidney

-Solitary and unilateral
-5-10% - bilateral
- Invasion into renal vein is grossly evident in half
the cases.
 180

Cut section -variegated appearance

- fish-flesh appearance
-grey white to cream yellow tumour
-with foci of necrosis and haemorrhage and
- grossly identifiable myxomatous or
cartilaginous elements.

Microscopically -Mixture of primitive epithelial and

mesenchymal elements.
-Consists of small , round to spindled, anaplastic ,
sarcomatoid tumour cells.
-Mesenchymal elements such as smooth and
skeletal muscle, cartilage and bone, fat cells and
fibrous tissue , may be seen.

CLINICAL FEATURES Palpable abdominal mass in a child

Haematuria
Pain
Fever
Hypertension
SPREAD blood especially to lungs
PROGNOSIS With combination therapy of nephrectomy , post
operative iirardiation and chemotherapy has
improved considerably and the 5 year survival
now is 80-90 %
 181

RENAL CELL CARCINOMA

INTRODUCTION (RCC) is an adenocarcinoma arising from tubular epithelium.
70 to 80% of all renal cancers
Age:-50 to 70 years most commonly occur in
Sex: males
ETIOLOGY AND Tobacco -is the major risk factor for RCC, (chewed or smoked )
PATHOGENESIS -accounts for 20-30% cases of RCC.
-Cigarette smokers have two-fold higher risk of developing RCC.

Genetic -hereditary and first degree relatives of RCC are at higher risk
factors -majority of cases are sporadic but about 5 % cases are inherited. These cases
have following associations:
1)von Hippel-Lindau Hereditary clear iii) Papillary iv)
(VHL) disease: cell RCC: RCC Chromophobe
RCC:

-VHL gene is a tumour -clear cell type bilateral and genetic defects
suppressor gene located RCC multifocal in the form of
on chromosome 3p . -confined to cancer with multiple losses
-Germ line mutation of the kidney papillary of whole
VHL leads to VHL - without other growth chromosomes
disease. manifestations pattern. i.e. they have
of VHL Genetic extreme degree
-Autosomal dominant -but having abnormality in of hypodiploidy.
cancer autosomal these cases
-Syndrome includes dominant lies in MET
1.Haemangioblastoma inheritance gene located
of the cerebellum, on
2 .retinal angiomas, chromosome
3.multiple RCC(clear cell 7.
type),
4.pheochromocytoma
and cysts in different
organs

- About 35% cases of

VHL develop RCC

3.Cystic Patients on longterm dialysis acquired cystic disease RCC and

disease adenomas.
of the Adult polycystic kidney disease and multicystic nephroma papillary
kidneys RCC.
4.Other i) Exposure to asbestos, heavy metals and petrochemical
risk products.
factors ii) In women, obesity and oestrogen therapy.
iii) Analgesic nephropathy.
v) Tuberous sclerosis.
 182

CLASSIFICATION

GROSS -arises from the poles of the kidney

(more often in the upper pole)
-solitary and unilateral tumour.
( About 1% RCC are bilateral.)
-Tumour:-
i)large,
ii)golden yellow
iii)and circumscribed.
-Papillary tumours have
i) papilla
ii) and may be multifocal.

Cut section of the tumour :-

i)large areas of ischaemic necrosis,
ii)cystic change and foci of haemorrhages.

Another significant characteristic is the frequent

presence of tumour thrombus in the renal vein which may
extend into the vena cava.
HISTOLOGY Clear cell type RCC(70%) -most common pattern.
-clear cytoplasm of tumour cells due to removal of
glycogen and lipid from the cytoplasm during processing of
tissues.
-The tumour cells have a variety of patterns:
solid, trabecular and tubular, separated by delicate
vasculature.
-Majority of clear cell tumours are well differentiated.
 183

Papillary cell type RCC(15%) -The tumour cells are arranged in papillary pattern over the
fibrovascular stalks.
-The tumour cells are cuboidal with small round nuclei.
-Psammoma bodies may be seen.
Granular cell type RCC(8%) -The tumour cells have abundant acidophilic cytoplasm. --
These tumours have more marked nuclear pleomorphism,
hyperchromatism and cellular atypia.
Chrmophobe type RCC(5%) - pale clear cells + perinuclear halo+acidophilic granular
cells.
-The cytoplasm of these tumour cells contains many
vesicles.
Sarcomatoid type RCC(1.5%) - most anaplastic and poorly differentiated form.
- The tumour is characterised by whorls of atypical spindle
tumour cells.
Collecting duct type -This is a rare type that occurs in the medulla.
RCC(0.5%) -It is composed of a single layer of cuboidal tumour cells
arranged in tubular and papillary pattern.
CLINICAL 1. Slow growing tumour
FEATURES 2. Gross haematuria+flank pain+ palpable abdominal mass(classical evidence)
3. By the time the tumour is been detected it has spread to distant sited via blood to
the lungs, brain, and bone and locally to liver and perirenal lymph nodes.
4. Systemic symptoms of fatiguability, weight loss, cachexia and intermittent fever
unassociated with evidence of infection are found in many cases at presentation.
5. Paraneoplastic syndrome due to ectopic hormoine production by the tumour
cells.These include :-
i)polycythaemia (by erythropoietin),
ii)hypercalcaemia(by parathyroid hormone and prostaglandins),
iii)hypertension (by renin),
iv)effects of feminisation or masculinisation(by gonadotropins) and
v)Cushing’s syndrome (by glucocorticoids).

PROGNOSIS -depends upon the extent of tumour involvement at the time of diagnosis.
-The overall 5-year survival rate is about 70%.
-Presence of metastases, renal vein invasion and higher nuclear grade of the tumour are
some of the predictors of poor prognosis.
 184

POLYCYSTIC KIDNEY DISEASE

Disorder in which major portion of the renal parenchyma is converted into cysts of varying size.
Two forms:-
1. Adult type inherited as Autosomal dominant disease
2. Infantile type inherited as Autosomal recessive disorder.

FEATURES ADULT PKD INFANTILE PKD

INHERITANCE Autosomal dominant disease Autosomal recessive
MUTATION PKD gene Chromosome 6
i)PKD-1 gene located in
chromosome 16 in over 85%
ii)PKD-2 gene located in
chromosome 4 in 15%.

FAMILY HISTORY OF SIMILAR present. Not present

DISEASE
FREQUENCY Relatively common Less common
CLINICAL FEATURES
Age of presentation Adults (3rd to 5th decade) Infancy ,perinatal
Presenting feature 1.Dull-ache in the lumbar regions 1.Depends upon the age of the
2.Haematuria or passage child
of blood clots in urine, 2.In severe form:-difficulty in
3.Renal colic, delivery
4.Hypertension, 3. In infancy:-
5.Urinary tract infections Early renal failure.
6.progressive CRF with polyuria associated multiple
and proteinuria. epithelium-lined cysts in the
liver or proliferation of portal
bile ductules.
4. In older children:-
congenital hepatic fibrosis
portal hypertension and
splenomegaly.
COMPLICATION End stage renal failure in 4% of result in death from renal
hemodialysis patients failure in early childhood.
GROSS -Always bilaterally enlarged -bilaterally enlarged
-Symmetrical and Heavy -normal reniform shape
-Lobulated appearance due to - smooth external surface.
cysts

Cut surface- Cut surface –

-Cysts throughout the renal -sponge-like appearance
parenchyma varying in size (tiny small,fusiform or cylindrical
cysts to 4-5 cm in diameter) cysts radiating from the
-Content of the cyst:- medulla and extend radially to
Vary from straw- yellow fluid to the outer cortex.
reddish brown material. No normal renal parenchyma is
Renal pelvis and calyces- distorted grossly recognised.
 185

by the cysts and may contain Pelvis, calyces and ureters are
concretions. normal.
Cyst do not communicate with the
pelvis of the kidney-(distinguishing
feature from hydronephrosis)

MICROSCOPY Dilated cyst collecting tubules show

Renal cystic dysplasia. cylindrical or saccular
Cysts lined by flattened dilatations and are lined by
epithelium while the intervening cuboidal to low columnar
parenchyma cosists of primitive epithelium. Many of the
mesenchyme and cartilage. glomeruli are also cystically
dilated.
 186

SKIN
 187

INTRODUCTION
- Skin is the largest organ in body composed of 2 layers-epidermis and dermis.

Epidermis-formed by keratinocytes, melanocytes, langerhan cells indeterminate

dendritic cells, merkel cells

Dermis-made of collagen

Subcutaneous tissue/subcutis/fatty panniculus - composed of lobules of fat cells/

lipocytes

All skin sites are composed of these three layers, though thickness varies. Epidermis is thickest at plams and soles.
Dermis thickest in back and subcutaneous fat generously on abdomen.

Epidermis may be divided into the following zones- beginning with innermost layer- Stratum basale, stratum spinosum,
granular and corneum.

Functions of skin:-

1. Mechanical barrier
2. Restriction of water loss
3. Providing an innate immune response
4. Thermoregulation
5. Melanin provides protection against DNA damage from UV rays
1- SQUAMOUS CELL CARCINOMA
- Malignant tumour

CAUSES PATHOGENESIS LOCATIONS

-Prolonged exposure to sun DNA damage -face,pinna,back of hands
-immunosuppression -mucocutaneous junction lips
P53 mutation deregulation and canal, glans penis etc.
of signalling pathway (any region of skin / mucous
membrane of skin lined by
squamous epithelium.)

-PREDISPOSING CONDITIONS

- xeroderma pigmentosa
-Epidermodysplasia verruciformis
-Solar keratosis
-Chronic infective condition-chronic ulcer
-draining osteomyelitis
-psoriasis
-MORPHOLOGY
 188

Gross Microscopy
2 patterns
Common- ulcerated growth
-elevated + indurated margin
Less common- raised fungating/polypoid
verrucous lesion without
ulceration

VARIANTS

a. Spindle cell carcinoma(spindle shaped tumour)

b. Adenoid squamous cell carcinoma
c. Verrucous carcinoma (Ackerman tumour)
2- Basal cell carcinoma (Rodent ulcer)
- Locally invasive, slow growing tumor of middle age
- Metastasis rarely
- Common location – face (usually above a line from the lobe of the ear to the corner of mouth)
 Predisposing factors  Pathogenesis
a. Light – skinned people who have little melanin Inherited defect in PTCH gene on chromosome 9
b. Prolonged exposure to strong sunlight ( a tumor suppressor gene)
c. Inherited defect in DNA repair mechanism
(in xeroderma pigmentosum) Dysregulation of Hedgehog pathway
d. Nevoid basal cell carcinoma syndrome.

 Morphology
 Gross:-  Histology:-
- Pearly papules often with prominent, dilated sub epidermal - Proliferation of basaloid cells .
blood vessels(telengectasia) - Irregular masses of basaloid cells
- Most common pattern – Nodulo-ulcerative basal cell carcinoma growing downward into the
( slow growing small nodule undergoes central ulceration with dermis with characteristic
pearly rolled margin_ peripheral palisade appearance
- Other variants of the nuclei.
 non-ulcerated nodular pattern
 Pigmented basal cell carcinoma
 Fibrosing variant

3- MALIGNANT MELANOMA
- Rapidly spreading malignant tumor of skin.
- Arise from melanocytes.
- Occur in skin, ano-genital mucosa, Esophagus, conjunctiva, orbit & leptomeninges

Risk factors
 189

 Persistent change in appearance of mole

 Family history
 Age
 Pre-existing neivus
 More than 50 moles
2mm or more in diameter

- Clinically appears as a flat or slightly elevated naevus with variegated pigmentation, irregular borders ,
secondary changes of ulceration, bleeding& increase in size
- Differentiated from benign pigmented lesions by ABCD ( Asymmetry, Border irregularity, Color change, Diameter
> 6mm )

Morphology

 Grossly: 5 types  Histology

- Lentigo malignant melanoma - Arise from dermo epidermal junction
- Superficial spreading melanoma - Grows downward to dermis
- Acral lentigenous melanoma - Cells are polygonal, spindle, or round & arranged
- Nodular melanoma in sheets
- Desmoplastic melanoma - The cells contain melanin pigmented
- Stain: masons Fontana

 Staging of melanoma – CLARKS staging

- level 1 – melanoma cells in epidermis & its appendages
- level 2 – extends to papillary dermis
- level 3 – extends to inter face between papillary and reticular dermis
- level 4 – invasion to reticulo dermis
- level 5 – invasion of subcutaneous fat
4- Difference between benign mole and malignant melanoma

Benign mole malignant melanoma

1. Clinical features
- Symmetry Symmetrical A = Asymmetry
- Border Well demarcated B = Border irregularity
- Colour Uniformly pigmented C = Colour change
- Diameter Small, < 6mm D = Diameter, > 6mm
2. Common locations Skin of face, mucosa Skin, mucosa of nose, bowel,
anal region
 190

3. Histopathology
a. Architecture Nest of cells Various pattern – solid sheets,
alveoli, nests.

b. Cell morphology Uniform looking nevus cells Malignant cells, atypia, mitosis,
nucleoli.

c. Melanin pigment Irregular, coarse clumps Fine granules, uniformly

distributed

d. inflammation May or may not be present Often present

4. spread Remains confined, possess Haematogenous or lymphatic
cosmetic problems only spread easily.
 191

MUSCULOSKELETAL SYSTEM
 192

INTRODUCTION TO MUSKULOSKELETAL SYSTEM

- Skeleton consists of cartilage and bone.

- Cartilage has a role in growth and repair and in adults forms the articular skeleton responsible for movement of
joints.
- Bone is a specialized form of connective tissue which forms the function of providing mechanical support and is
also a mineral reservoir or calcium homeostasis.
- There are 206 bones in the body and depending upon the size and shape maybe long, flat, tubular etc.
- Unlike bone, cartilage lacks blood vessels, lymphatics and nerves. It may have focal areas of calcification.

 JOINTS:

Most of the diseases of joints affect diarthrodial or synovial joints. Joints spaces lined by synovial membrane or
synovium which forms synovial fluid that lubricates the joint.

 MUSCLE:

The straiated muscle consists of bundles of fibres called fascicles. Each of which is surrounded by perimysium. Each
muscle fibre is enveloped by delicate fibrous stroma called endomycium.

CLASSIFICATION

OSTEOSARCOMA

- most common primary malignant tumour of the bone.

- Characterised by formation of osteoid or bone, or both, directly by sarcoma cells.
- Arise from primitive osteoblast-forming mesenchyme.

Depending upon their locations within the bone, osteosarcomas are classified into 2 main categories: central
(medullary){more common} and surface ( parosteal and perosteal).
 193

CENTRAL (MEDULLARY) OSTEOSARCOMA-

- AGE: Between the age of 10 and 20 years.

- Males > females.
- SITE: metaphysis of long bones
- Most common sites :- the lower end of femur and upper end of tibia> the upper end of humerus >
pelvis and the upper end of femur> jaw bones, vertebrae and skull.
- Based upon the pathogenesis, osteosarcoma is divided into 2 types: primary (genetic, environmental) and
secondary.

IMP: :- Cases of hereditary retino- blastoma have a

very high prevalence risk of development of
osteosarcoma implicating RB gene in their
pathogenesis.

MEDULLARY OSTEOSARCOMA SURFACE OSTEOSARCOMA

- highly malignant tumour. - includes 2 variants:
- Arises centrally in the metaphysis - parosteal
- periosteal.
extends longitudinally for variable distance into the - Parosteal or juxtacortical osteosarcoma:
medullary cavity - uncommon form of osteosarcoma.
- origin: From the metaphysis on the
expands laterally on either side breaking through the external surface of the bone.
cortex and lifting the periosteum. - Common locations: metaphysis of
long bones, most frequently lower end of
If the periosteum is breached, the tumour grows the femur and upper end of the humerus.
relentlessly into the surrounding soft tissues stopped. - X-ray examination: usually reveals
- Radiographic appearance:- a dense bony mass attached to the outer
1. Characteristic ‘sunburst pattern’ cortex of the affected long bone.
2. Presence of Codman’s triangle formed at the angle between - Grossly: the tumour is lobulated and
the elevated periosteum and underlying surface of the cortex. circumscribed, calcified mass in the
- Clinically- subperiosteal location.
- pain - Microscopically: the features which
- tenderness characterise the usual osteosarcoma
- swelling of affected extremity. (sarcomatous stroma and production of
- Laboratory- neoplastic osteoid and bone) are present,
- Serum alkaline phosphatase: RAISED but the tumour shows a high degree of
- calcium and phosphorus: NORMAL structural differentiation, and there are
- Spread: generally well-formed bony trabeculae.
+ haematogenous route
 disseminates commonly to the lungs, other bones, brain -Periosteal osteosarcoma:
and various other sites. - rare form of osteosarcoma that
 MORPHOLOGIC FEATURES. - arises between the cortex and the
+Grossly- overlying periosteum.
- Appears as a grey-white - common location is the diaphysis of the
- Bulky mass at the metaphyseal end of a long bone. tibia or the femur.
- Codman’s triangle, though identified radiologically, may Microscopically: periosteal osteosarcoma
be obvious on macroscopic examination . has cartilaginous differentiation and higher
- Cut surface of the tumour is grey-white with areas of degree of anaplasia than that seen in
 194

haemorrhages and necrotic bone. parosteal osteosarcoma.

+Histologically-
1. Sarcoma cells : Cells are undifferentiated mesenchymal stromal
cells showing marked pleomorphism and polymorphism. The
tumour cells have variable size and show hyperchromatism and
atypical mitoses.
2. Osteogenesis: They form osteoid matrix and bone directly. In
addition to osteoid and bone, the tumour cells may produce
cartilage, fibrous tissue or myxoid tissue.
=> Histologic variants-
a) Telangiectatic osteosarcoma.
b) Small cell osteosarcoma.
c) Fibrohistiocytic osteosarcoma.
d)Anaplastic osteosarcoma
e)Well-differentiated osteosarcoma

EWING’S SARCOMA

- Highly malignant
- small roundcell tumour
- occuring in patients with age of 5 & 20.
- Cells of origin –endothelial, pericytic ,bonemarrow, osteoblastic
,mesenchymal.
Common sites –
 3 variants- - shafts
-Classic Ewing’s sarcoma - metaphysis of long bones
- femur
-Soft tissue Ewing’s sarcoma - tibia
- humerus
-Primitive neuroectodermal tumor - fibula.
- Arises in medullary canal of diaphysis or metaphysis.

- X – RAY appearance – osteolytic lesion with patchy subperiosteal reactive bone formation producing onion –skin
appearance.

GROSS MICROSCOPY
- expansion of affected diaphysis , metaphysic 1] pattern –tumor is divided by fibrous septa into
extending into adjacent soft tissues. Cut surface irregular lobules of closely packed tumour cells. These
is grey white , soft and friable. are arranged in pseudorosette.
2] tumor cells-small, uniform ,ill defined cytoplasmic
outlines,scanty cytoplasm & round nuclei having salt &
pepper chromatin and frequent mitoses.
3] Richly vascularised & lacks the intercellular network of
reticulin fibres.
 195

OSTEOCHONDROMA
- Or exostosis is a benign cartilage-capped tumour attached to the underlying skeleton by a bony stalk.

2 types : Solitary sporadic exostosis(85%)

Multiple hereditary exostosis
- SITE : develop only in the bones of endochondral origin.
arising from metaphysis of long bones esp near knee.

- Pathogenesis: 1) hereditary is due to germline mutation in EXT1 & EXT2 genes.

2)sporadic is due to mutated EXT1 gene ONLY.

=> MORPHOLOGY:

Grossly,is a sessile or pedunculated mushroom shaped Microscopically, 1) outer cap composed of mature
cartilage capped exophytic growth enclosing a bone and cartilage resembling epiphyseal cartilage 2)inner mature
marrow. lamellar bone and bone marrow

Prognosis : both can transform to chondrosarcoma but the risk is high greater with multiple hereditary exostosis.

OSTEOCLASTOMA / GIANT CELL TUMOUR

- Named so because histology is dominated by multinucleated osteoclast type giant cells.It is an aggressive and
recurrent neoplasm.
- SITE : epiphysis of long bones
- Pathogenesis : tumour consist of both non neoplastic( major) & neoplastic part.

Neoplastic cells : primitive osteoblast precursors (express RANKL)

Non neoplastic : osteoclasts and their precursors

- Neoplastic cells express high level of RANKL which help in the proliferation and differentiation of osteoclasts.
Thus the feedback b/w osteoblast & osteoclast in bone remodelling is absent, resulting in highly destructive
bone resorption.

Morphology :

Grossly , Microscopically,
- large ,well circumscribed, red brown mass and 1) Giant cells containing as many as 100 nuclei.
covered by a thin shell of sub-periosteal bone. 2) stromal cells are mononuclear cells and are the real
- C/S shows hemorrhagic,necrotic and honey tumour cells.
combeddue to focal areas of cystic degeneration.

- Radiologically – large lobulated osteolytic lesion with soap bubble appearance.

OSTEOMYELITIS

- An infection of the bone.

- A number of systemic infectious diseases may spread to the bone such as enteric fever, actinomycosis,
mycetoma (madura foot), syphilis, tuberculosis and brucellosis.
 196

- 2 important ones are pyogenic and tuberculous osteomyelitis.

 PYOGENIC OSTEOMYELITIS-
- Caused by bacterial infection and rarely by fungi.

- Pyogenic osteomyelitis by haematogenous route occurs most commonly in the long bones of infants and young
children. Also from direct Etiology –
extension from adjacent areas. -- Staphylococcus aureus
-- Less frequently, other organisms such as streptococci, Escherichia coli,
Pseudomonas, Klebsiella and anaerobes are involved.
--Mixed infections are common in post-traumatic cases of osteomyelitis.
 Clinically- Child with acute
haematogenous osteo- myelitis has painful and tender limb. Fever, malaise and leucocytosis.
 Radiologic examination confirms the bony destruction.
 Draining sinus tracts may form which may occasionally be the site for development of squamous carcinoma.

MORPHOLOGIC FEATURES
- Depending upon the duration, osteomyelitis may be acute, subacute or chronic. The basic pathologic changes
in any stage of osteomyelitis are: suppuration, ischaemic necrosis, healing by fibrosis and bony repair.
The sequence of pathologic changes is as under
Infection begins in the metaphyseal end of the marrow cavity
It is largely occupied by pus.( microscopy reveals congestion, oedema and an exudate of neutrophils).

The tension in the marrow cavity is increased due to pus

spread of infection along the marrow cavity, endosteum , haversian and Volkmann’s canal,

periosteitis.

infection may reach the subperiosteal space

subperiosteal abscesses is formed

penetrate through the cortex  draining skin sinus tracts.

suppuration and impaired blood supply to the cortical bone

results in erosion, thinning and infarction necrosis of the cortex called sequestrum.

formation of new bone beneath the periosteum present over the infected bone.

This forms an encasing sheath around the necrosed bone and is known as involucrum.

continued neo-osteogenesis gives rise to dense sclerotic pattern of osteomyelitis called chronic sclerosing
nonsuppurative osteomyelitis of Garré.
- Occasionally, acute osteomyelitis may be contained to a localised area and walled off by fibrous tissue and
granulation tissue. This is termed Brodie’s abscess.
8. In vertebral pyogenic osteomyelitis, infection begins from the disc (discitis) and spreads to involve the
vertebral bodies.

 COMPLICATIONS-
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1. Septicaemia.
2. Acute bacterial arthritis.
3. Pathologic fractures.
4. Development of squamous cell carcinoma in long- standing cases.
5. Secondary amyloidosis in long-standing cases.
6. Vertebral osteomyelitis may cause vertebral collapse with paravertebral abscess, epidural abscess, cord
compression and neurologic deficits.

 TUBERCULOUS OSTEOMYELITIS-

Mycobacterium tuberculosis, reach the bone marrow and synovium most commonly by haematogenous dissemination
from infection elsewhere, usually from the lungs.

 MORPHOLOGIC FEATURES-
- Consist of central caseation necrosis surrounded by tuberculous granulation tissue and fragments of necrotic
bone.
- The tuberculous lesions appear as a focus of bone destruction and replacement of the affected tissue by
caseous material.
- formation of multiple discharging sinuses through the soft tissues and skin.
- Involvement of joint spaces and intervertebral disc are frequent.
- Tuberculosis of the spine, Pott’s disease ,
commences in the vertebral body

associated with compression fractures

destruction of intervertebral discs

producing permanent damage and paraplegia.

Extension of caseous material along with pus from the lumbar vertebrae
to the sheaths of psoas muscle produces psoas abscess or lumbar cold abscess.

The cold abscess may burst through the skin and form sinus.
Long-standing cases may develop systemic amyloidosis.

PAGET’S DISEASE OF BONE (OSTEITIS DEFORMANS)

 Osteolytic and osteosclerotic bone

 Males over age 50 years
 Etiology:-Slow virus infection
Autosomal dominant inheritance- RANK ligand
 Clinical features- monostotic form- asymptomatic
Polyostotic form- pain, fractures, skeletol deformities, sarcomatous transformation
MORPHOLOGIC FEATURES- three stages
1. Initial osteolytic stage
2. Mixed osteolytic-osteoblastic stage: mosaic patternor jigsaw
puzzle appearance of osteoid seams or cement lines.
3. Quiscent osteosclerotic stage:
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Radiologically cotton-wool appearance of theaffected bone.

RHEUMATOID ARTHRITIS

Autoimmuno basis – joints – non suppurative proliferative & inflammatory synovitis

Susceptibility genes[HLA & other} environmental factors{smoking,infections}

↓ ↓
Failure of tolerance, unregulated modified self proteins
Lymphocyte activation

Abnormal immune response

TH 17 cell TH 1 cell antibodies

↓
Fibroblast chondrocytes synovial cells → proliferation
↓
Inflammation
↓
Pannus formation, destruction of bone and cartilage, ankylosis

- Pannus – mass of edematous synovium , granulation tissue, inflammatory cells, fibroblast

 Morphology

Synovium becomes gross, edematous, thickened, hyperplastic, bulbous villi formation

Histology – synovial cell hyperplasia, cell infiltration, angiogenesis

Skin involevement – skin of elbow, occiput, sacral area – subcutaneous nodules

Vasculitis in blood vessels

OSTEOPOROSIS

- Acquired condition characterized by reduced bone mass leading to bone fragility &susceptibility
 Pathogenesis

occurs when the dynamic balance between bone formation by osteoblasts & bone resorption by osteoclasts tilts in
favour of resorption .

1.Age related changes : it is related to the peak bone mass earlier in life which is influenced by genetic
,nutritional &environmental factors. The greater the peak bone mass the greater the delay in onset
of osteoporosis.
2.Hormonal influences:the decline in estrogen levels associated with menopause correlates with an
acceleration of cortical &cancellous bone loss.
3.Physical activity :reduced physical activity increases bone resorption.
4.Genetic factors
5.Calcium nutritional state :Calcium deficiency occurs during a period of rapid bone growth.
6.Secondary cause :Prolonged glucocorticoid therapy,cigarette smoking,alcohol
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=>Pathophysiology of postmenopausal & senile osteoporosis.

Genetic factors

Physical activity Peak bone mass Nutrition

Menopause Ageing
1.Decreased serum estrogen 1.Decreased replicative activityosteoprogenitor cells
2. IL-1,IL-6,TNF levels. 2.Decreased synthetic activity of osteoblasts.
3. expression of RANK,RANKL 3.Decreased biologic activity of matrix bound growth
4. osteoclastic activity. Factors.
4.Reduced physical activity.

Osteoporosis
 Morphology
- Hallmark is loss of bone cortices thinned with dilated Haversian canals &trabeculae are reduced in thickness
& lose their interconnections.
- Postmenopause trabecular bone loss is severe results in compression fractures &collapse of vertebral
bodies.
- Senile osteoporosis cortical bone loss prominent predisposing to fractures.

OSTEOGENESIS IMPERFECTA

Also known as brittle bone disease.It is a group of genetic disorders caused by defective synthesis of type I collagen.

 Pathogenesis
- Mutation involve the coding sequence for α1 or α2 chains of type I collagen.
- Collagen synthesis &extra cellular export require formation of a complete &intact triple helix.Any primary
defect in a collagen chain tends to disrupt entire structure & results in premature degradation.
 Morphology
- Fundamental abnormality in all forms of OI is too little bone results in skeletal fragility.
- Type II variant fatal inutero or immediate postpartum as a consequence of multiple fracture that occur
before birth.
- Type I OI have a normal life span frequency of fracture decreasing after puberty.
- Blue sclera in type I OI due to decreased sclera collagen content.
- Hearing loss defect in middle ear & inner ear bones.
- Small misshapen teeth – dentine deficiency.

OSTEOARTHRITIS (OSTEOARTHROSIS)

- Degenerative joint disease. Mainly weight bearing joints.

- A synovial disease.
 Types & pathogenesis

Primary OA : common in old age women.

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Wear and tear with repeated minor trauma ,heredity , obesity , aging contribute to degenerative
changes in articular cartilage of joint.

Secondary OA : occur in any age. Result of previous wear and tear phenomena involving joint.

Morphology: common site : hip , knee , vertebrae ,interphalangeal joint of finger.

Pathological : articular cartilage

Loss of cartilaginous matrix progressive loss of normal metachromasia focal loss of chondrocytes & at other places ,
proliferation of chondrocytes forming .

Further progression of process losing ,flaking , and fissuring of cartilage breaking ,exposing subchondral
bone.

2. bone : subchondral bone appears like polished wory. Increased osteoclastic activation causes rarefaction, microcyst
formation & microfractures of bones remodeling of bone changes in shape of joint surface flattening and
mushroom like appearance of articular surface of bone.

3. synovium

low grade – chronic synovitis & villus hypertrophy.

Clinical features : joint stiffness , mobility , discomfort and pain

GOUT AND GOUTY ARTHRITIS

- Disorder of purine metabolism.

- Manifested by hyperuricemia , recurrent attacks of characteristic type of acute arthritis,deposition of
monosodium urate monohydrate , renal disease, uric acid nephrolithiasis.

Pathogenesis : serum uric acid raised.

A]metabolic origin :1)accelerated rate of denovo 2)enzyme defects[primary metabolic gout]

3)increased purine[secondary metabolic gout]

B]renal origin : reduced excretion of uric acid

Cause-diuretic therapy,drug induced.

Features :
1] Acute gouty arthritis – precipitation of needle shaped crystals.
2] Chronic tropheous arthritis : Deposits in the articular cartilage.
Synovial perfusion leads to pannus formation & progressive destruction of articular cartilage & suchondral bone.
3] Tophi in soft tissues –mass of urate, located in periarticular & subcutaneously. Surrounded by inflammation.
4] Renal lesion – involves kidneys 3 types.
1] Acute urate nephropathy.
2]Chronic urate nephropathy
3] uric acid nephrolitihasis
 201

EYE AND NOSE

 202

RETINOBLASTOMA
- Common intra ocular malignancy in children
- Sporadic (60%) or familial(40%)
- Familial tumours – multiple ,multifocal ,transmitted as autosomal dominant
- RB gene on chr 13 , ↑ed chance for osteogenic sarcoma
- Morphology: white mass in retina ,as solid as well as necrotic, may be endophytic as well as exophytic.
- Microscopy: undifferentiated retinal cells , in differentiated area tumour appear as rosette .

(1)Flexner –wintersteiner rosette : small tumour cells arranged around a lumen with, nuclei away from the lumen.
(2) homer right rosette : radial arrangement of tumour cells around central fibrillary structures

- Areas of necrosis, calcification present.

- Spread via hematogenous &optic nerve

- Clinical features: leukokoria ie white papillary reflex

RHINOSPORIDIOSIS
Causative fungi :Rhinosporidiumseeberi

Location : nasal polyp( most c’mon), nasopharynx , larynx and conjunctiva.

Microscopically : 1) psuedostratified epithelium with hyperplasia, thickening and ulceration 2)sporangium containing
thousands of spores which on rupture releases the spores into the submucosa or to the surface of mucosa.3)intervening
tissue consisting of inflammatory granulation tissue.
 203

SOFT TISSUE TUMOUR

 204

Benign -Lipomas,
TUMOURS OF ADIPOSE TISSUE -hibernoma(arisimg from brown fat),
-lipoblastoma(foetal lipoma-found predominantly
in children under 3 years of age)

Malignant -liposarcoma
LIPOMA
INTRODUCTION -commonest soft tissue tumour.
CLINICAL FEATURES -solitary, soft, movable and painless mass which may remain stationary
or grow slowly.
-Age group- 4th to 5th decades of life
-more common among females.
-Common sites are the subcutaneous tissues in the neck, back and
shoulder .

GROSS -small,
-round to oval and
-encapsulated mass.

-Cut surface is soft, lobulated, yellowish-orange and greasy

HISTOLOGY -lobules of mature adipose cells separated by delicate fibrous septa and
surrounded by a thin fibrous capsule.
-lipoma mixed with other tissue components may be seen.
These include:
1. fibrolipoma ( with fibrous tissue),
2. angiolipoma ( with proliferating blood vessels) and
3. myelolipoma(with bone marrow elements as seen in adrenals).
- benign lipoma may infiltrate the striated muscle (infiltrating or
intramuscular lipoma).
-Variants of lipoma:-
Spindle cell lipoma and
pleomorphic (atypical) lipoma(Atypical lipoma is difficult to distinguish
from liposarcoma.)

LIPOSARCOMA
INTRODUCTION - one of the most common soft tissue sarcomas in adults.
-arises from primitive mesenchymal cells, the lipoblasts.
CLINICAL -Peak incidence:-5th to 7th decades of life.
FEATURES -Sites-deep tissues,intermuscular regions in the thigh,buttocks and retroperitoneum.
GROSS -appears as a nodular mass, 5 cm or more in diameter.
-The tumour is generally circumscribed but infiltrative.
- Cut surface is grey-white to yellow, myxoid and gelatinous.
- Retroperitoneal masses are generally much larger.
MICROSCOPY -presence of variable number of lipoblasts which may be univacuolated or multivacuolated
 205

Four major histologic varieties:

1.Well- 2.Myxoid 3.Round cell 4. Pleomorphic liposarcoma
differentiated liposarcoma liposarcoma
liposarcoma

-resembles -most common -composed of -highly undifferentiated and the most anaplastic
lipoma histologic type. uniform, round to type.
-but contains -composed of oval cells having - numerous large tumour giant cells and bizarre
uni- or multi- monomorphic, fine multi lipoblasts.
vacuolated fusiform or stellate vacuolated
lipoblasts. cells , lying cytoplasm with
dispersed in central
mucopolysaccharid hyperchromatic
e-rich ground nuclei.
substance. -may resemble a
Occasional tumour signet-ring
giant cells may be carcinoma but
present. mucin stains help
Prominent in distinguishing
meshwork of the two.
capillaries forming
chicken-wire
pattern
PROGNOSIS -Depends upon the location and histologic type.
-Well-differentiated and myxoid varieties have excellent prognosis, while pleomorphic
liposarcoma has significantly poorer prognosis.
METASTASIS Round cell and pleomorphic variants metastasise frequently to the lungs, other visceral
organs and serosal surfaces.

SKELETAL MUSCLE TUMOURS

Rhabdomyoma and rhabdomyosarcoma are the benign and malignant tumours respectively of striated muscle.
RHABDOMYOMA
INTRODUCTION -rare benign soft tissue tumour.
-located in the head and neck, most often in the upper neck, tongue, larynx and pharynx.
HISTOLOGY large, round to oval cells, having abundant, granular, eosinophilic cytoplasm which is
frequently vacuolated and contains glycogen.
The tumour is composed of Cross-striations are generally demonstrable in some cells with
phosphotungstic acid-haematoxylin (PTAH) stain. The tumour is divided into adult and foetal
types, depending upon the degree of resemblance of tumour cells to normal muscle cells.
 206

RHABDOMYOSARCOMA
-more common soft tissue tumour than rhabdomyoma,
- commonest soft tissue sarcoma in children and young adults.
- highly malignant tumour arising from rhabdomyoblasts .
-Depending upon the growth pattern and histology, 4 types:
1. embryonal,
2. botryoid,
3. alveolar and
4. pleomorphic.

1.EMBRYONAL 2.BOTRYOID 3.ALVEOLAR 4.PLEOMORPHIC

RHABDOMYOSARC RHABDOMYOSARCOM RHABDOMYOSARCOM RHABDOMYOSARCOMA.
OMA A. A.
-Most common -A variant of less frequent variety
embryonal
rhabdomyosarcoma
Age children (<12years) children under 10 older children and older adults >40 years
grou years of age. young adults under
p the age of 20 years
Com 1. head and neck 1. vagina 1.extremities 1.extremities,mainly lower
mon (orbit) 2.urinary bladder limbs.
sites 2.urogenital tract 3.nose.
3.retroperitoneum
.

Gros The tumour forms The tumour forms a The tumour arise The tumour forms a well-
s a gelatinous mass distinctive grape-like directly from skeletal circumscribed, soft, whitish
growing between gelatinous mass muscle and grows mass with areas of
muscles or in the protruding into the rapidly as soft and haemorrhages and
deep hollow cavity. gelatinous mass. necrosis.
subcutaneous
tissues but
generally has no
direct relationship
to the skeletal
muscle.

Hist -small, round to The tumour grows -characteristic alveolar The tumour cells show
olog oval cells and underneath the pattern resembling considerable variation in
y spindle-shaped mucosal layer, forming pulmonary alveolar size and shape.
strap cells having the characteristic spaces formed by fine -composed of highly
tapering bipolar cambium layer of fibrocollagenous anaplastic cells having
cytoplasmic tumour cells. septa. bizarre appearance and
processes in which - The tumour is The tumour cells lying numerous multinucleate
cross-striations hypocellular and in these spaces and giant cells.
may be evident. myxoid with lining the fibrous Various shapes include
-The tumour cells predominance of trabeculae are racquet shape, tadpole
form broad small, round to oval generally small, appearance, large strap
fascicles or bands. tumour cells. lymphocyte-like with cells, and ribbon shapes
Mitoses are frequent mitoses and containing several nuclei in
 207

frequent. some multinucleate a row. Conventionally, the

tumour giantcells . cross-striations can be
Cross-striation present demonstrated with PTAH
in some. stain in a few
rhabdomyosracomas.
Immunohistochemical
stains include: myogenin,
Myo-D1,desmin, actin,
myosin, myoglobin, and
vimentin.

MYOSITIS OSSIFICANS
TUMOUR-LIKE LESIONS
- these are some proliferative conditions of the soft tissues which resemble clinically and
morphologically with soft tissue tumours.
Eg... nodular fascitis (pseudosarcomatous fascitis)
and myositis ossificans.

INTRODUCTION benign, tumour-like lesion characterised by osteoid and heterotopic bone formation in
the soft tissues. .
-it is generally preceded by history of antecedent trauma to a skeletal muscle or its
tendon.
e.g. to the adductor muscles of the thigh of a horseman, or may be single injury followed
by haemorrhage into the muscle.
-Richly vascularised granulation tissue replaces the affected muscle or tendon. Then
follows development of osteoid and bone at the periphery, giving characteristic X-
rayappearance.
-The patient generally complains of pain, tenderness and swelling.
GROSS -unencapsulated, gritty mass replacing the muscle.
MICROSCOPY -the central region:-loosely arranged fibroblasts having high mitotic activity.
-Towards the periphery, there is presence of osteoid matrix and formation of woven
mineralised bone with trapped skeletal muscle fibres and regenerating muscle (myogenic)
giant cells.
- condition is also called pseudomalignant osseous tumour of
the soft tissues.
 208

ENDOCHRINOLOGY
 209

ENDOCRINE SYSTEM
INTODUCTION TO ENDOCRINE SYSTEM
Consists of 6 different organs: adrenals, thyroid,parathyroid,gonadsand pituitary,pancreatic islets.

Hormones are divided into 5 classes which are further grouped under 2 headings.

1. Those interacting with cell surface membrane receptors

–amino acid derivatives: thyroid hormone, caecholamine
–small neuropepetide: GnRH,TRH,somatostatin,vasopressin
2. Interacting with intercellular nuclear receptors
-larger proteins: insulin,LH, parathormone
-steroid hormone:cortisol, estrogen
-vitamin derivative:vitamin a and vitamin D

Their synthesis occurs through a genetic pathway that involves transcription mRNA protein synthesis post
translational protein processing intracellular membrane integrations secretions

Functions

1. Growth and differentiation

2. Maintenance of homeostasis
3. Reproduction

Negative and positive feedback control system hormone production within normal range.

Disease occur due to hyper/hypo function/peripheral resistence of hormone.

1. PHEOCHROMOCYTOMA: (CHROMAFFIN TUMOUR)

- Arise from chromaffin cells of adrenal medulla
- Name – dark brown colour due to chromaffin oxidation of catecholamines
- Age group: 20-60 yrs
- 90% sporadic; 10% familial ass. With MEN- have b/l with medullary Ca thyroid & hyperPTH
- 10% RULE: 10% familial, 10% malignant, 10% extra-adrenal
- C/F : HTN, CHF, MI, pulm. Edema, cerebral hmg
- DIAGNOSIS : 24 HR urinary catecholamine / products – VMA, metanephrine
 MORPHOLOGY:
 Gross : Microscopy:
- Tumour soft, spherical. On C/S – 1. Tumour cells arranged as well defined nests(ZELLBALLEN
grey to dusky brown with areas of PATTERN) separated by abundant fibro vascular stroma
hmg, necrosis, calcification 2. Cells are large, pleomorphic, polyhedral with abundant
granular cytoplasm.
3. Stain +ve with NSE & chromogranin

2.HASHIMOTO’S THYROIDITIS: ( C/C LYMPHOCYTIC THYROIDITIS)

- SYNONYMS: diffuse lymphocytic thyroiditis; struma lymphomatosa or goitrous autoimmune Thyroiditis

- 3 FEATURES: 1. Diffuse goitrous enlargement of thyroid. 2. Lymphocytic infiltration of thyroid gland

 210

3. occurrence of thyroid autoantibodies: Thyroid microsomal, thyroglobin, TSH

receptor autoantibodies
- AGE GROUP: 30-50 yrs; SEX= M:F = 1:10

MCC of hypothyroidism in areas of world where I2 levels are sufficient

Gradual thyroid failure secondary to Auto Immune destruction of thyroid gland

=> PATHOGENESIS:
1. Other AI association (SLE, RA, DM-1)
2. Breakdown in SELF-TOLERANCE to thyroid auto antigens
3. CD 8+ cytotoxic T cell mediated cell death(Thyrocyte)
4. Cytokine mediated cell death
5. Anti thyroid auto antibodies
6. CTLA-4 association

 MORPHOLOGY:
 Gross:  Microscopy:
- diffuse, symmetric, firm & 1.Mononuclear inflammatory infiltrate(small lymphocytes, plasma
rubbery enlargement of cells , germinal centres)
thyroid; 2.Atrophied thyroid follicles
- weighs 100-300 gms; On C/S, 3.presence of HURTHE CELLS/ASKANAZY
fleshy with accentuated normal CELLS/ONCOCYTES/OXYPHIL CELLS
lobulations, but shape retained (degenerated follicular epithelial cells; contain
eosinophillic granular cytoplasm- due to abundant
mitochondria, bizarre nucleus)
=> C/F:

1. Painless, firm, moderate goitrous enlargement; Hypothyroidism

2. Middle aged women

3. Sometimes hyperthyroidism- HASHITOXICOSIS

ed
4. risk of developing LYMPHOMA

4.GRAVES DISEASE: (DIFFUSE TOXIC GOITRE)

- MCC of endogenous HYPERTHYROIDISM - Age : 20-40 yrs

- M:F = 7:1
- TRIAD of manifestations: - increased in emotional stress
- smoking
1. Thyrotoxicosis – Hyperthyroidism

2. Ophthalmopathy – exophthalmoses

3. Dermopathy – pretibial myxedema

- ETIOPATHOGENESIS :

1. Genetic factor association : HLA DR3, HLA DR5, CTLA-4

2. AI disease association

3. Auto antibodies:
 211

1. TSI (Thyroid Stimulating Immunoglobin)

2. TGI (Thyroid Growth Stimulating Immunoglobulin)

3. TBII (Thyroid Binding Inhibitor Immunoglobulin)

=> MORPHOLOGY:

=> Gross : Microscopy:

- Moderately, diffusely & symmetrically enlarged; 1. Epithelial hyperplasia, hypertrophy
weighs 70-90 gm 2. Colloid – diminished, light staining, watery, vacuolated
- On C/S, thyroid parenchyma homogenous, red 3. Stroma – Increased vascularity & accumulation of
brown, meaty, Lacks normal translucency lymphoid cells

=> C/F:

1. Young females  moderate enlargement of thyroid gland

2. Ocular abnormality  lid lag, upper lid retraction, stare, proptosis, weakness of eye muscle.

3. Dermatopathy  pretibial myxedema ( firm plaques).

5.THYROID CANCERS

- Female preponderance

- Etiology- 1)Radiation exposure 2)Iodine excess and TSH 3)genetic mutation in RET,RAS,p53

FEATURES PAPPILARY FOLLICULAR MEDULLARY ANAPLASTIC

FREQUENCY 75-80% 10-20% 5% 5%
AGE All ages Middle to old Middle old Old age
FEMALE TO MALE 3:1 2.5:1 1:1 1.5:1
RATIO
RELATION TO Maximum present None present
RADIATION
GENETIC RET over RAS mutation RET point P53
ALTERATION expression mutation
CELL OF ORIGIN follicular follicular parafollicular Follicular
CLINICALLY Slow growing Solitary or firm nodualar Unilateral solitary Dyspnea
Asymptomatic thyroid enlargement nodule or Dysphagia
Cervical bilateral multi Hoarseness of voice
lymphadenopathy centric because of invasion
involvemnet
GROSS Small multifocal Cut surface- greyish Cut section- well Large and irregular
greyish white white+necrosis+cyst defined firm to invading into
hard and scar like formation+heamorrhages hard grey white surrounding muscles.
to yellow brown Cut surface-
+area of white+firm+necrosis+
haemorrhage and hemorrahge
necrosis
MICROSCOPY Pappilae + orphan Follicular pattern+ Nest of tumour Poorly differentiated
annie+ hyperchromatic nuclei cells seperateed 3 types-
psammoma by fibrovascular Small cell
septa +C spindle cell
 212

cells+amyloid Gaint cell

stroma
PROGNOSIS Good good Familial better Worse
than sporadic

6.MULTIPLE ENDOCRINE NEOPLASIA (MEN) SYNDROME

- Multiple adenomas and hyperplasia of different endocrine organs due to a group of genetic disorders.

- Presentation at younger age and arise in multiple endocrine organs preceded by asymptomatic endocrine hyperplasia.

- Usually more aggressive and recurring.

MEN TYPE I(WERNER’S MEN TYPE-II(SIPPPLE’S MIXED SYNDROME

SYNDROME) SYNDEROME)
MEN 2A MEN 2B
Adenomas of medullary medullary Features of MEN I and
parathyroid, pancreatic carcinoma carcinoma MEN II(VHL syndrome)
islets and pituitary + +
Pheochro pheochrom
mocytoma mocytoma
+ +
Hyperpara mucosal
thyroidism neuromas,
intestinal
gangliomas,
marfanoid
features
Autosomal RET gene RAS gene mutation
dominant(MEN I gene mutation
affected)

10.SIMPLE NODULAR GOITRE:

 AETIOLOGY: 
- Epidemiologically, goitre in two forms –
endemic & sporadic
1.Endemic goitre : - Prevalance of goitre in
geographic area > 10% population
- due to goitrogens & genetic factors
2. Sporadic goitre: - suboptimal I2 intake in
conditions of increased
demands like pregnancy & puberty
-Genetic factors
-Dietary goitrogens
-Inborn errors of metabolism
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 MORPHOLOGY:
 Gross:
 Thyroid enlargement is moderate, symmetric, diffuse
 C/S is gelatinous & translucent brown
 Microscopy:
 2 stages: 1. Hyperplastic-> early stage having tall columnar follicular
epithelium showing papillary infoldings & formation of small new follicles

2. Involution -> large follicles distended by colloid & lined by

flattened follicular epithelium

10.MULTI NODULAR GOITRE:

 Enlargement of gland cause cosmetic disfigurement, dysphagia, choking due to compression of esophagus &
trachea
 Majority – eyuthyroid state ; 10% cases may develop thyrotoxicosis resukting in toxic nodular goitre( PLUMMER’S
DISEASE)
 LACKS features of OPTHALMOPATHY & DERMATOPATHY

Epithelial hyperplasia, generation of new follicles ,

irregular accumulation of colloid follicles

Incresed tension & stress in thyroid glands

Rupture of follicles & vessels resulting in hmg, cystic

changes, scarring & Calcification

 MORPHOLOGY:
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Gross: Microscopy:
 Thyroid gland is asymmetric & enlarged; weight Partial / incomplete encapsulation of nodules
= 100-500 gm  Small to large follicles with colloid
 5 cardinal features:  Areas of hmg, hemosiderin laden macrophages &
1. Nodularity with poor encapsulation cholesterol crystals
2. Fibrous scarring  Fibrous scarring with foci of calcification
3. Hemorrhages  Micro- macro cystic changes
4. Focal calcification
5. Cystic degeneration
contain 1/2 nodules with poor circumsition

11.Follicular adenoma Thyroid

- Benign

- Solitary nodule

- More in adult women.

- If no clinical problem caused –cold nodule

- May cause hyperthyroidism-then appear as hot nodule

- Gross –solitary nodule with complete encapsulation.

- Distinct architecture both inside & outside

- Compression of thyroid parenchyma outside. These three are the distinguishing feature from a nodular goitre.

- Small&spherical ,C/S grey white –red brown ,less colloidal

- Show degenerative changes such as fibrous scarring,focal calcification,haemorrhages &cyst formation.

- Microscopy :tumour cells-benign follicular epithelial cells .

6 types :
1] microfollicular:small follicle with little colloid &abundant storm.
2] normofollicular :closely packed follicles like normal gland
3] macrofollicular:large follicle distended with colloids
4]trabecular :like embryonal thyroid:closely packed trabecular pattern of epithelial cells with abortive follicle.
5]Hurthle cell:solid trabecular of large cells with granular oxyphilic cytoplasm&vesicular nuclei.
6]atypical :more cellular proliferation:malignant features like pleomorphism,increased mitosis&nuclear
atypia,but no capsular or vascular invasion.

12.SHEEHAN’S SYNDROME:

- Pituitary insufficiency due to post partum pituitary(sheehan’s) necrosis.

PATHOGENESIS:
1. Enlargement of pituitary during pregnancy foll. By hypotensive shock precipitating ischemic necrosis of
pituitary
2. DIC following delivery
3. traumatic injury to vessels
4. Excessive hmg(Greater risk : DM)
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=> C/F :

1. First manifestation : failure of lactation following delivery( due to def. Of prolactin)

2.Loss of axillary, pubic hair, amenorrhoea, sterility, loss of libido

3. ACTH result in HYPOTHYROIDISM, ADRENOCORTICAL insufficiency

=> Morphology : Early- ischemic necrosis ; later- fibrosis

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