Cell Injury

1. What are the differences between dystrophic calcification and metastatic

calcification? (3 marks)
Answer:
Factors Dystrophic Calcification Metastatic Calcification
Definition | Deposition of caleium in dead Deposition of calcium in
and degenerated tissue normal tissue
Calcium Metabolism Calcium metabolism is normal Calcium metabolism is
deranged
Serum Cazt Level Normal High
Extent Tends to be localized Widespread (ie., diffuse)
Pathogenesis Calcium is deposited in the High blood calcium and
necrotic tissue high pH favor tissue
mineralization
Causes Necrosis, atherosclerosis, Hyjperparathyroidism,
Monckeberg medial calcification, osteolytic lesions (e.g.
dead parasites umors (e9. multiple myeloma),
Papillary cancers of
the thyroid, milk-alkali syndrome
Ovary, and salivary gland),
CREST Syndrome, etc.
Psammoma Bodies Seen (Psammoma bodies: Not seen
cOncentric ring of calcium
|deposition)

Psammoma Body in Papillary Carcinoma of Thyroid

O Note: Stain for Calcium: Von Kossa
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 65

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MedEd FARRE: Pathology

2. () Define apoptosis and describe its underlying mechanism. (20 marks)

() Define necrosis and briefiy describe its various morphological patterns.
(i) Differentiate between apoptosis and necrosis.
Answer:
() APOPToSIs: Apoptosis is a form of genetically programmed cell death which
eliminates unwanted host celis.
o lt occurs in both physiological as well pathological conditions.
o Physiological apoptosis: During ernbryogenesis (implantation and organogenesis).
Hormone- dependent involution (like in breast)
* Apoptosis of neutrophils and lymphocytes after acute inflammation.
* Cell aging
o Pathological apoptosis: In cases of DNA damage
o Cell death is caused by the accumulation of misfolded proteins.
o Pathological atrophy in parenchyaal organs after duct obstruction, e.g., salivary
gland and pancreas
Sequence of morphological changes in Apoptosis
JCell shrinkàge1

Chromatin condensation followed by nuclear fragmentation

Cytoplasmic bleb formation followed by fragmentation into apoptotic bodies

Phagocytosis of apoptotic bodies

Mechaniswm of Apoptosis: There are two main pathways in apoptosis
o
Intrinsic/mitochondrial pathway
o
Extrinsic/death receptor pathway
Intrinsic/mitochondrial pathway
Unrepairable DNA damage triggers ps3

4BCL-2 activity (tBAX and BAK)

tMitochondrial permeability
 Cell injury

Cyt-c in the cytoplasm

tActivity of APAF-1

tCaspase 9, 10 (lnitiator)

1Caspase 3, 6, 7 (Executionary)

tActivity of protease and endonucleases

Cell death
Extrinsic/death receptor pathway:
Extracellular signals {receptor-ligand interactions (Fas-Fas ligand, TNF-TNF
receptor)}

Binding of Fas-L to Fas (receptowligand interactions)

Adapter proteins

Activation of initiator caspase 8 & 10

Activation of executioner caspases (caspase 3 and 6)

Nuclear fragmentation

Formation of cytoplasmic blebs

Phagocytosis
(in) NECROSIS: Necrosis is a form of cell injury which results in the premature death
of cells in living tissue by autolysis.
o It is always pathological and causes inflammation.

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 MedEd FARRE: Pathology

Morphological patterns of necrosis

o Coagulative necrosis: It is the most common pattern of necrosis
* It is caused by ischaewmic injury resulting in the hypoxic death of cells in all tisues
except the brain.
o Liquefactive necrosis:
It is caused by the digestion of the dead cels vesulting in a
viscous liquid ([Link], Pancreas)
* It is associated with bacterial or fungal infections.
o Gangrenous necrosis: It is
the necrosis of limbs due to loss of blood supply.
o
Caseous necrosis: It is associated with tuberculous infection.
* On gross, the necrotic areas appear cheesy white (caseous).
o Fat necrosis: It refers to a focal area of fat destruction, seen in acute pancreatitis
and traumatic fat necrosis of the breast.
o Fibrinoid necrosis: It is a form of vascular damage seen when complexes of antigen
and antibody are deposited in the walls of arteries e.g. PAN
() DIFFERENCE BETWEEN APOPTOSIS AND NECROSIS:

Characteristics Apoptosis Necrosis

Definition Programmed cell death (a Cell death causing an
process dependentb ATP)ninflammatory response
Pathophysiology OIntrinsic pathway: Oncosis (cellular and organelle
Unrepairable DNA damage swelling)
triggers ps3
Mitochondrial and
LBCL-2 activity (tBAX and endoplasmic reticulum swelling
BAK)

Inability to produce ATP

tMitochondrial permeability
Release of vibosomes into the
Cyt-c in the cytoplasm cytoplaswm

tActivity of APAF-1 Loss of RNA

1Caspase 9, 20(lnitiator) Nuclear changes (pyknosis,

karyorrhexis, karyolysis)
Caspase 3, 6, 7
(Executionary)
Autolysis
 Cell injury

1Activity of protease and o Membrane damage lnflux

endonucleases of Calcium

Cell
death
O
Extrinsic Pathway:
Ligand receptor interaction
Fas (CDA5) and Fas ligand
(FasL) or
TNF-alpha and TNF
receptor 1 (TNFR1)

Recruit and activate

caspase-8

activates downstream
caspases

Activates cytotoxic T-cells

Cytotoxic Tcells keleasean

granzyme B and perforin

Cell Death

Characteristics Apoptosis Necrosis

Nature Physiologic or Pathologic Always Pathological
|Adjacent No Yes
|tnflamimation
|Microscopy Single -cell or small group Large group of cells, tissues,
of cells, cell shrinkage, or organs, cell swelling,
eosinophilic cytoplasm, cell blebbing, organelle
nuclear changes, apoptotic destruction, nuclear changes,
|bodies,phagocytosis by inflammation, leukocyte
macrophages mediated tissue degradation,
granulation tissue formation
dUTP pattern Step ladder pattern Smear pattern

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Clinical Markers |Annexin: V staining lncreased LDH and other

intracellular components in
the extracellular space
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 37

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 Cell injury

3. Enumerate and deseribe in brief different types of cellular adaptations.

(5 marks)
Answer:
o Different types of adaptations:
» Hyperplasia
*Hypertrophy

* Atrophy
* Metaplasia
Process Definition Mechanism Types and Examples
Hyperplasia Increase in cell Proliferation of o Physiologic
number, leading to cells due to growth hyperplasia
increased size factors o (e.g., hormonal:
breast and uterus
during puberty)
o Compensatory
hyperplasia
o (e.g., liver
JalShreeRam regeneration
after partial
hepatectomy)
o Pathologic
hyperplasia
o (e.g., endometrial
hyperplasia,
prostatic
hyperplasia)
o Physiological
Hypertrophy lncrease in cell size, Increased cellular
leading to organ protein formation hyjpertrophy
enlargement o (e.g., uterine
enlargement during
pregnancy)
Pathological
hypertrophy
o (e.g.,cardiac muscle
in hypertension)

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|Atrophy Decrease in organ Decreased Physiological

or tissue size protein synthesis atrophy
or increased o (e.g., notochord
degradation during fetal
development)
o Pathological
atrophy
o (e.g., disuse,
denervation,
nutritional
deficiency)
Metaplasia Reversible change Altered O Coluwmnar
in differentiated differentiation of to squanmous
epithelium being stem cells due to (respiratory tract
replaced y another reprograwming irritation)
type o Squamous to
columnar (Barrett's
esophagus)
Connective tissue
metaplasia
O
(e.g., bone
JalShreeRam formation in
muscle)

(Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. S7

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 Cell injury

4. Write a short note on accumulation of pigments in cells. (3 marks)

Answer:
[Link] PIGMENTS
o Pigments are colored substances, with some being natural components of cells
(such as melanin), while others are considered abnormal and tend to accumulate
within cells under specific conditions.
Pigments Description Associated Conditions
Endogenous
Melanin
O
Non -hemoglobin-derived, Hyperpigmentation:
brown -black pigment. Present Addison's, Chloasma,
in skin, hair, etc. Synthesized etc. Hypopigmentation:
by melanocytes. Albinism, Vitiligo, ete.
| Lipofuscin o Lipid-derived "wear and o Associated with aging and
tear" pigment. Yellow-brown cell atrophy.
granules in cells.
Hemosiderin o Golden-brown crystalline o Hemochromatosis, localized
pigment. Stains with Prussian bruising.
blue.
Acid Haematino Brown-black pigwent sein in o Malaria infection.
malaria.
Bilirubin o Major bile pigment. Stains o Jaundice due to excess
with Gmelin reaction. Derived bilirubin.
from hemoglobin.
Exogenous
nhaled o
Carbon, silica, iron, asbestos, o Lung-related issues.
etc.
ingested o Metals like silver, lead, o Argyria, lead poisoning.
cathartics, carrots, etc. melanosis coli,
carotenaemia.
Injected O lndia ink, cinnabar, tatto0 O Tatto0 -related
pigments, etc. pigmentation issues.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 64

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 Hemodynamics
5. Write briefty on emboli and its type. (S marks)
Answer:

Classification TYpes of Emboli

Physical State o Solid: Atheromatous, thromboemboli, tumor emboli
O Liquid: Fat, bone marrow, amniotic fluid emboli
o Gaseou: Air emboli (seen in decompression sickness)
Site of Origin o Cardiac emboli(left side of heart)
o Arterial emboli (atheromas, aneurysms)
o Venous emboli(deep vein thrombosis)
o
Lymphatic emboli (tumor emboli)
Presence of tnfection o Sterile/bland emboli
o
Septic emboli
Flow o Paradoxical (Crossed) emboli: Emboli crossing over
from jyenoustozarterial circulation or vice versa due
to interatrial or interventricular defect.
o Retrograde emboli: Travel against the direction of
blood flow
Pulmonary Emboliswm: Pulmonary emboli originate from deep venous thromboses and
are responsible for the most common form of thromboembolicdisease.
o
Depending on the size of the embolus, it can occlude the main pulmonary artery,
lodge at the bifurcation of the right and left pulmonary arteries (saddle embotus),
or pass into the smaller pulmonary vessels.
o Emboli may pass through atrial or ventricular septal defects from the right side
to the left side of the heart to enter intoarterial circulation (paradoxical embol).
Consequences: Most pulmonary emboli are clinically silent.
o Sudden death due to right -sided heart failure (cor pulmonale)
o Pulmonary hemorrhage
o
Pulmonary infarction
o Pulmonary hypertension with right-sided heart failure.
Fat embolism

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 Hemodynamics

o lt is defined as the obstruction of vessels (arterioles and capillaries)

by fat globules
with or without marrow elements.
o Causes: Trauma to long bones or soft tissue (fracture with embolization of fatty
marrow)
O Extensive burns
O Pancreatitis
o
Diabetes mellitus
o Vigorous cardiopulmonary resuscitation
Amniotic fluid embolism
o Caused by infusion of amniotic fluid with all its contents (fetal cells and debris)
into maternal circulation due to tears in the placental membrane or rupture of
uterine vessels.
o
Pulmonarymicrocirculation shows fetal skin,squamous cells, lanugo hair, fat from
vernix caseosa and mucin derived from the fetal respiratory tract or GlT.
o Causes of Death: Mechanical blockage of pulmonary circulation, DIC, Anaphylactic
reaction or hemorrhage.
Air embolism
o Air bubbles in the circulation can obstruct the vessels and cause ischemic injury.
O Causes:
JaiShreeRam
* Operative procedures
* Trauma, particularly penetrating chest wall injury
* Decompression sickness (Caisson disease)
* lntravenous infusions
* Angiograhy/arteriography
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 130

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 Inflammation
6. Enumerate the differences between exudate and transudate. What are Light's
criteria? (3 marks)
Answer:
Features Exudate Transudate
Definition Oedema of inflamed tissue Filtrate of blood plasma
associated with increased without changes in endothelial
vascular permeability |permeability
Character lnflammatory Non -inflammatory
Protein cOntent High low
Glucose content Low Same as in plasma
|Specific gravity High Low
pH <7.3 >73
LDH High Low
Effusion LDH/ > O.6 <O.6
Serum LDH ratio
JiShreRn Few celis are present
Cells Many cels are present
Exampes Purulent exudate-like pus Edema in congestive cardiac
failure
o Light's criteria are used to differentiate between pleural effusions that are
transudates and those that are exudates.
o
To classify a pleural effusion as an exudate, at least one of the following criteria
must be met:
Pleural Fluid Protein to Serum Protein Ratio:
o
The pleural fluid protein level divided by the serum protein level is greater than o.s.
Pleural Fluid LDH to Serum LDH Ratio:
o The pleural fluid LDH level divided by the serum LDH level is greater than o.6.
Pleural Fluid LDH Level:
o The pleural fluid LDH level is greater than two-thirds of the upper limit of the
normal LDH level for serum.
If none of these criteria are met, the pleural effusion is classified as a transudate.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 75

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 Infiammation

7. Differentiate between red and white infarcts. Short note on the fate of thrombus.
(3 marks)
Answer:
Features Red infarct White infarct
Cause Venous occlusion Arterial obstruction
Organs involved Spongy organs like fungs |Solid organs, like heart, spleen
and gastrointestinal tract and kidney
Size of hemorrhage Large area Small area
Morpholog9 Congested and red due to Becomes progressively pale
|hemorrhage
Margins Not sharply defined |sharply defined
Oedema Present Absent
Fate of a thrombus:
o Dissolution (due to fibrinolysis)
o Organisation to a solid mass
o Propagation (spread locally)
o Embolisation JaiShreeRam

Reference: Pathologic Basis of Disease, Robbins andCotran, 10th Edition, Page No. 133

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8. Write a short note on (a) Phagocytosis; (6) Autophagy (5 marks)

Answer:
CA) PHAGOCYTOSIs
o Phagocytosis is the process of engulfment of a solid particle by a cell. It has 3
important steps
* Recognition and attachment to the particle
* Engulfment of the particle
* Killing and degradation of the particle engulfed.
Recognition and attachment
o Phagocytosis isinitiated by the expression of mannose and scavenger receptors,
cell surface receptors on macrophages that recognize microorganisms which is
further enhanced when microbes are coated with opsonins, specific serum -derived
proteins.
o This process is called ansonization (that is, preparation for feeding).
O The major opsonins present in serum are:
Opsonin Deseription
|gG Fe fragment Naturally dccurring antibodies in serum coat bacteria,
enhancing recognition by PMNs.
C3b opsonin A fragment produced by activation of the complement
pathway,highly chemotactic, attracting PMNS to
bacteria.
Lectins Carbohydrate-binding proteins in plasma that bind to
bacterial cell walls.
Engulfment:
o Opsonized particles or microorganisms attach to the phagocyte.
Pseudopodia form, wrapping around the particle.
o
Actin filaments activate beneath the cell membrane.
Phagosome Formation:
o Plasma membrane detaches from the particle.
o A
membrane -enclosed phagocytic vacuole (phagosome) forms.
Phagosome Maturation:
o Phagosome fuses with lysosomes in the cell.
O This fusion ereates a larger vacuole known as the phagolysosome.

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 Infammation

Killing and Decomposition:

o Phagocytes primarily function to killand break down microorganisms.
o Antibacterial substances are responsible for kitling microorganisms.
o Hydrolytic enzymes degrade microorganisms after they are killed.

Intracellular Mechanisms:
o Oxidative bactericidal mechanism involving free oxygen radicals:
* MPO-dependent: Enzyme MPO acts on H,0, with halides to form hypohalous
acids.
* MPO-independent: Production of OH ions and superoxide singlet oxygen (0')
from H,0, in the presence of O, (Haber-Weiss reaction) or Fer (Fenton reaction).
o Oxidative bactericidal mechanism by lysosomal granules.
o Non-oxidative bactericidal action.
Extracellular Mechanism:
o Granules: Release proteolytic effects outside the cell.

O Immune Mechanisms: lwmmune-mediated tysis of microorganisms occurs outside

the cell through cytolysis, antibodyFediated lysis, and cell-mediated cytotoxicity.
(B) AUTOPHAGY
Autophagy is a cellular process that recycles and degrades damaged or unnecessary
cellular cOmponents. It comes in several forms:
O Macroautophagy: Utilizes double -memorane structures (autophagosomes) to engulf
and break down cellular components.
o Microautophagy: Directly engulfs cellular components into lysosomes.
o Chaperone-mediated autophagy (CMA): Targets specific proteins for degradation.
O Autophagy serves these key functions:
* Celltular Cleanup: Removes damaged organelles and proteins.
* Nutrient Recycling: Provides nutrients during nutrient scarcity.
* Quality Control: Maintains cellular health by eliminating dysfunction.
* lmmunity: Helps fight intracellular pathogens.
* Ageing and Disease: Dysregulation is linked to diseases.

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o Regulation: Autophagy istightly regulated by a conplex netvwork of signalling
pathways, including the mTOR pathway. AMPK pathway, and various autophagy
related genes (ATGS).
o induction: Autophagy can be induced by stressors such as nutrient deprivation,
Oxidative stress, and intracellular pathogens.
o A commonly used marker of autophagy is the protin LC-3 (Microtubule -associated
protein 1A/13-light chain 3).
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 80

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 Infammation

9. (1) Write briefly on scar formation. (5 marks)

(U) write briefiy on healing by primary and secondary intention.

(u) Enumerate the factors afecting wound healing.

Answer:
o Repair (healing) is the body's response to injury in an attempt to restore normal
structure and function.
o It involves two processes:
Regeneration (restoration of normal cells) and Scarring
(connective tissue deposition)

O STEPS IN SCAR FORMATION

o Inflammation: wWithin 24 hours, there is an initial inflammatory response with the
exudation of plasma, neutrophils, and a few monocytes.
o Cellproliferation: Epitlhelial cells, endothelial and other vascular cells, and fibroblasts,
proliferate and migrate to the wound.
* Epithelial cells migrate to cover the wound
Endothelial cells proliferate to form new blood vessels (angiogenesis)
* Fibroblasts proliferate and deposit the collagen fibres.
o Formation of granulation tissue:, Fibroblasts, deposited loose connective tissue,
blood vessels and leukocytes form the gianulation tissue.
O Deposition of connective tissue: Granulation tissue is replaced by deposition of
collagen.

(I) HEALING BY PRIMARY INTENTION

o Wounds with opposed edges (clean and uninfected wounds) heal by primary
intention.
o
Steps involved in primary intention:
Wound

o
Filled with blood clot and infiammatory cells
o Neutrophils appear at the margin of the wound

O Neutrophils largely replaced by macrophages

o Granulation tissue formation begins and infitrates the incision space
o Macrophages clear the cellular debris

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 MedEd FARRE: Pathology
o
Granulation tissue fills the incisional space.
o Neovascularization is at its peak
o Colagen fibres become abundant and bridge the incisional gap
O
Epidermis regains its normal thickness

o Continued accumulation of collagen and proliferation of fibroblasts

o lnfiltration, edewma and vascularity decreases.

o Scar tissue formation by the end of the first month

o Wound strength increases
Healing by secondary intention:
o Associated with large defects filled with blood clots, necrotice debris and exudate.
O
Inflammatory reaction is more intense
o Large amounts of granulation tissue are deposited.
o Demonstrates 'wound contraction' which is mediated by myofibroblasts and aids
in decreasing the gap between the dermal edges of the large wound.
o
Substantial scar fornation and thinning, of the epidermis are seen.
Healing by Tertiary tntention (Delayed Primary Intention):
o
Definition: Healing by tertiary intention occurs when a wound is initialiy left open,
then surgically closed later after infection risk is reduced.
o Example: An abdominal abscess incision is initially left open to drain the infection,
then closed surgically once it's under control.
Healing by9
primary
Features
intention |Healing by secondary intention
|Nature of wound Seen in incised wounds with Seen in large, open, infected
well-opposed edges (clean wounds with separated edges;
and uninfected wounds) associated with extensive loss
of cells
|Amount of fibrin Filled with a moderate Filled with a large blood
and blood amount of fibrin and blood clot and necrotic debris and
exudate
tnflammatory Less intense More intense
reaction
Amount of Less granulation tissue Extensive granulation tissue
granulation tissue

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 inflammation

Wound cOntraction Wound contraction is not Wound cOntraction is seen

seen
|Complications Less common More cOMMOn

(u) FACTORS AFFECTING WOUND HEALING

Factors Affecting Wound Healing

Local Systemic
Decreased blood supply Old age, Malnutrition

Denervation Anemia
Local infection Obesity

Foreign body Systemic infection (DM), Collagen disorders

(Marfan, Ehler Danlos)
Mechanical stress Drugs (steroids)
Large amounts of hemorrhageVitamin and trace metal (zinc and copper)
and neCrosis deficiency

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 108

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MedEd FARRE: Pathology

10.(0 write briefly on factors contributing to thrombus formation (Virchow's triad)

(w) Differentiate betweenarterial and venus thrombi.
(u) Differentiate between antemortem clot and postmortem clot. (5 marks)
Answer:
O FACTORS AFFECTING THROMBUS FORMATION
O
Endothelial injury
o Abnormal blood flow: Stasis and turbulent blood flow
o Hypercoagulable state: inherited (e.g., factor V Leiden) or acquired (disseminated
cancer)

Endothelial injury

Virchow's
Traid
JaiShreeRam
Hypercoagulability Venous stasis

Hypercogulable state

Primary (Genetic) Secondary (acquired)

Factor V mutation: Strong risk factor:
o
Factor V Leiden (resistance to o Prolonged bed rest or immobilization
activated protein C) o Myocardial infarction
o lncreased levels of factors VIll, IX,
o Atrial fibrillation
XI or fibrinogen.
o Prothrombin mutation (leading to
O
Tissue injury (surgery, fracture, burn)
increased levels) O Cancer
o Antithrombin Ill deficiency o Prosthetic cardiac valves
o
o Protein C deficiency Disseminated intravascular coagulation
o
Protein S deficiency o Heparin -induced thrombocytopenia
O
Antiphospholipid antibody syndrome

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 Inflammation

D PIEFERENCE BETWEEN ARTERIAL AND VENOUS THROMBI

Features Arterial thrombi Venous thrombi

Sites Common in coronary. Superficial varicose veins and
cerebral, iliac and femoral deep veins of the leg, e.g.,
arteries (vessels with active femoral and iliac veins (vessels
blood flow) with less active blood flow)
Pathogenesis Due to endothelial injury Due to venous stasis
(as in atherosclerosis or
turbulent blood flow)
Progression Grows in a retrograde Extends in the direction of
direction from point of blood flow
attachment
Occlusion Do not occlude lumen Invariably occlusive
cOmpletely
Gross Grey-white, friable, Dark red with fibrin strands:
prominent lines of Zahn lines of Zahn less prominent
|Or absent
|Morphology Lines of Zahn show paler Constituted by mnore RBCs and
layers of fibrin and platelets less fibrin
alternating with darker
layers of RBCsiShrecRam
|Complications Ischaemia/infarction of vital Embolism, oedema, ulceration
Organs

(I) DIFFERENCE BETWEEN ANTEMORTEM CLOT AND POSTMORTEM CLOT.

Features Antemortem clotsthrombi Post-mortem clots
Origin Formed as part of normal Form in a dead person due
haemostasis or pathologicalto sedimentation and settling
derangement clotting down of blood components
a
pathway in living person
Gross Dry,granular, firwm and Gelatinous, soft and rubbery
friable Lines of Zahn are Dark red, dependent portion
prominent in arterial of the clot is called currant
thrombi jelly and yellow supernatant,
free of red cells is called
chicken fat
|Shape a
Do not form cast of the Take the shape of the vessel or
vessel its bifurcation forms a cast of
the vessel
|Attachnent to Presenti strong Very weak
vessel wall

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Location |Anywhere in the body in dependent parts of the

body
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 125
D00

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 inflammation

11. () What are the major components of acute inflamimation? (10marks)

(I) Enumerate the chemical mediators of inflammation.
(I) Write briefiy the causes of chronic inflammation.
() What is granulomatous inflammation? Enumerate the causes of granuloma.
(V) Differentiate between acute and chronic inflammation.
Answer:
() INFLAMMATION
o
tnflammation is defined as the local response of living tissues to injury from any
agent.
Inflammation

Acute inflammation Chronic inflammation

(Transient process which occurs (When causative agent of acute
within minutes of injury and inflamimation persists for
lasts for hours or days) long time)

Signs of Inftammation JaiShreeRam

o rubor (redness);
o tumor (swelling);
o calor (heat); and
o dolor (pain).
o There are two major comp0nents of inflammation:
Vascular events: Alteration in the microvasculature (arterioles, capillaries
and venules) is the earliest response to tissue injury. Vasodilation occurs and
permeability increases.
* Cellular events: Immigration of leukocytes from vessels to the site of injury.
The sequence of cellular events:
o Margination. Rolling, and adhesion to endothelium
o
Migration across the endothelium (diapedesis)
o
Migration in tissue towards chemotactic stimuli.

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 MedEd FARRE: Pathology
Normal axial flow (RBCs confined to acentral column with WBCs oriented
peripherally)

Margination and pavementing of wBCS

Rolling and Adhesion

Emigration and diapedesis

Chemotaxis
(in CHEMICAL MEDIATORS OF INFLAMMATION

A list of chemical mediators is given below

Chemical Mediator Source Function in lnflammation
Histamine |Mast cells, basophils Vasodilation, increased vascular
|permeability, itching
Prostaglandins Various cells Vasodilation, increased vascular
permeabilty, pan
Leukotrienes Various cells Bronchoconstriction, increased
vascular permeability
Cytokines (e.g., ILS. lmmune cells Immune cell communication,
TNFalpha) recruitment, activation
Chemokines Various cells Attraction of leukocytes to the
inflammation site
Complement Plasma proteins inflammation promotion,
System opsonization, celllysis
Bradykinin Plasma protein Vasodilation, increased vascular
|permeability, pan
Nitric oxide (NO) Various cells Vasodilation, blood flow regulation
Serotonin Platelets Vasoconstriction, blood clotting
Platelet-activating mmune celis Platelet aggregation, inflammation
factor (PAF) promotion
l() CHRONIC INFLAMMATION
o Chronic inflammation is a response of prolonged duration (weeks or months) in
which inflamimation, tissue injury, and attempts at repair exit simultaneously.
Causes of chronic inflammation

24
 Inflammation

o Persistent infections: Chronic infections caused by pathogens such as bacteria (e..

tuberculosis), viruses (e.g., hepatitis), or parasites (eg., malaria) can trigger long
lasting immune responses, leading to chronic inflammation.
o
Autoimmune Diseases: Conditions like rheumatoid arthritis, systemic lupus
erythematosus (SLE), and inflammatory bowel disease (IBD) involve the immune
systerm mistakenly attacking the body's own tissues, resulting in chronic
inflammation.
o Prolonged exposure to potentially toxic agent.
o Recurrent episodes of acute inflammation
Morphologic Features of Chronic Inflammation
o lnfiltration by mononuclear cells (lymphocytes, macrophages and plasma cels)
o Tissue destruction due to persistent offending agent/inflamimation
o Healing by connective tissue repacement of damaged tissue includes proliferation
of blood vessels (angiogenesis and fibrosis)
(IM GRANULOMATOUS INFLAMMATION
o Granulomatous inflammation is a distinct form of chronic infiammation
characterized by the formation of specialiedstructures called granulomas.
o Granuloma: A granuloma is a microscopic
aggregation of activated macrophages
which transform into epithelioid (epithelial-like) celis. Epithelioid cels have scanty
cytoplasm. These are surrounded by the rim of lymphocytes and plasma cells.
Necrosis may or may not be present, f present it is called a caseating type of
granuloma (eg. TB). Epithelioid cells fuse to form giant cells.
Types of Granuloma

Type Examples of Associated Conditions

| Infectious o Tuberculoid Granuloma (Mycobacterium tuberculosis)
Granuloma o Leprosy Granuloma (Mycobacterium leprae)
o Fungal Granuloma (Histoplasmosis, cryptococcosis, etc.)
Syphilitic Granuloma (Treponema palliduim)
o Cat Scratch Disease (Bartonella henselae infection)

MedEd
25
 MedEd FARRE: Pathology

Non-infectious o Sarcoidosis
or Immune o Granuloma annulare
Granuloma
o Wegener's granulomatosis
o Crohn's disease
o
Subacute granulowmatous thyroiditis

Foreign Body o Formed around foreign bodies such as talc, sutures, wood|
Granuloma splinters, etc.

() DIFFERENCE BETWEEN ACUTE AND CHRONIC INFLAMMATION

Features Acute Inflammation Chronic lnflammation

Major Cells Neutrophils, |Mononuclear Cells (e.., Monocytes,
nvolved Eosinophils, BasophilsMacrophages, Lymphocytes)
|Onset lmmediate/Rapid |Insidious/Delayed
Duration Few Days |Up to Many Months or Years
Outcomnes Resolution, Fibrosis, Tissue Destruction and Scarring
Chronic Inflammation
Cardinal Signs of Present (e.g..Redness144sent
nflammation Heat, Swelling)
|Angiogenesis Absent Present
Tissue Destruction Absent Present
and repair
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 75
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 85
Reference: Pathotogic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 96
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 100

26
 Inflammation

12. () Define and classify Shock. (10 marks)

() write down the pathogenesis and markers of shock.
Answer:
() SHOCK

Shock is defined as a state of circulatory faiure that impairs tissue perfusion and leads to
cellular hypoxia.
Classification
o Hypovolemic Shock: This type of shock occurs when there is a significant loss of
blood or plasma, causing a decrease in biood volume. It can result from trauma,
severe bleeding (eg.. hemorrhage), dehydration, or fluid loss from burns.
o Cardiogenic Shock: Cardiogenic shock arises from a malfunction of the heart, where
the heart's ability to pump blood is severely impaired. Common causes include
heart attacks (myocardial infarctions), severe arrhythmias, or heart failure.
o
Distributive Shock:
Septic Shock: Caused by a systemic infection that triggers a widespread
inflammatory response, resulting in blood vessel dilation and reduced vascular
tone. Septic shock is a subset ofidistributive shock and is often associated with
severe sepsis.
* Anaphylactic Shock: Occurs due to a severe allergic reaction, leading to the
widespread release of histamines and other chemicals, causing rapid blood vessel
dilation.
* Neurogenic Shock: Results from spinal cord injury or severe nervous system
dysfunction, leading to loss of vascular tone and dilation of blood vessels

(I) PATHOGENESIS OF SEPTIC SHOCK

The pathogenesis of septic shock involves several key steps:
O Infection: The process begins with the introduction of infectious agents into
the body. eading to localized infection at the site of entry or spreading to the
bloodstream (bacteremia).
o Inflammatory Response: The body's immune system recognizes the infection and
mounts an inflammatory respOnse to eliminate the pathogen. lmmune cells release
various signaling molecules, including cytokines (e.g., interieukin-1 and TNF
alpha), as part of the immune response.

(27 MedEd
MedEd FARRE: Pathology

o Systemic Inflammation: In septic shock, the immune response becomes dysregulated.

Excessive release of inflammatory mediators leads to widespread inflamwmation
throughout the body, causing blood vessels to dilate (vasodilation) and become
more permeable.
o Hypotension and Organ Dysfunction: Vasodilation and increased vascular
permeability vesult in low blood prassure (hypotension) and impaired blood low
to vital organs, leading to organ dysfunction. Organs most commonly affected
include the kidneys, liver, lungs, and heart.
o Coagulation Dysfunction: Septic shock can also lead to abnormal blood clotting
(disseminated intravascular coagulation or DIC), further impairing biood flow and
potentially causing bleeding complications.
o Cellular Dysfunction: Cells throughout the body experience impaired oxygen and
nutrient delivery, leading to celiular dysfunction and, in severe cases, multiple
organ failure.
o Hypoxia and Lactic Acidosis: As tissues become deprived of oxygen, lactic acid
builds up in the bloodstrean, contributing to wmetabolic acidosis and worsening
organ dysfunction.

icroba products (Pathogen-Assocated Nolecular Patterns or PAPS)

JSheeRm

Actvaton of G protein-coupled receptors which Actrvaton ol signat transducing proteins caied TLRs
recogniue bacterial peptdes and NOD 1 and 2

Complement actrvaton Açtvaton of innato immune cells. Actrvaton of coagu'stion cascade

Actvation of C3 to C3a Actvaton of endothelal cetls and leukOcyles and release of nediators. Release of procoagulants

Actrvaton of thrombin

actvatos
Release of vanous pro infarnnatory mediators and cytokines

tyocardial deprossion Fever

Low penpheral tesistanca ARDS Coagulabon Metabose abnormaltes Increased vascular permeabtty
Low cardiac output DIC Genetalzes decreased perfuson
ofgan dystuncton

Markers of Sepsis Description

28
 lnflammation

C-reactive protein (CRP) (ndicates inflammation and infection.

Procalcitonin (PCT) Suggests bacterial infection.

White Biood Cell Count Elevated or reduced levels can indicate infection.
(WBC)
Lactate Elevated leveis indicate tissue hypoxia.

Blood Cultures ldentifies the causative microorganism.

Sequential Organ Failure Assesses organ dysfunction.
|Assessment (SOFA) Score
Quick Sepsis-Related Organ ldentifies patients at risk of sepsis.
Failure Assessment (qsOFA)
Inflammatory Markers Elevated levels of various markers indicate sepsis.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 134

JaiShreeRam

29 MedEd
 MedEd FARRE: Pathology

13. (0) write down the coagulation pathways and Enumerate inhibitors of coagulation.
() write briefly on disorders of coagulation. (10marks)
Answer:
(0 There are two main coagulation pathways: the intrinsic pathway and the extrinsic
pathway. These pathways converge at a common final pathway to form a stable
blood clot.

The three pathways that makeup the classical blood coagulation pathway

Intrinsic Xl -Hageman factor, a serine protcase

XI - Plasma thromboplastin, antecedent serinc proteasd
IX -Christmas factor, scrine protcase
surface contact
VIl
-Stablc factor, serinc protcase
XII| - Fibrin stabilising facto, a transglutaminasc
PL - Platclct membranc phospholipid
Xl XII,
Ca*- Calcium ions
TF - Tissue Factor
(,
=active form)
XI XI,
Extrinsic
TE:VI, tissue damage
IX IX,
JaisyoeRam
vII, [Link]
X
X, X
Common
(v, PL, JCa") XII

prothrombin thrombin
(serinc protcasc)
Xl,
fibrinogen fibrin stable fibrin
clot

Inhibitors of coagulation
o Antithrombin ll: This protein inhibits thrombin (factor lla) and other clotting
factors, such as factor Xa, to prevent excessive clot formation.
o Protein C and Protein S: These proteins, in combination with thrombomodulin,
inactivate factor V and factor Vil, limiting clot propagation.
O TissueFactor Pathway Inhibitor (TFP): TFPI inhibits the tissue factor-factor VIla
complex, helping regulate the extrinsic pathway.

30
 Inflammation

o Plasmin: Plasmin is an enzyme that breaks down fibrin strands, leading to clot
dissolution (fibrinolysis).
o Heparin-like molecule: This anticoagulant enhances the activity of antithrombin
li, thus inhibiting mutiple coagulation factors.
(I) BLEEDING AND COAGULATION DISORDERS

Disorder Cause(s)

Hemophilia A Deficiency or dysfunction of clotting factor VI

Hemophilia B Deficiency or dysfunction of clotting factor IX

Von Willebrand Disease Deficiency or dysfunction of von Willebrand factor

Thrombocytopenia Abnormaly low platelet counts

Disseminated Intravascular Overactive clotting mechanisms and abnormal
Coagulation (DIC) coagulation and bleeding
|Antiphospholipid Syndrome Autoimmune production of antibodies against
|(APLA) phospholipids
Deficiency or dysfunction of platelet glycoprotein lb
Bernard-Soulier Syndrome receptor
Deficiencyor dysfunction of platelet glycoprotein
Glanzmann's Thrombasthenia
lb-làreceptor)
mimune Thrombocytopenic Autoimmune destruction of platelets
|Purpura ((TP)

Immune Thrombocytopenic Purpura (ITP)

o Immune Thrombocytopenic Purpura (ITP) is an autoimimune bleeding disorder
characterized by a low platelet count and an increased risk of bleeding
The pathogenesis involves an autoimmune response where the body's immune
o

system mistakenly attacks and destroys its own patelets.

o Laboratory findings include a significantly reduced platelet count (usually 10,000
SO.000/u),occasional large platelets in the blood film, increased megakaryocytes
in the bone marrow, prolonged bleeding time, normal clotting time, and the
presence of anti-platelet lga antibodies.
o
Plateiet survival studies indicate a markedly reduced platelet lifespan, sometimes
less than an hour, compared to the normal lifespan of 7-10 days.

31 RMedEd
MedEd FARRE: Pathology

o Management of ITP typically involves corticosteroids as first-line treatment to

suppress the immune response and increase platelet count, while second-line
options include ivIG, immunosuppressive drus, and splenectomy for refractory
Cases.
Von Willebrand
Characteristic Hemophilia A Hemophilia B Disease (WD)
Deficiency or Deficiency of Genetic (autosomal
Cause dysfunction of IX dominant), rarely
factor acquired
factor VIII
X-linked recessive X-linked recessive Autosomal
Inheritance (primarily affects (primarily affects dominant (genetic),
males) males) can be acquired
Symptoms o Prolonged Similar to Variable symptoms
bleeding after Hemophiia A depending on the
injuries, surgery. type:
or dental O Type 2: Mild
procedures to moderate
o Haemarthrosis deficiency of vWF.
Gastrointestinal o Type 2:
and genitourinary Dysfunction in
bleeding OthenaiShrecRam VWF function
bleeding (qualitative defect
manifestations in vWE)
O Type 3: Severe
deficiency of vwF,
and often factor
VIlas well
Laboratory o Prolonged APTT o Prolonged APTT o
Prolonged
nvestigations O o Low factor |X bleeding time and
Lowered factor|
VIIl
activity levels clotting time
O Reduced
plasma VWF
cOncentration
o Delayed
Ristocetin
induced platelet
aggregation
o
Reduced factor
VIll activity
Disseminated Intravascular Coagulation (DIC)
o It is a complex disorder involving intravascular thrombosis as well as bleeding.
32
 Inflammation

Pathogenesis:
o Tissue injury in conditions like Hemophilia A, Hemophilia B, and Von Willebrand
Disease exposes clot-promoting substances.
o This triggers the clotting cascade, forming tiny clots throughout the bloodstream.
o As clotting factors and platelets are consumed, it leads to a bleeding tendency.
o Simultaneously, the body activates fibrinolysis to break down these clots.
o
This process can cause organ dysfunction and, in severe cases, circulatory collapse
and shock.
Placental abruption (premature detachment of the
placenta)
o
Obstetric Complications Amniotic fluid embolism
O
Septic abortion
o Chorioamnionitis
o Sepsis (severe systemic infection)
Infection o
hemorrhagic fevers (e.g., Ebola, dengue)
Viral

Neoplasms Cancer with widespread metastasis (e.g.. APML)

o
Trauma (severe injuries and burns)
JaaShrCeRi
o Major surgery (especially involving blood vessels or
organs)
Others o Snake bites (some venomous snake bites)
Immunological reactions (e.g., acute graft -versus
host disease)
o Massive transfusion

Laboratory diagnosis: Consumption of clotting factors and platelets and intravascular

haemolysis:
o Decreased levels of Factors II, V and VIl

o Fibrinogen level below 1.0 g/L

o Increased FDP (fibrin degradation products, e.g.. FDP, D dimer)
o Platelet counts low, prolonged thrombin time.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 121

MedEd
33
 Immunology
14. (0) Write down the Mechanism of T cell depletion in HIV infection.
() Enumerate the tumors associated with AIDS. (3 marks)

Answer:
MECHANISMS OFT CELL DEPLETION IN HIV INFECTION
Direct Killing:
o Virus directly kills CD* T lywmphocytes.
o A
key factor in T cell loss.
Chronic Activation:
o Uninfected cells become chronically activated.
o This chronicactivation leads to apoptosis (cell death).
Inflammasome Pathway:
o Noncytopathic HIV infection
triggers the inflammasome pathway.
o
Resulting in cell death through pyroptosis.
Lymphoid Tissue Destruction:
o HIV JaiShrgcRn
infects cells in lymphoid tisšues (spleen, iynph nodes, tonsils).
o Leads to the destruction of these vital immune system components.
Thymic Progenitor Cell Infection:
o HIV directly infects thymic progenitor cels.
o Results in the loss of immature precursors of CD* T cells.
Syncytia Formation:
o Infected and uninfected cells fuse.
o This fusion creates syncytia (giant cells).
Qualitative T Cell Defects:
o Even in asymptomatic HIV-infected individuals, there are qualitative defects in T
cell function.

TUMORS ASSOCIATED WITH AIDS

34
 (mmunology

Patients with AIDS have an increased risk of certain tumors:

o
Kaposi's Sarcoma (KS)
o Non-Hodgkin Lymphoma (NHL)
o lnvasive Cervical Cancer
o Hodgkin Lymphoma
o Anal Cancer
O Lung Cancer
o Liver Cancer (Hepatocelular Carcinoma)
o Colorectal Cancer
Reference: PathologicBasis of Disease, Robbins and Cotran, 10th Edition, Page No. 2.51, 256

JaiShreeRam

35) (iMedEd
MedEd FARRE: Pathology

15. Describe the mechanism and types of graft rejection. (5 mark)

Answer:
o
Transplant rejection is defined as the recognition of grafted tissue as a foreign
body. it is a complex process and involves both cel-mediated immunity and
humoral immunity.
CELL-MEDIATED IMMUNE REACTIONS
o in cell -mediated graft rejection, recipient T cels. primarily CD and Cp T cells,
play a central role. It is mediated by two main pathways
* Direct pathway: Host CD and cD** T cells directly recognise MHC molecules on
the surface of the graft APCs.
* indirect pathway: Host T lymphocytes recognise antigens of the graft after they
are presented by their own APCs

HUMORAL IMMUNE REACTIONS

o These are due to preformed circulating antibodies due to pre-sensitisation of the
recipient before transplantation.
Types of graft rejection:

Type Time Mechanism Mediator Pathology

Pre-existing Pre-existing Graft necrosis
antibodies veact recipient and immediate
Within with donor antigens,antibodies removal.
Hyperacute
minutes to leading to rapid (lga, lgM)
Rejection
hours complement
activation and
thrombosis.
Mediated by T cells T cells and Tissue damage:
First fevw
Acute and antibodies antibodies can be cellular
weeks to
Rejection activated by graft (igG. lgM) or humoral.
months
alloantigens.
Slow, progressive T cells, Giradual graft
Chronic Over months immune response antibodies, deterioration
Rejection to years leading to graft and other and
fibrosis and scarring. factors dysfunction.
Difference between Acute and chronic rejection

36
 Immunology

Characteristics Acute Rejection Chronic Rejection

o
Typically occurs within Developsgradualy over
Timing weeks to months after months to years after
transplantation. transplantation.
o Sudden onset of rejection o Slow and insidious onset;
Onset may be asymptomatic in
symptoms. early stages.
o Predominantly cell o Cellmediated vejection
mediated immune characterized by
Mechanism response involving CD* progressiVe organ
and Cp- T cells. dysfunction
o Acute inflammatory O Chronic mmune response
response characterized by leads to fibrosis and
tmmune Response
the infiltration of immune scarring of graft tissue.
cells into the graft.
o Features include fibrosis,
o Cellular infiltraton,
Histological Features vasculitis, tissue damage, scarring, and narrowing
of blood vessels
and edema are cOmmon. (arteriosclerosis).
o
Tissue damage may be Results in irreversible
Graft Damage reversible
with prompt graft dawmage and
treatmentlShrteRm dysfunction.
o Responds well to high
o Challenging to treati
may require aggrressive
dose corticosteroids
Treatment and immunosuppressive immunosuppression, but
outcomes are often less
medications.
favorable.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 234

(37 RMedEd
 MedEd FARRE: Pathology

16. () Classify amgloidosis and write down the pathogenesis. (10 marks)
(U) Write down the stains used for amyloidosis.
Answer:
CLASSIFICATION OF AMYLOIDOSIS
Systemic Amyloidosis
Associated
Type Cause Manifestations
Conditions
o Plasma cell Cardiac (e.g.,
disorders restrictive
(eg., multiple cardiomyopathy)
myeloma)
o Gl (e.g., GI (e.g.
macroglossia, macroglossia,
hepatomegaly) |hepatomegaly)
o Renal (e.g., Renal (e.g.,
Primary Resulting from lg nephrotic nephrotic
amyloidosis Light chains (AL) syndrome) syndrome)
O
Hematologic (e.g..|Hematologic (e.g.,
JaiSHreceasylbruising. easy bruising)
splenomegaly)
Neurologic (e.g., Neurologic (eg.,
neuropathy) neuropathy)
o Musculoskeletal Musculoskeletal
(eg., carpal |(e.g., carpal tunne)
tunnelsyndrome)
|Secondary Resulting from O Chronic Seen in chronic
amyloidosis Serum Amyloid A inflammatory inflammatory
(AA) conditions (e.g., conditions
rheumatoid
arthritis, IBD)

38
 lmmunology

Dialysis-related Resutting from B2 o Patients with Seen in patients

microglobulin ESRD and/or with ESRD and
On long-term dialysis
dialysis
Localized Amyloidosis

TYpe Cause Characteristics

|Alzheimer disease Resulting from B-amyloid Cleaved from amyloid
protein precursor protein (APP)
Type 2 diabetes Resulting from Islet awmyloid Caused by deposition of
mellitus |polypeptide amylin in pancreatic islets
Medullary thyroid Resulting from Caleitonin Associated with medullary
cancer thyroid cancer
Isolated atrial Resulting from ANP Common in normal aging,
amyloidosis associated with increased
risk of atrial fibrillation
Systemic senile Resulting from Normal (wild-| Seen predominantly in
amyloidosis type) transthyretin (TTR) cardiac ventricles, cardiac
dysfunction more insidious
JaiShreeRam | than in AL amyloidosis
Hereditary Amyloidosis

Type Cause Characteristics

Familial amyloid Resulting from Mutated o Deposition in ventricular
cardiomyopathy transthyretin (ATTR) endomyocardium
o
Leads to restricive
cardiomyopathy.
arrhythmias
Familial amyloid Resulting from Mutated o Due to transthyretin gene
polyneuropathies |transthyretin (ATTR) mutation

o Amyloidosis is agroup of rare diseases characterized by the abnormal accumulation

of protein aggregates called amyloid fibrils in various tissues and organs throughout
the body.
o These amyloid fibrils are composed of misfofded proteins that can disrupt normal
tisue structure and funetion, leading to a range of symptoms and organ damage.

MedEd
39
 MedEd FARRE: Pathology

PATHOGENESIS OF AMYLOIDOSIS
Production of norma!
Production of abnomal protein
amounts of mulants

Acquired mutations Chronic infnammation

Native folded protein

Monoconal b-ymphocyte Macrophage activaton IL

Amyloidogenic intermediate protferation 1
and 6

Mutant protein
Beta-shoet scture occumulates Plasma ells teleasing aggregates
SAA protein
lightchains of
immunoglotbulins

Fibrl AA protein ATTR protein

AL protein

Stains for amyloidosis

o Congo red: Ordinary light-pink or red colour
o Polarized light-apple green birefringence (due to cross-b-pleated configuration)
o Metachromatic stains (Rosaniline dyes): Examples are methyl violet and crystal
violet. Awmyloid takes up a rose pink çolour with these dyes.
o ShyeeRam
Fluorescent stains of Thioflavin and S: In ultraviolet light, amyloid fluoresces
yellow.
o lmmunohistochemistry: Anti-AA and anti-lambda, anti-kappa antibodies can be
used to differentiate between different types of amyloid.
o Toluidine blue: Blue colour in ordinary light and dark red, birefringence under
polarized microscopy.
O Alcian blue: Blue-green colour.
O
PAS (periodic acid-schiff) and H&E stains: Pink colour.
Histopathology
O Kidney: Pale waxy kidney
o Spleen: Sago spleen (White) or Lardaceous spleen (Red)
o Liver: Causes hepatomegaly
o
Heart: Focal subendocardial accumulation.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 259

40
 (mimunology

17. A 25-year-old female presents to the clinic with a complaint of recurrent

skin rashes. She reports that over the past few mOnths, she has noticed the
development of itchy. red, raised hives on her skin, particulariy after eating
certain foods like shrimp, strawberries, and nuts. She also mentions occasional
difficulty in breathing during these episodes. Her medical history is unremarkable,
and she takes no medications.
Upon examination, the physician observes raised wheals on the patient's arms
Qnd neck, consistent with urticaria (hives). The patient's vital signs are within
normal limits
(0 Which type of hypersensitivity reaction is this? Also, write two more examples
of this.
(0) Write down the mechanism of all types of hypersensitivity with examples.
(u) Diferentiate between Type I
and Type I hypersensitivity. (10 marks)
Answer:
() Diagnosis: Type 1 hypersensitivity
o Two more examples are anaphylaxis, allergies, and bronchial asthma.
() Mechanism of Type 1 hypersensitivity
o Examples: Anaphylaxis, allergies, bronchial asthma.
Type 1
Activaton of Th2 colls and lgE class
switching in B cells
B coll

Production of lgE

Bindng of lgE to FceRl on mast cells

Ropoal oxposuro lo allorgon

Activaion of mast coll, reloaso of mediators

Vasoactive aminos, lipid medators Cytokings

Immedate hyporsonsitivity Late phase reacton

teaction (minutos ofter ropoat (2-24 hours after ropeat
Oxposuro to allorqen) xposure to altergen)

41 RU MedEd
MedEd FARRE: Pathology

o Mechanism of Type 2 hypersensitivity

o Examples: Goodpasture syndrome, Myasthenia gravis, Graves disease etc.
Type ll hypersensitivity

Antibody
Complement
modiated
Fc portion Lysis
Local tissue inlammation

Opsonisation
J and coll death

Macrophage receptors Attachos to

the Fc portion of an antigen
anlibody complex Antibody dependent cellular
cytotoxicity

o Mechanism of Type 3 hypersensitivity

o Examples: SLE, PSGN, Serum sickness, polyarteritis nodosa.

Type Ill

Deposition of antigen-antibody complexes

JaiShreRam

complement activation

recruitment of leukocytes by complement products

and Fc receptors

release of enzymes and other toxic molecules

o Mechanism of Type4 hypersensitivity
O Examples: Rheumatoid arthritis, Multiple sclerosis, and Psoriasis.

42
 Immunology

Type IV hypersensitivity reaction

Initial exOosure to allergen Since this takes several

(typically a drug) days, Type IV
Hypersensitivity is also
called "delayed-type
hypersensitivity
Macrophage engulfs antigen

Antigen presentation on MHC II molecule

Particular CD4+ Th cell recognises antigen or

allergens surface as potentially harmful
JaiShreKam

cells activate
macrophages,mast cells

infiammation and destruction of

involved tissue

(II) DIFFERENCE BETWEEN ALL TYPES OF HYPERSENSITIVITY REACTION

Features TYpe Type l Type ill Type iV
Reaction Anaphylactic Cytotoxic Serum sicknessDelayed
type Arthus reaction |hypersensitivity
Cells Mast cells, Non sensitized T cells,Sensitized
CD+

tnvolved basophils, macrophages, macrophages.|T-lymphocytes

eosinophils, NK cells, CDT Cells mediate the
neutrophils, neutrophils, release of
monocytes, CDeosinophils, B |gmphokines
T cells, B cells cells

43 RMedEd
 MedEd FARRE: Pathology

|Antibody lgE lgG, igM IgG, lgM None

Type
Chemical IL-3, 4, 5; Complement Lymphokines, Required
Mediators vasoactive System IL-12, IL-2,
amines INF-Y, TGF-B.
TNF-a
Antigen Required Not required Required Required
Presentation
by APC
Pre |Required Not required Required Required
sensitization
PathogenesisFormation of lgEOpsonization Formation T cell -mediated
and imwmediate and and deposition cytolysis,
velease of |phagocytosis, of Ag-Ab release of
mediators ADCC, anti complexes lysosomal
to recruit receptor activates enzymes, and
inflammatory antibody type complement other toxic
cells inducing system agents
inflammatory
changes
Time for Minutes Hours to daysHours to days Hours to days
Onset JaiShreRanh
Examples Allergic Transfusion qlomerulo Transplant
bronchial hemolytic nephritis, rejection
asthma reactions, rheumatoid
Serum sicknessarthritis
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 204

44
 Immunology

18. Deseribe the etiopathogenesis and clinicopathological features of systemic lupus

erythematosus (ŠLE). Short note on imimunologic tolerance. (20 marks)
Answer:
o SLE is an autoimmune disorder which involves multiple organs in the body.

PATHOGENESIS OF SLE
Genetic Factors:
o Specific polymorphiswns of HLA-DQ are associated with autoantibody production.

Environmental Factors:
o Triggers include drugs (e.g., hydralazine, procainarnide), UV light, and hormonal
factors (predominantiy affect femaes).
Immunologic Factors:
o
Susceptibility genes disrupt self-tolerance.
o Type I interferons (IFN) stimulate B cels.
o Tissue-damaging antibodies target self-antigens.
o lmmune complexes (type ll hypersensitivity) drive inflammation and tissue damage.
Clinical features: It is a multisystemic disorder
o Malar Rash (Butterfiy Rash): A characteristic rash that appears on the cheeks and
bridge of the nose, often in a butterflysháped pattern.
Discoid Rash: Red, raised patches with scaling and potential scarring that occur
on the skin, particularly on the face, scalp, and neck.
o
Photosensitivity
o
Oral and Nasal Ulcers
o Arthritis and Joint Pain
O Fever
o Fatigue
o Alopecia (Hair Loss)
o Renal lnvolvement (Lupus Nephritis)
o
Cardiovascular Symptoms: SLE can affect the heart and blood vessels, leading to
symptoms such as chest pain, pericarditis (inflammation of the lining around the
heart), and an increased risk of atherosclerosis.
O Pulmonary Issues: Pleuritis (inflammation of the lining of the lungs) and pleural
effusions (fluid around the tungs) can cause chest pain and discomfort.

45 (MedEd
MedEd FARRE: Pathology
o Neuropsychiatric Symptoms: the central and peripheral nervous
SLE can affect
systems, resulting in symptoms such as cognitive dysfunction, mood disorders,
seizures, and peripheral neuropathy.
o Hematological Abnormalities: SLE can lead to anemia, leukopenia (low white blood
cell count). lymphopenia (low lymphocyte count), and thronmbocytopenia (low
platelet count).
o Gastrointestinal Issues: Abdominal pain, nausea, vomiting, and diarrhea can ocCur,
sometimes due to lupus-related peritonitis or vasculitis of the gastrointestinal
blood vessels.
o Raynaud's Phenomenon: Fingers and toes may experience color changes (white,
blue, and red) in response to cold or stress.
o Lymphadenopathy and splenomegaly: Enlarged lywnph nodes and spleen can be
observed.
o Miscellaneous Symptoms: Other symptoms may include hair loss, dry eyes and
mouth (Sjogren's syndrome), and muscle pain
Diagnosis: EULAR/ACR 2019 criteria is
used for diagnosis.
o Antibodies to Sm antigen and dsDNAare diagnostic of SLE.
Morphological features of SLE
L. KIDNEY: Six morphological [Link] recognized
JlSireeKM)
> Class I: Minimal Mesangial Lupus Nephritis: Immune complex deposition In
mesangium
i* Class il: Mesangial Proliferative Lupus Nephritis: Mesangial cell proliferation.
* Class lIl: Focal Lupus Nephritis: Involve less than sO% of glomeruli with global or
segmental involvement of glomerulus.
* Class IV: Diffuse Lupus Nephritis: Involves more than half glomeruli. wire loop
lesions are seen on light microscopy.
* Class V: Membranous Lupus Nephritis: Severe proteinuria and nephrotic
syndrome.
Advanced Sclerosing Lupus Nephritis: Represents end-stage renal
*Class VI:
disease where more than 90% of glomeruli are sclerosed.
Prominent changes in other organs include:
o Heart: Libman-Sacks endocarditis (nonbacterial verrucous endocarditis) and
pericarditis.
o Spleen: Capsular thickening, folicular hyperplasia, increased plasma cells and
thickening of arteries (onion skinning)
o Lungs: Pleuritis, pleural effusion, alveolar injury in the form of oedema and
haemorrhage and chronic interstitial fibrosis.

46
 Immunology

Tolerance
o lmmune tolerance is a crucial concept in the body's defense system to prevent
harmful overreactions to antigens.
o There are two primary types: central tolerance and peripheral tolerance
Central Tolerance Peripheral Tolerance
o Early in iymphoid
LOcation celto in the immune periphery
development region (e.g., spleen, lymph nodes)

Aim o ldentify and eliminateo Control autoreactive T and

autoreactive T and B cells B cells that escape

|Mechanisms O Negative selection of T cells Anergy (lack of normal

O

o
Clonal deletion of immune vesponse)
autoreactive B cells Apoptosis of autoreactive
O

o
Development of regulatory T cells
T cells (CD*") o Suppression through
o Receptor editing for B cells regulatory T cells (TGF-B)
o lnhibitory receptos to
recognize self-antigens
Result O Ensuresself-toleranceduring|o Prevents harmful immune
lymphocyte development responses in the periphery
o
|Key Features Elimination of high-affinity|o Control of autoreactive
self-reactive lymphocytes lymphocytes that escape
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 221

47 MedEd
 Neoplasia
19. Write down the pathways of spread of the tumors.
Answer:
o Dissenmination of cancers occurs through three pathways:
1. Direct seeding of Body Cavities and Surfaces:
o Tumors penetrate natural body cavities and spaces, such as the pleural, pericardial,
subarachnoid, and synovial cavities.
o Certain mucinous tumors of the appendix and ovary, both benign and malignant,
can fill the peritoneal cavity with a gelatinous neoplastic mass, known as
"pseudomyxoma peritonei"
2. Lymphatie Spread:
o Tumor cells can spread through lymphatic vessels.
o Lymphatic spread often follows the natural routes of lymphatic drainage.
o It is the primary oute for the dissemination of epithelial malignancies, with
sarcomas also occasionally using this pathway.
o Tumor cell debris and antigens may induce reactive hyperplasia and lead to the
spread of tumor cells to regiona (ywphnodes.
o The "sentinel" lymph node is the first node in the regional lymphatic chain to
receive lymph flow from the primary tumor.
3. Hematogenous Spread:
O This is typical of sarcomas but can also occur in carcinomas.
o
Arteries, with their thicker walls, are less penetrable by tumor cells compared to
veins.
O
Liver and lungs are the most frequently involved organs in hematogenous
dissemination because all portal blood flows to the liver, and all caval blood flows
tothe lungs.
o Cancers near the vertebral column, such as thyroid and prostate cancers, can
metastasize to the vertebrae via the paravertebral plexus.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 274

48
 Neoplasia

20. Differentiate between Dysplasia and Metaplasia. (3 marks)

Answer:

Characteristic Metaplasia Dysplasia

Definition o Reversible change in which|o Loss of uniformity of the
one aduit cell type (epithelial individual cells (mainly
or mesenchyma) is replaced epithelia) as wel as a
by another adutt cell type. lack of architectural
orientation with respect to
One another.
Cellular O
Usualiy not seen o Present
Pleomorphism
|Nuclear Atypia o Usually not seen o Hyperchromatic and
abnormaly large atypical
nuclei may be seen.
|Mitotic Figures o Few o Many
Tissue ArchitectureoMaintained o Loss of ordered maturation,
as in dysplastic stratified
squamous epithelium.
Reversibility o [Link] triggeringum o May become irreversible
factors are removed. if it involves the whole
thickness of the epithelium.
Example o Columnar to squamousoCervical intraepithelial
epithelium in the respiratory neoplasia (CIN)
tract of chronic smokers.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 272

MedEd
49
MedEd FARRE: Pathology

21. Differentiate between benign and malignant tumors. (3 marks)

Answer:
Characteristic Benign Tuinors Malignant Tumors
|Growth Rate Generally slow ando Can grow rapidly and
progressive growth. invade nearby tissues.
Differentiation o Well-differentiated cells|o often poorly differentiated
that resemble normal tissue with abnormal cell
cells. morphology and nuclei.
Tumor Borders Typically well-defined
ando invasive growth with
ill
encapsulated, making them defined, irregular borders,
easy to distinguish from often infiltrating adjacent
Surrounding tissues. tissues.
Metastasis o Do not metastasize: theyo Capable of metastasizing.
remain localized to their site spreading to distant
of origin. organs Or tissues via blood
or lymphatic vessels.
Local Effects o May cause
compression or o Can invade, infiltrate, and
displacement of nearby destroy nearby tissues and
structures but do not structures.
infiltrate or destroy them.
Recurrence o Rarely recur after completeo May recur even after
Surgical removal, as they surgical removal due to
are often well-contained. the potential for residual
malignant cels.
Tissue Damage Typically do not Cause
o
Can cause tissue damage,
significant tissue damage or ulceration, bieeding, and
systemic effects unless they various systemic effects
grow in critical locations. (e.g., weight loss).

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 276

50
 Neoplasia

22. Describe cellular and molecular hallmarks of cancer. Deseribe the role of ps3 gene
and Rb gene in detail. (10 marks)
Answer:
o The following are the hallmarks of cancer:
1. Self-sufficiency in growth signals (Oncogenes)
o Proto-oncogenes are
normal cellular genes involved in regulating cell proliferation,
differentiation, and signal transduction.
o Oncogenes are mutated forms of proto -oncogenes. They differ in that they have
mutations in their structure, and when overexpressed, they can promote excessive
cellular proliferation even without normal mitogenic signals.
o Activation of Oncogenes: Oncogenes can be activated through various mechanisms,
including:
Point Mutations and Deletions: Mutations in the structure of the gene, such as
those seen in the RAS Oncogene in colon and pancreatic carcinoma.
* Chromosomal Translocations: For example, the Philadelphia chrom0some
involves the translocation of the C-ABL proto-oncogene from chromosome q to
chromosome 22. Translocation of the c-MYC proto-oncogene from chromosome
8 to chromosome 14 is observed in Burkitt lymphoma cases.
Gene Amplification: Chromosomal alterations can lead to an increased number
of copies of a gene. Examples include the lnaMYC oncogene in neuroblastoma and
ERB-B2 in breast and ovarian cancer.
2. Insensitivity to growth-inhibitory signals (Tumor suppressor genes)
o Tumor suppressor genes, also known as anti-oncogenes, are class of genes that
prevent cell division.
The following are the importanttumour suppressor genes involved in growth inhibition:
O
Retinoblastoma (RB) gene (Governor of proliferation):
* RB is an important negative regulator of G1/S cell cycle transition.
o It is located on the long arm of chromosome 13.

RB Gene
Inactive
State Active (Hypophosphorylated)
(Hyperphosphorglated)
Function |Acts as a "brake" on cell Loses its inhibitory function
| division
|tnteraction Binds tightly to No longer effectively binds
transcription factor E2F E2F
Cell Cycle Effect Prevents progression from Allows progression from G1
G1 to S phase to S phase

51 RMedEd
MedEd FARRE: Pathology

O ps3 gene (guardian if genome)

* It is a tumor suppressor gene that regulates cell cycle progression, DNA repair,
and apoptosis
* It is located on 17p
Role of p53 is given below:
lonizing radiation
Carcinogens Mutagens

Normal cell (p53 normal) Cell with mutations or loss of ps3

DNA dawmage
DNA damage

ps3 accumulates and binds to DNA 53-dependent genes not activated

No cell cycle arrest No DNA repair

Transcription dependent and Mutant cells

independent effects on targets Expansion and addition
JaiShrecRam mutations

Malignant tumor
Successful repair Repair fails

Other tumor suppressor genes include:

O TGF-beta: Linked to carcinomas of the pancreas, colon, and stomach.
o APC: Associated with familial adenomatous polyposis (FAP) and sporadic colonic
carcinomas.
O
WT-1: Connected to wilms tumor, a childhood kidney cancer.
o NE: tmplicated in neurofibromatosis-1 (NF1) and neurofibromatosis-2 (NF2)
O
BRCA1 and BRCA2: Linked to hereditary breast cancer, ovarian cancer, prostate
cancer, p ancreatic cancer, and malignant melanoma.
o VHL: Associated with hereditary renal cell carcinoma, pheochromocytoma,
hemangioblastoma of CNS, retinal angiomas, and venal cysts.
o PTEN: Implicated in various cancers, including breast cancer, prostate cancer,
brain tumors due to its role in regulating the PI3K/AKT/mTOR sgnaling pathway.

52
 Neoplasia

3. Altered cellular metabolism

o The growth -promoting metabolic alterations observed in cancer cells play a crucial
role in sustaining their rapid proliferation and survival.
Warburg Effect:
o
Cancer cells exhibit a phenomenon known as the Warburg effect, which involves
high levels of glucose uptake and increased fermentation of glucose to lactate, even
in the presence of sutficient oxygen.
o lin normal cells, glucose metabolism primarily occurs through mitochondrial
oxidative phosphorylation, which is an efficient process for generating energy
(ATP).
o However, cancer cells preferentially utilize glycolysis, a less efficient process, to
metabolize glucose. This glycolytic metabolism occurs even in the presence of oxygen.
o The Warburg effect is a halmark of nany cancer cells and can be visualized using
positron emission townography (PET SCans- FDG18).
4. Evasion of apoptosis
o
Evasion of apoptosis is a critical hallmark of cancer that enables cancer cells to resist
programmed cell death, allowing them to survive and proliferate uncontrollably
o Example: Overexpression of the Anti-Apoptotic Gene BCL2 in Follicular Lymphomas.
5. Limitless replicative potental JaiShrecRam
O
Three causes of the limitless replicative potential or immortality of cancer cells:
* lnactivation of Senescence Signals
* Reactivation of Telomerase
Presence of Cancer Stem Cells
6. Angiogenesis
o Angiogenesis is a crucial process in the growth and progression of tumors.
o Types of Angiogenesis:
* Neoangiogenesis: New blood vessels sprout from existing ones.
Vasculogenesis: Endothelial cell precursors form new blood vessels.
O Tumor Blood Vessels:
Different from normal vasculature.
* Often leaky and disorganized.
o Pro-Angiogenic Factors:
* Produced by tumor or inflammatory celis.
Examples: VEGF, bFGF, angiopoietins 1 and 2.

53 RMedEd
 MedEd FARRE: Pathology

o Hypoxia-Induced Angiogenesis:
Hypoxia in tumors activates HIF-1a.
* Leads to production of pro-angiogenic factors like VEGF and bFGF.
7. (nvasion and metastasis
Development of a rapidly proliferating clone of cancer cells

Emergence of metastatic subclones

Adhesion to and invasion of basement wmembrane by tumour cells

lnvasion of ECM

Development of leaky blood vessels with endothelial gaps having direct contact with
cancer cells

Intravasation (entry into vessels) by tumour cells

JaiSheRam
Interaction with host lymphoid cells to form tumour cell emboli

Adhesion to basement membrane of vessel wall

Extravasation at a distant site

Metastatic deposit and Proliferation as a secondary colony aided by

Angiopoietins-1a
8. Mechanisms of immune evasion in cancer:
o
Downregulation of Antigen Presentation(Decreased MHC expression)
o lmmune Checkpoint Activation
O
Antigenic Variation
o Tumor Heterogeneity
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 276

54
 Neoplasia

23. Define and classify paraneoplastic syndromes.

Write briefly about tumor markers (5 marks)

Answer:
o A paraneoplastic syndrome is a symptom complex in patients with cancer that
cannot be explained either by local or distant spread of the tumor or y
the
elaboration o hormones indigenous to the tissue of origin of the tumor
o They may be the earliest manifestation of hidden neoplasm
o They may manifest with signs and symptoms due to excessive production
O They may mimic metastatic disease.

Classification

Paraneoplastic Syndromes Underlying Cancer

Endocrinopathies
o Cushing syndrome o Small cel lung carcinoma
o Hypercalcemia o VariouS carcinomas (lung. breast, kidney,
ovary, Adult T cell leukemia)
o Carcinoid syndrowme e Bronchial adenomas, pancreatic carcinomas,
gastric carcinomas
Nerve and Muscle Syndrome
o
Myasthenia gravis Bronchogenic carcinoma
o Nervous system disorders o Breast carcinoma
|Dermatological Disorders
o Acanthosis nigricans o Lung, uterus, stomach carcinomas
Dermatomyositis Bronchogenic carcinoma, breast careinoma

Vascular and Hematological Changes

O Trousseau sign Pancreatic and bronchogenic carcinoma
o
DIC O AML, Prostatic carcinoma
o Anemia Thymic neoplasms (cause unknowm)

Bone and Soft-Tissue Changes

MedEd
55
 MedEd FARRE: Pathology

o Hypertrophic o Lung and cardiac tumors, thymic

osteoarthropathy and neoplasms.
clubbing of
fingers

TUMOR MARKER
Introduction
substances present in or synthesized by tumor itself or produced by host
o Biological

In response to a tumor
o Usually proteins
o Found in blood, urine or body tissues
ldealProperties
o Should be highly sensitive and specific
o Should have high positive and negative predictive value
o lt should be able to differentiate between neoplastic and non -neoplastic disease
o Should predict early recurrence and
o Should have prognostic value

Tumor Marker Associated Cancers or Conditions

|Alpha-fetoprotein (AFP) Hepatoman
o
Non-seminomatous testicular germ cell
tumors
o Yolk sac
(endodermal sinus)tumor
Beta human chorionic o Hydatidiform moles
gonadotropin (hcG) O
Trophoblastic tumors
o Choriocarcinoma
o
Dysgerminoma
Calcitonin Medullary carcinoma of the thyroid (alone
and in MEN2A, MEN2B)
|Carcinoembryonic antigen (CEA) o Major associations: Colorectal and pancreatic
Cancers
o Minor associations: Gastric, breast, and
meduilary thyroid carcinomas
|CA-125 o Malignant ovarian epithelial tumors

56
 Neoplasia

CA19-9 o Malignant pancreatic adenocarcinoma

Placental Alkaline Phosphatase O Seminoma
(ALP) o Metastases to bone or liver
o Paget disease of bone
Prostate-specific antigen (PSA) O Prostate cancer
Chromogranin o Neuroendocrine tumors
CA 15-3/CA 27-29 O Breast cancer

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 328

JaiShreeRam

57 R MedEd
 MedEd FARRE: Pathology

24. 1. Write brieiy on chemical carcinogenesis.

2. Write briefty on microbial carcinogenesis. (10 marks)
Answer:
CHEMICAL CARCINOGENESIS
o Chemical carcinogenesis refers to the process by which chemicals can induce cancer
or promote the development of cancerous cells within an organism.

Stages of Chemical Carcinogenesis: It lnvolves 3 stages

1. Initiation
o induced by initiator chemical carcinogens
o Causes permanent, irreversible damage
o
Not sufficient for tumor formation
2. Promotion
o Substances like phenols, artificial sweeteners, hormones, etc. act as promoters of
carcinogenesis
o No sudden change by promoters
O No direct effect on DNA JaiShreeRam
O lnduced changes are reversible
O lnitiated cells may result in tumor
3. Progression
o These cells acquire additional mutations and characteristics that make them
increasingly malignant.
MAJOR CHEMICAL CARCINOGENS
Direct-Acting Carcinogens
Category Examples of Carcinogens
|Alkylating Agents Cyclophosphamide, Chiorambucit, Busulfan, Melphalan,
Nitrosoureas, b-propiolactone, Dimethyl sulphate.
Diepoxybutane
|Acylating Agents |1-acetyl imidazole, Dimethyl carbamyl chloride
Indirect-Acting Procarcinogens:
Category Examples of Carcinogens

58
 Neoplasia

|Polycyclic Aromatic |Anthracenes, Benzopyrene, Methylcholanthrene

Hydrocarbons (PAHS)
Aromatic Amines and 2-naphthylamine, Benzidine, Azo dyes like butter.
Azo Dyes yellow, scarlet red
Naturally Occurring Aflatoxin B1, Cycasin, Safrole, Betel nuts
Products
Miscellaneous Nitrosamines and amides, Vinyl chloride, Nickel, lead,
cobalt, and chromium
Microbial carcinogenesis
o Viruses (DNA or RNA) result in mutation in the target host cell
o High wutation rate associated with RNA virus
DNA Oncogenic Virus
o Human Papilloma virus
O Epstein-Barr virus
o Poxvirus
o
Adenovirus, etc.
RNA Oncogenic Virus
o Human T celllymphotropic VirugaiShreeRam
o Hepatitis C virus
O HCV
o Slow transforming virus.

1. HPV
O
Types 1, 2, 4, and 7 are associated with benign squamous papillomas or warts.
o
HPV subtypes 16, 18, 31, 33, 35, and 51 are linked to the development of
squamous cell carcinomas (SCCs) in the cervix, and anogenital region, as well as
oral and laryngeal cancers.
O HPV 6 and 11 are responsible for causing genital lesions with low malignant
potential.
O Mechanism: High-risk strains of HPV Produce E6 and E7 proteins. EG inhibits the
p53 protein and E7 inhibits the RB protein causing uncontrolled cell proliferation.

59 RMedEd
MedEd FARRE: Pathotogy

Increased
telomerase Immortalization
TERT
expression

HPV E6
p53 Inhibits p53

Increased cell
proliferation

Inhibits p21

Increased activity
Genomic instability
HPV E7 of CDK4/cyclinD

Inhibits Rb

2. EBSTEIN BARR VIRUS (EBV)

o EBV is implicated in
the pathogenesis of
* African form of Burkitt lymphoma
* B-celllymphoma in immunosyppyessed individuals
* Hodgkin lymphoma
* Nasopharyngeal carcinoma
Gastric carcinoma
* NK cell lymphoma

60
 Neoplasia

EBV
arsgon

LATENT INFECTION
wITH EBV
CD 21 oct
as rocoplor

POLYCLONAL B-CELL
EXPANSION

INCREASED
MYC PROTEIN

OUTGROWTH OF
NEOPLASTIC CLONE:
URKITT LYMPHOMA

Mechanism of Cancer
Virus Associated Cancers
Association
DNAViruses
Epstein-Barr Virus o Promotes polyclonal B-cello Burkitt's lymphoma
(EBV) proliferation, increases the o CNS lymphoma in
risk of
translocation
(:RIY AIDS
o Mixed cellularity
Hodgkin's lymphoma
Nasopharyngeal
carcinoma
Human Herpesvirus 8 O Acts via cytokines releasedo Kaposi's sarcoma in
(HHV-8) from HIV and HSV AIDS
Human Papillomaviruso Type 16 (50% of cancers):o Squamous cell
(HP) E% gene product inhibits carcinomaof the vulva,
TPS3 suppressor gene vagina, cervix, and
anus (associated with
o
Type 18 (10% of cancers):
sexual intercourse)
E7 gene product inhibits
RB suppressor gene O Larynx
Oropharynx
RNA Viruses
|Hepatitis C Virus (HC)o Produces post -necrotic o Hepatocellular
cirrhosis CarcinOma

61 GMedEd
MedEd FARRE: Pathology

Human T-cell O
Activates TAX gene
o
T-cell leukemia and
Lymphotropic Virus 1 stimulates polyclonal Iymphoma
(HTLV-2) T-cell proliferation,
inhibits TPS3 suppressor
gene
Reference: Pathologic Basis of Dise ase, Robbins and Cotvan, 10th Edition, Page No. 321

JaiShrecRam

62
 Genetics
25. Briefiy give an insight on genomic imprinting and differentiate the two prototype
examples of it. (5 marks)
Answer:
o Genomic
imprinting is a way genes are controlled based on whether they come
from our mother or father (parent-of-origin effect).
o
There are four key rules for genomic imprinting:
* Gene activity is influenced.

* This infiuence can be passed down in body cels.

* It starts when eggs and sperm are formed.
* It gets reset in reproductive cels for the next generation.
o DNA methylation is the main proces: It switches off either the mom's or dad's
gene, allowing only one to work.
o "Differentially methylated regions" (DMRs) are vital control areas that manage
gene activity and are usually found in gene starters.
o Genomic imprinting problems can happenWhen an active gene is missing, changed,
or not working.
o Examples include Angelman and Prader-willi syndromes(15q11-q13)

Characteristic Prader-Wilti Syndrome Angelman Syndrome

|Main Genetic |Absence or mutation in Absence or mutation in the
Abnormalities |the paternal gene with maternal UBE3A gene on
maternal gene silencing. in chromosome 15, accompanied
|20-35% of cases, maternal by silencing of the paternal
gene.
Onset Evident from birth. Appears during infancy.
Speech Delayed or limited. Virtually absent.
Development
Seizures Occasional Frequent
Microcephaly Rare Common
Motor Symptoms Hypotonia, obesity Ataxia, limb hypertonia,
|hyperreflexia
Behavioral Traits Hyperphagia, Obsessive Inappropriate laughter,
behavior |hyperactivity

MedEd
63
MedEd FARRE: Pathology

o Uniparental disony (UPD) is when an individual inherits both copies ofa chromosome
from one parent and none from the other.
* Heterodisomy involves inheriting two different copies of a chromosome, typically
during initial chromosome formation.
* Isodisomy occurs when two identical copies of a chromosome are inherited,
often due to errors during later stages of chromosome development or post
fertilization duplication.
o
UPD usually doesn't cause noticeable issues and results in a normal appearance
and health.
o ln some cases, UPD can be associated with specific genetic conditions, such as
Prader-willi and Angelman syndromes, when particular genes are affected by this
inheritance pattern.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 178

JaiShreeRam

64
 Genetics

26. Short note on the pathophysiology and clinical features of Down Syndrome.
(5 marks)
Answer:
o Down
syndrome is the most common chromosomal disorder, characterized by
having an extra copy of genes on chromOSOMe 21.
o The
primary cause of Down syndrome is meiotic nondisjunction, typically occurring
in the mother's reproductive cells. Interestingly, maternal age significantly influences
its incidence, with higher visk in older mothers.
o ln around 95% of cases, the extra chromosowme in Down syndrome comes from
the mother, with the rest originating from the father.
o Mosaicism, seen in approximately 4% of cases, results from errors during early
embryonic development, leading to a mix of cells with either 46or47 chromosomes.

CLINICAL FEATURES
o Down syndrome is characterized by recognizable clinical features, including a
flattened facial profile, slanted eyes, and epicanthic folds.
o
It is a leading cause of severe mental retardation
o
Some mosaic cases display mildersysptoms and near-normal intelligence.
o Additional clinical aspects include congenital heart disease (in about 40% of
patients), a heightened risk of leukemia (tenfold to twentyfold), and susceptibility
to Alzheimer's disease after age 40.
Molecular Insights
o Understanding the molecular basis of Down syndrome is complex. Critical regions on
chromosome 21 contain genes involved in various pathways, such as mitochondrial
energy vegulation, CNS developmant, and folate wmetabolism.
Prenatal Diagnosis
o By analyzing cell-free DNA from maternal blood using next-generation sequencing,
precise gene dosage on chromosome 21 can be deterwmined, allowing for noninvasive
prenatal diagnosis.
o Positive results from this "liquid biopsy are routinely confirvmed using traditional
cytogenetic techniques, such as amniocentesis.
Down's Syndrome
Aspect Description

MedEd
65
MedEd FARRE: Pathology

Genetic Basis O Extra copy of genes on chromosome 21 (Trisomy 21)

Mechanisms o 21 (Approx. 9s%): Nondisjunction during
Full Trisomy
meiosis (wmostly materna)
o Translocation Trisomy 21 (3-42): Extra chromosome 21
attached to another chromosome (usually 14)
o Mosaic Trisomy 21 (1-2%): Two cell lines (trisomic and
nornal) due to mitotic nondisjunction
Clinical Features o Distinctive facial (Mongoloid slant) and cranial features,
mouth abnormalities, extremity (simian crease), and soft
tissue characteristics, skeletal anomalies
o Organ
malformations (e.g.. heart defects, gastrointestinal
issues)
o
Increased risk of associatedconditions(e.g.. hypothyroidism,
leukemia, alzheimer's)
Development & o Delayed motor skills, intellectual disability, behavioral and
Behavior psychiatric disorders
o
Prenatal Diagnosis Chromosomal testing (karyotyping, genetic testing)
O
Noninvasive prenatal testing ("liquid biopsy'") for early
detection
Reference: Pathologic Basis of Disease, JaLshrecRm
Robbins and Cotran, 10th Edition, Page No. 166

OD0

66
 Genetics

27. A 16-year-old female presented to the OPD with cowmplaints of amenorrhea and
short stature. Upon thorough examination and history. she was suspected to have
Turner Syndrome. Briefly discuss the same. (5 marks)

Answer:
o Definition: A genetic disorder in females characterized by complete or partial X
chromosome monosomy.
o Prevalernce: Occurs in approximately 1 in 2,500 live births.
o Etiology: Usually caused by chromosownal nondisjunction during meiosis or mitosis.
o Karyotype: Turner syndrome can resuit from meiotic nondisjunction (commonly
in paternal gametes), leading to complete sex chromosomal monosomy (45, XO)
or mitotic nondisjunction of an embryonic cell, resulting in sex chromosomal
mosaicisa (45, XÖ/46, XX) with mild phenotypic expression.
o Pathophysiology: Nondisjunction leads to X
chromosome monosomy/mosaicism,
resulting in impaired ovarian development, streak gonads, and deficiencies in
estrogen and progesterone.
o
Clinical Features: Manifestations include:
*A female phenotype with webbed neck, shield chest, widely spaced nipples
* Primary ovarian insufficiency with delagedpuberty and primary amenorrhea
* Lymphatic system abnormalities
* Musculoskeletal findings, cardiovascular issues(Bicuspid aortic valve, Coarctation
of Aorta)
* Other associated disorders such as gonadoblastoma, kidney malformations,
thyroiditis, and type 2 diabetes.
* lncreased risk of autoimmune disorders.
o Diagnostics: Diagnosis is based on clinical prasentation and confirmed by karyotyping.
Treatment: Management includes estrogen and progestogen substitution, growth
hormone therapy, and surgical removal of streak gonads when necessary.

Turner Syndrome
Feature Deseription
Definition o Genetic disorder with complete or partial X chromosome
monosomy in phenotypic females.
Prevalence o Approk. 1 in 2,50o live births.
Etiology o Chromosomal nondisjunction during meiosis or mitosis.

MedEd
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 MedEd FARRE: Pathology

Karyotype o Meiotie nondisjunction: 45, XO (complete monosony)

O
Mitotic nondisjunction: 45, XO/46, XX (mosaicisw)
Pathaphysiology o lmpaired ovarian development, streak gonads, estrogen
and progesterone deficiencies.
Clinical Features o Cardiac abnormalities (bicuspid aortic valve,Coarctation
of aorta)
o Lymphatic system abnormalities (e.g., cystic hygroma,
lgmphedema)
o
Ovarian insufficiency (primary amenorrhea, infertility)
o Webbed neck
o Nail abnormality (Nail dysplasia, Short 4th metacarpa).
Nipples widely spaced
O
Short stature (SHOX gene)
Diagnostics o Clinical presentation, karyotyping.
Treatment o Hormone replacement therapy, growth hormone, surgical
removal of streak gonads.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 171

JaiSHDDRam

68
 Genetics

28. Write briefly on lysosomal storage diseases. (5 marks)

Answer:
LYSOSOMAL STORAGE DISEASES

Lysosomal Enzyme Metabolite

Clinical Features
Storage Disease Deficiency Accumulation
Tay-Sachs |Lysosomal GM2 ganglioside Onset: Normal at
disease |hexosaminidase birth, severe mental
(AR) (a-subunit) retardation by 6
months
o
Cherry-red spot in
macula
o Muscle weakness
o Death by 2-3 years
Niemann-Pick Sphingomyelinase Sphingomyelin Types A and B:
disease (AR) (primarily in Severe neuronal
macrophages damage,
and neurons) hepatosplernomegaly.
psychomotor
JaiSlrecRam deterioration
o
Type C: Ataxia,
dysarthria,
psychomotor
regression
Gaucher diseaseGlucocerebrosidase Glucocerebrosideo Type i: Massive
(AR) |(primarily in hepatosplenomegaly.
macrophages) skeletal involvement,
bone marrow
involvement,
lymphadenopathy
O Types Il and Itt:
CNS involvement
(variable)

69 i MedE
 MedEd FARRE: Pathology

o
|Metachromatic Arylsulfatase A Sulfatide Mental retardation
|leukodystrophy o
Peripheral
(AR) neuropathy
o Visceral organ
abnormalities

Krabbe disease Galactosylceramidase Galactocere o Progressive

(AR) brosidase psychomotor
retardation
o
Multinucleated
globoid cells with
galactocerebroside
material in brain
sections
Fabry disease a-Galactosidase A Ceramide o
Angiokeratomas on
(X-linked trihexoside the skin
recessive) o Hypertension
o Renal failure
(X-linked recessive)
Hunter lduronate 2-sulfåtasel| Dermatan o Milder course
Syndrowe (IDS) deficiency sulfate and COmpared to Hurler
(MPS I) |heparin sulfate syndrome
(X-linked o
Absence of corneal
recessive) clouding
*AR: Autosomal recessive
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 156

70
 Genetics

29. Write briefly on glycogen storage diseases. (5 marks)

Answer:
Pathogenesis of GSD
o
The significance of a specific enzyme deficiency leads to accumulation of precursor
molecules and deficiency of the required substrates both of which together lead to
clinical manifestations of the disease.
o
They show an autosomal recessive pattern of inheritance. The key steps in glucose
metabolism are:
s Conversion to GlucOse-6 -Phosphate
Transformation to Glucose-1-Phosphate
* Formation of Uridine Diphosphoglucose
* Building Glycogen Polymer
* Degradation
* Lysosomal Degradation
Problems at these steps lead to 3 major forms of GSD which are:
o Hepatic Form: The liver plays a crucial role in glycogen metabolism
* lnherited deficiency of hepatic, evzymes responsible for glycogen degradation, it
leads to the accumulation of glycoein in the iver and hypoglycemia.
* These disorders result in glycogen storage in various organs, but the clinical focus
is on hepatic enlargement and hypoglycemia.

* Examples- Von-Gierke disease.

O Myopathic Forn: In skeletal muscles, glycogen serves primarily as an energy
source during physical activity. ATP is generated through glycolysis, leading to the
production of lactate.
lndividuals with myopathic forwms often experience muscle cramps after exercise,
and their blood lactate levels fail to rise after exertion due to glycolysis blockage.
* Example- McArdle's disease
o Other Glycogen Storage Diseases: Sowme glycogen storage diseases don't fit neatly
into hepatic or myopathic categories. Two examples are:
* Deficiency of Acid Alpha-Glucosidase (Pompe Disease): This condition leads to
glycogen storage in multiple organs, with cardiomegaly being a prominent
feature.
* Lack of Branching Enzyme: Lack of branching enzyme leads to glycogen storage
in various organs and is often fatal early in life.
GSD Type Role of Enzyme Key Features

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 MedEd FARRE: Pathology

|Type I Glucose -ó -phosphatase Severe fasting hypogtycemia,

(von Gierke disease)(G6-phosphatase) |hepatomegaly. hgjperlipidenmia,
dol-ike facies, hyperuricemia
Type ll Lysosomal acid maltase Hypertrophic cardiomyopathy.
(Pompe disease) deficiency macroglossia, myopathy.
cardiomegaly, early death,
aneurysms
Type ll Glycogen debranching Muscle weakness, cirrhosis, wmild
(Cori disease) enzyme hypoglycemia, hyperlipidemia.
risk of cardiomyopathy
Type Iv Glycogen branching Symptoms in infancy,
(Andersen disease) enzyme |hepatosplenomegaly, cirvhosis,
myopathy. neuropathy.
|hypoglycemia
Type v Myophosphorylase Muscle weakness, exercise
(MCArdle disease) (skeletal muscle glycogen intolerance, rhabdomyolysis,
phosphorylase) cardiac arrhythmias, normal
glucose
7ype Vi Liver phosphorylase Hepatomegaly, fasting
(Hers disease) lhypoglycemia, hyperlipidemia
JaiShreeByn
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 160

72
 RBC and WBC
30. Differentiate between leukaemoid reaction and chronic myeloid leukaemia.
(3 marks)
Answer:
Feature Leukemoid Reaction CML
>
TLC 25,000-100,00o/u 100,00o/uL
DLC O Dominant cells: PMNs O Dominant cells: All
O
lmmature cells: maturation stages
Predominantly O Immature cells: All
stages, mnyeloblasts and
O metamyelocytes and
promyelocytes < 1O%
myelocytes
o (5-15%), myeloblasts o Basophils present
and pronmyelocytes >5%%

NAP Score Elevated Reduced

Philadelphia Absent Present
ChromOSOme
|ABL-BCR Fusion Gene Absent iatshrcciRn Present
Major Etiology O lnfections o RNAviruses, HTLV
o Intoxication oncogenesis,

o Disseminated maliqnanculO Genetic factors, radiation

o Severe hemorrhage o Certain drugs, and
chemicals
O
Additional O
Anemia Anemia
Hematologic Findings O Normal to raised platelet
count
o Normal
count
to raised platelet

O
Myeloid hyperplasia in O Myeloid hyperplasia in
bone marrow bone marrow
Organ Infiltration Absent |May be present
Massive Splenomegaly Absent Present

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 102 and
622

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RBC and WBC

31. Write briefly on the pathophysilogy, clinical features and laboratory diagnosis
of sickle cell disease. (5 marks)
Answer:
o Sickle cell disease is a common hereditary hemoglobinopathy caused by a point
mutation in the beta-globin at the oth position which results in the production of
Hbs hemoglobin. HbsS polymerizes when deoxygenated.
Pathogenesis: Hbs molecules have a tendency to stack into polymers under low
Oxygen tension which causes sickling of RBCs. These sickled RBCs cause microvascular
occlusion and lead to several key pathophysiological processes:
Process Result
Vaso-Occlusion Sickle -shaped RBCs obstruct small blood vessels,
causing painful crises.
Hemolysis Fragile sickle cells rupture, leading to the destruction
|of RBCs
and anemia.
Ischemia-Reperfusion injury Sickle cells block and release, causing tissue damage
and inflammation.
Chronic Organ Damage |Repeated vaso-pcclusive events and chronic anemia
can damage organs.
HOS
Deoxygcnation

HbS polymers

Hbs fiber

Distortion of RBC and forwmation of a sickle cell

Repcated cycles of oxygenation
and deoxygenation

Irveversibly sickled cells

Intravascular haemoysis
Extravascular haemolysis (in spleen)
Factors affecting sickling

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 RBC and wBC

o Amount of Hbs: lncreases sickling risk in SCD.

o Interaction with other types of Hb: HbF decreases sickling, while HbC and HbD
increase it.
o MCHC value: Increased MCHC increases sickling.
o pH: A
fil in pH (acidic conditions) increases sickling.
o Oxygen concentration: Increased oxygen concentration increases sickling.
CLINICAL FEATURES OF SICKLE CELL DISEASE (SCD) INCLUDE
o Severe Anemia and lmpaired Growth: SCD results in severe anemia, leading to
generalized inpairment of growth and development due to chronic hypoxia.
o VasoOcclusive Complications: These include acute chest syndrome, dactylitis (hand
foot syndrome), and stroke. Vaso -occlusive events occur when sickle -shaped red
blood cells block blood vessels, eading to tissue damage and pain.
o Chronic Hyperbilirubinemia and Cholelithiasis: lndividuals with SCD often have
chronic igh levels of bilirubin, which can lead to jaundice and the formation of
gallstones (cholelithiasis).
o Susceptibility to Infections: SCD patients are prone to infections, especially
pneumococcal and Haemophilus influenzae infections. They are also at increased
risk of Salmonella osteomyelitis.
o JaiShreRam
Aplastic Crisis: This is characteried' by à"sudden cessation of bone marrow
erythropoiesis, often triggered by parvovirus infection. It manifests as anemia
without reticulocytosis (an increase in immature red blood cells).
o Splenic Sequestration Crisis: It involves the sudden pooling of blood in an enlarged
spleen, leading to hypovolemia and shock.
o Tender Hepatomegaly: Enlargement of the liver can occur due to infarction (tissue
death) caused by blocked blood vessels.
o Renal Complications: Progressive loss of renal function can occur due to infarction
of the renal medulla. SCD patients may also experience papillary necrosis and
recurrent urinary tract infections.
LABORATORY INVESTIGATION
O General Blood Picture: Presence of sickle celis, Howell-Jolly bodies, and nucleated
red blood cells.
o Sickling Test: Increased sickling tendency with reducing substances like sodium
metabisulfite.
o Solubility Test: Turbid (cloudy) solution when Hbs polymerizes with reducing
substances like sodium dithionite.
Hemoglobin Electrophoresis:
* Decreased or absent HbA (normal adutt hemoglobin).

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* increased HbS (abnormal hemogiobin responsible for sickling).

* lncreased HOF (fetal hemoglobin, ranging from 2% to 20%, as a compensatory
response).
o Osmotic Fragility Test: Decreased osmotic fragility due to
the sickle -shaped red
a
blood cells, which have larger capacity to expand in volume without rupturing.

2. Approach to a patient with features suggestive of Anemia

2. Obtain CBC with General Blood Picture and Reticulocyte Index(RI)
RI <2.5 RI >2.5

Non: Hemolytic
Hemolytic
3. RBC Morphology
Normocytic Microcytic Macrocytic Intrinsic Extrinsic
o Anemia Defective qlobin Megaloblastic: o
Hereditary O AIHA
of Chronic Chain: o Folate Spherocytosis o Microangi
Disease o Thalassemia Deficiency O PNH opathic
o Aplastic hemolytic
Defective Hemeo B12 O GoPD
Anemia Synthesis: Deficiency deficiency anemia
o
IDA in o IDA(Late) o OrotieeeRarto Pyruvate O Macro
early 1TIBC "Aciduria Angiopathic
Kinase
stage o Deficiency Hemolytic
Sideroblastic Non
anemia
Anemia Megaloblastic: o Sickle Cell
o o Hemolytic
O AoCD Liver Disease Anemia
anemia due
o Chronic o HbC disease to infection
Alcoholic

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 641

(76
 RBC and WBC

32. Write briefly on transfusion reactions. (5 marks)

Answer:
o Transfusion reactions can occur as imnmediate or delayed responses to blood
transfusions.

IMMEDIATE REACTIONS

Type Feature
Febrile Reactions o Common early reactions.
o
Symptoms include fever, chills, and headache.
o Caused by cytokines produced by leukocytes during
storage.
o Reduced by leukocyte depletion from the blood
product.
Allergic Reactions
O
Results in symptoms like flushing, urticaria (hives).
fever, tachycardia, wheezing. dyspnea (shortness
of breath), and cyanosis.
o
Caused by antibodies against plasma proteins in
the donor unit, including lgA.
O
Categorized [Link] I hypersensitivity reactions
|Acute Hemolytic o Typicallydue to a mismatch in transfusion.
Transfusion Reactions o Manifest as hypotension, heat and burning at
the transfusion site, fever, lower back or chest
pain, bleeding due to disseminated intravascular
coagulation (DIC), and oliguria due to renal failure.
o
Can be intravascular (ABO mismatch, Type |
hypersensitivity) or extravascular (presence of
undetectable atypical antibodies in the recipient).
Circulatory Overload o Occurs due to rapid transfusion, leading to
congestive heart failure.
o More likely in patients with severe anemia and a
history of
heart disease.
Endotoxic Shock and Fever o Results from bacterial contamination of transfused
blood
Transfusion-Related Acute o Characterized by acute respiratory distress,
Lung injury (TRAL) dyspnea, hypoxia, and pulmonary edema.
o
Caused by antibodies in transfused blood reacting
with antigens in the recipient's lungs, leading to
inflammation and capillary leakage.
O
Typically occurs within 6 hours of transfusion.

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Delayed Transfusion Reactions:

o Delayed Hemolytic Transfusion Reactions: These reactions occur 3-1o days after
blood transfusion and are often due to extravascular hemolysis resulting from an
atypical antibody reaction against donor red blood cells.
o Transfusion Hemosiderosis: This condition is caused by chronic or multiple
transfusions and results in the accumulation of iron in the body.
o Graft-Versus-Host Reaction: This reaction occurs when granulocytes or white
blood cells from the transfused blood target and attack the recipient's tissues,
especially in immune-deficient patients.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 671

JaiShreeRam

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 RBC and wBC

33. Write in detail on the pathology, clinical features and laboratory diagnosis of
multiple myetoma. (5 marks)
Answer:
Pathology of Multiple Myeloma: Multiple myeloma is a malignancy of plasna cells. in
this disease, abnornal plasma cells proliferate in the bone wmarrow and often produce
a monoclonal (or M) protein, which is a single type of abnorwmal antibody.

Pathological features of multipte myeloma include:

o Monoclonal Proliferation: Multiple myeloma is characterized by the clonal
expansion of malignant plasma cells in the bone marrow. These cells produce
abnormal antibodies, and their uncontrolled growth interferes with normal blood
cell production.
o Bone Marrow Infiltration: Malignant plasma cells infiltrate the bone marrow,
leading to reduced production of normal blood cell.
o Monoclonal Protein: The abnormal plasma cells produce a monoclonal protein (M
protein or paraprotein) that can be detected in blood and urine.
o Bone Lesions: Myeloma cells can cause lytic bone lesions, weakening the bones and
increasing the risk of fractures. These lesions result from the release of cytokines
and factors that activate osteoclasts and inhibit osteoblasts, leading to bone
destruction.
lCLINICAL FEATURES OF MULTIPLE MYËLOMAM
o Bone Pain: Common in the back, ribs, and hips due to bone lesions.
O Anemia: Reduced red blood cell production causes fatigue and weakness.
o Renal Dysfunction: Kidney damage results in increased creatinine, decreased urine
output, and electrolyte imbalances.
o Hypercalcemia: Elevated blood calcium levels lead to thirst, frequent urination,
and confusion.
o Infections: Weakened immunity increases infection risk.
Neuropathy: Monoclonal proteins damage nerves, causing numbness and weaknes.
o Bleeding: Platelet reduction leads to easy bruising.
o
Hyperviscosity: Elevated monoclonal proteins cause headaches and mucosal bleeding.
LABORATORY DIAGNOSIS (CRAB CRITERIA)
o C: Calcium increased: Check serum calcium.
O R: Renl involvement: Assess kidney function (oreatinine, BUN).
o A: Anemia: ldentify anemia (CBC, hemoglobin).

O B: Bone lytic lesions: Use imaging to detect bone lesions.

KMedEd
 MedEd FARRE: Pathology

BLOOD AND URINE TESTS

O Complete Blood Count (CBC): Reveals anemia and blood cell cOunts.
o Serum Protein Electrophoresis: Detects M protein.
o Serum Calcium Levels: Measure calcium levels.
o Renal Function Tests: Assess kidney health.
o Serum Beta-2 Microglobulin: lndicates disease sevevity.
o
24-Hour Urine Protein Electrophoresis: ldentifies Bence Jones proteins in urine.
Bone Marrow Aspiration and Biopsy: Confims diagnosis and assesses plasma cell
percentage. Russel bodies (intracytoplasmic inclusion) or Dutcher bodies (intranuclear
inclusions) are seen.
Imaging: X-rays, CT scans, or MRI scans may reveal lytic bone lesions and fractures.
Multiple Myeloma
Pathophysiology o Oncogenes like cyclin D1 and cyclin D3 genes are
fused with the lgH locus which causes dysregulation of
cyclin D contributing to increased cell proliferation.
o Proliferation supported by the cytokine IL-6.
is
O
MYC translocations are particularly associated
with abgresšive: disease.
Clinical Features o Hypercalcemia, Renal issues (renal failure-Bence
Jone Proteinuria), Anemia, Bone lesions (MIPia)
o Rouleaux formation (High levels of M protein in the
blood cause red cells to stick to one another)
o
Recurrent lnfections
Primary amyloidosis (AL)
|Laboratory o
Bone marrow: >10% monoclonal plasma cells,
clock -face chromatin patterns.
o Increased calcium, deranged KFT.
o M spike on protein electrophoresis
o Osteolytic lesion of bones (Skull).
Staging o Revised International Staging System (R-1Ss) and
International Staging System ((sS)

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 RBC and wBC

Treatment o Autologous Hematopoietic Stem Cell Transplant|

(HSCT)
Reference: Pathologic Basis of Disease, Robbins and Cotran, 1Oth Edition, Page No. G07
O00

JaiShrecRam

81 MedEd
 MedEd FARRE: Pathology

34. A 20-year-old female resident of Ludhiana, punjab present with Fatigue,

weakness, and pale skin. No significant prior medical history. (10 marks)
Physicat Examination:
Pale skin and mucous membranes
Enlarged spleen (splenomegaly)
No signs of jaundice

Laboratory Findings:
Hemoglobin level: 7.5 g/dL
MCV: s8 fL

MCH: 2O pg
Mentzer index: 11
Hb electrophoresis: Increased levels of HbA2 and HbF, decreased HbA
() What is the diagnosis? write down the pathogenesis, cinical features and
laboratory diagnosis of this disease.
(II) Classify anemias.
Answer: JaiShrecRam
() DIAGNOSIS: THALASSEMIA
o ln thalassemia, there is a genetic mutation that affects the production of either
the alpha (o) or beta (B) globin chains, which are the two main types of chains
that make up hemoglobin.
Alpha Thalassemia: This form of thalassemia involves a mutation in one or more of
the alpha globin genes. The severity of alpha thalassemia depends on how many alpha
globin genes are affected. Common types include:
* Alpha Thalassemia Minor: Two alpha gtobin genes are affected (usually one from
each parent). lndividuals with this forwm may have mild anemia.
* Hemoglobin H Disease: Three alpha globin genes are affected. This results in
moderate to severe anemia and can require egular blood transfusions.
* Hydrops Fetalis: Al four alpha globin genes are affected. This condition is usually
fatal before or shortly after birth.
Beta Thalassemia: This form of thalassemia involves mutations in the beta globin

82
 RBC and wBC
genes. Theve are twO main types:
o Beta Thalassemia Major (Cooley's Anemia): lndividuals with this severe form of
beta thalassemia have two mutated beta globin genes and require regular blood
transfusions throughout life.
o Beta Thalassemia Minor: lndividuals have one mutated beta globin gene and usually
experience mild or no anemia.
PATHOGENESIS

Reduced beta-globin chain synthesis with relative excess

of alpha-chains

Insoluble alpha-chains aggregate in erythroid precursors

forming abnormal erythroblasts

Apoptosis of abnormal erythroblasts in bone marrow leads

to ineffective erythropoiesis

JaiShrpRam
Extramedullary Anaemia - Increased dietary
haematopoiesis iron absorption

Blood translusion Systemic iron overload

Increased dietary
iron absorption

Secondary hemochromatosis

Clinical Features of Beta-Thalassaemia:

o Anemia: It is hallmark feature of thalassemia.
o Jaundice
O
Enlarged Spleen (Splernomegaly)
o Delayed Growth and Development
o
Facial Changes: May develop characteristic facial features, such as prominent
cheekbones and frontal bossing (enlarged forehead).
o
Bone Abnormalities
o Fatigue, pain

(83 (HMedE
MedEd FARRE: Pathology

o lron Overload
o lnfections
LABORATORY DIAGNOSIS OF BETA-THALASSEMIA MAJOR
CBC:
o Severe anemia (Hb 2-6 g/dL).
o Decreased Hb, hematocrit, MCV, MCH, MCHC.
o lncreased WBC count with left shift.
O RBC count is decreased.
o Platelet count may be normal or decreased (decrease is due to massive splenomegaly).
Peripheral Blood Smear
o Severe microcytic hypochromic anaemia
O
Marked anisopoikilocytosis.
o Basophilic
stippling, target cells, poikilocytes, fragmented red cells, pencil cells,
cells with Cabot rings and numerous nucleated red cells.
Bone Marrow
o Normablastic erythroid hyperplasia.
o
lncreased reticuloendothelial ironiwith siderotic granules in the cytoplasm of
normoblasts.
Ho electrophoresis
o
Absent or markedly decreased HbA, markedly increased HbF, and often decreased
HbA2.
Other Findings
o Increased unconjugated bilirubin, urinary urobilinogen, serum iron, ferritin.
o Decreased osmotic fragility.
LABORATORY DIAGNOSIS OF BETA-THALASSAEMIA TRAIT
General Blood Parameters
o Hb and haematocrit mildiy decreased with increase in the reticulocyte count.
o MCV, MCH and MCHC decreased out of proportion to degree of anaemia.
o
RBC count higher as compared to iron deficiency anaemia for the same haemoglobin
value.
Peripheral Blood Smear

84
 RBC and WBC
o Hypochromic microcytic RBCs with mild anisopoikilocytosis.
o Target celtis, basophilic stippling, poikilocytes, pencil cels, cells with Cabot rings
and nucleated red cells may be present but are fewer.
BOne Marrow
o Mild erythroid hyperplasia.
Haemoglobin Electrophoresis
o HbA2 increased (3.6-9%; normal 1-3.5%)
Osmotic Fragility:
o Test Shows decreased osmotic fragility.
{() CLASSIFICATION OF ANEMIA

Etiological Classification of Anemia

Anemia of Blood Loss
Acute Trauma, major surgical procedures, postpartum bieeding
Chronic Hookworm infestation, bleeding peptic ulcer, carcinoma
colon, IBD, hemorrhoids, excessive menstrual loss
Decreased Production of Red Cels
|Nutritional Deficiency lron (affects hemoglöbin synthesis), vitamin B12, and folate
(affect DNA synthesis)
Inherited Genetic Stem cell depletion (Fanconi anemia)
Defects Erythroblast maturation defects (Thalassemia syndromes)
Erythropoietin Renal failure, anemia of chronic disease
Deficiency
Immune-Mediated Hypoplastic or aplastic anemia, pure red cell aplasia
rjury of Progenitors
Marrow lnvasion |Leukemia, (ymphoma, secondary carcinoma,
granulomatous disease
Inflammatory iron Anemia of chronic disease
|Sequestration
Due to Excessive Destruction of Red Cells
|Genetic Disorders Red cell membrane abnormalities, enzyme abnormalities,
|hemoglobinopathies (e., sickie cell disease, thalassemias)
|Acquired Disorders lmmune-mediated, toxic, mechanical, and infectious
Causes

85 RMedEd
 MedEd FARRE: Pathology

Classification of Hemolytic Anemia

Intrinsic Hemolytic Anemias
Hereditary Hemolytic o Sickle Cel Anewmia
|Anemias o Thalassemia
o Hereditary Spherocytosis
o Enzyme Deficiency Hemolytic Anemias
o Glucose -6-Phosphate Dehydrogenase(GGPD) Deficiency
O Pyruvate Kinase Deficiency

Extrinsic Hemolytic Anemias

Immune Hemolytic o Autoimmune Hemolytic Anemia
|Anemias o
Alloimmune Hemolytic Anemia
|Mechanical Hemolytico Microangiopathic Hemolytic Anemia
Anemias o (e.g., in conditions like throwmbotic thrombocytopenic
purpura)
o March Hemogobinuria
tnfections and Toxins o Malaria (caused by Plasmodium parasites)
tnduced Hemolytic O
Toxin -lnduced Hemolysis (resulting from exposure to
Anemias varioustoxinteKan
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No.636

86
 RBC and wBC

35. A 55-year-old fewmale, presented to her primary care physician with complaints
of increasing fatigue and night sweats over the past few months. She also
mentioned that her appetite had decreased, leading to unintentional weight loss.
On physical examination, her physician noted mild pallor and an enlarged spleen
upon palpation. Concerned about her symptoms, her doctor ordered a complete
blood count (CBC) and peripheral blood smear.
The CBC results showed a markediy elevated white blood cell count of 120,00o/
L, with a significant increase in granulocytes,
a
including immature forms. The
differential leukocyte count revealed predominance of neutrophils. Additionally,
her platelet count was slightly elevated at sO0,000/ulL.
() What is the diagnosis? Describe the pathogenesis, clinical features and
laboratory diagnosis of this.
(I) Enumerate the other disorders of this class. (10 marks)
Answer:

DIAGNOSIS-CHRONIC MYELOID LEUKEMIA

Pathogenesis:
BCR JaiShrecRam ABL
(chromosome 22) (chromosome q)

BCR-ABL (9:22) translocation -

Philadelphia chromosome

BCR-ABL fusion protin (210kDa)

Constitutive kinase activity

Growth factor independent proliferation

CLINICAL FEATURES

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MedEd FARRE: Pathology
o Anaemia: Patients may experience weakness, pallor (pale skin), dyspnoea (shortness
of breath), and tachycardia (rapid heartbeat) due to decreased red blood cell
production.
o Hypermetabolism Symptoms: These can include weight loss, lassitude (lack of
energy), anorexia (loss of appetite), and night sweats. These symptoms are related
to the increased metabolic demands of the leukemia cells.
o splenomegaly: Enlargement of the spleen is a hallnark of CML and is almost always
present. ln some cases, splenomegaly may be massive and can cause abdominal
disconfort and fulliness. Acute pain may occur due to splenic infarction (death of
splenic tissue).
o Bleeding Tendencies: Patients may have a tendency to bleed easily, ieading to
symptoms such as easy bruising. epistaxis (nosebleeds). menorrhagia (excessive
menstrual bleeding), and the formation of hematomas (collections of blood outside
blood vessels).
o Less Common Features: These may include gout (a type of arthritis caused by
the buildup of uric acid crystals in the joints), visual disturbances, neurologic
manifestations (such as headaches or altered mental status), and priapism
(persistent, painful erection of the penis unrelated to sexual arousal.
o Juvenile CML: This is a distinctive variant of CML seen in children. ln juvenile CML,
lymph node enlargement is more common than splenomegaly. Other features of
juvenile CML include frequent infeGtions bleeding manifestations, and a facial rash.

ACCELERATED PHASE OF CML

o Erythrocytopenia (anemia)
o Neutropenia (increased risk of infection and fever)
o Extreme pleocytosis (elevated cell count in cerebrospinal fluid)
o infarctions (splenic and myocardial infarctions, retinal vessel occlusion)
o Leukemic priapism (painful, persistent erection)
o Terminal phase progresses to myelofibrosis
o Extreme splenomegaly (enlarged spleen)
o Risk of splenic rupture due to splenomegaly

Blast Crisis:
O
Rapid progression to pancytopenia (low blood cell counts)
o Bone pain
o Severe malaise
o Subtypes:
* Myeloid blast crisis transforms into AML (about 2/3 of cases)

88
 RBC and wBC

* Lymphod blast crisis transforms into ALL (about 1/3 of cases)

LABORATORY INVESTIGATIONS
Blood Picture:
o
Anaemi: Anemia in CML is usualy of a moderate degree and is characterized as
normocytic normochromic anemia. Occasional normoblasts (immature red blood
cells) may be present.
o
White Blood Cells: CML is characterized by marked leukocytosis, often exceeding
200,000 l at the time of diagnosis. This inereased white blood cell count primarily
consists of myeloid cells in various stages of maturation. Basophils are significantly
elevated and can make up to 10% of the total white blood cell count. An increasing
basophil count may indicate the progression of the disease.
o
Platelets: Platelet counts may vary but are frequently elevated in about half of
CML Cases.
Bone Marrow Examination:
o Cellularity: Bone marrow examination typically reveals hypercellularity. with the
bone marrow spaces partialy or entirely replaced by proliferating myeloid cells.
o Myeloid Cels: Myeloid cells are the predominant population in the bone marrow,
leading to an increased myeloid -erythroid ratio. The differential counts of myeloid
cells in the marrow resemble those observed in the peripheral blood, with a
predominance of myelocytes. JaiShreeRam
o Erythropoiesis: Although erythropoiesis is normoblastic (normal). there is a
reduction in the number of erythropoietic celis.
o Megakaryocytes: Megakaryocytes, which give rise to platelets, are present in the
bone marrow but are usually smaller in size than normal.
Cytogenetics:
o Cytogenetic studies on blood and bone marrow cells show the characteristic
chromosomal abnormality known as the Philadelphia (Ph) chromosome. The Ph
chromosome is observed in approximately a0-45% of CML cases and results
from a reciprocal balanced translocation between parts of chromosome 22 and
chromosome 9, forming the BCR/ABL fusion gene.
Cytochemistry:
o Cytochemical staining reveals reduced neutrophil alkaline phosphatase (NAP)
scores. This reduction helps distinguish CML from myeloid leukemoid reactions, in
which NAP scores are elevated.
Other investigations:
o
Serum Levels: Serum vitamin B12 and itamin B12 binding capacity may be
elevated in CML.

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 MedEd FARRE: Pathology

(I) oTHER MYELOPROLIFERATIVE DISORDERS

O CML
o Polycythaemia vera
o Essential thrombocythaemia
o
Primary myelofibrosis
o Systemic mastocytosis
o Chronic eosinophilic leukaemia
Note: Smudge cells are seen in CLL in peripheral blood smear.

JaiShreeRam

Smudge Cells
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 622

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 RBC and wBC

36. (0) Classify AML (10 marks)

() write the prognostic factors of AML and ALL

() Differentiate between AML and ALL.

Answer:

CLASSIFICATION OF AML
AML Subtype
AML with Recurrent Genetic Abnormalities
O
AML Wwith t(8: 21) (422: 4q22)
o AML with
inv(16) (p13: q22) or t (16 16) (p13; q22); (CBFb/MYH11))
o Acute Promyelocytic Leukemia (APL) AML Wth t(15; 17) (422; q12) (PM/
RARA) and variants
AML with 11423(MLL) abnormalities
O

AML with Myelodysplasia-Related Changes

O
AML With multilineage dysplasia
o AML, not otherwise specified
Therapy-Related Myeloid Neoplasinsi ShrecRam
o
Therapy-related AML, not otherwise specified
o Therapy-related AML with recurrent cytogenetic abnormalities
AML, Not Otherwise Categorized
o
AML, minimally differentiated
o AML without wmaturation
AML with maturation
O

o Acute myelomonocytic
leukemia
O
Acute monocytic leukemia
o Acute erythroid leukemia
o Acute megakaryoblastic
leukemia
I(u)

Prognostic factors of ALL:

Traits Poor pronosis Good prognosis

Age Younger age (<2yr) 2-10 years
Sex Male Female
TCL >5O*10^a/L >20*10^a/L

91 RMedEd
MedEd FARRE: Pathology

Ploidy Hypoploidy, pseudodiploid Hyperploidy

chromoSOmes
Race Black White

organomegaly Present Nil

CNS manifestation Present Nil

Testicular involvement Present Nil

FAB L2-L3 L1
Hb <7gm/dl >10gm/dl
Platelet <30,000/mm^s >1,00,0Oo/mmA3
Cytochemistry PAS negative PAS positive

Chromosome Philadelphia chromosome Absent

abnormality present
Prognostic factors of AML:
Traits Poor prognosis Good prognosis
Age Younger age (<2yr) <45 yr
Sex JaiMaieRam Female
TCL >1,00,0Oo/mm (very high) <25,00o/mm (low)
Infection Present absent
Serum LDH Increased Normal
Extramedullary Present Absent
involvemnent
CNS manifestation Present Absent
Other haematological Present Absent
disorders
FABtype M5, Mo, M7 M2, M3,M4
Auer rod Absent Present
Response to therapy Delayed/incomplete Rapid
(I) Difference between AML and ALL
Acute Lymphoblastic Acute Myelogenous
Characteristic Leukemia (ALL) Leukemia (AML)

92
 RBC and wBC

Age Group Children (more common), Adults (more common),

adults children
Lymphadenopathy Prominent in children, less Less cmmon
COMmOn in adults
Hepatosplenomegaly More cOmmon Less cOmmon

Testicular lnvolvement More cOmmon in children Less common

Eye tnvolvement Less cOmmon More cOmmon

Leukemic blast Lymphoblasts Myeloblasts

Size Smaller Larger

N/CRatio (Nuclear-to High Low
Cytoplasmic Ratio)
Chromatin Clumped Spongy, skein-like
Nucleoli <
2, indistinct 2-5, distinct
Auer Rods Not present Present in 10-20% of
cells
TdT Often positive Negative
Myeloperoxidase Negative, Positive

Sudan Black B Negative Positive

Chloroacetate Esterase Negative Positive
Periodic Acid-schiff Positive Positive in <25%
(PAS) (shows block pattern)
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 618
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 596

93 KMedEd
MedEd FARRE: Pathology

37. (0) Write down the pathogenesis and classification of Hodgkin's tymphoma.
(u) Differentiate between Hodgkin's and Non-Hodgkin's lymphoma. (10 marks)
Answer:
(0
PATHOGENESIS OF HODGKIN LYMPHOMA (HL)
Activation of Transcription Factor NF-KB:
o This is a common feature in classical Hodgkin lymphoma (HL).
O
NF-KB is a transeription factor that plays a crucial role in regulating genes involved
in cell survival, inflammation, and immunity.
o lIts abnormal activation can contribute to the growth and survival of Hodgkin and
Reed-Sternberg (RS) cells, the characteristic cells in HL.
Secretion of Cytokines, Chemokines, and lmmunomodulatory Factors:
o RS cells, which are large and abnormal B cels, secrete various molecules such
as interleukin -s (|L-5), interleukin-10 (IL-10), macrophage colony-stinulating
factor (M-CSF), and chemokines like eotaxin.
o These molecules can create a microenvironment that supports the growth and
Curvival of RS
celis ana the immune response against them.
s4pPaiSbreRtociated
o lnfections: Some viral infections with an increased risk of
developing HL. Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), human
T-cell leukemia virus-1 (HTLV-1), and HTLV-2 are among the viruses that have
been tinked to Hodgkin lymphoma.
o It is believed that these infections may contribute to the development of HL by
altering the immune response or directly affecting lywphocytes.
CLASSIFICATION OF HODGKIN'S LYMPHOMA

Subtype Morphology9 Immunop EBV

Clinical Features
henotype Association
Mixed Mononuclear CD15+, 70% EBV+ve Common in (ndia,
Cellularity cells CD30+ stage lll or IV; M>F;
biphasic: prognosis
is good
Lymphocyte Mononuclear CD15+, 40% EBV+veUncommon, M>F,
Rich cells CD30+ prognosis is good
Lymphocyte Reticular CD15+, 90% EBV+veMore common in
Depletion variant CD30+ males; HIV infected:
not good prognosis

94
 RBC and wBC

Nodular Lacunar cells, CD15+, Commonly Common

Sclerosis plasma cells, CD30+ EBV-ve worldwide; M=F;
and fibrous usually stage or
I

strands I; mediastinal
involvement is
commonj good
prognosis
|Lymphocyte Lymphocytic CD20+, EBV-ve Not common;
Predominanceand Histiocytic CD15-, young males with
(popcorn cell) CD30 cervical or axillary
Iymphadenopathy
(I) Difference between Hodgkin's and Non-Hodgkin's (ymphoma:
Feature Hodgkin's Lymphoma Non-Hodgkin's Lymphorma
|Cell Derivation B-cell mostly 40% B, 10% T
Nodal involvement Localized, may spread Disseminated nodal spread
to contiguous nodes
Extranodal Spread Uncommon Common
Bone Marrow Involvement Uncommon Common
Constitutional Symptoms CommonhrecBan Uncommon
Chromosomal Defects |Aneuploidy Translocations, deletions
|Spill-over Never |May spread to blood
Prognosis Better (75-85% cure) Poor (3o-40% cure)

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 611
O00

95 RMedEd
 Infections
38. () Write down the pathogenesis of tuberculosis. (5 marks)
() Differentiate between primary and secondary tuberculosis.
Answer:
() Pathogenesis of Tuberculosis
Infection with [Link]: lnitial contact with Mycobacterium tuberculosis ([Link]).

Entry into Macrophages: Phagocytosis of [Link] by macrophages through CR3

receptors.

Replication in Macrophages: inhibition of phagosome maturation and

phagolysosome formation. Recruitment of host protein coronin to inhibit fusion.

Initial Innate lmmune Response: Recognition by TLR2 and TLR9, initiating innate
and adaptive immune responses.
JaiShrecRam
Thi Resp0nse: Thi cell activation is triggered by antigen presentation and IL-12
production.

Thi-Mediated Macrophage Activation: IFN-Y production, phagolysosome

maturation, iNOS, NO production, ROS production, defensin production, and
autophagy activation.

Granulomatous inflammation: Formation of granulomas, giant cell formation, TNF

and chemokine secretion, caseous necrosis occurs.
() Difference between primary and secondary tuberculosis
Features Primary TB Secondary TB
Evolution of Seen in individuals who have Occurs due to reactivation of a
disease not been previously sensitized primary focus or reinfection
to tubercle bacilli
Age group Common in children |Any age (usually occurs later
affected individuals of younger age; than primary infection)
may be seen in adults in
developed countries

96
 nfections

Distribution Lower of upper lobe and Apex of one or both lobes due
part
upper part of lower lobe to high oxygen tension in apices

Lesion Ghon focus Simon focus

Involvement of Early involvement of Dueto pre -existing
ymphatics lymphatics and lymph nodes |hypersensitivity, bacilli induce
an immediate tissue response
that walls off the lesion and
prevents early involvement of
ymphatics and lymph nodes
Severity Generally asymptomatic, less Usually symptomatic, more
severe Severe

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 367

JaiShreeRam

MedEd
 CVS
39. (0) Define and classify aneurysms. (3 marks)
(I0) Differentiate between Syphilis and Aortic Aneurysm.
Answer:
()
An aneurysm is a perwmanent abnormal dilatation of a blood vessel occurring due to
congenital or acquired weakening or destruction of the vessel [Link] is commonly
seen in large elastic arteries especially aorta and its major branches.
CLASSIFICATION

Classification Deseription
Based on Composition of Wall
True Aneurysm Composed of all layers of vessel wall or thinned out
wall of the heart
False or Pseudoaneurysm A breach in the vascular wall leads to formation of
an intravascular hematomna, which has a fibrous wall,
and occurs secondary to trauma
Based 'önšhape
Saccular Aneurysm |Large spherical outpouching
Fusiform Aneurysm Spindle -shaped dilatation
Cylindrical Aneuryswm Continuous parallel dilatation
|Serpentine or Varicose Tortuous dilatation
|Aneurysm
(I) Difference between Syphilis and Aortic Aneurysm.
Characteristic Syphilitic Aneurysm Aortic Aneurysm
Site of Thoracic aorta Abdominal aorta
|Involvement
Shape Saccular (3-5 cm diameter) Fusiform (larger than s-ocm)

98
 CVS

Histological o Healed syphilitic aortitis o Atherosclerotic aneurysm

Features with adventitia showing wall loses its normal
fibrous thickening and arterial structure.
endarteritis obliterans of o lntima and inner part of
vasa vOsorum. media exhibit remnants of
o Predominance of fibrous atheromatous plaques and
tissue in the media and mural thrombus.
adventitia with mild
chronic inflammatory
reaction.
o Spirochetes may be found
in syphilitic aneurysm,
sometimes mural thrombus
Can be seen.
Effects o Rupture into pleural cavity.o Rupture into peritoneum
pericardial sac, trachea, or into retroperitoneum
and esophagus. leading to sudden and
o Compression on trachea massive bleeding.
o
causing dyspnea, on Compression of the ureter
esophagus causing and erosion on vertebral
dysphagia, on recurrent bodies.
laryngeal nerve leadingam o
Arterial occlusion
to hoarseness, erosion of
vertebrae, sternum, and
ribs.
o
Cardiac dysfunction
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. s04

99 MedEd
MedEd FARRE: Pathology

40. Write briefly on Laboratory diagnosis, complications and morphological evolution

of Myocardal infarction. (i1) Diferentiate between transmural and subendocardial
infarcts. (5 marks)
Answer:
LABORATORY DIAGNOSIS
Electrocardiogram (ECG) changes:
o ST-segment elevation.
O T-wave inversion.
o Appearance of wide and deep Q waves.

SERUM CARDIAC MARKERS

Creatinine phosphokinase (CK):
o CK-MB (from cardiac muscles and extracardiac tisue):
o
lncreased CK-MB indicates myocardial damage.
o
Ratio of CK-MB2: CK-MB1 above 4:1 is highly suggestive of acute MI after 4-6
hours of onset.
o Disappears from blood after 48 hours.
o CK-MM (from skeletal muscle) and cK-BB (from brain and lungs).
Lactate dehydrogenase (LDH):
o LDH 1 and LDH 2 are the two isoforms.
O A ratio of LDH 1:LDH 2 greater than 1 suggests MI.
o
LDH levels rise after 24 hours, peak in 3-6 days, and return to normal in around
14 days.
Cardiac-specific troponins (cTn):
O Twotypes: cTnT (cardiac troponin T) and cTnl (cardiac troponin i).

o cTnT and cTnl levels increase after myocardial injury.

O CTnT emains elevated for 7-10 days, and cTnl remains elevated for 10-14 days.
Myoglobin:
o The first cardiac marker to increase after MI.
o Rapidly excreted in urine.
o
Returns to normal after 24 hours following an MI.
Complications of MI
o
Arrhythmias
o Cardiogenic shock

100;
 CVS

Rupture
o Congestive heart failure
o Cardiac aneurysm
o Pericarditis
o Postmyocardial infarction syndrome
o Mural thrombosis and thromboembolism
O
Papillary muscle dysfunction
Morphological evolution of Myocardial infarction:

Time Gross Changes Microscopic Changes

O-4 hours None Usually none; variable waviness of
fibers at border
o
4-12 hours Occasionally dark Beginning coagulation neerosis;
mottling edema; hemorrhage
12-24 hours Dark mottling Ongoing coagulation necrosiS;
pyknosis of nuclei:hypereosinophilic
appearance of myocytes: marginal
contraction band necrosis; beginning
JaiShredRaneutrophilic infiltrate
2-3 days Mottling with yellow o Coagulation necrosis with loss of
tan infarct center nuclei and striations; interstitial
infiltrate of neutrophils
3-7 days Hyperemic border: o Beginning disintegration of dead
central yellow -tan myofibers, with dying neutrophils:
softening early phagocytosis of dead cells by
macrophages at infarct border
7-10 days Maximally yellow o Well-developed phagocytosis of
tan and soft, with dead cells: early formation of
depressed red-tan fibrovascular granulation tissue at
margins margins
10-14 days Red-gray depressed O
well-established granulation tissue
infarct borders with new blood vessels and collagen
deposition
2-8 weeks Gray -white scar, o lncreased collagen deposition, with
progressive from decreased cellularity
border toward core of
infarct
>2 months Scarring complete o Dense collagenous scar

101 MedEd
 MedEd FARRE: Pathology

(II) Difference between transmural and subendocardial infarcts

Features Transmural lnfarct Subendocardial Infarct

Extent Involves the whole thickness Involves only the innerone -third
of the ventricular wall in to one half of the ventricular
the distribution of a single thickness. May be multifocal
Coronary artery and has circumferential
distribution.
Frequency More common (95%) Less common (5%)
Causes Associated with coronary Noplaque disruption seen
atherosclerosis, acute plaque
change, superimposed
completely obstructive
thrombosis
Epicarditis Common Not common
Cardiac May be seen Not seen
AneurySm
ECG Changes Elevation of ST segment |No ST elevation

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 543
JaiShreeRam

(102)
 CVS

41. (0) Write in detail on the aetiopathogenesis, clinical features and laboratory
diagnosis of acute vheumatic fever and rheuwmatic heart disease.
(I1) Compare the features of vegetation in major forms of endocarditis.
(5 marks)
Answer:
ACUTE RHEUMATIC FEVER
o Acute immune -mediated multisystem disease involving the heart, joints, central
nervous System, skin, and subcutaneous tissues.
o Peak incidence between 5 and 15 years; rare in infants and chidren under s
years.
o More common in poor economic conditions and overcrowding.
o Progresses to chronic rheumatic heart disease over time.
Aetiology:
o Delayed inflamimatory response to pharyngeal infection with group A streptococci.
o Latent period between pharyngeal infection and onset ranges from 1 to weeks.
o
Rheumatogenic serotypes include 1, 3, 5, 6, 14, 18, 14, and 24.
o Antibodies develop against streptococcal antigens but cross-react with cardiac
myosin and sarcolemmal membrane piroteín!I1
Pathology:
o Pancarditis involves all three layers of the heart.
* Myocardium: Aschoff body, lymphocytes, plasma cells, fibroblasts, Anitschkow
cells.
Endocardium: Verrucous lesions, fibrous thickening, adhesions.
* Pericardium: Serofibrinous pericarditis, 'bread and butter' appearance.
CLINICAL MANIFESTATIONS
o Sore throat: Antecedent upper respiratory tract infection in the past 1-5 weeks.
o Polyarthritis:
* Acute migratory or fleeting polyarthritis, mainly large joints.
Pain and swelling move from one joint to another.
o Carditis:
* Myocarditis: Tachycardia, arrhythmias, features of congestive heart failure.
* Endocarditis: Murmurs of mitral and aortic regurgitation, nodules on the mitral
valve leaflets.
* Pericarditis: Pericardial pain, friction rub, small pericardial effusion.

103} MedEd
MedEd FARRE: Pathology

o Subcutaneous Nodules: Small, painless nodules over extensor surfaces and bony
prominences.
o
Erythema Marginatum: Erythewnatous macules with clear centers and serpiginous
margins, trunk and extremities.
o
Chorea(Sydenham Chorea): Involuntary movements, muscle weakness, emotional
instability, tics, and psychotic features.
Laboratory Investigations for Acute Rheumatic Fever:
o
lsolation of group A streptococci from throat swab cultures.
o
Streptococcal antibody tests: ASO, anti-DNase B, AH, ASTZ levels.
O Acute phase reactants: Raised ESR, increased CRP.
o Hematological abnormalities: Neutrophilic leukocytosis, increased serum complement
and mucoproteins.
Electrocardiogram: Prolongation of the PR interval.
o X-ray chest: Cardiomegaly. pulmonary congestion.
o Echocardiography: Myocardial and valvular dysfunction, pericardial effusion.
Diagnosis: Revised Jones criteria is used.
Major Manifestations Minor Manifestations
Carditis FeveriSIhreeRann
Polyarthritis |Arthralgia
Chorea (Sydenham Chorea) Previous rheumatic fever or rheumatic heart disease
Erythema marginatum Raised Erythrocyte Sedimentation Rate (ESR)
Subcutaneous nodules o Positive C-Reactive Protein (CRP)
o Prolonged PR interval (first-degree A-v block)
(0) Features of vegetation in major forms of endocarditis:

Features Rheumatic Libman-sacks IE (Bacterial) NBTE

Valves Mitral alone Mitral and Mitral, aortic, Mainly mitral:
commonly Ormitral tricuspid or combined less commonly
affected and aortic mitral and aortic and
cOmbined aortic |tricuspid

104)
 CVS

Distribution of Occur along Occur on On valve Occur along

vegetations lines of closure: cusps/leaflets Cusps, wMay ines of closure
atrialsurface either on extend into the(on one side)
of A-Vvalves One or both chordae
and ventricular surfaces
Surface of
semilunar
valves
Gross Small, Small to Large Small but
appearance multiple, medium irregular. larger than
warty. firwmly sized, multipledestructive, RHD; loosely
attached, vegetations; friable masses, attached:
produce |generaly do damage the usually does
thickening. not produce underlying not damage
and shortening much myocardium the valve
of leaflets |deformity
as well as
fusion of valve
cOmmissures
leading to
permanent
valvular
deformity
HaiShreeRan
|Constituents Fibrin and Granular, Fibrin and Fibrin-platelet
platelets, fibrinoid. platelets with thrombi, no
no bacteria; eosinophilic bacterial bacteria
adjacent material: colonies
endocardium sterile and acute
may show vegetations inflammatory
presence of may contain cells
Aschoff bodies haematoxylin
bodies
equivalent to
LE cells
Embolization Less common Less common Very common Very common

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. S6o

105) MedEd
 MedEd FARRE: Pathology

42. Enumerate and describe the various types of cardiomyopathies. (5 marks)

Answer:

o Cardiomyopathy (CMP) is a
heterogeneous group of diseases associated with
mechanical and electrical dysfunction of the myocardium. Cardiomyopathies may
be tocalized to the heart or may form a part of a systemic disease

TYPES
Cardiomyopathy

Primary Secondary
(Diseases confined to (The myocardial involvement
heart muscle) isseenorasa a componentdisorder)
of a
systemic multiorgan

(a) Dilated (congestive) CMP (a) Nutritional deficiencies

(6) Hypertrophic (obstructive) (alcoholic CMP and beriberi)
CMP (o) Toxic chemicals (cobalt, arsenic,
(c) Restrictive/obliterative or JaiShrecRamithiuwm and hydrocarbons)
infiltrative CMP (c) Drugs (emetrine,
cyclophosphamide, adriamycin
and catecholamines)
(d) Metabolic diseases (cardiac
anyloidosis, hemochromatosis
and glycogen storage diseases)
(g) Connective tissue diseases
(rheumatoid arthritis, systemic
sclerosis and drug induced)

Dilated (Congestive) CMP

Definition Systolic dysfunction with dilatation of all four chambers
|Incidence 40% of all CMPs
Age affected 20-50 years

106
 CVS

Causes Familial or genetic inhenitance (mainly autosomal dominant)

Acquired causes include viral myocarditis, toxic damage (e.g.
alcohol. chemotherapy), peripartum CMP, iron overload,
excessive catecholamines
Clinical features Slowly progressing heart failure, shortness of breath, easy
fatigability, poor exercise tolerance
Mechanism of heart| Systolic dysfunction
|failure
Gross appearance Dilatation of all four chambers gives rise to a typical globular
appearance. Presence of mural thrombi.
Microscopy Hypertrophy of some myocardial fibers. atrophy of others.
lnterstitial fibrosis with focal wmononuclear infiltrate.
Small subendocardial scars may be seen. Myocardial cell
disorganization in the ventricular septum,
Outcomne Mitral regurgitation/arrhythmias may be observed. The
average survival from onset to death is 5 years.

Hypertrophic (Obstructive) CMP

Definition Diastolic dysfunction (reduced chamber size and impaired
diastolic filling)
tncidence Less commonlShrecRam
|Age affected 25-40 years
Causes Genetic inheritance with mutations in sarcomere proteins
Clinical features Usually asyptomatic: symptowmatic on heavy physical|
activity. May manifest with dyspnea, angina, congestive
cardiac failure, or sudden death.
|Mechanism of heart Diastolic dysfunction
failure
Gross appearance Heavy hypercontracting heart. Asymmetric myocardial
hypertrophy. A transverse section may show a banana -like
appearance.
Microscopy Myocardial fibers are irregularly and haphazardy arranged
(normaliy paralle). Interstitial fibrosis. Individual muscle
hypertrophy and presence of large prominent nucleoli
Outcome Medical treatment to relax ventricles and surgical reduction
of the septum can be undertaken.

Restrictive/Obliterative or lnfiltrative CMP

107 MedEd
 MedEd FARRE: Pathology

pefinition Diastolic dysfunction (restriction in ventricular filling due to

reduction in the volume of ventricles)
Incidence Less common

|Age affected Variable

Causes tdiopathic: associated with conditions like amyloidosis.

radiation -induced fibrosis, sarcoidosis, metastatic tumor, or
inborn errors of metabolism
Clinical features Presentation is dependent on the specific type. May manifest
with dyspnea, angina, congestive cardiac failure, or sudden
death
Mechanism of Diastolic dysfunction
|heart failure
Gross appearance Ventricies are normal or slightiy enlarged, cavities not dilated.
Myocardium is firwm.
Microscopy Patchy or diffuse interstitial fibrosis, which varies from
minimal to extensive.
Outcomne Gradually progressive cardiac disease

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. S67

JaiSDORam

108
 CVS

43. (0) write down the risk factors, pathogenesis and complications of atherosclerosis.
(U) Differentiate between Fatty streak and atheroma. (10 marks)
Answer:

o Atheroscierosis a condition marked by the development of fibrofatty plaques

is
within the innermost layer (intima) of large and medium -sized muscular arteries,
notably affecting arteries such as the aorta, coronary arteries, and cerebral arteries.

MAJOR RISK FACTORS

Type Factor
Risk
o
Nonmodifiable Genetic abnormalities
o Family history
o lncreasing age
o Male gender
o Hyperlipidemia
Modifiable
o Hypertension
JalhCigarette smoking
o Diabetes
o
lnflammation
Pathogenesis of atherosclerosis:
o Atheromatous plaques, also known as fibrous plaques, fibrofatty plaques, or
atheromas, are fully developed lesions associated with atherosclerosis.
Gross Appearance:
o
Color: White to yellowish-white
o Size: Typically 1-2 cm in diameter
o Elevation: Raised above the luminal surface
o Composition: Consists of a grey-white fibrous cap and a central core of yellowish
white, soft, grumous lipid material

109) MedEd
MedEd FARRE: Pathology

Chronic endothelial "injury*:

•
Hyperlipidemia
•Hypertonsion
•Smoking
•
Homocysteino
•
Homodynamic factors Toxins
•Virusos
• Immuno
reactions

Endothelial dysfunction
(o.g., ncreased
permeability, leukocyte
adhosion). monocyte
adhesion
and emigration

Mactophage
activation,
smooth musclo
recruitment

Macrophages and smooth Fibromuscular

muscle celis engutt lipid am cap

Macrophago Core of lipid

debris
Smooth muscie proliferation, Tlymphocyte
collagen and other extracellular Smooth muscle
malrix deposition, extracellular lipid

Microscopic Features: The microscopic characteristics of atheromatous plaques can

vary depending on the age of the lesion:
Superficial (Luminal) Part of Fibrous Cap:
o Composed of smooth muscle cells and collagen
Cellular Area (Shoulder of the Lesion):
O Contains more cellular elements
o Comprises foamy macrophages, T lymphocytes, and a few smooth muscle cells

110
 CVS

Deeper (Central) Softcore:

o Located deep into the fibrous cap
o Comprises extracellular lipid material
o
Contains cholesterol clefts, fibrin,necrotic debris,lipid-laden foam cells
COMPLICATIONS OF ATHEROSCLEROSIS
Calcification:
o Occurs in advanced plaques, particularly in the aorta and coronary arteries.
o The diseased intima becomes calcified, making it vigid and brittle.
o When incised, the calcified plaque may crackle like an eggshell.
Ulceration:
o Layers covering the soft, pultaceous material within an atheroma may ulcerate.
o Ulceration can result from trauma or hemodynamic forces acting on the plaque.
Thromboembolization:
o Thrombosis can occur due to ulceration of the plaque and endothelial damage.
o Emboli, composed of lipid material and debris, may arise from the thrombi.
o ajShrceRm
These emboli can travel through the bloodstream and block smaller blood vessels,
potentially causing ischemic events in various organs.
Hemorrhage:
o Hemorrhage can originate either from the luminal biood or firom the rupture of
thin capillaries within the adventitia of the affected artery.
o
Hemorrhage contributes to the instability and progression of the plaque.
Aneurysm Formation:
o Severe atherosclerosis can lead to atrophy and thinning of the media layer of the
arterial wal.
O Fragmentation of the internal elastic lamjna weakens the vessel wal.
O Weakened vessel walls are prone to bulging and dilation, resulting in the formation
of an aneuryswm.
Progressive Plaque Growth:
o Ongoing plaque growth can lead to critical stenosis (narrowing) and obstruction
of the affected blood vessel.

111 MedEd
i
 MedEd FARRE: Pathology

o Severe stenosis can significantly reduce blood flow, potentially leading to ischemic
events in the tissues supplied by the affected artery.

C) DIFFERENCE BETWEEN FATTY STREAK AND ATHEROMA

Features Fatty Streak Atheroma

Age of Onset Initiated in children as Typically affects older
young as 1 year individuals
|Composition Mainly consists of Characterized by a large
intracelular lipid core of extracellular lipid
accumulation (lipid -filled
foam cells); the presence
of T lymphocytes and
|imited extracellular lipid
Gross Appearance Multiple yelow, flat Whitish -yellow, raised
lesions less than 1 mn in lesions, typically measuring
diameter O.5-1.5 Cm in diameter;
often eccentric
Vasculature Involved May be found in areas Primarily affects elastic
not commonly affected by and large -/medium-sized
atherosclerosis muscular arteries
Clinical tmplications Typicallydöes not .am Can lead to myocardial
obstruct blood flow and cerebral infarction,
significantly aortic aneurysms, and
peripheral vascular disease
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 494

112)
 CVS

44. () Define and classify vasculitis. (10 marks)

(1) Write briefly about Takayasu arteritis.
(u) write briefiy about wegenergranulonatosis (granulomatosis with polyangitis).
() write briefty about the Raynaud phenomenon.
Answer:
o Vasculitis, also known as
angitis, is an inflammatory condition characterized by
inflammation within blood vessels.
CLASSIFICATION OF VASCULITIS
Vasculitis

Non infectious Infectious

Large Vessel Vasculitis: Endarteritis obliterans

Giant Cell(Tempor) Arteritis Syphilitic arteritis
Takayasu's Arteritis (Pulseless DISeeccRam Non-specific infective arteritis
Medium Vessel Vasculitis:
Polyarteritis Nodosa (PAN)
Kawasaki's Disease
Buerger's Disease
(Thromboangitis Obliterans)
Small Vessel Vasculitis:
Wegener's Granulomatosis
Microscopic Polyangitis
Churg-Strauss Syndrome
(Eosinophilic Granulomatosis with Polyangiitis)
Henoch-Schonlein Purpura

(I) TAKAYASU VASCULITIS

Takayasu Arteritis
Definition o Granulomatous vasculitis affects medium and large -sized
arteries. Also known as "pulseless disease."

MedEd
13
MedEd FARRE: Pathology

Primary Affected o Aorta and its major branches lead to aortic arch syndrome.
Arteries Significant narrowing or obliteration of major arteries
Supplying the upper body.
Pathogenesis o Autoimmune reaction targeting aortic tissue.
Clinical Features O
Occurs in younger women, unlike giant cell arteritis.
o
initial symptoms: fever, weight loss, fatigue.
o Later stages: low blood pressure, weak pulses in upper
extremities, ocular disturbances, neurological deficits, leg
claudication (with distal involvement).
Gross Pathology o Aortic wall is iregularty thickened, intima becomes
wrinkled.
o
Microscopy Severe transmural granulomatous inflammation, giant
cells, patchy areas of necrosis within the tunica media.

(Un WEGENER GRANULOMATOSIS (GRANULOMATOSIS WITH POLYANGIITIS)

Wegener Granulomatosis
Definition Necrotizing vasculitis is characterized by a clinicopathological
triad involving
o Necrotizing granulomas in the upper and lower respiratory
tract JaiShrecRam
o Focal necrotizing granulomatous vasculitis in small- to
medium-sized blood vessels
o Focal necrotizing crescentic glomerulonephritis in the
kidneys.
Pathogenesis T-cell-mediated hypersensitive response to inhaled infectious
or environmental agents. Presence of immune complexes in
vessel walls and glomeruli. Associated with PR3-ANCA (anti
neutrophil cytoplasmic antibody).
Clinical Features Typically affects adult males, primarily in their fifth decade
of life.
o Multi-organ involvement
O
Manifestations: Persistent pneumonitis, chronic sinusitis,
kidney disease, skin rashes, muscle pain, joint involvement.
O Limited form if kidneys are not affected.

114
 CVS

Microscopy Necrotizing vasculitis affects small and sometimes large

blood vessels.
o
Granulomatous inflammation with geographic necrosis.
o Infiltration by neutrophils, mononuclear cells, epithelioid
cells, giant cells, and fibroblasts.
o Merging granulomas form nodules, which can cavitate.
o
Renal lesions: focal necrotizing or diffuse crescentic
glomerulonephritis.

(IV) RAYNAUD PHENOMENON

o Raynaud's phenomenon is not categorized as a true vasculitis but rather as a
functional vasospastic disorder primarily impacting the small arteries and arterioles
located in the extremities. This condition is typicaly observed in young, healthy
females.
o
Raynaud's phenomenon is characterized by episodes of pallor, followed by redness
and then cyanosis in the digits (fingers and toes) and, in some cases, the tips of
the nose or ears.
o The exact cause of Raynaud's phenomenon remains unknown, but it is believed
to result from vasoconstriction induced by autonomic stimulation affecting the
involved blood vessels.
JaiShrecRam
o Cold temperatures are a comimon trigger for the ischemic effects, although
emotional stress, physical trauma, hormonal changes, and certain medications
can also contribut.
Pathological Changes:
o Typicaliy, no significant pathological changes are observed in the vessel walls,
except for mild intimal thickening that may develop as the disease progresses.
Classification:
Raynaud's phenomenon can be categorized as either primary or secondary.
o

o Primary Raynaud's phenomenon 0CCUrS independently without an underlying

cause.
o
ln contrast, secondary Raynaud's phenomenon is associated with an underlying
condition, such as atherosclerosis, connective tissue diseases (e.g., systemie sclerosis
or lupus), multiple myeloma, or Buerger's disease.
o One
that primary Raynaud's phenomenon tends to
key distinguishing feature is
exhibit symmetrical involvement of the extremities.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. sO8

1L5) MedEG
 Lung
45. () Write briefly on chronic obstructive pulmonary disease (COPD). (10 marks)
() Differentiate between emphysema and chronic bronchitis.
() Write briefly on bronchiectasis.
Answer:
(0
Obstructive lung disease

Chronic Asthma Bronchiectasis

obstructive lung
disease (COPD)

[Link]
[Link]
EMPHYSEMA
JaiShrecRam
o Emphysema ischaracterized by the abnormal permanent entargement of the air
spaces distal to the terminal bronchioles, which include the respiratory bronchioles,
alveolar ducts, and alveoli. This eniargement is accompanied by the destruction of
their walls, without the presence of fibrosis.
o Types: There are four major types of emphysema based on the anatomic distribution:
1. Centriacinar (Centrilobular) Ewmphysema:
o Affects the central or proximal part of the acini, sparing the distal part (although
severe cases may involve the distal acinus, leading to panacinar emphysema).
o More commonly observed in the upper obes of the lungs.
o Often seen in heavy smokers, often in association with chronic bronchitis.
2. Panacinar (Panlobular) Emphysema:
o
Acini throughout the respiratory bronchioles to the terminal blind alveolar sac are
uniformy enlarged.
o Predominantly found in the lower lung zones with the most severe involvement
at the bases.
Commonly associated with alpha-s antitrypsin (a-1 A) deficiency.
3. Paraseptal (Distal Acinar) Emphysema:

116)
 Lung

o Involves the distal part of the acinus while the proximal part remains normal.
o
Typically seen in the upper parts of the lungs, often adjacent to areas of fibrosis
and atelectasis.
4. Irregular (Paracicatricial) Emphysema:
o Characterized by irregular involvement of the acinus.
o Usually asymptomatic and clinically insignificant.
PATHOGENESIS
Role ofthe 'Protease-Antiprotease' Mechanism:
o lndividuals homozygous for genetic deficiencies in the protease inhibitor alpha-1
antitrypsin (a-1 AT) have an elevated susceptibility to developing emphysema.
Smoking exacerbates this risk.
o Alpha-1 antitrypsin is synthesized in the liver and is present in serum, tissue fluid,
and macrophages.
o The typical phenotype for normal alpha-1 AT is PiMM, whereas the deficiency
phenotype is Pizz. Approximately s0% of PizZ individuals develop emphysema.
o The Pi null phenotype lacks detectabte levels of alpha -1 AT.
Role of Neutrophils:
o Neutrophils serve as a source ofivarious eñzymes and substances that contribute
to emphysema development, including elastase activity,cellular proteases (such as
proteinase 3 and cathepsin), matrix metalloproteinases, and oxygen-derived free
radicals.
o These factors can inactivate native antiproteases through oxidative injury.
Role of Smoking:
o
Smoking plays a pivotal role in emphysema pathogenesis by enhancing elastase
activity within macrophages.
Chronic Bronchitis:
o Definition Persistent cough with sputum production for at least three months in
two consecutive years.
O lt is cOmmon in habitual smokers.
Pathogenesis

MedEd
17
MedEd FARRE: Pathology

Chronic irritation (eg, tobacco Proteases, eg, neutrophil elastase,

smoke and pollutants) cathepsin and matrix
metalloproteinase
• Supcrimposcd
bacterial and viral
infections
• Histamine and IL-13

Hypersecretion of mucous and hyperplasia of submucosal glands

CLINICAL FEATURES
o Persistent cough with production of sputum
o Later stages, hypercapnia, hypOxQemia and mild cyanosis
o Death is due to severe infection or cor pulmonale and cardiac failure
() Difference between emphysema and chronic bronchitis:
Features Chronie Bronchitis Emphysema
Age 40-45 years 50-75 years
Dyspnoea Mild and late Severe and early
Cough Early onset Late onset with scanty
sputum sputum
Infections Common Occasional
Respiratory insufficiency Repeated Terminal
Cor Pulmonale Common Rare and terminal
Airway Resistance Increased Normal or slightly
increased
|X-ray Chest Large heart Small heart
Physical Appearance Blue bloater Pink puffer

(II) Bronchiectasis
o Bronchiectasis is characterized by the abnormal and permanent dilatation of
proximal and medium-sized bronchi, typically those with a diameter greater than
2 mm. This condition results from the destruction of the muscular and elastic
cOmponents of the bronchial walls.

Bronchiectasis
|Acquired Forms o More common in adults and older children, usualy triggered
by infectious insults, iwmpaired drainage, airway obstruction,
or defects in host defense mechanisms.

(118)
 Lung

Primary tnfections o Causative organiswns include Klebsiella species, Staphylococcus

aureus, Mycobacterium tuberculosis, Mycoplasma
pneumoniae, Mycobacterium avium complex, and certain
Viruses.
Bronchial o Conditions endobronchial tumors, foreign body
like
Obstruction impactions, and right middle lobe syndrome (resulting from
an' abnormally angled tobar bronchus) can cause bronchial
obstruction.
Cystic Fibrosis (CF)o Associated with mucus plugging in proximal airways and
chronic pulmonary infections, often involving Pseudomonas
aeruginosa.
Primary Ciliary o Characterized by imimotile or dyskinetic cilia and/or sperm,
Dyskinesia leading to impaired mucocitiary clearance, recurrent
pulmonary infections, and bronchiectasis.
o Kartagener's syndrome is a variant characterized by situs
inversus, nasal polyps, sinusitis, and bronchiectasis due to
immotile cilia in the respiratory tract.
Microscopy:
o Active cases may display acute and chronic inlammation of bronchi and bronchioles,
epitheliat desquamation, and necrotizing ulceration.
Clinical Presentation: JaiShreeRam
Patients often experience a persistent cough with mucopurulent, sometimes foul
o

Smelling sputum, which can last for months or years.

o Haemoptysis may occur due to airway damage associated with acute infections.
o
Additional symptoms may include dyspnea, pleuritic chest pain, wheezing, fever,
weakness, and weight loss.
Signs:
o Clinical signs can include pallor, cyanosis, abnormal chest sounds, foul-smelling
breath, and digital clubbing.
Complications:
o Recurrent pneumonias, Lung abscess
o Respiratory failure
o Cor pulmonale
o
Empyema
o Amyloidosis
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 678

I19) MedEd
 MedEd FARRE: Pathology

46. A S8-year-old retired factory worker. presented with a persistent dry cough
dull chest pain on the right side, and an unintended weight loss of about Tkg
over six months. He has smoked for the past 30 years. Physical examination
revealed fatigue, diminished breath sounds on the right side, tenderness on chest
wall palpation, and a non-clubbed finger appearance. A chest X-ray disclosed a
sizable mass in the right upper lung lobe and associated pleural effusion. Further
assessment through a CT Scan unveiled a 6 cm mass in the right upper lobe and
mediastinal (ymph node enlargement. Diagnostic procedures included sputum
cytology, bronchoscopy, and blood tests. The preliminary diagnosis is lung cancer.
likely non-small cell lung carcinoma (NSCLC). (10 marks)
Classify lurng tumors. Briefiy describe their aetiopathogenesis and morphology.

Answer:
TUMOR CLASSIFICATION

Tumor TYpe Subtypes/Variants

o Lepidic,
Adenocarcinoma acinar, micropapillary. papillary, solid
o lnvasive Mucinous Adenocarcinoma
o
Minimally invasive adenocarcinoma (nonmucinous,
mucinous)
Squamous Cell Carcinoma O
Keratizinga nonkeratinizing, basaloid
|Neuroendocrine Tumors o Small cell carcinoma
o Combined smal cell carcinoma
o Large-cell neuroendocrine carcinoma
o Combined large-cell neuroendocrine carcinoma
o Carcinoid
tumar (Typical, atypical)
Other Uncommon Types o Large cell carcinoma,
O
Adenosquamous carcinoma
o Sarcomatoid carcinoma
Epidemiology
O Adenocarcinoma is the most common lung carcinoma in females
o Strongest velationship with smoking is seen in squamous cell and small cell carcinoma
AETIOLOGY AND PATHOGENESIS
Tobacco Smoking:
o
Strong association with lung cancer.
o
Heavy smokers (more than 40 cigarettes/day for many years) face a 20-fold
increased risk.

120}
 Lung

o lncidence of lung carcinoma in smokers is approximately eight percent.

o Precursor histological changes, including hyperplasia and dysplasia, observed in
respiratory tract lining epithelium of smokers.
Industrial Hazards:
o Lung carcinoma is linked to occupational hazards such as radiation exposure,
uranium exposure (in miners), asbestos exposure (particularly in smokers), and
exposure to0 substances like nickel, chromates, coal, mustard, and arsenic.

Indoor Air Pollutants:

o Implicated in lung cancer development.
o Examples include radon gas.
Molecular Genetics:
o Genetic alterations play a significant role in lung carcinowma.
Tumor suppressor genes affected include ps3, RB1, and CDK inhibitor pi6,
o

observed in both adenocarcinoma and squamous cell carcinoma.

o Small cell carcinomaoften demonstrates amplification of genes in the MYC family.
Scarring:
o Scars are commonly found near adenocarcinomas.
o Scars may result from a desmoplastic iresponse to the tumor.
o Scar tissue can precede carcinoma development, occurring in areas of old infarcts,
foreign bodies, wounds, and granulomatous inflammation.
SQUAMOUS CELL CARCINOMA
Epidemiology:
O More common in males.
o Strong association with smoking.
Location:
o
Typicaly central in location.
o A recent increase in the incidence of peripheral lesions.
Histological Features:
o
Well-differentiated lesions show minimal atypia, intercellular bridges, and
abundant keratin.
o Keratinization is evident in numerous keratin pearls and individual cell keratinization.
o Squamous cells with intracellular keratin display dense eosinophilic cytoplasm.

o Moderately differentiated lesions exhibit moderate atypia.

121 MedEd
 MedEd FARRE: Pathotogy
o
lndividual cell keratinization is present, with occasional keratin pearls, if any.
fewer intercellular bridges compared to well-differentiated forms.
o Poorly
differentiated lesions have focal keratinization, which may not be easily
recognizable.
o Severe atypia is evident, making it challenging to identify them as squamos in
origin.
Adjacent Changes
o Squamous metaplasia, dysplasia. and squamous cell carcinoma in situ may be
observed in the adjacent tissue.
ADENOCARCINOMA
Epidemiology:
o Most common carcinoma in females and nonsmokers.
Location and Growth:
o Tends to be peripheral, smaller, and slow-growing compared to other lung cancers.
Histological Features:
o glands with occasional papillary differentiation.
Well -formed
o Mucin production is easily demonstrable.
o Solid sheets of poorly differentiatet dlis Ram
o Special stains or immunohistochemistry may be required to detect mucin
producing cels.
ln the lepidic pattern, tumor celis crawl along the alveolar septae while maintaining
O

the septal architecture.

Microinvasive Adenocarcinoma:
o Tumors than 3 cm in size.
less
O An invasive component is less than S mm,
O
Associated with a peripheral lepidic pattern and scarring.
O
Mucinous adenocarcinoma has a tendency to spread easily and form satellite
nodules.
Simall Cell Carcinoma:
o Highly malignant tumor with a strong association with cigarette smoking.
o
Tends to metastasize widely.
Location:
o May occur in hilar or central locations.

122)
 Lung

Histological Features:
o Epithelial cells are smal, round to oval, and have scanty cytoplasm.
o These cells resemble lymphocytes in size(2x the size)
O They are often referred to as oat
cells."
o
Necrosis and mitotic activity are cOmmon.
o Basophilic staining of vessel walls is commoniy observed due to smudging by DNA
from necrotic cells, known as the Azzopardi effect.
o
Prominent nuclear moulding results from close apposition of tumor cells with
scanty cytoplas.
Electron Microscopy:
o Tumor cells demonstrate dense core neurosecretory granules.
o These tumors are thought to originate from neuroendocrine or Kulchitsky cells.
o
Positive for chromogranin, synaptophysin, CD-57, NSE, PTAH and polypeptide
hormones
Large Cell Carcinoma:
o Comprises large anaplastic polygonal cels.
o These cells have vesicular nuclei.
o Often considered as undifferentiated and adenocarcinowmas that are no
longer recognizable under light microscopy.
o lncludes variants such as giant cel, clear cell, spindle cell, and large cell
neuroendocrine carcinoma.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 715

123) MedEd
MedEd FARRE: Pathology

47. A 45-year-old male presents to the oPD with complaints of progressive

shortness of breath and a persistent dry cough for the past 6 months. He
reports no significant fever or chest pain but notes that his exercise tolerance
hás significantiy decreased. He is a former smoker but quit 10 years ago. Vital
Signs within normal limits. Respiratory: Decreased breath sounds and inspiratory
crackles heard bilaterally on lung auscultation.
Investigations:
Chest X-ray: Reveals bilateral reticular opacities.
Pulmonary Function Tests (PFTS): Demonstrates a restrictive pattern with reduced
tung volumes and decreased diffusing capacity for carbon monoxide (DLCO).
High-Resolution Computed Tomography (HRCT) Chest: Shows ground-glass
opacities and honeyconmbing predominantly in the subpleural regions of both
[Link] on these the doctor made a diagnosis of idiopathic interstitial fibrosis.
(A) Classify interstitial lung disease and the difference between UIP and NIP
(B) Write a note On sarcoidosis
(C) Explain in brief about Anthracosis, silicosis and asbestosis.
(D) Write in brief about hypersensitivity pneumonitis. (10 marks)
Answer:
(A)
UIP (Usual Interstitial NSIP (Non-Specific tnterstitial
Characteristic
Preumonia) Pneumonia)
Definition A
type of interstitial lung An interstitial lung disease
disease characterized by marked by inflammation
fibrosis (scarring) of the lung and scarring of the lung's
tissue. interstitial spaces.
Progression Tends to progress slowly Progression is generally stower
and can lead to severe lung COmpared to some other
damage over time. interstitial lung diseases, and
it may be less severe.
Radiological Radiological findings often Radiological findings usually
Findings include honeycombing show ground -glass opacities
(distinctive cystic spaces) in and a more uniform
the lungs. appearance.
Histopathology Histopathological examination Histopathology shows
reveals areas of dense fibrosisinflammation and scarring in
alternating with relatively a more uniform pattern with
normal lung tissue. |less honeycombing.
Prognosis Prognosis tends to be Prognosis is relatively better,
poorer, with a higher risk of and individuals with NSIP may
|progression and mortality. respond well to treatment.

124
 Lung

Intersttial ung disease

4 Fbrosing aveoltis Granulomatous ILD Eosinophiha ILD

Smokng-eiatedID Pulmonary aveclar
proteinosis

Usual intersstaa! Desquamatng intersttal

preumona (UIP) pneumonia (DIP)
-Surcoidoss

-Hypersenstbvity preumonitis -Respitatory tronchiolts

Non-specific
interstiial pneumonia associated interstsal tung
(NSIP) disease

Cryptogenic organising
preumonia

ILD a'w
a) Pneumoconiosis
b) Colagen vascular disease
c) Drug reactions and radiaton injury

(B)

Sarcoidosis
Definition o A systemic disorder of unknown origin characterized by
noncaseating granulomas in various tissues and organs.
Etiology and o Believed to,jresutt from immune system dysregulation,
Pathogenesis genetic predisposition, and environmental factors.
o
Involves CD4+ T cell accumulation, leading to an elevated
CD4:CDg T cell ratio.
O
Elevated TH1 cytokines like IL2 and IFN-Y cause T cell
expansion and macrophage activation.
o
Elevated cytokines (IL-8, TNE, MIP-10) attract more T
cells and monocytes, contributing to granuloma formation
|Morphology o Noncaseating granulomas in affected tissues, cowmposed of
densely packed epithelioid cells, Langhans or foreign body
giant ceils.
o "Naked granutomas" with few lymphocytes.
o Long-standing granulomas may have fibrous rims,
Schaumann bodies (calcium-protein concretions), and
asteroid bodies (stelate inclusions).

125) MedEd
MedEd FARRE: Pathology

Clinical o Lungs are most commonly affected, with pulmonary nodules

Manifestations around lymphatics, bronchi, and blood vessels.
o Enlarged lymph nodes, especially in hilar and mediastinal
regions.
o Variable symptoms: respiratory symptoms,
clinical
constitutional symptoms, lymphadenopathy. skin lesions,
eye problems, hepatosplenomiegaly, and imuscle -related
symptoms.
o Chronic, progressive course with remission and activity
periods.
o Some cases may lead to pulmonary fibrosis and cor
pulmonale.
(C)
Coal Worker Silicosis
Characteristic Asbestosis
Pneumoconiosis
Causative Agent Coal dust |Asbestos fibers Silica dust
(crystaline)
Occupational Coal mining Asbestos-related Mining
Exposure jobs cOnstruction, etc.
Pathology |Inflammation lShrFibrosis of lung Fibrosis of fung
fibrosis tissue tissue
Fibrotic PatternsSimple CWP, Interstitial fibrosis Nodular, Diffuse
Cowplicated CWP
Biopsy Findings Coal dust-laden |Asbestos bodies, Silica particles,
macrophages, asbestos fibers fibrotic lesions
fibrotic nodules
|Symptoms Breathlessness, Breathlessness, Breathlessness,
cough cough cough
Risk Factors Prolonged coal dust Prolonged asbestosProlonged silica
exposure exposure exposure
Pathogenesis lnhalation of coal Inhalation of Inhalation of sillica
dust asbestos dust
(D)

Hypersensitivity Pneunmonitis
Definition O An immune system-mediated response to external
antigens, progressing from Type l hypersensitivity to Type
IV hypersensitivity.

126)
 Lung

Examples o Farmer's (ung (moldy hay with actinomycetes)

o Pigeon breeder's disease (bird proteins)
o Humidifier or air-conditioner lung (thermophilic bacteria
in heated water reservoir)
Clinical Features o Acute form: Recurring episodes of fever, dyspnea, cough,
increased white blood cell counts.
o Chronic form: Progressive respiratory failure, dyspnea,
cyanosis, reduced lung compliance.
X-Ray Findings o Diffuse or nodular infiltrates on chest X-rays.
Pulmonary o Typically indicate a restrictive lung disorder.
Function Tests
Morphology o Histological changes primarily affect bronchioles.
o Interstitial pneumonitis with lymphocytes, plasma cells,
and macrophages.
o Noncaseating granulomas.
o lnterstitial fibrosis and obliterative bronchiolitis in late
stages.
Reference: Patholoic Basis of Disease, Robbjns and Cotran, 1oth Edition, Page No. 689
JaiShreeRam

127 RMedEd
 GIT and Hepatobiliary
48. Write briefiy about pleomorphic adenowma. (3 marks)
Answer:
CLASSIFICATION OF SALIVARY GLAND TUMORS

Benign Tumors Malignant Tumors

Pleomorphic Adenoma Mucoepidermoid Carcinoma
Warthin Tumor Acinic Cell Carcinoma
Oncocytoma Adenoid Cystic Carcinoma
Canalicular Adenoma Adenocarcinoma, Not Otherwise Specified (NOS)
Basal Cell Adenoma Carcinoma Ex Pleomorphic Adenoma
Other Adenomas |Squamous Cell Carcinoma
Ductal Papillomas Other Carcinomas
Pleomorphic Adenoma:
o Accounts for over 907% of benign saliyary gland tumors.
O Typically presents as painles swelindaam
atthe angle of the jaw.
o Most commonly found in the superficial lobe of the parotid gland, followed by the
submandibular gland. Rarely occurs in minor salivary glands.
o Predominantly diagnosed in individuals aged between their fourth and sixth
decades, with rare cases in children. More common in wOmen.
o
Believed to originate from veserve cells of the epithelial, myoepithelial, or ductal
types.
Gross Morphology:
o
Exhibits small, well-demarcated, round, and multilobulated characteristics.
O
Appears encapsulated but often shows finger-like extensions crossing the tumor
capsule at multiple sites.
o Tumors are typically solid, but the cut surface may display a variegated appearance,
with gray -white, myxoid, and blue translucent pseudochondroid areas.
Microscopic Features:
o Pleomorphic adenomas exhibit both epithelial and mesenchymal differentiation,
earning them the name "mixed tumors because they were once thought to arise
from multiple germ cell layers. They can undergo secondary malignant changes.

126
 GIT and Hepatobiliary

o The epithelial component comprises ductal and myoepithelial cells, forming

ducts, acini, tubules, strands, or sheets. Ductal cls are typically cuboidal, while
myoepithelial cells appear flattened or spindled.
o The background stroma may have various charactevistics, such as mucoid, myxoid,
pseudochondroid, or hyaline components.
Warthin Tumour (Papillary Cystadenoma Lymphomatosum):
o Also known as papillary eystadenoma lymphomatosum, it is a benign tumor
exclusively found in the parotid gland.
o Typically affects males in their fifth to seventh decades of life.
o May occasionally wmanifest as multicentric tumors.
o The origin of this tumor is debated, but it is believed to arise from heterotopic
salivary tissue trapped within a regional lymph node during embryonic development.
Gross Morphology:
o Originates in the superficial parotid gland and appears as a smal, round-to-oval,
lobulated, and encapsulated mass.
O The cut surface may veveal mucin-containing narrow cysts or cleft-like spaces
with papillary projections.
Microscopic Features:
o Warthin tumor is a biphasic tumorcharäcterized by both epithelial and myoepithelial
components, accompanied by a lymphoid stroma.
o The epithelial components consist of glandular or cystic structures lined by a
double -layered epithelium.
o The inner cell layer comprses columnar cells with abundant, finely granular
cytoplasm (oncocytie cells).
o The outer cell layer appears cuboidal to polygonal in shape.
o Secretory cells are dispersed within the iner layer of columnar cells.
o The myoepithelial component consists of spindle-shaped or flattened cells.
o A lympbhoid stroma is located beneath the epithelium, forming lymphoid follicles.
often with germinal centers.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No.
748

MedEd
127
MedEd FARRE: Pathology

49. Differentiate between tuberculous and typhoid ulcer. (3 marks)

Answer.
Feature Tuberculous Ulcer Typhoid Ulcer
Causative Mycobacterium tuberculosis Salmonella typhi
Organism
Site Anywhere in the swmall Most common in terminal
intestine; most common in ileum (Peyer's patches): may
terminal ileum and caecum, Occur in jejunum
rarely colon
Orientation of Perpendicular to the long axis Parallel to the long axis of the
the Ulcer of the bowel (transverse ulcer) bowel (longitudinal ulcer) due
due to spread by lacteals to the involvement of Peyer's
Cymphatics) patches
Microscopic Epithelioid cell granulomas | Lymphoplasmacytic infiltrate
Features with or without caseous with histiocytes, some of which
necrosis show erythrophagocytosis:
Fibrosis and stricture
formation
Common Fibrosis and stricture Rare
Complication formation (Common; intestinal
tuberculosis may present lwith
subacute or acute intestinal
obstruction)
Perforation May be present Common
Bleeding Absent Present

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 791

128
 GIT and Hepatobiliary

so. Diferentiate between amoebic and ulcerative colitis. (3 marks)

Answer:
Feature Amoebic Colitis ulcerative Colitis
Cause o lnfective, caused by o Unknownj may result
Entamoeba histolytica from dysregulated immune
responses, in genetically
Susceptible individuals
o Transwmission by o Genetic
Pathogenesis the fecal predisposition with
oral voute (infection is immunologic dysregulation
spread through ingestion
of the cyst form of the
parasite, a resistant
structure found in stools)
Distribution
O
Localized to the cecum and o Involves the rectum and
ascending colon, sigmoid, extends proximally to
rectum, and appendi in involve the whole colon in
decreasing order. In severe severe cases
cases, the entire large
intestine may be involved
Ulcer o Pin-head to large-sized o Broad-based ulcers with
ulcers seen. MuscuarisRam cOntinuOUs involvement; no
propria acts as a barrier to intervening normal mucosa.
trophozoites. O Usually superficial: limited
o The ulcer fans out laterally to mucosa and submucosa
just above the muscularis
propria, forming discrete
flask-shaped ulcers (narrow
neck and broad base).
Intervening mucosa is
normal
Morphology O Liquefactive necrosis; few o Diffuse mononuclear
inflammatory cells, mainly infiltrate, crypt abscesses
neutrophils
Pseudopolyps o
Absent O Present
Risk of Cancer o Nil O Present
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 797 and
801

MedEd
129
MedEd FARRE: Pathology

S1. Write briefly about Budd chiari syndrome. (3 marks)

Answer:
Budd-Chiari Syndrome
Budd-Chiari syndrome is characterized by hepatic vein obstruction, leading to liver
cOngestion and damage.
Involves blockage of hepatic veins, from intrahepatic to extrahepatic levels.
Etiopathogenesis
o Multiple causes, including thrombosis, compression by tumors, and hypercoagulable
states.
o Thrombosis
* Blood clots form within hepatic veins, blocking normal blood flow.
o Compression
* Tumors or masses in or nearthe liver compress hepatic veins, causing obstruction.
o Hypercoagulable State
* Conditions increasing blood clot risk, such as genetic disorders or autoimmune
diseases, predispose to Budd-Chiari syndrome.
Clinical Presentation o Symptoms include abdominal pain, hepatomegaly.
ascites, and jandice. Severe cases can lead to liver
failure.
Diagnosis o lmaging studies (Doppler ultrasound, CT, MRI)
reveal venous obstruction, and blood tests show
liver enzyme elevation.
Treatment O Management depends on the cause and severity,
including anticoagulants, angioplasty, stent
placement, and liver transplantation.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 862

130
 GIT and Hepatobiliary

52. Differentiate between Primary Biliary Cholangitis (PBC) and Primary Sclerosing
Cholangitis (PSC). (3 marks)

Answer:
Primary Biliary Cholangitis Primary Sclerosing
Feature (PBC) Cholangitis (PSC)
Average age affected 50 years 30 years
Gender 90% females 70% females
Evolution Progressive Unpredictable
Pathology o Small- and medium-sizedo lnflammatory
intrahepatic bile ducts are destruction of
affected. extrahepatic and large
o Large intrahepatic ducts intrahepatic ducts.
and the extrahepatic biliary o Fibrotic obliteration
structures are not involved. of medium and small
O Florid intrahepatic ducts.
duct lesion On
histopathology o Ductular reaction in
smaller portal tracts.
o Onion skin lesion on
histopatholgy
JaiShreeRam
Associated conditions Sjogren syndrome Inflammatory bowel
disease, Pancreatitis
Serology 95% AMA positivity, s0% |5% AMA positivity, 6
ANA positivity,40% ANCA ANA positivity, 65% ANCA
positivity positivity
Radiological features Normal Beaded appearance of the
affected segment on a
retrograde
is
cholangiogram
diagnostic
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 857

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53. () Write briefy on achalasia cardia. (10 marks)

(U) write briefly on gastroesophageal reflux disease (GERD)

(u) Write briefly on Barrett's esophagus.

() Write briefly on carcinoma esophagus.
Answer:

GERD
Definition Chronic condition with diffuse erosive/ulcerative oesophagitis.
Protective Abundant submucosal glands secrete mucin and bicarbonate.
Mechanisms
o The
Pathogenesis & development of GERD involves both genetie and
Pathology environmental factors contributing to decreased LES pressure
and gastric veflux into the esophagus, leading to pathological
changes such as: tnitially normal mucosa in one-third of
patients.
o Progression frowm erythema and red streaks to erosions and
ulcers in thelesophageal lining.
O
lncreased friabitity leading to contact bleeding.
o Dilated blood vessels and inflammatory cells conmmonly
observed.
o ln some cases, eosinophilic esophagitis may occur, associated
with atopy and eosinophilia.
Predisposing Pregnancy,Ascites, Obesity, Delayed gastric emptying, Peristaltic
Factors |disorders (eg., scleroderma)
Clinical Features Heartburn, Regurgitation, Dysphagia/ odynophagia, Water brash
(hypersalivation), Intermittent chest pain
Complications o Esophageal lining ulceration
o Haematemesis (vomiting blood)
o Melena (black, tarry stools)
O
Esophageal strictures
o Barrett's esophagus

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 GIT and Hepatobiliary

(I)
ACHALASIA CARDIA
Features of Achalasia Cardia:
o Complete absence of peristalsis and elevation of resting LES pressure or low
amplitude non -peristaltic contractions.
o Increased intraesophageal pressure.
o Functional obstruction of the oesophagus with a dilated fluid and food-filled
proximal portion.
Age Group Affected:
o Usually affects individuals in the age range of 20O-40 years.
Symptoms:
o Progressive dysphagia for solids and liquids.
o Regurgitation.
o
Chest pain.
o Weight loss.

Aetiology:
o
Primary Achalasia: The exact cause is unknown, but it may be related to neuronal
dysfunction rather than a myopathic disorder. Auerbach's plexus may show a
decrease in the number of ganglion cells, suggesting ganglion cell degeneration.
o Secondary Forms: Typically associated with conditions such as Chagas disease
(Trypanosoma cruzi infection), polio, diabetic autonomic neuropathy, infiltrative
disorders (eg., malignancy, amyloidosis, and sarcoidosis), and coexistence with
other autoimmune diseases like Sjogren syndrome or thyroiditis, indicating
potential immune-wmediated destruction of inhibitory oesophageal neuron.
Microscopy Findings:
o In achalasia cardia, the oesophageal wall demonstrates the following microscopic
features:
* Thickening of the oesophageal wall in the distal portion, characterized by smooth
muscle hypertrophy. particularly in the inner circular layer.
* The proximal dilated segment is actually thinned out.

()
o Barrett's esophagus is acomplication of long-standing GE reflux.
Hallmark is replacement of distal squamous mucosa by metaplastic columnar
epithelium as a response to prolonged injury.

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Pathogenesis and consequence of Barrett's esophagus:

Prolonged recurrent GE reflux

Re-epithelialization and in growth of pluripotent

stem cells

Inflammation and ulceration of squamous epithelial

lining of the lower segment of oesophagus

Squamous epithelium replaced by metaplastic columnar epithelium

of the intestinal type [Barrett's Esophagus]

In an environment of sustained low pH,

these cells may become dysplastic
(02-2% patients)

Dysplasia

Low gradelaiShreigh grade

Adenocarcinoma
Gross Morphology
o Red and velvety mucosa with raised patches.
o Most important complication is the development of adenocarcinoma.
(IV) CARCINOMA ESOPHAGUS
o Individuals over the age of 5o are predominantly affected by esophageal carcinoma.
Males are more commonly affected than fenales.
Predisposing Conditions/Factors
o Adenocarcinoma: Incidence ison the rise in western countries due to obesity which
in turn is vesponsible for increasing the incidence of GERD and Barrett mucosa.
O Squamous cell carcinoma: Most common type worldwide.
o Predisposing factors
Achalasia
* Plummer-Vinson syndrome

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 GIT and Hepatobiliary

Strictures, diverticula and webs

* Alcohol, hot and spicy foods, betel chewing, smoking, aflatoxins and silica
* Diet deficient in vitamins A, C and trace elements
* Diet high in nitrosamines.
Clinical features:
o Dysphagia or odynophagia
o
Weight loss
o Iron deficiency
o Tumor-related hemorrhage
o Sepsis
o Chest pain
o Vomiting
Other Points:
o Most esophageal cancers are squamous cell carcinomas (SCcs) primarily affecting
the upper thoracic segwment, with approximately half located in the middle third
of the esophagus.
o These tumors can be categorized as superficial, limited to the mucosa and submucosa,
or advanced, involving infiltration into the muscularis propria. Superficial lesions
generally have a better prognosis.
o ln addition to SCCs, adenocarcinomas and undifferentiated carcinomas are also
observed, but less frequently.
o Adenocarcinomas often originate from the mucous glands of the esophagus or may
develop in individuals with Barrett's esophagus.
o Esophageal cancers tend to metastasize early and commonly involve visceral organs
such as the liver, lungs, and kidneys.
o
Unfortunately. the overall prognosis for esophageal cancer is generaly very poor.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 759
Reference: Pathologic Basis of Disease, Robbins and Cotvan, 10th Edition, Page No. 767
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 761

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s4. (0) write briefly on the etiology. pathology and complications of peptic ulcer.
(u) Differentiate between benign and malignant peptic ulcer. (5 marks)
Answer:

o Peptic ulcers are chronic, recurrent lesions that can develop in various parts of
the gastrointestinal tract exposed to acidic and peptic juices. They are typicaly
diagnosed in individuals of middle to old age.
Sites:
o First portion of the duodenum
o The antral region of the stomach (most common)
o The gastroesophageal junction
o Occasionally in Meckel's diverticulum.

Pathogenesis:
o Peptic ulcers occur when the stomach's defense mechanisms are compromised,
allowing damaging factors to take precedence.
Gastroduodenal defence mechanisms
O Mucous layer on surface
JaiShreeRam
o Bicarbonate secretion into mucosa
o Adequate mucosal blood flow
o Apical surface membrane transport
o Epithelial regenerative capacity
o Prostaglandin secretion
Damaging factors: Several factors can exacerbate gastric acid and peptic enzyme
secretion, contributing to ulcer formation.
o Use
of nonsteroidal anti-inflammatory drugs (NSAIDs) like aspirin, which directly
irritate the mucosa and reduce prostaglandin and bicarbonate secretion.
o Cigarette smoking and alcohol consumption can impair blood flow and the mucosa's
healing capacity.
o Ischemia, shock
o
Iron preparations
o Viral infections
O
Aging (which reduces mucin and bicarbonate secretion)
o Urease-secreting H. pylori

136
 GIT and Hepatobiliary

o
Chemotherapy
o Additionally. duodenal-gastric reflux, psychological stress, and hyperkalewmia are
potential contributing factors.
ROLE OF H. PYLORI IN PEPTIC ULCERATION
o Urease Activity: H. pylori seceretes urease, leading to increased ammonia production,
which raises pH and creates a less acidic environment, favoring bacterial survival.
o Reduction of Acidity: Ammonia generated by urease binds with stomach acid (H+),
reducing overall acidity and promoting H. pylori colonization.
o Protease and Phospholipase Activity: H. pylori secretes enzymes that damage
gastric mucosal glycoproteins and surface epithelial cells, weakening mucosal
defenses.
o lnduction of Inflammation: H. pylori infection triggers an inflammatory response
with cytokine release and immune cell recruitment, contributing to tissue damage.
o Thrombotic Occlusion: In some cases, H. pylori can cause localized ischemia, further
damaging the muCOSa.
o Toxin Production: H. pylori toxins, such as VacA and CagA, contribute to cellular
damage and ulcer formation.
o
Determinant of Ulcer Development: H. pylori infection is strongly associated with
peptic ulcers, with strain virulenee nflucnging ulcer risk.
Giross Morphology:
o Active peptie ulcers typically exhibit small, round-to -oval, well-defined lesions
ranging from 2 to 4 cm in size. They appears clean and smooth due to peptic
digestion.
Microscopic Features: Active ulcers exhibit four distinct zones, known as Askanazy
ZOnes:
o Zone of fibrinoid necrosis.
o Zone of nonspecific inflammatory infiltrate, mainly composed of neutrophils.
o Zone of granulation tissue, characterized by proliferating blood vessels, fibroblasts,
and mononuclear cells.
o Zone of fibrosis, where collagenous or fibrous scar tissue forms.
Complications:
o Bleeding
o Perforation
o Obstruction

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() DIEFERENCE BETWEEN BENIGN AND MALIGNANT PEPTIC ULCER

Feature Benign Ulcer Malignant Ulcer

Age Comparatively younger age Older age
Sex Clear-cut wmale predominance Slight male predominance
Site Usually along lesser curvature Along greater curvature of
of pyloruS and antrum stomach
Size Generally less than 4 cm Generally more than 4 cm
Ulcer Base Clear; rarely haemorrhagic Necrotic debris may be
present
Mucosal Folds Radiating from the ulcer Interruptedi flattening
Crater of the rugae around the
ulcer due to infiltration by
malignant cells
Margins No or minimal heaping Heaping prominent
Barium Meal Sharply punched-out lesion Irregular lesion

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 770
JaiSAD0Ram

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 GIT and Hepatobiliary

ss. write briefly on the aetiopathogenesis, gross and microscopic features of gastrie
adenocarcinoma. (5 marks)
Answer:
PREDISPOSING FACTORS
Dietary factors:
o Consumption of foods containing nitrites or their precursor nitrates.
o lntake of smoked and salted foods, as well as pickled items.
o lnsufficient consumption of fresh fruits and vegetables.
Host factors:
o H. pylori infection and chronic gastritis, can lead to multifocal mucosal atrophy
(resulting in hypochlorhydria favoring H. pylori colonization) and intestinal
metaplasia (increasing the risk of intestinal-type gastric cavcinoma),.
o Prior partial gastrectomy, can cause reflux of irritant biliary contents and chronic
gastritis.
o Presence of gastric adenomas.
o
Cigarette smoking.
o Menetrier disease.
Genetic factors:
o Blood group A JaiShreeRam
o Familial gastric cancers are due to mutations in CDH1, Which encodes E-cadherin,
responsible for the epithelial intercellular adhesion (loss of E-cadherin is usually
associated with diffuse gastric cancer).
O
Mutations in B-catenin, microsatellite instability and hypermethylation of several
genes like TaFBRII, BAX, IGFIIR and p16INK4a are noted in sporadic intestinal
type gastric cancer.
MICROSCOPIC OR HISTOLOGICAL (LAUREN) CLASSIFICATION
(a) Intestinal Type:
o Loss of function mutation in APC gene and qain of function mutation in beta
catenin
o Tumour cells form glands resembling colonic adenocarcinoma.
o Cells have apical mucin vacuoles.
o Growth is expansile, meaning it grows as a cohesive mass along broad fronts.
(b) Diffuse/Gastric Type:
o Loss of function mutation in CDH1 gene.

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O No gland formation.
o Cells show a signet ring appearance, with the nucleus pushed to the periphery due
to the presence of a large intracytoplasmic mucin vacuole.
o Scattered individual cells or small cell nests permeate the gastric wall, exhibiting
an infiltrative pattern.

Characteristic Intestinal Type Diffuse Type

Incidence Decreasing No change
Average Age 55 years 48 years
Male: Female Ratio 2:1 1:1
Chronic Gastritis Frequently associated No particular association
Macroscopic Growth Exophytic, polypoid Ulcerative and/or diffusely
Pattern infiltrative resulting in a
rigid thickened wall (linitis
plastica)
Microscopic Growth Gland -forming columnar lnfiltrative growth;
Pattern epithelium; associated noncohesive: poorly
with intestinal metaplasia, differentiated, often signet
usually mucin -producing ring cells: mucin -producing

CLINICAL FEATURES JaiShreeRam

o Abdominal pain, Anorexia, Anaemia, Weight loss
o Vomiting
o Dysphagia due to involvement of the cardiac end
o
Obstructive symptoms due to involvement of pylorus
Mechanisms of Spread: Gastric carcinomas spread through various mechanisms:
O Local spread to adjacent structures
o Lymphatic spread to local and distant lymph nodes
o Hematogenous spread
o Transperitoneal spread
Metastatic Sites: Gastric carcinomas can metastasize to several sites:
o Supraclavicular lymph nodes (Virchow lymph node)
o Periumbilical region to form a subcutaneous nodule (Sister Mary Joseph nodule)
o
Bilateral ovaries, leading to Krukenberg tumors
o Other common sites for visceral metastasis include the stomach, breast, pancreas,
and gallbladder.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 774

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 GIT and Hepatobiliary

s6. Write short note on celiac (nontropica) sprue and environmental or tropical
a
enteropathy. (5 marks)
Answer:
Celiac disease

It is also known as:

o Gluten-Sensitive Enteropathy
o Nontropical Sprue
PATHOGENESIS

Gluten digested by luminal and brush-border enzymes

a-gliadin is a peptide that is resistant to degradation

These peptides induce intestinal epithelial cells to express IL-15

triggers activation and proliferation of CD8+ cells

JaiSheRam
These lymphocytes express NKG2D, a natural killer cell marker
and receptor for MIC-A.

The induced cells are then attacked by NKG2D-expressing intraepithelial

lymphocytes.

Epithelial damage
Enhance passage of other gliadin peptides into the lamina propria

These gliadin peptides interact with HLA-DQ2 or HLA-DQ8 on APC and stimulate
CD4+ T cells that exacerbate tissue damage.

Morphological Characteristics:
o The smal intestine exhibits diftuse enteritis, accompanied by villus atrophy or
even complete los.

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o Surface epithelium shows signs of vacuolar degeneration, microvilli loss, and an
increased presence of intraepithelial cDs+ T lymphocytes.
o fn an effort to maintain mucosal thickness, the crypts undergo hyperplasia,
becoming elongated and convoluted. often displaying elevated mitotic activity.
Genetie Predisposition:
o HLA(DQ2 and DQ8) association accounts for nearly half of the genetic component
of celiac disease.
o Other genetic factors include polymorphisms of imwmune regulatory genes such as
IL-2 and IL-21.
Distribution:
o Celiac disease primarily affects the proximal part of the small intestine, where
there is higher gluten exposure compared to the distal part.
Associated Clinical Conditions:
o Dermatitis Herpetiformis
o Neurological Disorders
Secondary Malignancy:
o Celiac disease is associated with an increased risk of secondary wmalignancies,
including intestinal lymphoma, small intestinal adenocarcinoma, and esophageal
squamous cell carcinoma. JaiShrecRam
Treatment:
o The primary treatment for celiac disease is a gluten -restricted diet, which involves
avoiding foods containing gluten.

TROPICAL SPRUE
Pathogenesis:
o Environwmental or tropical enteropathy is primarily a post-infectious condition.

o It occurs exclusively in individuals living in or visiting tropical regions.

o No specificcausal agent has been identified, but there is evidence of enterotoxigenic
bacterial overgrowth, including Cyclospora and E. coli.
o There is no known genetic predisposition associated with environmental or tropical
enteropathy.
o
Thiscondition affects the distal (lowe) part of the small bowel.
Clinical Features:
o Patients with envionmental enteropathy often experience frequent folate or
vitamin B12 deficiency due to the involvement of the distal smal bowel.

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 GIT and Hepatobiliary

o This deficiency can lead to atypical enlargement of nuclei in epithelial cells, a

condition known as megaloblastic change.
Treatment:
o Broad-spectrum antibiotics are a common treatment approach for environmental
or tropical enteropathy.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 784

JaiShrecRam

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S7. A 6o-year-old male presented with a six-month history of altered bowel habits,
including episodes of constipation and diarrhea. He also reported noticing bright
red blood in his stool and experiencing fatigue. over this period, he unintentionally
lost 10 pounds due to a decreased appetite. The patient denied experiencing any
significant abdominal pin or changes in his appetite. His past medical history
included well-controlled hypertension, with no known allergies or prior surgeries.
There was no family history of colorectal cancer or gastrointestinal diseases,
and the patient had a non-smoking history and occasional alcohol consumption.
Physical examination revealed pallor and fatigue, with no palpable masses or
tenderness upon abdominal examination. Digital rectal examination detected
fresh blood on the glove and revealed an enlarged, firm rectal mass. Further
diagnostic tests were conducted, including a colonoscopy, which identified a
large, ulcerated mass obstructing the lumen in the sigmoid colon. Biopsy samples
were taken for histopathological examination, which confirmed the presence of
adenocarcinoma in the sigmoid colon.
(0 Explain the pathogenesis of colorectal carcinoma.
(I) write briefiy on hereditary cancer syndromes of colon.
(u) Differentiate between Crohn's disease and Ulcerative colitis. (10 marks)
Answer:
PATHOGENESIS
JaiShreeRam
Two distinct molecular pathways have been implicated in colonic cancer and they are
1. Adenoma-carcinoma sequence (APC b-catenin pathway)

Normal mucosal epithelium

Germline (inherited) or somatic (acquired) mutation of cancer suppressor

'gatekeeper APC (adenomatous polyposis coli) gene located at sq2i (first hit)

Hyperproliferative epithelium

Methylation abnormalities or inactivation of normal alleles of APC, B-catenin, and

MutS Homolog 2 or MSH2 (second hit)

Early adenoma

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 GIT and Hepatobiliary

Mutation in proto-oncogene (K-RAS at 12p12)

Intermediate adenoma

Homozygous loss of additional cancer suppressor genes LOH at 18q21 (Mothers

against decapentaplegic homolog 2 or SMAD2 and 4, which affect TGF-ß signaling)

Late adenoma

Homozygous loss of additional cancer suppressor gene p53 at 1 7p13

Additional mutations and gross chromosomal alteration of many genes

Carcinoma
2. Microsatellite instability pathway (defective DNA repair):
Normal Colon
JaiShrpeRam
Germline or somatic mutations of mismatch repair genes (MLH1, MSH2, MSH6 etc.)
Alteration of the second allele by LOH, mutation or promoter methylation

Sessile serrated adenoma

Accumulation of mutations in genes that regulate growth, diferentiation and

apoptosis

Carcinoma

(I) The wmost commOn colonie cancer-associated syndromes include:

1. Familial Adenomatous Polyposis (FAP):
o
FAP is an autosomal dominant disorder caused by a genetic defect in the APC
gene on chromosome Sq21.

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MedEd FARRE: Pathology

with FAP develop a large number of polyps throughout the colon,

o Individuals

typically numbering over 100, and may also have adenomas in other parts of the
digestive tract, such as the duodenum.
o Polyps can appear as early as adolescence or early aduthood, and the risk of these
age.
polyps progressing to colonic cancer is virtually 100% by middle
o Variants of FAP include Gardner syndrome (characterized by osteomas, epidermal
cysts, desmoid tumors, and thyroid tumors) and Turcot syndrome (involving
intestinal adenomas and central nervous system tumors).
o The morphology of the polyps in FAP is similar to sporadic adenomas.
2. Hereditary Nonpolyposis Colorectal Cancer (HNPCC) or Lynch Syndrome:
o HNPCC is an autosOmal dominant condition characterized by an earlier onset of
colorectal cancer compared to sporadic cases. These cancers are typically located
in the right colon and often have a mucinous histology.
o While the name implies a lack of polyps,some adenomas can develop in HNPCC,
although they are usually few in number.
o HNPCC is associated with germline mutations in DNA mismatch repair (MMR)
genes responsible for correcting errors during DNA replication Tumors in HNPCC
often exhibit a high rate of microsatelite instability (MSI), which is a hallmark of
MMR deficiency.
o Beyond colorectal cancer, HNPCC is linked to an increased risk of extracolonic
cancers, including those affecting the stomach, small intestine, endometrium,
ovary, and urinary bladder.
(U) Differences between Crohn disease and ulcerative colitis

Features Crohn Disease Ulcerative Colitis

Gross Features
Bowel Region Afected lleum, sometimes colon Colon
Pattern of Distribution Skip Lesions Diffuse, Continuous
Involvement
Stricture Formation Earty Late, Uncommon
Intestinal Wall Thickened ThinnedOut
Intestinal Dilatation Absent Present
Progression Antegrade Retrograde
Microscopic Features
Ulcers Deep Linear Superficial
Pseudo Polyps Absent Present

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 GIT and Hepatobiliary

Lymphoid Reaction Marked Mild

Fibrosis Marked Mild

Serositis Marked Absent or Mild

Granulomas Present in so% of the Absent
Cases
Fistula/Sinus Present Absent
Clinical Features
Fat/Vitamin Present Absent
Malabsorption
Malignant Potential Less More
Response to Surgery Poor Good

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 813

JaiShreeRam

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s8. Write briefty on the etiopathogenesis of gallstones. (5 marks)

Answer:
TYPES
o Cholesterol (contains more than so% of crystalline cholesterol monohydrate):
mOre cOmmon in the west
o Pigment (main constituents are bilirubin and calcium); more common in Asians

CHOLESTEROL STONES
o Cholesterol gallstones are more common in Western populations.
o Risk factors include advancing age, female gender, oral contraceptives, pregnancy,
obesity, rapid weight reduction, reduced gallbladder motility, inborn disorders of
bile acid metabolism, and hyperlipidemia syndromes.
o
These stones can occur in two forms:
* Pure cholesterol stones: These are rare, large, solitary, spherical stones with a
yellow, glistening. radiating crystalline internal structure.
* Mixed cholesterol stones: These are the majority of clinically found stones and
are composed mainly of cholesterol but also contain variable amounts of bilirubin
and calcium salts. They are often multiple and radiolucent, making them invisible
On regular X-ray films.
JaiShE
o Pathogenesis involves excess chotesterot accumulating in the bile, supersaturating
it and leading to the nucleation of solid cholesterol wmonohydrate crystals:
Supersaturation of bile with cholesterol

Establishment of nucleation sites by microprecipitation

of calcium salts
Hypomotility of gallbladder (stasis)
promotes nucleation

Mucous hypersecretion to trap crystals, enhancing their

aggregation into stones
PIGMENT STONES
o Pigment gallstones are more common in Asian populations.
o Risk factors include chronic hemolytie syndromes, biliary infections, gastrointestinal
disorders such as ileal disease, and cystic fibrosis with pancreatic insufficiency.

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 GT and Hepatobiliary
o Pigment stones can be either black or brown:
• Black stones: Composed of calcium bilirubinate,phosphate. carbonate, and
minimal cholesterol. They are usually multiple, smal, and friable, often forming
in chronic hemolytic anemias like sickle cell anemia or thalassemia.
* Brown stones: Composed of calcium bilirubinate, calcium salts of palmitate and
stearate, and some cholesterol but lacking calcium phosphate or carbonate. They
are typically seen in bacterial infections causing deconjugation of bilirubin and in
prolonged biliary stasis. These stones appear laminated, soap-like, and greasy.
Pathogenesis:
lnfection of biliary tract

Release of microbial B-glucuronidase Intravascular haemolysis

Hydrolysis of bilirubin glucuronides Increased unconjugated bilirubin

Formation of piginent stones

Reference: Pathologic Basis of Disease, Robbins and Cotvan, 10th Edition, Page No. 8 73

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s9. (0) Define cirrhosis. Enumerate its causes and consequences. (10 marks)
(u) outline the aetiopathogenesis and clinical features of portal hypertension.

(u) write briefly on alcohotic liver disease and Nonalcoholic fatty liver disease
(NAFLD).

Answer:
(0) Cirrhosis is a widespread liver disease characterized by several key features:
o Hepatocyte Necrosis and Regeneration: This leads to the formation of nodules of
varying sizes, including micronodules (less than 3 mm) and macronodules (more
than 3 mm).
o Bridging Fibrous
Septae: Cirrhosis is marked by the presence of bridging fibrous
septae that distort the normal hepatic architecture.
o Destruction of Hepatic Vasculature: Eventually leads to the development of
portosystemic shunts. This, in turn, results in portal hypertension, gastroesophageal
varices, and splenomegaly.
Classification

Morphologic Classification Etiologie Classification

Micronodular 1. Alcoholic cirrhosis (the most cOmmOn,
(nodules less than 3 mim) 60-70%)
Macronodular
JaiShreeRa
2. Post-necrotic cirrhosis (1O2)
(nodules more than 3 mm)

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 Gtr and Hepatobiliary

Mixed 3. Biliary cirrhosis (5-10%)

4. Pigment cirrhosis in haemochromatosis (5%)

5. Cirrhosis in Wilson's disease

6. Cirrhosis in o-1-antitrypsin deficiency
7. Cardiac cirrhosis
8. lndian childhood cirrhosis (1CcC)

9. Cirrhosis in autoimmune hepatitis

10. Cirrhosis in non-alcoholic steatohepatitis
11. Misellaneous forms of cirrhosis (metabolic,
infectious, GI, infiltrative diseases)
12. Cryptogenic cirrhosis.

PATHOGENESIS
o ln cirrhosis, there is an aCcumulation of Types I and Il collagen and other
components of the ECM within the space of Disse. This deposition leads to the loss
of sinusoidal endothelial cell fenestrations, impeding the free exchange of solutes
between plasma and hepatocytes.
o
Cirrhotic nodules develop, characterized by fibrous septae, inflammatory cell
infiltration, and bile duet hyperplasia.
o This
pathological process significantly impairs the movement of proteins, including
albumin, clotting factors, and lipoproteins, between the bloodstream and
hepatocytes, resulting in profound functional alterations in the liver.
CLINICAL FEATURES
o Abdowminal distension due to ascites
o Menstrual irregularities
o Hypogonadism
o Gynecomastia
o Easy bruising
o Gastrointestinal bleeding
o Splenowmegaly
o Jaundice
o Palmar erythema

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o Hepatic encephalopathy
o
Flapping tremors
o Progressive renal dysfunction due to decreased renal perfusion
(I) Portal hypertension
o Portal hypertension is defined as a clinical condition in which there is prolonged
elevation of portal venous pressure due to increased resistance to portal blood flow.
O Causes:
o Prehepatic: Portal vein thronbosis and fibrosis of bile ducts (schistosowmiasis)
* Intrahepatic: Cirrhosis, schistosomiasis, massive fatty change, sarcoidosis and
miliary tuberculosis

• Posthepatic: Obstruction of hepatic vein by thrombosis (Budd-Chiari syndrome)

or tumOurs
Pathogenesis of Portal Hypertension in Cirrhosis:
Perivenular fibrosis and compression of sinusoids by parenchymal nodules

Increased resistance to blood flow at the level of sinusoids

JaiShieeRam
Increased portal vascular resistance leads to:
Reduction in the flow of portal blood to the liver
Development of collateral vessels allowing portal blood to bypass the liver and
enter systemic circulation

Collateral vessel forwmation occurs in the esophagus, stomach, rectum, anterior

abdominal wall and in the renal, lumbar, ovarian and testicular (spermatic)
vasculature.
With the development of collateral vessels,initially sowme of the portal blood and
later almost all of the portal blood is shunted directly to the systemic circulation,
bypassing the liver

CLINICAL FEATURES
o Haematemesis and melena (from variceal bleeding)
o Fetor hepaticus (musty breath odor due to portal-systemic shunting of mercaptans)

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 GIT and Hepatobiliary

o Caput medusae (prominent collateral vessels radiating from the umbilicus)

o Splenomegaly (a diagnostic sign of portal hypertension)
o Hypersplenism (results in thrombocytopenia and leukopenia)
o Small, contracted, and fibrotic liver (associated with high portal venous pressure)
o Haemorrhoids (caused by dilatation of rectal veins)
o Ascites (due to portal hypertension and hypoalbuminemia from liver cell failure)
(II) Alcoholic liver disease
o The spectrum of alcoholic liver disease varies from alcoholie steatosis to hepatitis,
to cirrhosis.

PATHOGENESIS

Normal liver

Severe exposure
Exposure Abstinence

HEPATITIS
bAbstinenca Liver cell necrosis
STEATOSIS aietinenc Inflammation
Fatty change Mallory bodies
Perivenular fibrosis Fatty change
Severe exposu
Repeated
Continued attacks
exposure

CIRRHOSIS
Fibrosis Regenerative
nodules

Nonalcoholic fatty liver disease (NAFLD).

o NAFLD is a group of disorders which resemble alcoholic steatohepatitis but occurs
in the absence of alcohol intake.

I53 WMedEJ
 MedEd FARRE: Pathology

RISK FACTORS
o Obesity: Excess body weight, particularly abdominal obesity, is a major višk factor
for NAFLD.
o Type
Il Diabetes Mellitus: lnsulin resistance and inpaired glucose metabolism
contribute to the development of NAFLD.
o
Hyperlipidaemia: Dyslipidacmia plays a role in fat accumulation in the liver.
o Metabotic
Syndrome: NAFLD is often part of metabolic syndrome, which includes
a cluster of conditions like obesity, high blood pressure, abnormal lipid levels, and
insulin vesistance.

PATHOGENESIS
o Insulin Resistance: lnsulin resistance is a key factor in the development of NAFLD.
It leads to increased fat accumulation (steatosis) in the liver.
o Dysfunctional Lipid Metabolism: Lipids stored in the liver become dysfunctinal,
resulting in reduced production of the lipid hormone adiponectin' Simultaneously.
inflammatory cytokines like IL-6 and TNF-a increase, promoting hepatocyte
apoptosis andoxidative damage,leading to hepatocellularnecrosis and inflanmmation.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 873
Jai ShggRam

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 GIT and Hepatobiliary

6o. Write briefly on the etiology. clinical features and morphology of hepatocelular
carcinoma (HCC)/hepatoma. (5 marks)
Answer:
o Prevalence: HCC accounts for 80-9O% of all liver cancers and is more common
in men than women.
o Predisposing Factors: Several risk factors increase the likelihood of developing HCC,
including:
* Chronic hepatitis B and C infections
* Exposure to aflatoxin, a fungal toxin produced by Aspergillus flavus found in
moldy grains and nuts
* Alcoholic cirrhosis
Primary biliary cirrhosis
o Non-Alcoholic Fatty Liver Disease (NAFLD) and metabolic syndrome

* Hemochromatosis
Alpha-1 antitrypsin deficiency
Wilson disease
* Exposure to anabolic steroids, thorotrast, and arsenic
Hormonal factors, such as thel use of estrogens and androgens
* Synergistic Effects: Aflatoxin and alcohol exposure can synergize with hepatitis B
and C infections and even cigarette smoking, further increasing the risk of HCC.
PATHOGENESIS
o Chromosomal Aberrations: HCC is associated with structural and numerical
chromosomal aberrations, possibly due to:
o Repeated cycles of cell death, inflammation, and hepatocyte regeneration in
chronic hepatitis, leading to genomic instability.
O Point mutations or overexpression of cellular genes like beta-catenin and loss of
heterozygosity of tumor suppressor genes, such as Ps3.
o Defects in DNA repair mechanisms.
o Potential oncogenic properties of the HBV-X gene.

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MORPHOLOGY
o HCC may present as solitary (unifocal), mlticentric (wmultifoca), or diffuse
infiltrating lesions.
o Classic HCC exhibits large, wel-differentiated polygonal cells with central nuclei,
often arranged in a trabecular pattern. Other patterns include acinar, cord-like,
and nests.
o Poorly differentiated lesions show sheets of less -differentiated clls interspersed
with anaplastic giant cells, often accompanied by areas of hemorrhage and necrosis.
o HCCcan invade nearby vascular and abdominal structures and metastasize to
distant sites such as the lungs, adrenals, lymjph nodes, or bones.
o A
distinct variant called fibrolamellar carcinoma occurs predominantly in young
individuals and is characterized by large polygonal well-differentiated cells arranged
in nests, cords, or islands separated by dense collagen bundles. This variant tends
to have a more favorable prognosis.
INVESTIGATIONS
o Elevated alpha -fetoprotein (AFP) and carcinoembryonic antigen (CEA) levels.
o lmaging studies such as abdominal ultrasonography and CT scans.
o Hepatic artery angiography may reveal characteristic "tumor blushes."
aiSh
o Diagnosis confirmation through aspiratfon (FNAC) or biopsy.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 868

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 GIT and Hepatobiliary

61. () Write the difference between Hepatitis A, C and E. (10 marks)

() What are the clinical features, laboratory diagnosis and sequelae of HBV.
Answer:

Hepatitis A Virus Hepatitis C Virus Hepatitis E Virus

Aspect (HAV) (HCV) (HEV)
TransmissionFecal-oral route, Bloodborne, often Fecal-oral route,
contaminated food through sharing cOntaminated food
or water needles or unsafe or water
medical procedures
Chronic Typically not Often leads to Usually not chronic,
Infection chronic, usually self- chronic infection. self-limiting
limiting
Vaccination Yes No In some regions,
Available vaccines are
available
Severity of Generally milder, Can lead to chronieSeverity varies,
Illness rarely fatal liver disease., often mild but can
cirrhosis, and be severe in some
JaiShepatocellular cases
CarcinOma
Incubation 2-6 weeks 2-12 weeks 2-9 weeks
Period
Diagnosis Serology tests (lgM Blood tests for HCV Serology tests (lgM
and lgG) and liver RNA, antibodies and lga) and liver
function tests function tests
Treatment |Supportive care, Antiviral |Supportive care,
no specific antiviral medications (Direct-no specific antiviral
treatment acting antivirals) treatment
Risk Groups Anyone can be People who share Pregnant women
infected needles,healthcare and those with
workers at risk comprowmised
immune system.
(I) CLINICAL FEATURES
o Incubation Period: The incubation period for Hepatitis B is relatively long, ranging
from about 30 to 18o days. During this time, the virs begins to replicate in the
liver.
o Subclinical Infection: Some individuals may have a
subclinical infection, which
means they are infected with the virus but do not show significant symptoms.

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o Acute Hepatitis: Many individuals experience acute hepatitis, which can manifest
with symptoms.
* Pre-icteric phase: These symptoms can include fatigue, abdowminal discomfort,
gastrointestinal symptoms.
• lcteric Phase (Jaundice): Jaundice is characterized by yellowing of the skin and
eyes and often indicates liver dysfunction.
o Hepatic complications: Cirrhosis, HCC and fulwminant hepatitis
o Extrahepatic complication: Serum-sickness syndrome.
LABORATORY DIAGNOSIS
Viral markers
Hepatitis B
Surface Antigen (HBSAg)
o HBSAg is one of the earliest markers to appear following HBV infection, usually
within 1 to 12 weeks (most commonly between 8 and 12 weeks).
o Its presence indicates the onset of infectivity, meaning the patient is capable of
transmitting HBV.
o HBSAg remains elevated throughout the acute phase of hepatitis, and it typically
becomes undetectable 1 to 2 months after the onset of jaundice. However, in some
cases, it may persist for more extended periods if the disease progresses to chronic
hepatitis or a carrier state. JaiShreeRam
Hepatitis Precore Antigen (HBeAg) and HBV DNA
B
o HBeAg and HBV DNA typically appear in seruwm concurrently with or shortly after
HBSAg.
They serve as markers of active viral replication and high viral infectivity, indicating
o

a high transmission rate. However, they cannot distinguish between acute, chronic,
Or carrier states.
o Their presence indicates that the virus is actively multiplying
Hepatitis B Core Antibody (anti-HBc):
o Anti-HBc antibodies are divided into two types: lgM anti-HBc and lgG anti -HBc.
o lgM anti -HBc appears early in infection and is a marker of acute hepatitis.
O lga anti-HBc persists long-term and indicates a past or ongoing HBV infection.
Hepatitis B Surface Antibody (anti-HBs):
o Anti-HBs antibodies develop as a response to HBSAg and indicate immunity to
HBV.
o The presence of anti-HBs indicates either a past infection that has resolved or
vaccination -induced immunity

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 GIT and Hepatobiliary

Anti-HBc
HBV
particles

HBsAg

Diagnostic
markers Anti-HBs
HBeAg

Anti-HBe

tt| 2 6
Months of exposure

SEQUELAE OF HBV

Recovery

Subclinical disease
Fulminant hepatitis Death or transplant

Acute infection Acute hepatitis

Recovery

Chronic hepatitis
Cirrhosis Death or transplant

And/or

Hepatocellular
carcinoma

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 831

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MedEd FARRE: Pathology

62. () write briefly on the etiology and clinicopathological features of haemo

chromatosis. (10 marks)
(u0 write briefy on the etiology and clinicopathological features of wilson's
disease.
(un write briefly on the etiology and clinicopathological of a-1 antitrypsin
deficiency.
Answer:
() HEREDITARY HEMOCHROMATOSIS
o Genetic Mutations: Hereditary hemochromatosis results from mutations in genes
associated with iron regulation, including the HFE gene (located on chrowmosome
6), transferrin receptor 2 (TFR2) gene, haemojuvenile (HJ) gene, or the hepcidin
gene (HAMP). Hepcidin, a protein produced by the liver, regulates iron absorption,
and mutations in these genes can disrupt this regulation, leading to iron overload.
o
Classic vs. Neonatal Hemochromatosis: Mutations in the HFE gene and TFR2 gene
ave associated with classic adult hereditary hemochromatosis, while mutations in
the HAMP gene or HJV lead to neonatal hemochromatosis, a severe form of the
condition.
o Autosomal Recessive Inheritance: The most common form of hereditary
hemochromatosis is inherited as an, autosomal recessive disorder. Mutations in
the HFE gene result in reduced hepcidin lévels, leading to increased dietary iron
absorption over time.
O Prevalence: Hereditary hemochromatosis is more common in males (90% of
patients) as females are partially protected by iron los during menstruation and
pregnancy.
o Iron Toxicity: Excessive iron can be directly toxic to various tissues through
mechanisms such as lipid peroxidation, DNA damage, and stinulation of collagen
production by Ito cells (hepatic stellate cells).
PATHOLOGY
O Tissue Damage: Excess iron deposits in tissues can danage the liver, pancreas,
heart, pituitary gland, and skin.
o Pancreatic Changes: The pancreas may exhibit diffuse interstitial fibrosis,
parenchymal atrophy, and haemosiderin deposits in both acinar and islet cells,
contributing to diabetes.
o Cardiac Involvement: The heart can enlarge, with haemosiderin deposits in
myocardial fibers leading to arrhythmias and cardiomyopathy.
o Joint Involvement: Haemosiderin deposits in the synovium can result in acute
synovitis.

I60
 GIT and Hepatobiliary

o
Testicular Atrophy: Testes may become small and atrophic, causing loss of libido
and infertility.
Clinical Features:
o Total Body lron: Total body iron levels decrease to approximately 2g (normal is
4 g).
o
Age of Presentation: Typicaly presents in men over 40 years of age.
o Triad of Symptoms: Fully developed cases often display a triad of symptoms:
O
Micronodular cirrhosis:
* Diabetes mellitus (referred to as "bronze diabetes")
* Skin pignentation, attributed mainly to excess melanin production and partly
to hemosiderin deposits
o
Additional Manifestations: Other manifestations may include loss of libido, spider
nevi, loss of body hair, jaundice, ascites, heart failure, cardiac arrhythmias, and
an increased visk of hepatocellular carcinoma.
Acquired (Secondary) Hemochromatosis:
o Causes: Acquired hemochromatosis, also known as haemosiderosis, can develop
secondary to various conditions, including:
o Chronic anemias like thalassemia major and sideroblastic anemia
o Exogenous iron. overload from multiple blood transfusions, repeated iron injections,
or prolonged oral iron intake (e.g. African iron overload or Bantu siderosis)
o
Chronic liver diseases
o Porphyria cutanea tarda
o Iron Accumulation: ln secondary iron overload, iron tends to accumulate in
Kupffer cells within the liver, in contrast to hereditary hemochromatosis, where
hepatocytes are primarily afected.

(I) ETIOLOGY OF WILSON DISEASE:

o Wilson disease is a hereditary disorder with autosomal recessive inheritance.

Mutation in ATP7B: It results fromn mutations in the ATP7B gene located on

O

chromosome 13. This gene encodes for ATPase metal iron transporter, which
is localized to the Golgi region of hepatocytes. A deficiency in this transporter
impairs the excretion of copper into bile.
Normal Copper Physiology:
Absorption of ingested copper in duodenum and jejunum

Transportation to portal circulation as a cownplex with albumin and histidine

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MedEd FARRE: Pathology

Uptake by hepatocytes followed by incorporation into an a-2 globulin

(apoceruloplasmin) to form ceruloplaswnin

Secretion of ceruloplasmin into plasma (accounts for ao-95% of plasma coppen)

Hepatic uptake of senesecent ceruloplasmin from plasma followed by lysosomal

degradation and secretion of free copper into bile
PATHOGENESIS
o lIt results from mutations in the ATP7B gene located on chromosome 13. This gene
encodes for ATPase metal iron transporter, which is localized to the Golgi region
of hepatocytes. A deficiency in this transporter impairs the excretion of copper
into bile.
o Wilson disease is characterized by two primary abnormalities:
* Failure to secrete ceruloplasmin into plasma
* Failure of biliary copper excretion, leading to copper accumulation in the body
Copper-Induced Toxicity:
o Excess copper in Wilson disease leads to toxic liver injury through several mechanisms,
including the induction of free radicals. binding to sulphydryl groups of cellular
proteins, and displacement of other metas from hepatic metalloenzymes.
Clinicopathological Features of Wilson Disease:
O Wilson disease typically presents between the ages of 5 and 30 years.
Liver Involvement:
o Liver manifestations include:
o
Fatty change
o Acute and chronic hepatitis with hepatocytic ballooning
o Presence of 'Mallory-Denk bodies'
o Massive liver cell necrosis
o Cirrhosis
Brain (Basal Ganglia) Involvement:
o The basal ganglia in the brain show atrophy and cavitation, leading to various
neuropsychiatric manifestations:
• Neurological manifestations include movewment disorders, especially resting
tremors. Less commonly, spasticity, rigidity, chorea, dysphagia, and dysarthria
may be observed.
o Psychiatric manifestations resemble bizarre behavioral disturbances similar to
schizophrenia, manic -depressive psychosis, and neurosis.

162
 GIT and Hepatobiliary

Eye Involvement:
o Kayser-Fleischer rings, which are green to brown copper deposits, may be seen
in the Descemet membrane in the limbus of the cornea. These rings may be
associated with 'sunflower cataracts.'

OTHER MANIFESTATIONS
o Wilson disease can affect various other tissues and organs, including:
o RBCs, leading to hemolysis
o Kidneys, causing venal tubular damage
o Skeleton, potentially vesulting in osteoporosis
(H) A-1 ANTITRYPSIN DEFICIENCY
Pathogenesis:
o a-1 antitrypsin is an a-1 globulin primarily produced by the liver, constituting
90% of a-1 globulins.
o It functions as a serine protease inhibitor (P), specifically inhibiting protease
enzymes such as neutrophil elastase, cathepsin G, and proteinase 3. This inhibition
prevents the breakdown of elastin and collagen by these enzymes.
o The a-1 antitrypsin gene is located on chromosome 14 and is highly polymorphic
o Commonly encountered forms include:ree Ram
* PiM (medium)
o PiS (slow)
* Piz (very slow)
* The normal phenotype is PiMM, while Pizz is associated with significantly low
a-1 antitrypsin concentrations, typically less than 10% of normal levels.
CLINICOPATHOLOGICAL FEATURES:
O In neonates, it can manifest as hepatitis and cholestatie jaundice.
o In adults, individuals with a-1 antitrypsin deficiency may present with various
clinical conditions, including:
o Chronic hepatitis
o Cirrhosis
O Hepatocellular carcinoma
O Emphysema
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 848

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63. Write briefly about acute pancreatitis and chronic pancreatitis. (5 marks)
Answer:
o Acute pancreatitis is characterized by sudden inflammation of the pancreas,often
stemming from injury to the exocrine pancreas.
o The causes of acute pancreatitis can be categorized as follows:
1. Metabolic Causes:
o Hyperlipoproteinemias
o Hypercalcemia
o Alcoholism
o Certain drugs like diuretics, azathioprine, and mercaptopurine
2. Genetic Causes:
o Inherited mutations in genes responsible for pancreatic enzymes or their inhibitors,
such as SPINK1 (serine peptidase inhibitor Kazal type 1), which inhibits trypsin.
o Hereditary pancreatitis associated with trypsinogen mutation is an autosomal
dominant condition caused by PRSS1 gene mutations. These mutations affect a site
on the trypsinogen molecule required for trypsin cleavage, resulting in continuous
activation of other digestive proenzymes and the development of pancreatitis.
3. Mechanical Causes:
JaiShreeRam
o Trauma, including seat-belt injuries
o Gallstones
o Injuries during endoscopic procedures like endoscopic vetrograde cholangiopan
creatography (ERCP)
o Perioperative injuries
4. Vascular Causes:
o Shock
O Embolus
o
Polyarteritis nodosa
5. Infections:
o
Mumps
o Coxsackie virus
o Mycoplasma pneumoniae
o
Epstein-Barr virus (EBV)
o Cytomegalovirus (CMV)

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 GIT and Hepatobiliary

6. ldiopathic Pancreatitis:
o Occurs without an obvious cause and accounts for approximately 10% of cases. It
is the most common cause of pancreatitis after alcohol and biliary disease

PATHOGENESIS

Duct obstruction Acinar cell injury Defective intracellular

transport

Cholelithiasis Alcohol /Drugs/Trauma /Ischemia Niruses/

Ampullary obstruction Hypercalcemia
Chronic alcoholism Metabolic injury
Ductal concretions
Alcohol
Duct obstruction

Interstitial edema
Release of intracellular enzymes and
lysosomal hydrolases Delivery of
proenzymes to
lysosomal
Impaired blood flow compartment

Enzyme activation Intracellular enzyme

Ischemia
activation
JaiShreeRam

Acinar cell injury

ACTIVATED ENZYMES

Interstitial inflammation Proteolysis Fat Hemorhage

necrosis

Acute pancreatitis

Repeated attacks p acute pancroatitis

Increase in local fibroggnic factors like TGF-beta

Chronic pancreatitis
Clinical Features
o
Sudden onset of severe abdominal pain usually in the left upper quadrant of the
abdomen may radiate to the back

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o Nausea and vomiting, fever, sweating, tachypnea and tachycardia followed by

peripheral vascular collapse.
LABORATORY FINDINGS
o Neutrophilic leukocytosis: An increase in the number of neutrophils in the blood.
o Serum amylase: This enzyme is a sensitive marker for acute pancreatitis, particulary
within the first 24 hours. Significant elevation, especially four times above normal
values, is indicative of the condition.
o
Urinary amylase: Amylase is excreted in urine, and its levels become elevated from
the second day onward in pancreatitis cases. However, this test lacks specificity
and sensitivity.
o Serum lipase: Lipase levels in the blood increase slightly later than amylase, but
this marker is more specific for pancreatitis.
o
Trypsin: Trypsin is the enzyme with the highest speciticity and sensitivity for
pancreatic injury. However, its measurement typically requires a radioimmunoassay.
which may not be available in allhealthcare facilities.
o Hypocatlcemia: This condition occurs due to calcium precipitation in areas of fat
necrosis and may indicate a p0or prognosis if it persists.
o Chronic pancreatitis is characterized by ongoing inflammation and fibrosis, leading
toa gradual decline in pancreatiç function, The pancreas often becomes smaller in
size and can exhibit calcificationalShreeRäm"

Causes of chronic pancreatitis include:

o
Chronic alcohol abuse
o Cystic fibrosis affecting the pancreas
o Familial cases of chronic pancreatitis
o "Tropical chronic pancreatitis"
O ldiopathic cases with no clear cause
Pathological changes seen in chronic panereatitis include:
o Persistent chronic inflammation characterized by the presence of lymphocytes,
macrophages, and pasma cells.
o Fibrosis, calcification, and the formation of intraductal concretions.
o Loss and atrophy of acini (functional units of the pancreas), with
partial preservation
of ducts and islets of Langerhans.
o Cystic dilatation of ducts beyond areas narrowed by fibrous tissue

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 8 82

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 Kidney
64. Differentiate between nephritic and nephrotie syndrome. (3 marks)

Answer:
Feature Nephritic Syndrome Nephrotic Syndrome
Proteinuria Usually <1.0 g/day >3.5 g/day
Hematuria Present Absent
oliguria Present Absent
Lipiduria Absent Present
Casts Red cell casts Lipid casts

Color of Urine Coca colored/smoky urine Frothy urine

Azotemia Present Absent
Hyperlipidemia Absent Present
Edema Less marked More marked

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No.896
JaiShrecRam

MedEd
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65. Write briefiy about Minimal Change Disease (MCD). (3 marks)

Answer.
MINIMAL CHANGE DISEASE (MCD)
Pathogenesis:
o
Predominantly affects children.
o Exact cause is often unknown, but it's believed to be related to imnmune system
dysfunction.
o T-cell dysfunction may lead to the release of factors that damage the glomerular
filtration barrier.
o Abnormal expression of cytokines like interleukin-13 may play a role.
Histopathology:
o Microscopic
examination of kidney biopsy typically appears normal under light
microscopy.
o
The characteristic feature is the absence of visible changes, hence the name
"minimal change."
o On electvon microscopy, foot process effacement of podocytes is observed.
o
Immunofluorescence shows no immune complex deposits in the glomerli.
JaiShreeRam
CLINICAL FEATURES
o Presents
with nephrotic syndrome: massive proteinuria, hypoalbuminewmia, edema,
and hyperlipidemia.
o Edema is often the most noticeable symptom.
o Typically responds well to corticosteroid therapy, making it an important
consideration in children with nephrotic syndrome.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 914

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 Kidney

66. write briefy about focal segmental glomerulosclerosis (FSGS). (3 marks)

Answer:
FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS):
Types:
o ldiopathic or Primary (10-3S% patients)
o FSGS wth another primary glomerular lesion
o Renal ablation FSGS (associated with reflux nephropathy and analgesic abuse)
o
Secondary FSGS (linked to heroin abuse,HIV, sickle cell disease)
o Rare inherited type caused by gene mutations (eg.. podocin and a-actinin)
Clinical Presentation:
o s0% of patients present with nephrotic syndrome.
O 50% progress to end-stage renal disease.

Diferences from Minimal Change Disease:

o More common haematuria and hypertension.
o Non-selective proteinuria.
o Poor vesponse to steroids and potential progression to chronic glomerulonephritis.
JaiShréekam
PATHOGENESIS:
1. Genetic Mechanisms:
o Mutations in genes affecting the glomerular filtration barrier (e.g., NPHS genes,
podocin, ox-actinin-4, TRCP6).
2. Circulating Factors:
o
Unknown circulating factors likely contribute to epithelial damage, as the disease
can recur after transplantation.
Light Microscopy:
o Segmental involvement.
o
Basement membrane collapse, hyalinosis, and lipid droplets in affected segments
leading to global sclerosis.
o Unaffected glomeruli show increased mesangial matrix/mesangial proliferation.
Electron Microscopy:
o Loss of foot processes.
O
Epithelial cell detachment and denudation of the glomerular basement membrane.

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MedEd FARRE: Pathology

Immunofluorescence:
o lgM and C3 deposits in sclerotic areas.
Membranous Minimal Change Disease
Feature Glomerulonephritis
Age Adults Children
Light Thickening of GBM (GBM Normal GBM
Microscopy width in healthy adults is
300-4OO nm)
Electron Granular subepithelial deposits Foot process effacement and
Microscopy lipid -laden cells in PCT
Immuno Granular deposits of lgG and No deposition
fluorescence C3

Hypertension Present Absent

Haematuria Present Absent
Corticosteroid Minimal response Good response
Therapy

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 914
JaiShseRam

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 Kidney

67. Describe the aetiopathogenesis, gros appearance and complications of renal

calculi/urolithiasis. (3 marks)
Answer:

Type of Calculi Incidence Gross

Causes Pathogenesis
Characteristics
Calcium Stones 75-80% ldiopathic 1% Seen in young
Hypercalciuria patients
Hypercalcemia
Hyperoxaluria
Hyperuricosuria
Primary
hyperthyroidism
Distal renal tubular
acidosis
Struvite Stones 10-15% Urinary infection by Alkaline Large, solitary,
urease -containing urinary branching
[MgNH,(PO)] organiswms like structure
pH due to
triple stone/
stag-horn production
ProteuishrecRamof ammonia formed due
stone to progressive
from urea (byaccretion of
urease) salts
Uric Acid 6% ldiopathic Acidic urine Smooth, yellow
Stones and low to brownish,
Malignant tumors solubility of hard, and
Gout uric acid multiple
Dehydration

Cystine Stones 1-2% Hereditary Cystine Small, smooth,

precipitates yellow,
in acidic urine multiple, and
round
Others Up to Inherited Xanthinuria
10% abnormalities
of amino acid
metabolism

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Complications of Urolithiasis:
o Loss of function in
the affected kidney
o Obstruction of the ureter and hydronephrosis; secondary infection gives rise to
pyonephrosis
o Urinary tract infection, Haematuria
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 947

dEe
JaiShrecRam

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 Kidney

68. Differentiate between Benign and Malignant Nephrosclerosis. (3 marks)

Answer:
Characteristic Benign Nephrosclerosis Malignant Nephrosclerosis
Occurrence Occurs in the benign phase of Occurs in the malignant phase
Phase |hypertension |of hypertension
Frequency Most frequent form of renal Uncomwmon form
disease
Age Occurs in persons above 60 Occurs in 5% of cases due to
years of age due to increased complications of pre -existing
severity of hypertension or |benign essential hypertension
diabetes wmellitus or chronic renal diseases
Gross Kidney Reduction in size and weight Variable size, oedematous,
Appearance petechial hemorrhages, and
flea-bitten kidney appearance
Kidney Surface Finely granular with V-shapedOedematous, enlarged, with
areas of scarring flea-bitten appearance
Microscopic Hyaline arteriosclerosis and Necrotizing arteriolitis and
Changes intimal thickening |hyperplastic intimal sclerosis
JaiShreeRam (Onion skin proliferation)
Blood Pressure Variation in blood pressure Malignant hypertension with
Symptoms with headache, dizziness, |headache and impaired vision
palpitations, and nervousness
Papilloedema Absent Present
Proteinuria May or may not be present Present
Renal Failure Rare Occurs in 90% of patients

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 935

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69. Differentiate between acute and chronic pyelonephritis. (5 marks)

Answer:.

Characteristie Acute Pyelonephritis Chronic Pyelonephritis

Definition |Acute suppurative Chronic tubulointerstitial
inflammation of the kidney disease showing tubular
caused by bacterial infection inflammation and renal
scarring with pathologic
involvement of calyces and
pelvis
Predisposing Urinary obstruction, Obstructive pathology.
Factors instrumentation, presence of reflux
catheterization, pregnancy.
diabetes mellitus, and pre
existing renal lesions
|Subtypes No subtypes Chronic obstructive -
pyelonephritis and reflux
associated nephropathy
Gross Discrete yellow, raised abscessesCoarse corticomedullary scars
are seen on the renal surface overlying blunted or dilated
calyces
Microscopy Tubules show SuDpstam Tubules show atrophy in
necrosis with preserved outline some areas and dilation
in others; dilated tubules
filled with colloid -like casts
|(thyroidization)
Clinical Features Sudden onset with back pain, |Insidious (silent) onset with
fever, and malaise a progressive decline in renal
function

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 927

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 Kidney

7O. (0) Classify renal tumors and deseribe the clinicopathological features of renal cell
carcinoma (RCC). (10 marks)
(i) write briefty on Wilms tumor.
Answer:
()
Collecting Xp11
Clear-Cell Chromophobe
Features Papillary RCC Duct Translocation
RCC RCC
Carcinoma Carcinoma
Incidence 70-80% 10-15% 5-8% 1% Seen in young
patients
Genetics Majority Cuiprit Multiple Several Associated
over
sporadic. 98% (tyrosine chromosomal chromosomalwith
show loss of kinase loss and abnormalitiesexpression
material on receptor hypodiploidy. seen but of TFE3
the short for the no definite transcription
Arise from
arm of hepatocytic pattern factor due to
chromoso me growth intercalated recognized. translocations
3; second Factor) is on cells lining of TFES gene
collecting
allele lost chromosOme located at
by somatic ducts. Xp11.2 with
7431. a number of
mutation. Duplication of
Loss of both chromosome other genes.
copies of 7 increasesi ShreeRam
VHL gene gene dosage
gives rise to of MET
clear-cel Oncogene,
carcinoma. leading to
abnormal
growth of
distal tubular
cells.

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Gross Solitary 1:1 Tan -broWn Seen in the

unilateral, Multifocal, color with medullary
bright yellow bilateral, an excellent region.
to grey less yellow prognosis.
white with due to lower
prominent lipid content,
cystic papillae may
be seen,
changes and
hemorrhage. haemorrhagic
Aggressive; and cystic
may areas
infiltrate intopresent.
surrounding
tissue,
collecting
System,
calyces.
ureters, and
renal vein.
Microscopy Solid to Papillae Solid sheets of Irregular Clear
tubular lined by cells arranged channels lined cytoplasm
growth cuboidal to around by malignant with papillary
pattern, low columnar blood vessels, cells with architecture
round cells cells; individual cell a hobnail
with clear psammoma is eosinophilic appearance:
(due to bodies with well cells
glycogen present. JaiShdefinedm enmeshed
and lipid) cytoplasmic within a
or granlar margins and fibrotic
cytoplasm, perinuclear stroma.
may show halo.
nuclear
atypia and
giant cels.
(I) Wilmns tumour/nephroblastoma is the most common primary renal tumour of
childhood. It is associated with three syndrowmes:

Syndrome Associated Genetic

Features Mutation
WAGR Syndrome O Aniridia (absence of the iriso WT-1 gene mutation
in the eye) (located at 11p13)
o Genital anomalies
O Mental retardation
Denys-Drash o Gonadal dysgenesis (maleo Missense mutation
Syndrome pseudohermaphroditism) of WT-1 affecting
o Renal abnormalities (diffuse its DNA-binding
mesangial sclerosis leading properties
to renal failure)

176
 Kidney

Beckwith-Wiedemanno Enlargement of body o WT-2 abnormalities

Syndrome organs (organomegaly) (WT-2 gene located on
o Hemihypertrophy 11p15.5; function is
(asymmetrical ovegrowth unknown)
of body parts)
o Macroglossia (enlarged
tongue)
o Omphalocele (abdominal
wall defect)
o Renal medullary cysts
o Abnormal large cells
in adrenal cortex
(adrenocytomegaly)

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 948

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71 A 42-year-old male, presented to the clinic with complaints of persistent dull
abdominal pain and swelling in the right upper quadrant for the past few months.
He deseribed the pain as aching and localized, and he had noticed a gradual
increase in his abdominal girth. He had a family history of kidney disease, as both
his mother and older brother had experienced kidney-related problems. He had
been managing hypertension with antihypertensive medication for the past five
years but had no signiicant history of diabetes or other chronic illnesses. Physical
examination revealed a palpable mass in the right upper quadrant, tender on
deep palpation. Blood pressure was elevated at 150/95 mm Hg. Urinalysis
showed no evidence of hematuria or proteinuria. Abdominal ultrasound revealed
multiple cystic lesions in both kidneys, consistent with polycystic kidney disease.
Blood tests showed normal serum creatinine and BUN levels, indicating preserved
kidney function. Genetic testing confirmed the diagnosis of autosomal dominant
polycystic kidney disease (ADPKD).
() Enumerate the cystic diseases of the kidney. (20 marks)
(I) Write down the possible mechanism of cyst formation in cystic kidney diseases
(Pathogenesis)
() Differentiate between adult and childhood polycystic kidney disease.
Answer:
JaiShreeRam
(0 Cystic diseases of kidney include:
o
Autosomal Dominant (Adult) Polycystic Kidney Disease (ADPKD)
o Autosomal Recessive (Childhood) Polycystic Kidney Disease (ARPKD)
o Medullary sponge kidney
o Simple Renal Cysts
o Multicystic renal dysplasia
o Acquired renal cystic disease

178
 Kidney

() Pathogenesis involved in cystic kidney disease:

Mutations in polycystin1, 2 or fibrocystin or nephrocystins

Altered mechanosensation by tubular cilia Altered calcium flux

Altered tubular epithelial growth and differentiation

Abnormal extracellular matrix Cell proliferation Fluid secretion

Glomerular. CYST vascular damage Interstitial inflammation/fibrosis

CysT
(u) Difference between adult and childhood polycystic kidney disease
Features Adult PKD Childhood PKD
Inheritance Autosomal dominant Autosomal recessive
(PKD1 or PKD2 gene) (PKHD1 gene)
Frequency More cOmmon Less coOmmon
Presentation o Presents after the fourth o Presents in the perinatal/
decade neonatal age group.
o May be associated with o Associated with
cystic liver, berry aneurysm, splenomegaly and hepatic
subarachnoid hemorhage, fibrosis
colonic diverticula, mitral o Esophageal varices may
valve prolapse occur due to hepatic fibrosis
o Large, multicystic kidneys
origin of Cysts May arise from any level of |Arises from collecting ducts,
the nephron, from tubules to |lined uniformly by cuboidal
collecting ducts cells

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Clinical FeaturesoHaematuria o Bilateral abdominal mass

O Flank pain
o Hypertension
o Urinary infection
o Bilateral abdominal mass
Outcome
o
Chronic renal failure typically o Young infants usually die of
begins at the age of 40-60 hepatic and renal failure
years. o Patients who survive develop
congenital hepatic fibrosis.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 941

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180
 Male & Female Tract Lesions
72. Write brielty about the neoplasms involving the penis. (3 marks)
Answer:
BENIGN LESIONS
Condyloma Acuminatum:
o Also known as anogenital wart."

o Associated with HPV 6 and 11.

O May appear as solitary or multiple lesions.

o Common sites include the coronal sulcus of the penis and the perianal area.
o Can hae a large cauliflower-like exophytic
variant called "Buschke-Lowenstein
or
tumor' Verrucous carcinoma.
o Microscopy shows papillary projections with a connective tissue core lined by
squamous epithelium.
o Histopathologic hallimark: Koilocytosis.
Premalignant Conditions:
o
PeiN (Penile Intraepithelial Negplasia): e Cannoccur on the glans or foreskin
(erythroplasia of Queyrat) or the shaft (Bowen disease).
o Erythroplasia of Queyrat: Common in uncircumcised men, presents as reddish,
velvety pigmentation on the glans.
O Bowen Disease: Characterized by well-wmarginated, reddish plaques over the penile
shaft that may ulcerate and crust.
o Bowenoid Papulosis: Histopathologically similar to Bowen disease and erythroplasia
of Queyrat,associated with HPV 16, presents as multiple reddish verrucous papules.

MALIGNANT LESIONS
Carcinoma Penis:
O Almost all penile cancers are squamous cell carcinomas.
o lncidence is less than 1% of all male cancers.
o
Causal association with high-risk HPV types 16 and 18.
o More cOmmon in black populations and rare in Jews and Muslins who typically
undergo circumcision (circumcision helps prevent smegma accumulation, considered
carcinogenic).
o
Typicaly affects men over sO years old.

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Gros Morphology:
o Tumors may be exophytic (papillary or cauliflower-ike) or ulcerative.
o Common locations include the fraenum, prepuce, glans, and coronal sulcus.
Microscopy:
o Most cases show well -to-moderately differentiated squamous cellcarcinoma.
o These carcinomas commonly metastasize to regional lymph nodes and viscera

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 964

JaiShreeRam

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 Male &e Female Tract Lesions

73. Write briefly on cryptorchidism. (3 marks)

Answer:
o
Cryptorchidism refers to the condition where one or both testes are absent from
the scrotum.
Onset:
o Cryptorchidism is usually present at birth but can rarely develop later in life.
Approximately so% of cryptorchid testes descend into the scrotum within the
first year of life.
Risk Factors:
o The exact cause of cryptorchidism is not fully known, but risk factors include
intrauterine growth retardation, prematurity, perinatal asphyxia, C-sectin
delivery, and toxemia of pregnancy.
Location of Undescended Testes:
o An undescended testis can be found along the normal path of descent, which can
be anywhere from the retroperitoneum (25% of cases) to the inguinal ring (70%
of cases).
o ln some instances, it may be located in the inguinal canal (5% of cases) or even
outside the typical pathway, such as the thigh, perineum, opposite scrotum, or
femoral canal, leading to the term "ectopic" or "wandering" testis.
o An underdeveloped undescended testis is labeled as "hypoplastic."
Retractile and Gliding Testes:
o
An undescended testis can be classified as "retvactile" if it can be manipulated into
the serotum and remains there without tension. If it can be manipulated into the
upper serotum but retracts when released, it is called "gliding'
Unilateral vs. Bilateral:
o Cryptorchidism is unilateral in about s0% of cases and bilateral in the vemaining
cases. Most cases are clinically asymptomatic and are discovered during physical
examination.
Treatment:
o Cryptorchid testes can be surgically brought into the serotum through a procedure
called " orchiopexy"

MedEd
I83
 MedEd FARRE: Pathology

Complications:
o
Untreated cases of cryptorchidism may be associated with reduced fertility, an
increased risk of testiculargerm cell tumors, and a higher susceptibility to testicular
torsion, infarction, and inguinal hernia.
Gross and Histological Changes:
o On gross examination, the cryptorchid testis appears small and fibrotic.
Histologicaly, there is a marked reduction in the number of germ cells.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 966

JaiShrecRam

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 Male &e Female Tract Lesions

74. Write briefty on testicular torsion. (3 marks)

Answer:
o
Testicular torsion is characterized by the twisting of the spermatic cord, which
can cut off the venous drainage of the testis.
o It can lead to testicular infarction.
o Vascular Impact: Testicular torsion typically affects the venous drainage of the
testis, while the thick -walled arteries remain patent. This imbalance results in
intense vascular engorgement, followed by hemorrhagic infarction.
Testicular torsion can occur in two settings:
o Neonatal Torsion: This occurs either in utero or shortly after birth. It often lacks
an associated anatomic defect to explain its occurrence.
o
Adult Torsion: Typically seen in adolescence, it presents with the sudden onset of
severe testicular pain. It can occur without any obvious injury.
o Cremasteric reflex is absent.
O Prenh's sign is negative.
o Treatiment: If the testis is manually untwisted within approximately 6 hours of
the onset of torsion, it may be possible to spare the affected testis frowm removal
(orchiectomy). Timely intervention is essential.
o Bell-Clapper Abnormality: In addts,iShreeR
torsioh dften results from a bilateral anatomic
defect known as a "bell-clapper abnormality." This defect increases the mobility of
the testes and predisposes them to torsion. To prevent recurrence in the unaffected
testis, contralateral orchiopexy (surgical fixation) is often performed.
Morphological Changes:
o The morphological changes in the testis due to torsion depend on the duration
of torsion. They can range from intense congestion to widespread hemorrhage
and eventual testicular infarction. In advanced stages, the affected testis becowmes
swollen and consists entirely of soft, necrotic, hemorrhagic tissue.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 968

185 MedEd
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75. () Write briefy on cervical intraepithelial neoplasia (CIN). (5 marks)

() write briefly on predisposing factors, pathogenesis and prevention of
carcinoma cervix.
Answer:
()Cervical intraepithelial neoplasia (CIN) is a precancerous lesion often linked to HPV
(human papillomavirus) infection.
o HPV, a sexually
transmitted DNA virus, can lead to CIN and eventually invasive
squamous cell carcinoma of the cervik.
o
According to the Bethesda system, precancerous cervical lesions are classified into
two groups:
Low-grade squamous intraepithelial lesion or LSIL (CIN ): LSIL is associated with
HPV types 6, 11, 42, and 44, which have low oncogenic potential
* High-grade squamous intraepithelial lesion or HSIL (CIN II and l): HSIL includes
CIN I! and CIN II and is associated with high-risk HPV types 16, 18, 31, 33,
and 45, which have a higher oncogenic potential.
I
CIN
o Dysplasia affects the lower one-third of the stratified squamous epithelium.
o It can appear as raised (stmiar acuminatum) or flat (macular).
o Abundant low-risk HPV nucleic acid is
areRaa present.
o Koilocytic atypia or viral cytopathic effects, characterized by nuclear abnormalities
with a perinuclear halo, are observable.
CIN II

o Dysplasia is confined to the basal two-thirds of the stratified squamous epithelium.

o Increased numbers of atypical cells in the lower layers are evident, along with
features like an increased nucleus-to -cytoplasm ratio, anisokaryosis, loss of
polarity,the presence of mitotic figures, and hyperchromasia.
o The upper layer cells display signs of differentiation.
o High-risk HPV types are associated with CIN II.
CIN II/Carcinoma in Situ
o
Dysplasia involves the entire thickness of the epithelium.
o It's important to note that not all low-grade lesions progress to high-grade
lesions. While most low -grade lesions spontaneously regress, the majority of high
grade lesions tend to advance.
(I) Risk Factors for Cervical Carcinoma:
O
HPV Infection: Almost all cases of cervical carcinoma are associated with HPV
infection, particularly HPV types 16, 18, 31, 45, etc.

186
 Male &&
Female Tract Lesions

o Early Initiation of Sexual Activity

o Having Multiple Sexual Partners or a Male Partner with Mutiple Sexual Partners
o Use of Oral Contraceptives
o Cigarette Smoking
o High Number of Pregnancies (Parity)
o Family History of Cervical Cancer
o Presence of Associated Genital lnfections
Pathogeness: High-risk strains of HPV Produce E6 and E7 proteins. E6 inhibits the
p55 protein and E7 inhibits the RB protein causing uncontrolled cell proliferation.
Diagnosis and Prevention:
o Pap
Smear Examination: The primary and most crucial tool for screening cervical
carcinoma is the Pap smear exawmination. This procedure involves the cytological
examination of exfoliated cervical cells, which are stained using the Papanicolaou
method. To obtain the material for examination, the transformation zone is gently
seraped with an Ayer's spatula or a cytological brush.
o Screening with pap smear: Recommendations for the frequency of Pap screening
vary, but in general, the first smear should be at 21 years of age or within 3
years of onset of sexual activity, and thereafter every 3 years. After 30 years of
age, wowmen who have had normal cytology results and are negative for HPV may
be screened every s years. Wonen who have a normal cytology result but test
positive for high-risk HPV DNA should have cervical cytology repeated every 6 to
12 months.
o HPV DNA Testing: ln addition to Pap smear testing, HPV DNA testing can be
performed to assess the patient's HPV status.
o Colposcopic Examination: If an abnormality is detected in the Pap smear, further
evaluation isconducted through colposcopic examination of the cervix and vagina.
During colposcopy, acetic acid may also be applied to highlight abnormal areas.
o Biopsy: when an abnormal lesion is identified during colposcopy, a biopsy is typically
performed to confirm the diagnosis.
o Prophylactic HPV Vaccine: A preventive measure for cervical carcinoma is the
use of prophylactic HPV [Link] HPV subtypes covered by the vaccine
include HPV 6, 11, 16, and 18.
Reference.: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. q97

187 MedEd
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76. () write briefly on gestational trophoblastic disease. (5 marks)

(I) Differentiate between complete mole and partial mole.
Answer:
Hydatidiform Mole (H. Mole)
o Traditionally diagnosed during the 12th to 14th weeks of pregnancy.
o Uterine enlargement exceeds expectations for the gestational period.
o Symptowms inelude vaginal bleeding and the pasage of grape-like tissue masses.
o Diagnosis is based on elevated levels of HCG. particularly the beta subunit, in the
blood and urine, along with the absence of fetal parts or fetal heart sounds on
sonography.
o H. Mole is
categorized into two types: complete and partial mole.
Complete Mole
o A cOmplete mole results from the fertilization of an egg with lost female
chromosomes, leading to entirely paternal genetic material.
o Approximately q0% of complete moles have a 46, XX karyotype, arising from the
duplication of genetic material from a single sperm (androgenesis)
Partial Mole
o Partial moles occur due to fertili2ation Of an eg by two sperm.
o The karyotype in partial moles is typically triploid (e.g., 69, XXY) or occasionally
tetraploid (92, XXXY).

188
 Male & Female Tract Lesions

Complete mole

Chromosomal
duplication 46XX

23X
Homozygous complete mole
Empty ovum

Complete mole

23X or Y 46XX

Dispermy

46XY
23X or Y
Empty ovum
Heterozygous partial mole

Partial mole
23X or Y

23*hreeRa 69XXX
Disperny

23X or Y 69XXY
Ovum

69XYY

Triploid partial mole

Gross Morphology
o The uterine cavity or ectopic site is filled with delicate, friable masses consisting of
thin-walled, translucent, cystic structures resembling grapes.
o The amniotic sac is typically very small and collapsed.
O
In complete moles, no fetal parts are present, while they may be observed in
partial wmoles.
(I) DIFFERENCE BETWEEN COMPLETE MOLE AND PARTIAL MOLE

Features Complete Mole Partial Mole

Karyotype |46, XX (46, XY) Triploid (69, XXY)

189 RMedEd
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Incidence
of Missed
Abortion
Villous OedemaAll chorionic villi are Only some villi are edematous
edematous
Trophoblastic Diffuse, circumferential Focal; mild
Proliferation

Vascularization Absent or inadequate Present

of Villi
Fetal Parts No embryonic development, soThe embryo is viable for weeks,
no fetal parts present so fetal parts may be present
Atypia Frequently present Absent

Serum HCG Markedly elevated Elevated, but comparatively

less than the complete mole
HCG in TissuesVery high high

Behavior Incidence of choviocarcinoma Incidence of choriocarcinoma is

JaiShreeRam negligible

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Paqe No. 1033

190
 Male & Female Tract Lesions

77. Define endometriosis. Enuwmerate the theories that are proposed to explain its
origin. (3 marks)
Answer:
o
Endometriosis is characterized by the presence of endomnetrial glands and/or
stroma outside the uterus.
SITES INVOLVED
o Ovaries
o Uterine ligaments
o Recto vaginal septum
o Pelvic peritoneum
O
Laparotomy scar
o
Rarely, in umbilicus, vagina, vulva, appendix
Theories that have been proposed to explain the origin of endometriosis:
o
Regurgitation/Transplantation Theory: This is the most widely accepted theoy
and suggests that endometriosis results from the regurgitation of menstrual blood
through the fallopian tubes. Menstrual blood carries endometrial tissue into the
peritoneal cavity and other sites.
o Metaplastic Theory: According to this theoryacoelomic epithelium has the potential
to undergo metaplasia, transforming into endometrial tissue.
o Benign Metastasis (Vascular or Lymphatic Dissemination) Theory: This theory
proposes that endometrial tissue may reach extra -pelvic sites, such as the lungs
or lymph nodes, through vascular or lymphatic dissemination.
o The Extrauterine Stem or Progenitor Theory: A more recent theory suggests that
extrauterine endometrial tissue may arise from stem cells originating in the bone
marrOW.
Clinical Features
o Dysmenorrhoea
o Dyspareunia
o Infertility
o Pelvic pain due to intrapelvic bleeding and periuterine adhesions
o Pain on defecation or urination (due to involvement of bowel or bladder)

191 MedEd
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Gross Morphology:
o Red-yellow -brown, often bilateral, nodules present on or just beneath the serosal
Surface.
o Extensive
hemorrhage can lead to the formation of fibrotic adhesions, affecting
various tissue layers.
o Large cystic spaces are present, filled with brown, bloody debris, often vesulting in
the distortion of the ovaries, commonly known as "chocolate cysts."
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1004

JaiShree Ram

192
 Male & Female Tract Lesions

78. () write down the pathogenesis and morphology of endometrial carcinoma.

(I) Differentiate between type I and type lIl
endometrial carcinoma.
(5 marks)
Answer:
Pathogenesis of type I
endometrial carcinoma

Proliferative endometrium
PTEN abnormality

Hyperplasia without atypia

MLH1 and KRAS abnormalities

Microsatelite instability

Atypical hyperplasia

RID 1A, PIK3CA, CTNNB1 and FGFR2

abnormalities

Grade 1 endometrioid carcinoma

Pathogenesis of type Il endometrial carcinoma

Atrophic endometrium

TP53 mutation

Serous endometrial intraepithelial carcinoma

FBXW7, PPP2RIA, CCNE1 abnormalities

Serous carcinoma (Type Il)

Gross Morphology
o Can exhibit exophytic or infiltrative growth patterns.
o
Frequently shows areas of hemorrhage and necrosis, which can result in a shaggy,
tan-colored appearance of the endometrium.

193 KMedEJ
MedEd FARRE: Pathology

(I) DIFFERENCE BETWEEN TYPE IAND TYPE II ENDOMETRIAL CARCINOMA

Endometrial Carcinoma Endometrial Carcinoma

Features Type l Type Il

Age 55-60 years 65-75 years

Predisposing factors o Unopposed estrogen o Thin physique
stimulation
o
Obesity
O Hypertension
o Diabetes
o Nalliparity/infertility
o Breast carcinoma
Morphological type Endometrioid carcinoma Serous or clear cell type
(mimics normal (mimics subtypes of
endometrial glands) ovarian carcinoma)
Precursor Endometrial hyperplasia Atrophic endometrium
Endometrial
intraepithelial carcinoma
Molecular genetics Mutations in PTEN, Mutations in PS3 and
ARIP1A,(chromatin PIK3CA
regulator), KRAS
B-catenin, p53,
PIK3CA, FGF2 (growth
factor), CTNNB1
(Wnt signaling) and
microsatellite instability
Outcome |Low -grade malignancy: Aggressive:
spreads mainly via intraperitoneal and
|ywphaties ymphatic spread is
CommOn.

Reference: Pathologic Basis of Disease, Robbins and Cotvan, 10th Edition, Paqe No. 1009

194
 Male & Female Tract Lesions

74. (0 Write briefly on the etiopathogenesis, and morphology of Benign prostatic

hyperplasia (BPH). (10 marks)
(u) Describe the aetiopathogenesis, clinical features and morphology of the
carcinoma prostate.
Answer:
() BPH
o Benign prostatic hyperplasia (BPH) is characterized by the proliferation of both
prostatic stromal and epithelial cells.
o This proliferation leads to the development of distinct nodules within the prostate
gland, primarily in the transitional and inner periurethral zones.
o These nodules exert pressure on
the prostatic urethra, resulting in the clinical
symptoms associated with BPH.
o BPH is most commonly observed in individuals aged so and older.
o The incidence of BPH tends to increase with advancing age.
Pathogenesis:
Testosterone
(5-alpha reductase)
Dikjdrotistosterone
(DHT constitutes 9O% of the total androgens in the prostate)

Binds to nuclear androgen receptors in stronmal and epithelial cells

Release of growth factors:

o Autocrine action
O Paracrine action
o Stromal cell hyperplasia
o Epithelial cell hyperplasia
Morpholog9:
o The affected prostate gland becomes enlarged and can weigh 300 grams or wmore.
o When
the gland is cut open, it reveals multiple well-defined nodules that protrude
from the surface.
o
BPH is characterized by two types of proliferation: glandular and stromal
(fibromuscular).

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MedEd FARRE: Pathology
o Nodules with primarily glandular proliferation have a yellow-pink appearance,
and their consistency is soft, often with milky -white fluid oozing out.
o In
nodules with primarily stromal (fibromuscular) proliferation, the surface appears
pale-grey and feels tough, without any fluid oozing.
o While a true capsule is absent, a plane of cleavage is typically present, allowing for
separation of the affected tissue.
() ETIOPATHOGENESIS

Dietary exposure
Chronic inflammation
Androgens
Germline MYC variants
Prostate epithelium
TMPRSS-ETS Fusion gene
Critical telomere shortening
Hypermethylation of GSTP1 promoter

Prostatic intraepithelial neoplasia

p27 loss

Localized prostatic adenocarcinoma

JaiShreeRiLoss of PTEN
Telomerase activation

Metastatic prostatic adenocarcinoma

Clinical features:
o Typically, it occurs in men aged so years and older.
o Most commonly it originates in the peripheral zone of the prostate, which makes
it less likely to cause early urethral obstruction.
o Many cases remain clinically asymptomatic and are often discovered incidentally
when prostate tissue is removed for BPH.
o When the disease is extensive, it can lead to "prostatism," characterized by local
discomfort and lower urinary tract obstruction.
o Some cases may become evident due to the presence of bone metastases, which
can manifest as blastic lesions.
Microscopy
o There is loss of basal cell layer in the glands (ie. they are lined by only single layer
of cuboidal or low columnar epithelium)

196
 Male & Female Tract Lesions

o Four histological types:

* Adenocarcinoma (most common)
* Transitional cell carcinoma
o Squamous cell carcinoma
* Undifferentiated carcinoma
Grading of Carcinowma Prostate:
o cleason grading is the most widely used grading system for adenocarcinoma
prostate. lt is based on the glandular architectural patterns and the relationship
of the tumor cells with the stroma.
o Primary grade is assigned to the dominant pattern and secondary grade is assigned
to the second most frequent pattern.
o
Grade l(scores 6) is a very low risk group while grade s (score q or 10) is very
high risk group.
Diagnosis and Staging of Carcinoma Prostate:
o Digital vectal examination: Used to palpate tumors, often located in the posterior
lobe.

o Transrectal ultrasonography with guided biopsy: Enables early tumor detection.

o
Computed tomography and magnetiG- resonance imaging scans: Used to assess
lymph node involvewment.
o Pelvic lymphadenectomy: Performed to identify microscopic metastases in regional
pelvic lymph nodes.
o Skeletal survey or radionuclide scanning: Aims to detect osteoblastic metastase.
o Tumor marker assays: Including Prostatic Acid Phosphatase (PAP) and Prostate
Specific Antigen (PSA):
o PAP: Elevated levels may indicate prostatic cancer extending beyond the capsule
Or metastases.
o PSA: Used as a diagnostic marker; levels greater than 4 ng/m are indicative
of prostatic cancer. Additional indicators include free PSA levels (less than 10%
Suggests cancer), vatio of free and bound PSA, PSA density, and PSA velocity.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 976

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80. Classify testicular tumors. Deseribe their clinicopathological features.

(10 marks)
Answer:
CLASSIFICATION OF TESTICULAR TUMORS

Testicular Tumor Type Subtypes

Germ Cell Tumors (a) Seminomatous Tumors:
o Classical Seminoma
O
Spermatocytic Seminoma
(b) Nonseminomatous Tumors:
o Yolk Sac Tumor
o Choriocarcinoma
o Embryonal Carcinoma
o Germ Cell Tumors with Multiple
Histological Patterns (eg., embryonal
carcinoma with teratoma and
choriocarcinoma with others)
(c) Teratoma
aiSth
Sex Cord-Stromal Tumors a
Sertoli Cell Tumors
(b) Leydig Cell Tumors

Cryptorchidism Germline variants

in KiT, BAK Environmental Germ cell neoplasia in situ
exposures

KIT mutation Other Puberty

Acquired genetic or growth stimulating Jsochromosome
epigenetic modiflcation events 12p
(in uter)

Arrested differentiation

Primordial germ cell

Invasive germ cell

tumor

198
 Male & Female Tract Lesions

1. SEMINOMATOUs GERM CELL TUMORS (SGCTS)

() Typical/Classical Seminoma (85)

Clinical Features:
o Most common type of germ cell tumor.
o Typically occurs
in the third decade of life: rarely seen in infants.
o Extremely sensitive to radiation.
Gross Morphology:
o Classical seminomas are large tumors that can replace the entire testis while
maintaining its shape.
o Cut surface is homogeneously grey-white and lobulated.
o Hemorrhage and necrosis are rare.
o The tunica albuginea is generally intact: however, occasional extensin to the
epididymis, spermatic cord, and scrotal sac may occur.
Microscopy:
o
Classical seminomas consist of sheets of monomorphie -looking seminoma cells
divided into poorly demarcated lobules by delicate fibrous septae.
o Seminoma cells are large, round -to -polyhedral cells with a well-defined cell
membrane, clear cytoplasm (due, to, glycogen or lipid contents), large central
nucleus with one or two prominent nucleoli
o Mitoses are infrequent.
o Septae are infiltrated by T lymphocytes, and granulomas may form at times.
Immunohistochemistry:
O Tumor cells stain positive for PLAP (placental alkaline phosphatase), kit, and
OCT 3/4.
o HCG (human chorionic gonadotropin) is positive in some cases where syncytial
giant cells resembling syneytiotrophoblasts of the placenta are present.
() Spermatocytic Senminoma (4-62)
Clinical Presentation:
O Presents as a large testicular swelling.
o Most commonly affects individuals over 6s years.
o Slow-growing tumor that rarely metastasizes and has an excellent prognosis.
Gross Morphology:
o
Larger than typical seminoma: the cut surface is pale grey, soft, and friable.

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Microscopy:
o Composed of three distinct cell populations: medium-sized cells with round nuclei
and'eosinophlic cytoplasm, smaller cells resembling secondary spermatocytes
with scanty eosinophilic cytoplasm, and scattered giant cells (uninucleate or
multinucleate).
o Lacks lynmphocytes, granulomas, and syncytiotrophoblasts.

2. NONSEMINOMATOUS GERM CELL TUMORS (NSGCTS)

() Yolk Sac Tumor

Clinical Features:
o Also known as endodermal sinus tumor.
o Most common testicular tumor in infants and children up to three years of age.
o The pure form uncommon in adults and often occurs in combination with
is
embryonal carcinoma.
o
Elevated AFP (alpha -fetoprotein) levels are found in all cases of yolk sac tumors.
Gross Morphology:
o
Unencapsulated: the cut surface is yellow -white, mucoid, with areas of necrosis,
hemorrhage, and microcyst formation.
Microscopy:
JaihreeRam
o Tumor cells are flattened to cuboidal with clear to vacuolated cytoplasm, arranged
in various patterns.
o Cells may form distinct perivascular
structures called Schiller-Duval bodies.
O Tumor cells may also contain AFP and alpha-1 antitrypsin.

(i) Choriocarcinoma
Clinical Features:
o Highly malignant form of testicular cancer.
o May arise in placental tissue, ovaries, mediastinum, and abdomen
o Pure choriocarcinoma is rare, and it often occurs in mixed tumors.
o Serum and urinary levels of HCa (human chorionic gonadotropin) are greatly
elevated.
Gross Morphology:
o
Generally does not cause testicular enlargement and is detected only as a small
palpable nodule.
o Areas of hemorrhage and necrosis are comnmon.
o Tumor may undergo extensive ischaemic necrosis, leading to the formation of a
fibrous scar with extensive metastasis.

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 Male & Female Tract Lesions

Microscopy:
O Two types of cels are seen: syncytiotrophoblasts and cytotrophoblasts.
o Syncytiotrophoblasts are large, mltinucleated cells with abundant eosinophilic
cytoplaswm, irregular or lobular hyperchromatic nuclei, and contain HCG.
o Cytotrophoblasts are regular, polygonal cells with distinct cell borders, clear
cytoplasm, single uniform nuclei, and grow in cords and masses.
(i) Embryonal Carcinoma
o
Typically occurs in individuals in their third decade.
o The tumor consists of highly pleomorphie cels arranged in tubules, acini, or sheets.
o Tumor cellshave hyperchromatic nuclei with prominent nucleoli.
o Prominent necrosis is a characteristie feature.
o The tumor secretes alpha -fetoprotein (AFP) and human chorionic gonadotropin
(HCG).

(C) TERATOMA
o Teratowmas are
tumors composed of differentiated tissues derived from more than
One germ celllayer, arranged in an irregular but organoid pattern within a fibrous
or myxoid stroma.
o They are more common in infants and children. In prepubertal children, teratomas
are considered benign, while in -pubertal males, they are considered malignant.
o Many teratomas are mixed tumors and often occur in combination with embryonal
carcinOma.
o Half of teratoma cases exhibit elevated levels of HCG or AFP.

3. SEX CORD-STROMAL TUMORS

(a) Sertoli Cell Tumors
O These tumors typically have a yellowish, homogeneous cut surface.
Histologically, they exhibit small cells arranged in trabeculae or cords, resembling
immature seminiferous tubules.
o Sertoli cell tumors are often associated with hormonal effects.
(6) Leydig Cells
o
Derived from and closely resemble normal testicular interstitial cells.
o These tumors present as well-defined nodules.
o They are characterized by a characteristic golden -brown color due to the presence
of intracytoplasmic inclusions known as Reinke's crystalloids and lipofuscin.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No.
469

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81. () Classify ovarian tumors. Briefly describe the ovarian tumors. (10 marks)
(I) Write briefly on krukenberg tumor
Answer:
CLASSIFICATION OF OVARIAN TUMORS

1. Surface epithelial-stromal ovarian tumors

o Serous tumors
o Mucinous tumors
o Endometrioid tumors
o Epithelial-strowmal tumors
o Clear cell tumors
o Transitional cell tumors
2. Sex cord stromal tumors
o Granulosa cell tumor
o Fibromas
o Fibrothecomas
o Thecomas
o Sertoli Leydig cell tumors
o Sertoli lipid cell tumors JaiShrecRam
3. Germ cell tumors
Teratoma
O

o Dysgerminomas
O Endodermal sinus (Yolk sac) tumors
o Choriocarcinomas
o Mixed germ cell tumors
4.
Metastatic cancer from non ovarian primary
o Colonic, appendiceal
o Gastric
o
Pancreaticobiliary
o
Breast
[Link] Ovarian Tumors (Surface Epithelial Tumors):
The behavior of surface epithelial tuwmors depends on their pathological characteristics:
o Benign tumors: These tumors exhibit simple, non-stratified epithelium with no
cytological atypia.
o
Borderline tumors: These tumors display epithelial proliferation with stratification,
tufting, variable mitotic activity, and nuclear atypia. However, they do not show
stromal invasion.

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 Male &&
Female Tract Lesions

O Malignant tumors (carcinOmas): These tumors exhibit stromal invasion and marked
cytological atypia.

TYPES
o Serous: The lining of serous tunmors resembles fallopian tube epithelium.
o Mucinous: The lining of mucinous tumors resembles
gastrointestinal tract or
endocervical epithelium.
o Endometrioid: The lining of endometrioid tumors resembles proliferative
endometrium.
o
Clear cell: The lining of clear cell tumors resembles gestational endometrium.
o
Transitional cell (Brenner): The lining of transitional cell tumors resembles urinary
tract epithelium.
2. Tumors of germ cell origin
(a) Dysgerminoma:
o Dysgerminoma is a malignant tumor that typically develops in individuals in their
second to third decades of life.
o It is considered the female counterpart of testicular seminoma.
o Dysgerminoma is often associated with gonadal dysgenesis.
o
The majority of dysgerminonmas are wnilateral and present as solid, large tumors.
They are characterized by sheets and nests of cells with clear cytoplasm and
well-defined cytoplasmie margins. These cellular structures are separated by thin
fibrous strands. Additionally. the stroma of dysgerminomas contains lymphoid
cells and may exhibit granulonmatous inflammation.
o Dysgerminomas are known to be vesponsive to radiotherapy, with an associated
80% survival rate.
(6) Teratoma: Teratomas are divided into three categories:
Benign Mature Cystic Teratomas:
O The most common type of benign mature cystic teratoma is known as a dermoid
cyst. Typically, these cysts are filled with sebaceous secretion and tangled hair
and are lined by stratified squamous epithelium. They often contain appendageal
structures indicating ectoderwmal differentiation.
o Occasionally, these cysts may exhibit elements like bone, cartilage, bronchial and
intestinal epithelium, suggesting development along other germ cell layers. In rare
cases, malignant transformation can occur, usually resulting in squamous cell
carcinoma when it is referred to as a teratoma with malignant transformation.
Immature Malignant Teratomas:
o Immature malignant teratomas are typically bulky. predominantly solid tumors
with areas of necrosis.

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o On microscopic examination, these tumors show immature elements such as bone.
cartilage, muscle, nerves, and other structures.
o They may also contain areas of neuroepithelial differentiation, and tumors with
such areas tend to be aggressive and have a high propensity for widespread
metastasis.
Specialized (Monoderma) Teratomas:
o Specialized teratomas are characterized by the presence of specialized tissue.
For example, struma ovarii consists entirely of mature thyroid tissue. which can
sometimes lead to hyperfunction and the production of hyperthyroidism. Another
example is the ovarian carcinoid, which can produce carcinoid syndrome.
(c) Yolk sac (endodermal sinus) tumor of ovary
o Tumor secretes alpha fetoprotein
o Schiller duval body seen on histology
(a) Choriocarcinoma
o They secrete chorionic gonadotrophins
4. Sex Cord Tumors:
(a) Granulosa cell Tumors:
o The majority of granulosa theca tumors occur in postmenopausal women, although
they can develop at any age. JaiShreeRam
o These tumors are typically unilateral, varying in size from small to large, and have
a yellow appearance with cystic spaces.
o
They ave composed of cuboidal granulosa cells, arranged in cords, sheets, or
strands, alongside spindled or plump lipid -laden theca cells. The theca cells produce
significant amounts of estrogen.
O In some cases, these tumors may exhibit features reminiscent of primitive ovarian
follicles, known as Call-Exner bodies.
(b) Thecoma-Fibroma:
o Thecoma-fibroma tumors can affect individuals of any age.
o These tumors are typically unilateral and appear solid with a grayish color. They
contain spindled fibrous cells and plump lipid-laden theca cells.
o Most of these tumors are hormonally inactive, but a minority can secrete estrogen.
O Approximately 4o% of cases are associated with the development of ascites and
hydrothorax, a condition known as Meigs syndrome.
o Malignant transformations in thecoma-fibroma tumors are rare.
(c) Sertoli-Leydig Cell Tumors:
O Sertoli-Leydig cell tumors can affect individuals of all ages.

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 Male & Female Tract Lesions

o These tumors are typically unilateral and appear as small, solid growths with
colors ranging from gray to red-brown. They are masculinizing tumors that
recapitulate the developmental process of testes.
o Malignant transformations of Sertoli-Leydig cell tumors are rare.
4. Metastasis to the ovary: GIT (most often Stomach origin) carcinoma metastasises
to ovary and is caled krukenberg tumor.
(I) Krukenberg tumor primarily affects women who are over 45 years old.
Pathogenesis:
o Krukenberg tumor most comwmonly originates from diffuse -type gastric cancer,
with metastasis occurring in the ovaries.
o There are two wmain theories explaining the metastasis of tumors from the
gastrointestinal tract (GI) to the ovaries:
o Spread occurs due to the shedding of cancercells into the peritoneum (transcoelomic
spread).
o Lymphatic spread.
o Other primary cancers associated with the development of Krukenberg tumors
include breast cancer, uterine cancer, colon cancer, and lung cancer.
Gross Morphology:
o Krukenberg tumors typically iavolve ebilateral ovaries, causing symmetrical
enlargement.
Microscopy:
o In Krukenberg tumors, signet ring cells are found. These cells are characterized
by having abundant mucin, which pushes the nucleus to the periphery of the cel.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1017

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 Breast
82. Write briefty on stromal tumors of the breast. (3 marks)
Answer:
1. FIBROADENOMA OF THE BREAST (FA)
Salient Features
o Most conmmon benign
neoplasm of the female breast.
o Thought to result from increased estrogen activity.
o Biphasic tumor with stromal and epithelial components.
o Occurs in reproductive age,with a peak in the third decade.
o Presents as a palpable, well-defined, mobile mass.
o Rarely progresses to malignancy.
o Two-thirds of fibroadenomas harbor driver mutations in MED12.

Gross Morphology
o Discrete spherical nodule (1-10,co), termed "giant fibroadenoma' (> 10cm).
JaiShreeRam
o Well-circumscribed, freely mobile, and easily enucleated.
Microscopic Features
o Stromal overgrowth and ductal proliferation with two patterns:
* Intracanalicular pattern: Myxoid stroma compresses ducts into slit-like spaces.
* Pericanalicular pattern: Abundant stroma surrounds patent or dilated ducts.
o Aging patients may exhibit stromal hyalinization and atrophic epithelium.

2. PHYLLODES TUMOR (CYSTOSARCOMA PHYLLODES)

Salient Features
o Uncommon bulky breast tumor with leaf-like appearance.
o Occurs at any age but more common in the sixth decade.
o Arises from intralobular, periductal stroma, not pre-existing fibroadenomas.
o Like fibroadenomas, the majority of phyllodes tumors have MED12 mutations
o High-grade tumors linked to HOXB13 overexpression.
Gross Morphology

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 Breast

o Variable size, may involve the entire breast.

o
Grey-white cut surface with cystic areas, hemorrhage, and necrosis.
Microscopic Features
o Low-grade tumors resemble fibroadenomas but exhibit increased cellualarity and
mitotic figures.
o High-grade tumors resemble soft tissue sarcomas, distinguished by factors
like cellularity, mitotic rate, nuclear pleomorphism, stromal overgrowth, and
infiltrative borders.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1062

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83. Write briefly on benign epithelial lesions of the breast. (5 marks)

Answer:
o Benign epithelial lesions of the breast encompass various non -cancerous alterations
in the breast ducts and lobules.
o They are classified into three categories based on the associated risk of developing
breast cancer:
2. Nonproliferative Breast Changes (Fibrocystic Changes):
o These changes involve benign alterations in the breast tissue.
o They do not involve excesive cell growth or abnormal tissue proliferation.
o Common clinical features include ill-defined lumps, nodularity, mammographic
densities, calcifications, or nipple discharge.
o These changes are usually multiple and bilateral.
o Nonproliferative breast changes do not increase the risk of developing cancer.
o
Fine needle aspiration of cyst contents may lead to the disappearance of the mass.
o There are three principal nonproliferative morphologic changes: (1) cystic change,
often with apocrine metaplasia: (2) fibrosis: and (3) adenosis.
2. Proliferative Breast Disease without Atypia:
o These changes involve the proliferation of Bells within breast ducts, ductules, and
lobules.
o Subtypes include epthelial hyperplasia, sclerosing adenosis, Complex sclerosing
lesion and papilloma.
o Epithelial hyperplasia is characterized by more than two cell layers in the lining of
ducts and lobules, often presenting with cuboidal cells and fenestrations.
o Sclerosing adenosis is marked by intralobular fibrosis, proliferation of small ductules
and acini, and myoepithelial cells, making it resemble invasive carcinoma.
o Complex sclerosing lesions are breast lesions characterized by a combination of
features including sclerosing adenosis, papilloma, and epithelial hyperplasia. One
specific type within this category is the radial sclerosing lesion'' or "radial scar"
o Papillomas can be large duct or small duct papillomas and often present with
nipple discharge.
o These proliferative changes do carry some risk but are not highly associated with
breast cancer.
3. Proliferative Breast Disease with Atypia:
o
These changes involve atypical cell growth within breast ducts and lobules.

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 Breast
o Atypical ductal hyperplasia (ADH) is characterized by mononmorphic hyperplasia
with a regularly spaced pattern of cells lining ducts.
O Atypical lobular hyperplasia (ALH) resembles lobular carcinoma in situ but does
not fill or distend wmore than sO% of the acini within a lobule.
o Both ADH and ALH are associated with an increased risk of developing invasive
breast carcinoma.
Reference: Pathologic Basis of Disease, Robbins and Cotvan, 10th Edition, Page No. 1042

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84. (0 Describe the risk factors, etiopathogenesis and morphology of carcinoma

breast.
(I) Enumerate the prognostic factors of breast carcinoma. (10 marks)
Answer:
() Risk Factors for Breast Carcinoma:
Age: Incidence increases with age, peaking at 70-80 years.
o

o Genetic Factors: Mutations in BRCA1, BRCA2, p53, and CHEK2, as well as a

family history of breast cancer, are risk factors.
o Hormonal influences: Factors like prolonged reproductive life, nulliparity, late -age
first childbirth, and exogenous estrogen exposure.
o Breastfeeding: Longer duration reduces the risk.
o Environmental Factors: Radiation exposure, organochlorine pesticides, and alcohol
intake.
o Obesity: Age-dependent effects; obesity in younger women decreases risk, while
postmenopausal obesity increases it.
o Familial Breast Cancer: BRCA1 and BRCA2 mutations are responsible for most
familial cases.
o Other Factors: Hormone therapy, oophorectomy, and certain medications like
tamoxifen and aromatase inhibitors influence risk.
CLASSIFICATION OF BREAST CARCNOMERam
1. Molecular Classification:
o ER-positive, HER2-negative (Luminal ): They are the most common type. These
tumors respond well to hormOnal therapy. They can be further categorized into
low and high proliferation types.
o Pathogenesis
Normal breast
Mutations in BRCA2
14 gain
L6q loss

Flat epithelial atypia

PIK3CA mutations

Atypical ductal hyperplasia

Ductal carcinoma in situ or DCIS

ER-positive HER2-negative carcinoma

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 Breast
o HER2-positive: These tumors (10-20% of cases) are associated with HER2 gene
amplification and affect young women. Some may have an apocrine histological
subtype.
o Pathogenesis:
Normal breast
Gevmline TPS3
mutations
HER2 amplification

Atypical apocrine adenosis

DCIS

HER2-positive carcinoma
o ER-negative, HER2-negative: Also known as triple-negative breast cancer.
o
Triple -negative: high grade: poorly ditferentiated: poor prognosis
o Histological types include medullary, adenoid cystic, secretory and metaplastic
o Pathogenesis:
JaiShreeRam
Novmal breast
Germline BRCA1
mutations
TPS3 utations

DCIS

ER-negative, HER2-negative
carcinoma
2. HISTOLOGICAL CLASSIFICATION
(A) Noninvasive Lesions:
o DCIS (Ductal Carcinoma in Situ): Frequently presents as mammographie
calcifications or as a palpable mass. It is characterized by malignant cells limited
to the ducts and may be categorized into conedocarcinoma and noncomedo DCIS.
o LCIS (Lobular Carcinoma in Situ): Often incidental, it involves the entire lobular
unit without clinically apparent masses.

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(B) Invasive Lesions:

o Invasive Carcinoma of No Special Type (NST): The most comwmon type, often
characterized by infiltrating borders with fibrous stroma. It can vary from well
differentiated to less -differentiated forwns.
o Invasive Lobular Carcinoma: Presents as ill -defined thickening/ mass, typically with
loss of E-cadherin expression and discohesive tumor cells which shows indian file
arrangement on histology.
o Medullary Carcinoma: Presents as well-circuwmscribed, soft masses, characterized
by solid syncytial arrangements, lymphoplasmacytic infiltrates, pushing tumor
margins, and a better prognosis. It is triple negative breast cancer.
o Mucinous (Colloid) Carcinoma: Often presents as a circumscribed mass with a
gelatinous appearance. Histopathology shows pools of mucin with clusters of
malignant cells.
o Tubular Carcinoma: Typically affects older women, and histopathology shows well
formed tubules lined by malignant cells.
O Invasive Papillary Carcinomas: A rare invasive carcinoma with papillary architecture.
o Metaplastie Carcinoma: A group of invasive breast cancers showing differentiation
into squamous and mesenchymal elements mixed with carcinoma of usual type.
() Major Prognostic Factors
o Lymph Node Metastases JaiShreeRam
o Locally Advanced Disease
o Inflammatory Carcinoma
o Tumor Size
o Distant Metastasis
o Invasive Carcinoma vs. In Situ Disease
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1046

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85. Deseribe the aetiopathogenesis, clinical features and morphology of the different
types of De Quervain thyroiditis. (3 marks)
Answer:

o Granulomatous thyroiditis is also known as de Quervain thyroiditis.

o
Clinical Presentation: Patients present with symptoms such as pain in the upper
neck, jaw, throat, ears, fever, fatigue, malaise, anorexia, myalgias, and enlargement
of the thyroid gland.
Pathogenesis:
Viral infection

Provision of antigen (viral antigen or virus -induced/altered host antigen)

Antigen presentation in association with HLA-B3S

JaiSheçRam
Formation of cytotoxic T cells

Damage to thyroid follicular cells

Rupture of thyroid follicles and velease of thyroid hormones

Transient hyperthyroidism (~ 2 to 6 weeks)

Hypothyroidism (due to loss of thyroid substance, lasting 2 to 8 weeks)

Recovery
Gross Morphology:
o The thyroid gland may show unilateral or bilateral enlargement.
o
On the cut surface, the tissue appears yellow-white, rubbery, and firm.

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MICROSCOPY
Early Changes:
o Scattered disruption of folicles.
o Replacement by neutrophilic microabscesses.
Late Chánges:
o Aggregates of lywmphocytes, histiocytes, and plasma cells.
o Presence of multinucleated giant cells around pools of colloid.
o Fibrosis may be present.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1080

dE
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 Endocrine

s6. Deseribe the etiopathogenesis and clinicopathological features of Graves disease.

(5 mark)
Answer:
o qraves disease is the most common cause of endogenous hyperthyroidism
It is characterized by a triad of features:
o Hyperthyroidism: Resulting from diffuse hyperplasia of follicular epithelium.
o Infiltrative ophthalmopathy: Leading to exophthalmos (abnormal protrusion of
the eyebal) and other eye-related symptoms.
o Localized
Infiltrative Dermopathy: Known as pretibial wmyxoedema, which affects
the skin overlying the shins.
Pathogenesis:
Graves disease is an autoimmune disorder characterized by the presence of multiple
autoantibodies, primarily directed against the TSH receptor:
o Thyroid-stimulating immunoglobulin (TSI): This lgG antibody binds to the TSH
receptor on thyroid follicular cells and mimics the action of TSH. TSI is hghly
specific for Graves disease.

TSI
JaiShreeRam
Binds to TSH receptor and mimics its action

Release of thyroid hormones

o Thyroid growth stimulating immunoglobulin (TG): Also targeting the TSH receptor,
TGI induces the proliferation of thyroid follicular epithelium, leading to diffuse
hyperplasia of the thyroid gland.
o Thyroid binding inhibitor immunoglobulin (TBI): TBII, also called anti-TSH
receptor antibody, prevents TSH from binding to its receptor on follicular cells.
Some forms of TBIlcan mimic TSH action, causing hyperthyroidism, while others
inhibit thyroid function, leading to hypothyroidism.
Clinical Features:
o Thyrotoxicosis (elevated free T3, T4, and TSH levels).
o Diffuse hyperplasia of the thyroid gland.
o Ophthalmopathy with exophthalmos, a wide staring gaze, and lid lag.
o
Dermopathy with thickening and induration of the skin over the shins (pretibial
myxoedewma).

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o
ophthalmopathy is characterized by an increase in the voume of retro-orbital
connective tissue and extraocular wmuscles due to inflammation, accumulation of
extracellular matrix components, and fatty infiltration.
Laboratory Findings:
o Elevated levels of free T3, T4, and TSH.
o Increased diffuse radioactive iodine uptake.
Gross Morphology:
o Enlarged thyroid gland weighing more than 80 9.
o Smooth and soft gland with an intact capsule.
o Cut surface appears soft and meaty.
Microscopy:
o Follicles show crowding and pale scalloped colloid.
o Hyperplasia results in the formation of hyperplastic papillae.
o Large reactive lymphoid follicles with germinal centers may be present in the
interfollicular stroma.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1081

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87. Explain hypothyroidism and write in brief about two common causes of
hypothyroidism. (10 maks)
Answer:
o Hypothyroidism is a condition characterized by a structural or functional problem
that disrupts the production of an adequate level of thyroid hormones.
CAUSES
Thyroidal Causes:
1. Insufficient Thyroid Parenchyma:
o Developmental issues (thyroid dysgenesis)
o Radiation injury
o Surgical removal of the thyroid gland (ablation)
o Hashimoto thyroiditis (an autoimmune thyroid disease)
2. Interference with Thyroid Hormone Synthesis:
o ldiopathic
primary hypothyroidiswm (unknown cause)
o Heritable defects affecting hormone synthesis
o
lodine deficiency
o Certain medications (e.g., lithium, iodijdesIPramino salicylic acid)
o Hashimoto thyroiditis (autoimmune)
SUPRATHYROIDAL CAUSES
1. Pituitary Lesions:
O Tumors
o Radiation damage
o Surgical removal of the pituitary gland, which reduces the secretion of thyroid
stimulating hormone (TSH)
2. Hypothalamic Lesions:
o Conditions affecting the hypothalamus can reduce the release of thyrotropin
releasing hormone (TRH), which in turn affects TSH production.
Clinical Manifestations:
o Cretinisim: This refers to hypothyroidism that develops in infants and children. It is
characterized by severe developmental inpairments, including delayed milestones,
delayed bone maturation, severe mental retardation, short stature, coarse facial
features, a protruding tongue, and umbilical hernia.

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o Myxoedema: Myxoedema represents hypothyroidism that develops in older children

or adults. Its clinical features include:

* Decreased physical and mental activity

• Fatigue,apathy, mental sluggishness, and depression
o Slow speech and intellectual functions
o Weight gain and cold intolerance
• Reduced cardiac output leading to shortness of breath and decreased exercise
capacity
* Constipation and decreased sweating
* Edema (sweling). broadening and coarsening of facial features, tongue
enlargement, and deepening of the voice
Laboratory Findings:
o Elevated TSH levels
o Decreased levels of T3 and T4
Hashimoto thyroiditis
thyroiditis is the mosti common cause of autoimmune thyroiditis.
o Hashiwmoto

o lt can occur in children and is a leading cause of nonendemic goiter (enlarged

thyroid) in this age group.
o It is associated with specific HLA-DR3 and- DRS, and an increased risk of other
autoimmune conditions such as systemic lupus erythematosus (SLE), Sjögren
syndrome, pernicious anemia, Type I diabetes mellitus, and rheumatoid arthritis.
o
Patients typically present with painless enlargement of the thyroid gland.
o The disease's onset is insidious, and it often progresses to hypothyroidism after a
transient phase of thyrotoxicosis known as hashitoxicosis.
PATHOGENESIS

218)
 Endocrine

Plasma cel

CD8ve T
cell

Macrophage

Antibodies

T-cel-mediated cytotoxicity Cytotoxic

qranules
Thyrocyte injury released

NK cell

Antibody-dependent cell-mediated cytotoxicity

Gross Morphology:
o Hashimoto thyroiditis vesults in zaifuse otararely localized enlargement of the
thyroid gland.
o The thyroid capsule typically remains intact.
o On the cut surface, the gland appears pale, grey-tan, firm, and rubbery, with
accentuated lobulation.
Microscopy:
o Microscopic examination veveals extensive infiltration of the thyroid parenchyma
by mononuclear cells, including lymphocytes with well-developed germinal centers
and plasma cells.
o There is atrophy of thyroid follicles, and Hürthle cells (degenerated follicular cells
with abundant granular eosinophilic cytoplasnm and prominent nucleoli) may be
present.
o Increased interstitial connective tissue is observed, but fibrosis usually does not
extend beyond the thyroid capsule.

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GoITRE
Pathogenesis
Dietary iodine deficiency or intake of goitrogens

Decreased thyroid hormone synthesis

Conpensatory increase in TSH

Hypertrophy and hyperplasia of thyroid folicular cells

Enlargement of thyroid (goitre)

Inadequate compensation

Diffuse nontoxic (simple) goitre Increased production of thyroid homones

Multiple cycles of hyperplasia and involution

Mutirodudar goitrg
ai ShreeRam Euthyroid state

Characteristic Diffuse Non-Toxic Goiter Multinodular Goiter

Definition Enlargement of the Enlargement of the thyroid
|thyroidgland without gland characterized by the
associated overproduction or presence of multiple thyroid
underproduction of thyroid nodules or growths.
hormones.
Size The thyroid gland is uniformly Multiple nodules of varging
enlarged, often symmetrically. sizes within the thyroid gland:
and may be visibly enlarged in the gland may be unevenly
the neck. enlarged.
Thyroid Typically, thyroid hormone Thyroid hormone levels may
Hormone Levels| levels (T3 and T4) remain vary depending on the activity
within the normal range. of the nodules; some nodules
may produce excess hormones
(toxic nodules), while others
may not.

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 Endocrine

o
Microscopic Histology shows hyperplastico Multiple thyroid nodules of
Findings thyroid Folicles without signs varying sizes.
of malignancy. o Histology may reveal nodules
o Colloid -filled follicles may be with different characteristics,
enlarged. Such as adenomatous changes
or areas of hypevactivity
(toxic nodules).
o Uniform enlargement of
Gross Findings
thyroid gland.
Multiple nodules within the
theo thyroid gland.
o
May appear smooth and o The gland may have an
symmetric. irregular or "lumpy"
appearance due to the
presence of nodules.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1079

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88. write briefly about multiple endocrine neoplasia (MEN). (5 marks)

Answer:
o MEN
Syndromes encompass a group of inherited diseases characterized by
proliferative lesions (hyperplasia, adenomas, carcinomas) involving multiple
endocrine organs.
o MEN-associated tumors can arisesynchronously (simultaneously) or metachronously
(at different times) in multiple endocrine organs.
1. MULTIPLE ENDoCRINE NEOPLASIA TYPE 1 (MEN-1) SYNDROME
o MEN-1 is also known as Wermer syndrome.
The Three P's: Manifestations of MEN-1
o Parathyroid Involvement:
Prinary hyperparathyroidism is the most common
manifestation of MEN-1. It usually appears as the initial sign. Parathyroid
abnormalities include both hyperplasia and adenomas.
o
Pancreatic Involvement: MEN-1 is associated with endocrine tumors of the
pancreas, a leading cause of morbidity and mortality. Multiple "microadenomas"
may be scattered throughout the pancreas, alongside one or two dominant lesions.
These pancreatic tumors are often functional, with Zollinger-Ellison syndrowme
(gastrinomas) and hypoglycemia/neurologic manifestations (insulinomas) being
cOmmon presentations.
JaiShrecRam
o Pituitary Involvement: In MEN-1, the most frequent anterior pituitary tumor
is prolactinoma, while some patients develop acromegaly from somatotropin
secreting tumors.
BEYOND THE THREE P'S
o MEN-1 manifestations extend beyond the three primary sites.
o Gastrinomas in MEN-1 are most commonly found in the duodenum, surpassing
the frequency of pancreatic gastrinomas.
o Synchronous duodenal and pancreatic tumors can occur.
o Additionally, MEN-1 patients may experience carcinoid tumors, thyroid and
adrenocortical adenomas, and lipomas at higher rates than the general population.
Genetic Basis: MEN1 Tumor Suppressor Gene
o MEN-1 syndrome is caused by germline mutations in the MEN1 tumor suppressor
gene. This gene encodes the protein menin, which plays a role in various transcription
factor complexes. Depending on the binding partner, menin can either promote
or inhibit tumorigenesis.

2. MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 (MEN-2) SYNDROME

o MEN-2 is subdivided into three distinct syndromes: MEN-2A, MEN -2B, and
MEN-4.
 Endocrine

MEN-2A (Sipple Syndrome):

o Characterized by pheochromocytoma, medullary carcinoma of the thyroid, and
parathyroid hyperplasia.
o Almost 1oO% of patients develop medullary thyroid carcinomas, which are usually
multifocal and associated with C -cell hyperplasia in the adjacent thyroid tissue.
o Medullary carcinomas often produce calcitonin and are clinically aggressive.
o Approximately 40% to sor of individuals with MEN-2A have bilateral
pheochromocytomas, sometimes occurring in extra-adrenal location.
o Parathyroid hyperplasia with hypercalcemia or renal stones is observed in 10% to
20% of patients.
o MEN-2A isgenetically distinct from MEN-1 and is caused by gain-of-function
mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase.
MEN-2B Syndrome
o lt includes medullary thyroid carcinomas, which tend to be multifocal and more
aggressive, pheochromocytoma.
o Unlike MEN-2A, primary hyperparathyroidism is not a characteristic feature.
o MEN-2B presents additional manifestations, including neuromas
ganglioneuromas involving various tissues (skin, oral mucosa, eyes, respiratory
tract, gastrointestinal tract), a jwmarfanoid habitus with elongated axial skeletal
features and hyperextensible joints.
o MEN-2B is primarily associated with a germline missense mutation in RET that
causes constitutive activation of the receptor, distinct fromn MEN-2A mutations.
MEN-4 Syndrome
o Patients with MEN -4 exhibit clinical characteristics similar to those of MEN-1
patients.
o However, in contrast to MEN-1, MEN-4 is associated with germline mutations in
the CDKN1B gene.
o These wmutations lead to reduced levels of the cell -cycle checkpoint protein known
as p27.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10oth Edition, Page No. 1129

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MedEd FARRE: Pathology

89. () write briefiy on the pathogenesis, clinical features and morphology of Cushing
syndrome. (5 marks)
(i) write briefty on the pathogenesis, clinical features and morphology of
hyperaldosteronism.
Answer:
() CUSHING SYNDROME
Pathogenesis:
Endogenous Cushing Syndrome:
o
Primary Hypothalamic-Pituitary Disease: Hypersecretion of ACTH, also known as
"Cushing disease" (constitutes 70-80% of cases).
o Hypersecretion of Cortisol by Advenal Abnormalities: Adrenal adenoma, carcinoma,
or nodular hyperplasia, known as "ACTH-independent Cushing syndrome"
(constitutes 10-207% of cases).
o Ectopic ACTH Secretion: Seen in small cell carcinoma of the lung, carcinoid tumors,
medullary carcinoma thyroid, and islet cell tumors of the pancreas.
Exogenous or latrogenic Cushing Syndrome:
o Resulting from the administration of exogenous corticosteroids.
Clinical Features:
JaiShreeRam
o Central Obesity: Particularly in the upper trunk and back, along with "moon
faces" and a "buffalo hump."
o
Weakness and Fatigability: Due to selective atrophy of fast-twitch (Type I)
myofibrils and decreased muscle mass.
o
Hirsutism and Menstrual Irregularities
o Hypertension
o
Glucose Intolerance/Diabetes: Resulting from the induction of gluconeogenesis
and decreased glucose uptake by cells, leading to hyperglycemia, glycosuria, and
polydipsia.
o Osteoporosis and Skin Striae: Catabolie effects on proteins causing collagen loss
and bone resorption.
Morphology
o Pituitary Glands: Common alteration includes Crooke hyaline change, where the
granular basophilic cytoplasm of ACTH-producingcells isreplaced by homogeneous
lightly basophilic wmaterial, caused by the accumulation of intermediate keratin
filaments.

224
 Endocrine

o Adrenals: Morphological changes vary depending on the cause of hypercortisolism,

including cortical arophy, difiuse hyperplasia, nodular hyperplasia, adenoma, or
carcinowma.

(I) HYPERALDOSTERONISM
Hyperaldosteronism is a collective term encompassing various related syndromes
characterized by excessive aldosterone secretion, which leads to sodium retention and
potassiuwm excretion.

TYPES OF HYPERALDOSTERONISM
1. Primary Hyperaldosteronism:
o Characterized by autonomous overproduction of aldosterone.
o Results in the suppression of the renin-angiotensin system and decreased plasma
renin activity.
Main Causes:
() Adrenocortical neoplasms:
O Adenoma (80% of cases) or Conn syndrome.
o Carcinoma (20% of cases).
() Primary idiopathic adrenocortical hyperplasia: Bilateral nodular enlargement.
(ii) Glucocorticoid -remediable hyperaldosteronism (familial): Caused by a chimeric
gene formed by the fusion of CYP11B1 and CYP11B2 genes.
2. Secondary Hyperaldosteronisn:
O Aldosterone release occurs due to the activation of the renin-angiotensin system.
o Various causes include decreased renal perfusion, arteriolar nephrosclerosis, venal
artery stenosis, arterial hypovolemia, edema, congestive cardiac failure, cirrhosis,
pregnancy, and increased estrogen levels.
Morphology of Aldosterone-Producing Adenomas and Bilateral ldiopathic Hyperplasia:
Aldosterone-Producing Adenomas:
o Solitary, small (less than 2 cm in diameter), and well-circumscribed with a yellow
cut surface.
o Typically affect patients in their third to fourth decades, with a higher incidence
in females.
o Composed of lipid -laden cortical cells.
o Presence of eosinophilie, laminated inclusions known as spironolactone bodies
Bilateral ldiopathic Hyperplasia:
o Characterized by diffuse or focal hyperplasia.

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o
Hyperplastic cells resemble those of the normal zona glomerulosa.
o Focal hyperplasia is wedge -shaped and extends from the periphery to the center
of the adrenal gland.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1115

dEC
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 Endocrine

90. Classify malignant lesions of thyroid. Describe the pathogenesis, clinicopathological

features of various thyroid malignancies. (10 marks)
Answer:
MALIGNANT THYROID LESIONS IN ADULTS
o Most malignant thyroid lesions, specifically carcinomas, are prinmarily observed in
adults. Females are more commonly affected than males.
Subtypes of Thyroid Carcinoma:
o Papillary Carcinoma (most common)
o Follicular Carcinoma
o Medullary Carcinoma
o
Anaplastie Carcinoma
PATHOGENESIS OF THYROID CARCINOMA
o The development of thyroid carcinoma results from a combination of genetic and
environmental factors. Two major genetic pathways play a significant role in the
pathogenesis of follicular epithelium -derived thyroid malignancies:
L. Genetic Factors
o Mitogen-Activated Protein (MAP) Kinase Pathway and Phosphatidylinositol
3-Kinase (Pl3K/AKT) Pathway:a1ShreeRam
o In thyroid carcinoma, gain-of-function mutations along these pathways result
in continuous activation, promoting carcinogenesis.
o Examples of genetic abnormalities in thyroid carcinowma include:
* Follicular Carcinoma: Abnormalities in the PI3K/AKT signaling pathway. often
due to mutations in NRAS, HRAS, KRAS, and mutations in the PTEN tumor
suppressor gene. Additionally, the forwmation of the PAX8-PPAR gamma 1
fusion product due to translocation (23) (q13: p25) is observed, inducing
terminal differentiation of cells.
Papillary Carcinoma (PTC): The MAP kinase pathway plays a major role in PTC.
Abnormalities in this pathway can occur through rearrangements of tyrosine
kinase receptors (TKRS), RET, or NTRK1, mutations in signal transduction genes
(RAS and BRAF oncogene mutations), and activation of the MAP kinase pathway.
* Medullary Carcinoma: Medullary carcinoma is sporadic in s0% of cases, with the
remaining cases occurring in the context of Multiple Endocrine Neoplasia (MEN)
IIA or IIB or as familial tumors not associated with MEN syndrome. Familial
tumors in MEN Type Il are associated with germline mutations in the RET
proto -oncogene, leading to constitutive activation of tyrosine kinase receptors
and cellular proliferation.

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2. Environmental Factors
o There is an association between thyvoid carcinoma and exposure to ionizing
radiation.
o Pre-existing thyroid pathologies, such as nodular goiter, adenomas, and Hashimoto's
thyroiditis, may also contribute to the development of thyroid carcinoma.
PAPILLARY THYROID CARCINOMA
Clinical Features:
o Papillary thyroid carcinoma the most common type of thyroid malignancy.
o lts peak incidence is between 20 and 40 years, but it can occur at any age.
o Typically presents asa
solitary (cold) nodule in the thyroid gland.
o In most cases, the primary thyroid nodule is asymptomatic, and the first sign may
be the presence of cervical lymph node metastasis.
o Occasionaly, the primary thyroid nodule may cause symptoms such as hoarseness,
dysphagia, cough, or dyspnea.
Predisposing Factors:
o Previous exposure to ionizing radiation increases the risk of developing papillary
thyroid carcinoma.
o Increased incidence is observedl inStonditions like Gardner syndrome (familial
adenomatous polyposis col) and Cowden disease (fawnilial goitre and skin
hematomas).
Microscopy:
o
Itischaracterized by branching true papillae with fibrovascular cores covered by
multiple layers of cuboidal epithelium.
o Cells exhibit finely dispersed chromatin, leading to "orphan Annie" or ground
glass nuclei.
o Invaginations of the cytoplasm may give the appearance of eosinophilic intranuclear
inclusions or pseudoinclusions.
o Psamwmoma bodies (concentrically calcified structures) are often seen within the
cores of papillae.
o Lymphatic invasion is common, while involvement of blood vessels is relatively
rare.
Variants:
o Encapsulated variant: Has a well-encapsulated structure, with rare vascular or
lymph node dissemination and an excellent prognosis.

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 Endocrine

o Follicular variant: Presents as unencapsulated tumors with follicular architecture,

characteristic nuclear features of papillary thyroid carcinoma, and psammoma
bodies.
o Tall cell variant: Characterized by tallcolumnarneoplastic epithelium with intensely
eosinophilic cytoplasm. Typically, larger tumors with vascular invasion and a worse
prognosis, especially in older individuals.
Diffuse selerosing variant: Affecting younger individuals, this variant shows diffuse
fibrosis, abundant psammoma bodies, and squamous morules (metaplasia).
O
Hyalinizing trabecular tumor: Exhibits organod growth resembling extra-adrenal
paraganglioma, with intra - and extracelular hyalinization.
Prognosis:
o Papillary thyroid carcinoma generally has a favorable prognosis.

FOLLICULAR CARCINOMA
Clinical Features:
o Follicular carcinoma is the second most common type of thyroid carcinoma.
o Areas with iodine deficiency have a higher incidence of follicular carcinoma,
suggesting a potential association with nodular goiter.
o It typically presents as a slowly enlarging, painless, cold nodule.
o Regional lymph nodes are rarely involved,but Vascular invasion is common, leading
to metastasis in bones, lungs, and the liver.
Microscopy:
o Most tumors display a follicular pattern, although some may show less apparent
follicular differentiation, with a trabecular pattern or sheets of polygonal to
spindle-shaped cells.
o Anaplasia varies but is generally not marked.
o Vascular invasion is more common
than lymphatic invasion.
o
Degenerative changes such as central fibrosis and calcification are common.
MEDULLARY CARCINOMA
Clinical Features:
o Medullary carcinoma is a neuroendocrine neoplasm derived from the parafollicular
or 'C cells.
o
It secvetes calcitonin, which is erucial for diagnosis and postoperative follow-up.
o Some cases may also secrete other polypeptide hormones, such as somatostatin,
serotonin, and vasoactive intestinal peptide (VIP),

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o Sporadic lesions are common in adults (40-so years), while cases associated with
are observed in younger patients or during childhood.
MEN Syndrome
o Clinicat presentations may include a paraneoplastic syndrome (eg., diarrhea due
to excessive VIP or hypocalcemia due to increased serum calcitonin) or mass
related symptoms.
Microscopy:
o Medullary
carcinoma is composed of polygonal to spindle -shaped cells, which can
form nests, trabeculae, and follicles.
o Acellular amyloid deposits derived from altered calcitonin may be present in the
stroma.
o Multicentric C-cell hyperplasia is often seen in the surrounding thyroid tissue in
familial wmedullary carcinoma but is absent in sporadic cases.
o Electron microscopy reveals wmembrane-bound, electron-dense granules.
Anaplastic Carcinoma
o Anaplastic carcinowma is an undifferentiated tumor derived from thyroid follicular
epithelium.
Clinical Features:
o It presents as a rapidly enlarging bulky neck mass that can invade contiguous
structures. JaiShreeRam
o Anaplastic carcinoma is typically seen in older patients, with a mean age of 65
years.
Genetic Defects:
o Differentiated tumors may progress to anaplastic carcinoma with the loss of P53.
Morphology:
o
Anaplastic carcinoma is highly anaplastic and can exhibit various histological
patterns.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1129

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 Endocrine

91. A 46 year old male presents to the OPD with complaints of increased frequency
of urination and increased thirst and appetite. He has gained s kg weight in the
last 1 [Link] Random blood sugar came out to be 300 mg/dL.
(A) What is the likely diagnosis?
(B) What are the clinical features and complications of the disease and its
Pathogenesis and morphology?
(C) write the difference between the two predominant type of the disease.

(10 marks)
Answer:
(A)
The most likely diagnosis based on the given history is Type 2 Diabetes mellitus. It
shows the classic triad of diabetes ie. polyuria, polydipsia and polyphagia along with
high random blood sugar.
(B) CLINICAL FEATURES OF DM
Type I DM:
o Polyuria and Polydipsia: Hyperglycemia exceeding the renal threshold for
reabsorption leads to glycosuria,causing oswmotic diuresis, increased urine production
(polyuria), and intense thirst (polydipsia): Ram
o Polyphagia: Deficiency of insulin leads to a catabolic state, causing increased
appetite and hunger (polyphagia).
o Weight Loss: Catabolism of proteins and fat reslts in a negative energy balance,
leading to progressive weight loss and muscle weakness.
o Ketoacidosis: Insulin deficiency coupled with glucagon excess increases blood glucose
levels, resulting in severe osmotic diuresis, dehydration, and ketoacidosis (nausea,
vomiting, respiratory difficulty).
Type IlDM:
O
High portal insulin levels in Type DM prevent excessive hepatic fatty acid oxidation,
lI
regulating ketone body production and minimizing the risk of ketoacidosis.
o Dehydration can still ocur, leading to hyperosmolar nonketotic coma, especially
with poor fluid intake.
o Most of these patients are obese.
Complications of DM:
O Macrovascular Disease: Accelerated atherosclerosis affects large- and medium
sized muscular arteries, increasing the risk of myocardial infarction, stroke, and
lower extremity gangrene.

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o Microvascular Disease: Capillary dysfunction occurs in target organs, particularly
affecting the retina, kidneys, and periplheral nerves, leading to diabetic retinopathy.
nephropathy, and neuropathy.
PATHOGENESIS OF COMPLICATIONS
Formation of Advanced Glycation End Products (AGE):
o Nonenzymatic veactions between glucose and amino groups of proteins lead to
AGE forwmation.
o AGES
bind to the RAGE receptor on inflammatory cells (macrophages, T cells).,
endothelium, and vascular smooth muscle.
o AGES exhibit various chemical and biological properties:
* Crosslink polypeptides of the same protein, impairing elasticity in large vessels
and thickening basement membranes.
• Trap nonglycated proteins, promoting cholesterol deposition in blood vessels.
Resist proteolytic digestion, hindering protein removal and increasing deposition.

* Activate reactive oxygen species, NF-kB, monocyte emigration, cytokine/growth

factor secretion, vascular permeability. procoagulant activity, ECM production,
and cellular proliferation.
Activation of Protein Kinase C (PKC):
o Intracelular hyperglycemia leads toShreeR
increased diacylglycerol (second messenger)
synthesis.
o PKC activation, mediated by calcium ions and second messengers, has downstream
effects such as VEGF production, increased endothelin-1 activity, decreased nitric
synthase (NOS) activity, TGF-b stimulation, elevated plasminogen activator
Oxide
inhibitor (PAI-1) production, and proinflammatory cytokine release.
Polyol Pathway:
o Elevated glucose levels lead to increased aldose reductase activity, producing
sorbitol and fructose.
o Sorbitol and fructose are osmotically active, causing tissue damage.
o Complications include Schwann cell destruction (causing neuropathy and cataracts)
and pericyte damage (resulting in microaneurysms in diabetic retinopathy).
o NADPH depletion in the polyol pathway reduces cellular resistance to oxidative
stress.

MORPHOLOGY OF DM
Pancreas:
o Reduction in the number and size of islets (more in TiDM).
o Insulitis, characterized by leukocytic infiltration of the islets.

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 Endocrine

o Amyloid deposition within islets in long-standing T2DM.

Vascular System:
o Accelerated atherosclerosis is a hallmark of diabetes.
o lncreased risk of gangrene and myocardial infarction.
o Hyaline arteriolosclerosis, presenting as amorphous hyaline thickening of arteriolar
walls leading to luminal narrowing.
Diabetic Nephropathy:
o Microalbuminuria: Early manifestation marked by the presence of low levels of
albumin in urine.
o
Glomerular lesions:
* Capillary basement membrane thickening.
Diffuse mesangial sclerosis.
* Nodularglomerulosclerosis, known as Kimmelstiel -wilson lesion, is pathognomonic
for diabetes.
o Renal vessels arteriosclerosis and atherosclerosis.
o Pyelonephritis leading topapillary necrosis (necrotizing papillitis).
Diabetic Ocular Complications
o Retinopathy: Characterised by proliferation bf new vessels in the retina and
tractional retinal detachment.
o Cataract
O Glaucoma
Diabetic Neuropathy:
o Affects both the central and peripheral nervous systems.
O Alters motor and sensory functions.

Type 1 Diabetes Type 2 Diabetes

Clinical
Onset: usually childhood and Onset: usually adult; increasing
adolescence incidence in childhood and adolescence
Normal weight or weight loss preceding Vast majority are obese
diagnosis.
Progressive decrease in insulin levels Increased blood insulin (early); normal
or moderate decrease in insulin (late)

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Circulating islet autoantibodies (anti No islet autoantibodies

insulin, anti-GAD, anti-ICAS 1 2)
Diabetic ketoacidosis in absence of Nonketotic hyperosmolar coma more
insulin therapy COmmon
Genetics
Major linkage to MHC class 11 genes: No HLA linkage; linkage to candidate
also linked to polymorphisns in CTLA4 diabetogenic and obesity-related genes
and PTPN22, and insulin gene.
Pathogenesis
Dysfunction in T-cell selection and Insulin resistance in peripheral tissues,
regulation leading to breakdown in failure of compensation by 13 cells.
self-tolerance to islet autoantigens
Pathology
lnsulitis (inflammatory infiltrate of T No insulitis: amyloid deposition in islets
cells and wmacrophages) B-celldepletion, Mild ß-cell depletion
islet atrophy

Reference: Pathologic Basis of Disease, Robbins Cotran, 10th Edition, Page No. 1097
JaiShrecRam

34
 CNS
q2. Write a short note on Craniopharyngioma. (5 marks)
Answer:
ETIOLOGY
o Originates from vestigial remnants of Rathke's pouch.
o Predominantly located above the sella (suprasellar) with possible sellar extension.
o Bimodal age distribution with peaks in childhood (5 to 15 years) and among
adults aged 65 or older.
o Clinicat
presentations include headaches, visual disturbances, and growth
retardation (in children) due to pituitary hypofunction and GH deficiency.
MORPHOLOGY
o Tumor size approximately 3 to 4 cm in diameter.
is
o Can be
encapsulated solid masses or commonly cystic and multiloculated.
o Compression of adjacent structures such as the optic chiasm and cranial nerves.
Adamantinomatous Craniopharyngioma (Mostly in Children):
o Nests or cords of stratified squamous epithelium in a spongy reticulum.
O
Palisading of squamous cells at the periphery.
o Radiologicaly visible calcifications.
o "Wet keratin" is a diagnostic feature.
o Cyst fornation, fibrosis, chronic inflammation, and extension into adjacent brain
tissue.
o
The cysts within adamantinomatous craniopharyngiomas frequently contain a
thick brownish -yellow fluid rich in cholesterol, which has been compared to the
consistency of "machine oil"
Papillary Craniophargngioma (Mostly in Adults):
o Solid sheets of cells and papillae lined by well-differentiated squanmous epithelium.
o Lacks features seen in the adamantinomatous type.
o
Characterized by BRAF oncogene mutations.
Clinical Features:
o
Prognosis is generally favorable, especially for tumors smaller than 5 cm in
diameter.
O Low recurrence rates and good overall survival.
o Larger lesions may be more invasive but do not significantly impact prognosis.

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o Malignant transformation into squamous carcinomas is rare and usually follows

irradiation.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1074

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 CNS

43. (0) Write briefly about Neurofibromatosis Type and Type 2.

(5 marks)
(I) write briefly about schwannomas.
Answer:
NEUROFIBROMATOSIS TYPE 1 (NF1)
o ComwOn autosomal dominant disorder.
o
Systemic Disease associated with non-neoplastic manifestations and various
tumors.
Tumors:
o Neurofibromas (all types).
o Malignant Peripheral Nerve Sheath Tumors (MPNSTS).
o Gliomas (optic nerve and other glial tumors).
o Hamartomatous lesions.
o Pheochromocytomas.
Other Features:
o lntellectual disability or seizures.
o Skeletal defects. JaiShreeRam
o Pigmented nodules of the iris (Lisch nodules).
o
Cutaneous hyperpigmented macules (café au lait spots).
Pathogenesis:
o NE1 gene on 17q11.2, encoding the tumor suppressor neurofibromin.
o Neoplastic cells in NE1-related tumors lack neurofibromin due to bialelic NF1
gene defects.
o Neurofibromin has GTPase activity, regulating RAS Function.
O Absence of NF-1 leads to persistent RAS activation.

NEUROFIBROMATOSIs TYPE 2 (NF2):

o Autosomal dominant disorder.
Tumors:
o
Bilateral eighth nerve schwannomas (common).
o Multiple meningiomas.
o Ependymomas of the spinal cord.

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Nonneoplastic Lesions:
o Schwannosis (nodular ingrowth of Schwann cells into the spinal cord).
O
Meningioangiomatosis (proliferation of meningeal cells and blood vessels into the
brain).
Pathogenesis:
NF2 gene on chromosome 22q12 codes for merlin.
O

o Merlin is a cytoskeletal protein involved in regulating cell shape, growth, and cell
adhesion.

(i) sCHWANNOMAS (ACOUSTIC NEUROMA):

o Origin: Benign tumors originating from Schwann cell differentiation, often
associated with peripheral nerves.
o Association with NE2: Schwannomas are linked to Neurofibromatosis Type 2 (NF2)
and frequently exhibit inactivating mutations in the NF2 gene on chromosome 22.
Loss of merlin, the NF2 gene product, is consistently observed in schwannomas.

Morphology:
o Encapsulation: Schwannomas are well-circumseribed, encapsulated masses loosely
attached to peripheral nerves, allowing for
JaiShreeCaresection without nerve damaae.
o Gross Appearance: Firm, gray masses.
Microscopic Characteristics:
o They are comprised of an admixture of dense and loose areas veferred to as Antoni
and Antoni B areas
A
* Antoni A: Dense eosinophilic areas with spindle cells arranged in intersecting
fascicles, palisading nuclei, and Verocay bodies.
* Antoni B: Loose, hypocellular areas with spindle cells separated by a myxoid
extracellular matrix, sometimes with microcysts.
o Electron Microscopy: Basement membrane deposits encasing single cells and
collagen fibers.
o Immunoreactivity: Uniformly positive for S-100, confirming Schwann cell origin.
Clinical Features of Schwannomas:
o Common Locations: Schwannomas are often located at the cerebellopontine angle,
attached to the vestibular branch of the eighth nerve.
O Symptoms: Schwannomas typically cause symptoms due to local compression of
the involved nerve or adjacent structures, such as the brainstem or spinal cord.

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 CNS

o Common presenting symptoms inlude tinnitus (Ringing in the ears) and hearing
Loss.
o Other Locations: In locations outside the cranial vault, sensory nerves are more
frequently affected, including branches of the trigeminal nerve and dorsal roots.
o Extradural Schwannomas: These tumors can arise in association with large nerve
trunks or as soft tissue lesions without an identifiable associated nerve.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1239

JaiShreeRam

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44. Write briefty on Neurodegenerative diseases. (10 marks)

Answer:
o Neurodegenerative diseases are charactevized by the progressive loss of neurons.
o The formation of protein aggregates is a common pathologic mechanism in the
majority of neurodegenerative disorders.
o The following table shows the major Neurodegenerative diseases and protein
inclusions found in them:

Disease Clinical Pattern Protein Inclusions

Alzheimer Dementia AB (plaques)
disease(AD) Tau (Tangles)
Frontotemporal Behavioural changes, Tau
lobar degeneration language disturbance
TDP-43
(FTLD)
Others(rare)
Parkinson Hypokinetic movement Alpha-synuclein
disease(PD) disorder Tau
Huntington Hyperkinetie movmentim Huntingtin(polyglutamine
disease(HD) disorder repeat expansion)
Spinocerebellar Cerebellar ataxia Various proteins
ataxia (polyglutamine repeat
expansion)
Amyotrophic lateral Weakness with upper and SOD:l
sclerosis(ALS) lower motor neuron signs
TDP-43
1. Alzheimer's Disease: In older persons, Alzheimer's disease (AD) is the most frequent
cause of dementia.
o Pathogenesis: The primary anomaly in AD is the accumulation of two proteins
AB and tau in the forms of plaques and tangles, respectively. These changes
result in secondary effects including neuronal dysfunction, neuronal death, and
inflammatory reaction.

40
 CNS

Normally the APP( amyloid

precursor protein) If cleaved beta
secretase

Produces Aß peptide
Cleaved by alpha
secretase to produce
non-amyloidogenie These monomers
protein aggregate to form
oligomers and affects
neurons by

Kinase Synaptic Death of cell and These peptides form

activation dysfunction pathways of my injury aggregates in form of
amyloid fibrils

Tau phosphorylation Neuron damage

Microtubule
disassembly JaiShreeRam
Tau also Plaque and
aggregates tangles

2. Parkinson's disease: Parkinson's disease (PD) is caused by the loss of dopaminergic

neurons from the substantia nigra.
o Parkinsonism includes tremor, rigidity, bradykinesia, and instability and it is most
comimonly caused by PD.
o Pathogenesis: PD is associated with protein accumulation and aggregation, and
neuronal loss in the substantia nigra.
o The diagnostic feature of the disease is the presence of Lewy body in the neurons
which consists of fine filaments, composed of a-synuclein and other proteins.

Destruction of dopaminergic neuronal cells in the substantia nigra

in thebasal ganglia

Degeneration of the dopaminergic nigrostriatal pathway

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Depletion of dopamine store

Imbalance of excitatory (acetylcholine) and inhitbiting (dopamine)

neurotransmitters in the corpus striatum

Impairment of extrapyramidal tracts controling complex body

movements

Tremors, Rigidity, Bradykinešía

3. Huntington disease (HD):
JaiShreçRam
Huntington disease (HD) is an autosomal dominant
movement disorder associated with degeneration of the striatum (caudate and
putamen).
o It is characterized by involuntary jerky movements of all parts of the body
o
Pathogenesis:

Mutation in the HTT gene, located on chromosome 4

mutation involves excessive expansion of the CAG repeat sequence in

the HTT gene

242
 CNS

it leads to the production of a mutant huntingtin protein (mHTT)

It has increased number of glutamine (encoded by the CAG repeat)

residues

mHTT is toxic to neurons and accumulation of mHTT causes toxic

effects lead to progressive dysfunction and ultimately the death of
neurons in specific brain regions, including the striatum and cortex.

The degeneration of neurons in these regions results in the

characteristic symptoms of HD, including Involuntary movements
(chorea), Muscle rigidity etc.
[Link] lobar degeneration (FTLD): FTLD refers to a set ofneurodegenerative
conditions where the frontal and temporal lobes of the brain gradually atrophy.
o Pathogenesis: It is characterized by the accumulation of tau or TDP43 protein
o FTLD has two subgroups based on the predominant protein pathology:
o Tauopathies: Characterized by tau protein abnormalities.
o TDP-43 proteinopathies: Characterized by TDP-43 protein abnormalities.
s. Spinocerebellar ataxia: Spinocevebellar ataxias (SCAs) are a group of hereditary
neurodegenerative disorders characterized by progressive problems with coordination
and balance.
6. Amyotrophic Lateral Sclerosis: ALS involves the degeneration of upper motor
neurons in the motor cortex of the brain and lower motor neurons in the spinal cord.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1273

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95. Classify Brain tumors. (10 marks)

Answer:
Brain tumors

Primary Secondary

Metastasis from other malignant

Glial Neuronal Medulloblastoma tumors like lung, breast,
melanoma etc.
Astrocytoma
Oligodendroglioma

Ependymoma
o The most common tumor in the brain is metastasis.
o Metastasis secondaries in the brain come from the lungs, breast, kidney, skin
tumours etc.
o The most common primary tumor ie meningioma(benign)
O The most common primary malignant tumour is glioma.
(1) GLIOMAS
Gliomas are tumors of the brain parenchyma that have been classified as astrocytomas,
oligodendrogliomas, and ependymomas.
(A) Astrocytoma: Based on histologic features, astrocytomas are classified into four
groups: pilocytic astrocytoma (grade ), diffuse astvocytoma (grade l), anaplastic
astrocytoma (grade i), and glioblastoma (grade IM).
o Pilocytic Astrocytonma (Grade ): It is a low-grade tumour having a good prognosis.
o Usually occurs in children and young adults.
O Microscopy: ()These are glial fibvrillary acidic protein (GFAP) positive. (i) Rosenthal
fibres and eosinophilic granular bodies are found.
o Diffuse Astrocytoma (arade I): It is also called fibrillary astrocytoma and is the
most conmmon form of gliowma occurring in 3rd to 4th decades of life.
o
lt is a poorly defined,grey, infiltrative tumour.
O Anaplastic
Astrocytoma (Grade li): It generally evolves from a lower grade of
astrocytoma.

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 CNS
o lIt has anaplastic characteristics such as mitoses, nuclear hyperchromatism,
pleomorphism, and hypercellularity.
o
alioblastoma Multiforme (Grade IV): It is tlhe most aggressive of astrocytomas
o Gross: (i) It has a variegated appearance, with some regions appearing grey-white
and others yellow and soft with foci of haemorrhages and necrosis.
o Microscopy: () It has highly anaplastic and cellular appearance
(i) lt shows a pseudopalisading pattern around the tumor necrosis.
(B) Oligodendroglioma: it originates from oligodendrocytes.
Morphology:
o It is well-circuwmscribed.
o It shows a chicken wire capillary pattern.
o It has a fried egg appearance on microscopy.
(c) Ependymoma: Derived from the layer of epithelium that lines the ventricles and
the central canal of the spinal cord.
o Most commonly it involves the fourth ventricle.
o ependymomas are associated with mutation of NF1 and NF2 genes.
o Morphology
* Mostly well-differentiated tumòr dells are present.
Perivascular pseudorosettes are present.

2. MEDULLOBLASTOMA
o It is the most common malignant tumour in childhood.
Most commonly involves the cerebellum.
O

o This tunmor is highly malignant but also highly radiosensitive.

o It can send "drop metastases" to the spinal cord.
Morphology
o
The tumour is well-circumseribed.
O Medulloblastoma appears as densely packed, small round blue cells.
o Homer-Wright Rosettes are characteristic features of medulloblastoma.
o
The most common molecular genetic feature of medulloblastoma is the deletion
of 17p.
3. MENINGIOMA
o Meningiomas arise from the cap cell layer of the arachnoid.
o They are attached to the dura.

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o Most
meningiomas are benign, with a low chance of recurrence after surgical
removal.
o
They are also associated with Neurofibromatosis type 2
Morpholog9
o Meningiomas are divided into s subtypes: meningotheliomatous (syncytial), fibrous
(Fibroblastic), transitional (mixed), angioblastic and anaplastic (malignant).
o Some meningiomas express hormone receptors, particularly progesterone receptors.
Sothey can get enlarged during pregnancy.
o Psammoma bodies are also present in some types of meningioma.
o Meningiomas commonly show up as well-defined extra-axial masses on imaging
tests like CT scans and MRIs, which may compress the surrounding brain tissue.
It also has a dural tail sign.
4. OTHER PRIMARY INTRAPARENCHYMAL TUMORS
o Hemangioblastoma: It may occur sporadically or be a part of von Hippel-Lindau
syndrome
o Primary CNS Lymphoma: Brain lymphomas can develop as a separate CNS
lymphoma or as a component of disseminated non-Hodgkin's lywmphoma.
o Germ Cell Tumors: The most common primary CNS germ cell tumor is germinoma.
JaiSireekm
Approach to Brain Tumor
o When to suspect: Sudden onset headache, signs of raised ICP, new onset seizures,
FND (focal neurological deficit). Symptoms are usually insidious when underlying
etiology is primary and sudden when it is seconday like metastasis.
o thorough history and clinical examination are to be done.
A
o Obtain neuroimaging(MRI preferred over CT)

O Management: Multidisciplinary approach to be used. Palliative therapy for advanced

tumors or metastasis (along with treating the primary tumor). For primary tumor
Surgical resection, chemotherapy and radiotherapy can be tried depending on the
tumor.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1293

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 Bone
q6. Describe in brief Paget disease of bone (osteitis deformans). (5 marks)
Answer:
o Paget's disease of bone, also known as osteitis deformans.
Pathogenesis:
o Genetic Factors: Mutations in the SQSTM1 gene increase osteoclast activity. RANK
and OPG gene mutations are linked to some cases, too.
o Environmental Factors: Chronie infections, possibly by measles or other RNA
viruses, may contribute to the overactivity of osteoclasts.
Clinical Features:
o Incidence: More common in males over the age of 5o.
o Types: Can be monostotic (involving one bone) or polyostotic (involving multiple
bones).
o Common Sites: Monostotic Paget's disease typically afects the pelvis, femur, skull,
and vertebrae. in polyostotic Paget's disease., the order of involvement is usually
vertebrae, pelvis, femur, skull, sacrum, and tibia.
R
O Symptoms: Monostotic form isoPten asumptomatic and may be discovered
incidentally on X-rays. Polyostotic form can cause pain, fractures, skeletal
deformities, bone overgrowth (leontiasis ossea, characterized by overgrowth of
the craniofacial skeleton), and, rarely, sarcomatous transformation.
o Other Manifestations: Paget's disease may also present with platybasia (lattening
of the base of the skull due to weakened bone), chalkstick-type fractures in long
bones, or severe secondary osteoarthritis. It is associated with a marked elevation
of serum alkaline phosphatase and normal-to -high serum calcium levels.
Pathology:
o Stages: Paget's disease progresses through three sequential stages:
* Initial Osteolytic stage: This stage is characterized by large areas of osteoclastic
resovption, resulting from an increased number of osteoclasts.
o Mixed Osteolytic-Osteoblastic Stage: in this stage, tlhere is an inbalance between
osteoblasts depositing new bone and osteoclastic resorption. Mineralization of
the newly formed matrix lags behind, creating a characteristic mosaic pattern
of osteoid seams or cement lines.
* Quiescent Osteosclerotic Stage: After many years, excessive bone formation occurs,
leading to osteosclerosis. However, the newly formed bone is poorly mineralized,

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soft, and prone to fractures. Radiologically. this stage is characterized by a

"cotton wool" appearance of the affected bone.
MORPHOLOGY
Sclerotic Phase (Hallmark):
O Mosaic pattern of lamellar bone.
o Prominent cement lines.
O
Haphazardly oriented lamellar bone units.
Lytie Phase:
o Waves of osteoclastic activity.
o Numerous resorption pits.
o Abnorwmally large osteoclasts with many nuclei.
Mixed Phase:
o Presence of both osteoclasts and plump osteoblasts.
o Marrow is replaced by connective tissue with osteoprogenitor cells and blood
vessels.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1182
JaiSbuRam

248
 Bone

97. () Classify primary bone tumors. (10 marks)

(U) Describe the pathogenesis and morphological features of OsteosarcOma,
Giant cell tumor and Ewing Sarcoma.
Answer:
CLASSIFICATION OF PRIMARY BONE TUMORS

Histological Types Benign Tumors Malignant Tumors

Chondrogenic (22%) o Osteochondroma o Chondrosarcoma
o Chondroma
o Chondroblastoma
o Chondromyxoid fibroma
Osteogenic (20%) o Osteoid osteOma o Osteosarcoma
o Osteoblastoma
Unknown origin o Giant cell tumor o Adawmantinoma
(10%) o Unicameral bone cyst
O
Aneurysmal bone cyst
Fibrogenic o Metaphyseal fibrous defecto Fibrosarcoma
O
Nonossifying fibromam
o Fibrous histiocytoma

O Desmoplastic fibroma
Notochordal Benign notochordal tumor o Chordoma
Neuroectodermal o Ewing tumor
L. Osteosarcoma:
o
Osteosarcoma is the most common primary malignant bone tumor.
o The age distribution of osteosarcoma is biwmodal.
o
Originates in the metaphyseal region of long bones.
o Clinical Presentation: Osteosarcomas often present with pain, which can be
attributed to the tumor's growth and, in some cases, pathologic fractures.
o
Radiographic Features: Radiographically. the periosteum is lifted, prompting
reactive periosteal bone formation. This radiographic appearance is referred to as
a Codman triangle, which is indicative of an aggressive tumor.

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PATHOGENESIS
Genetic Contribution:
o Germline mutations in PS3 gene (Li -Fraumeni syndrome) increase osteosarcoma
incidence.
o RB gene mutations are found in about 70% of sporadic osteosarcoma cases.
Hereditary retinoblastoma patients are at significantly higher risk.
o INK4A inactivation in some osteosarcowmas affects p16 (a CDK inhibitor) and p14
(enhancing p53 function).
o CDK4 and MDM2 involvement in low-grade osteosarcomas as cell cycle vegulators
inhibiting p53 and RB genes.
Environimental Contribution:
o Radiation exposure, including therapeutic irradiation and thorotrast exposure, is
associated with increased osteosarcowna visk.
o Alkylating agents used in childhood cancer treatment elevate the visk of developing
osteosarcoma.
Morphology:
o The stromal tissue exhibits clear sarcomatous features, characterized by the
presence of large, abnormal spindle-shaped cells with strikingly unusual, giant
tumor cells and frequent occurrences ofcel division (mitoses).
o Notably, there is direct production of tumor-derived osteoid, a bone-like tissue,
by the neoplastic (cancerous) cells. This osteoid material exhibits a delicate,
interconnected lace-like pattern, presenting as eosinophilic, glassy, and uniformly
structured when examined under H&E staining.
o In addition to the osteoid component, there may be the presence of chondroblastic
and fibroblastic elements within the tumor.
o Spontaneous cell death (necrosis) and invasion of blood vessels by the tumor cells
are common observations in these pathological sawmples.
2. Giant cell tumor
O Also known as osteoclastoma, GCT is themost common tumor affectinq the
epiphyses in individuals with closed growth plates.
o lt often exhibits wmetaphyseal extension.
o
Common sites include the lower end of the fewmur, upper end of the tibia, and
lower end of the radius.
Pathogeness:
Neoplastic cells in GCT are primitive osteoblast precursors

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 Bone

They express high levels of RANKL

Promotes the proliferation of osteoclast precursors and their differentiation into

mature osteoclasts
o Lackof normal feedback between osteoblasts and osteoclasts in giant cell tumors
(GC) result in Localized and highly destructive bone resorption.
o Neoplasticcells in GCT carry mutations in the gene encoding histone 3.3.
Radiographic Features (X-Ray):
o GCT typically presents as a lytic and expansile lesion.
o Peripheral sclerosis or periosteal reaction is usually absent.
o Thinning and destruction of the bone cortex are common, often extending into
intermuscular septae and joint spaces.
Gross Morphology:
O GCT Varies in size and appears as a solid, tan-brown mass.
o It often displays a trabeculated pattern.
o Presence of hemorrhage and necrosis within the tumor is frequently observed.
Microscopic Features:
o GCT cOnsists of two distinct histopathöfogical tomponents:
o Stromal Cells: These are uniform oval mononuclear cells with indistinct cell
membranes, arranged in a syncytial pattern. The number of these cells correlates
with the clinical progression of the tumor.
o Giant Cells: Large cells with 20 to 30 (or even up to 10o) nuclei, arranged toward
the center of the tumor.
o Occasionally, there may be focal deposition of osteod or bone, especially in cases
presenting with pathological fractures.
3. Ewing Sarcoma
oAdifferentiation.
malignant bone tumor characterized by primitive round cells without clear

o Ranks as the second most common group of bone sarcomas in children after
osteosarcoma.
O Common Sites:
Typically arises in the diaphysis (shaft) of long tubular bones.

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Frequently found in bones like the femur.

* Also occurs in flat bones of the pelvis.
Pathogenesis:
o More than 90% of Ewing sarcomas exhibit a balanced translocation event.
o This translocation involves the EWSR1 gene located on chromosome 22.
o In
the majority of cases, the other partner in the translocation is the FLI1 gene
on chromosome 11.
o This translocation results in the formation of an EWSR1/FLI1 fusion gene.
The fusion gene encodes a chimeric EWS/FLIL protein.
o

o This chimeric protein has the ability to bind to chromatin (the material that
makes up chromosomes) and disrupt normal transcription processes.
o Dysregulation of transcription leads to uncontrolled cell growth and abnormal
differentiation.
o Cell of Origin: Mesenchymal stem cells and primitive neuroectodermal clls ave
cOnsidered likely candidates.
Clinical Presentation:
o Presents with symptoms such as a painful, enlarging mass at the affected site.
o The site is often tender, warm, and swollen.,
JasrCeRaIm
o Systemic manifestations may mimie infection, including fever, elevated
sedimentation rate, anemia, and leukocytosis.
o Radiographic Features:

* Radiographs reveal a lytic tumor with destructive features.

* Tumor margins are permeative, resembling a "moth-eaten" appearance.
The characteristic periosteal reaction results in layers of reactive bone deposited
in an "onion-skin" fashion.
Morphology:
o Typically originates within the medullary cavity of bones and subsequently infiltrates
the cortex, periosteum, and adjacent soft tissues.
o Tuimor appearance: Soft in texture and tan -white in color.
o Often contains areas of hemorrhage and necrosis.
o Composed of sheets of uniform, small, round cells.
o Cells exhibit scant cytoplaswm, which wmay appear clear due to the presence of
abundant glycogen.
O Homer-wright Rosettes are found in ewing sarcoma. This finding indicates
neuroectodermal differentiation.

252
 Bone

o Geographic necrosis within the tumor may be a noticeable feature.

Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1188

dEC
JaiShrecRam

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 Skin
98. Deseribe the clinicopathological features of basal cell carcinoma (BCC). (S marks)

Answer:
BASAL CELL CARCINOMA (BCC)
o
Arises from the basal layer of the epidermis.
o Constitutes approximately sO% of all nonmelanoma skin cancers.
o Commonly affects individuals aged 40-60 years.
o Is locally aggressive and rarely metastasizes.
o Advanced wmay
ulcerate and locally invade underlying structures.
lesions
o Commonly located on sun-exposed parts of the body, especially the face.
o Appears as an insidious, painless, nonhealing ulcer or raised nodule containing a
central crater.
o Recurrent or deeply infiltrative tumors can involve the facial nerve or branches of
the trigeminal nerve.
Pathogenesis:
o Risk is related to skin type andldegree cof lexposure to sunlight, particularly UVB
radiation.
o Mutations in the protein patched homolog-1 (PCTH)-1 tumor suppressor gene
implicated in sporadic and inherited forms.
loss of PTCH function

constitutive activation of SMO and GLI1

This leads to unregulated celldivision leading to abnormal growth (basal cell

carcinoma)
O p53 mutations are seen in 40-60% of BCCs.

GENETICSYNDROMES INVOLVING BCC:

Xeroderwma Pigmentosa:
o Autosomal vecessive disorder.
o Hypersensitivity to UW radiation.
o Defects in DNA repair mechanisms.
o Predisposition to cutaneous cancers (e.g., BCC, SCC, melanoma).

254)
 Skin

Nevoid Basal Cell (Gorlin) Syndrome:

o Autosomal dominant disorder.
o
Multiple BCCs.
o Odontogenic keratocysts.
o Calcification of falk cerebri and rib abnormalities.
Epidermodysplasia Verruciformis:
O Autosomal recessive disorder.
o
Development of BCC and sccfrom warts.

TYPES OF BCC
Nodular or Noduloulcerative BCC:
o Most cOmmon (>60% of BCCS).
o Well-circumscribed, dome-shaped, pearly nodule with or without ulceration.
Superficial BCC:
o Appearsas a red scaly patch resembling chronic dermatitis.
o Predominantly seen in the extremities.
o Spreads superficially and can involve a large surface area.
Morphea Type or Sclerosing BCC: JaiShreeRam
O Accounts for 1O% of cases.
o Flat or slightly depressed, fibrotic, and firm lesion.
o Deeply infiltrative, tends to extend beyond clinically obvious margins.
Micronodular BCC:
o Manifests as a plaque-like indurated lesion with poorly demarcated contours.
o High recurrence rate and aggressive behavior.
o Other types include keratotic BCC, infundibulocystic BCC, follicular BCC, and
pleomorphic BCC.
Morpholog:
o Tumor cells are basaloid, arranged in islands with prominent peripheral palisading.
forming cords and nests.
o Central cells in epithelial islands appear syncytial (ill-defined cytoplasmic margins).
o Stroma exhibits varying collagen deposition with abundant mucin.
o Retraction artifact or clefting is seen in the stroma adjacent to islands/nests of
tumor cells on H&E staining.
Reference: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1147

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q9. Deseribe the clinicopathological features of squamous cell carcinoma (SCC).

(5 marks)
Answer:
PRESENTATION OF SCC
o May present as crusted or scaly patches on the skin with a red, inflamed base.
o Can manifest as a growing tumor.
o May appear as a nonhealing ulcer.
Salient Features of SCC:
o Commonly occurs in sun-exposed areas, primarily among individuals over the age
of SO.
o Can occur on the lips, inside the mouth, genitalia, or anywhere on the body.
o Associated with long-standing skin inflammation.
RISK FACTORS
o Excessive radiological exposure (X-rays).
o Exposure to arsenic and industrial carcinogens (tar and oils).
o Exposure to ultraviolet radiation, leading to DNA damage.
JatSnreKahi"
o Chronic immunosuppression (chemotherapy or organ transplantation).
o Chronic nonhealing ulcers and burn scars (Marjolin ulcer).
Pathogenesis:
o Malignant transfornmation of normal epidermal keratinocytes.
o Key event: Development of apoptotic resistance through TPS3 loss (a tumor
suppressor gene).
O UV radiation causes DNA damage, including TP53 mutations.
o Other genetic abnormalities: Mutations in BCL2, RAS, alterations in signal
transduction pathways (EGFR and cOX), and DNA repair genes.
Morphology:
Precursor: Squamous cell carcinoma in situ (Bowen disease).
O

o Characterized by naclear atypia, frequent mitoses, cellular pleomorphisnm, and

disorganized cell progression.
o Actinic keratosis (AK): Solar damage -related precancerous skin lesion in air
skinned individuals.
o Invasive scc: Invasion of basement membrane by malignant cells.
o Malignant cell nests in the dermis, surrounded by an inflammatory infiltrate.

256
 Skin

o Three histological grades for conventional scc: well-differentiated, moderately

differentiated, and poorly differentiated.
o well-differentiated scC: Normal-appearing nuclei, abundant cytoplasm, keratin
pearls.
O
Moderately differentiated ScC: lntermediate features between well-differentiated
and poorly differentiated.
O
Poorly differentiated SsCC: High nuclear atypia, frequent mitoses, higher nuclear
to-cytoplasmic vatio, less keratinization, increased metastatic potential.
Reference: Pathologic Basis of Disease,Robbins and Cotran, 1oth Edition, Page No. 1146

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100. Deseribe the clinicopathological features of Melanoma. (5 marks)

Answer:
MELANOMA
The most deadly of all skin cancers.
o

o Strongly linked to acquired mutations caused by exposure to UV radiation in

sunlight.
o
Can be cured if detected and treated in its earliest stages.
o Primarily arises in the skin but can also originate in other sites, including oral and
anogenital mucosal surfaces, esoplhagus, meninges, and uvea of the eye.
Pathogenesis
o [n about 10% to 15% of cases, melanoma risk is inherited as an autosomal dominant
trait with variable penetrance.
o In most cases, melanoma is sporadic and strongly related to UV radiation exposure
from sunlight.
o Driver mutations in melanoma affect cell cycle control, pro-growth pathways,
and telomerase.
Disrupt Cell Cycle Control Genes:
o CDKN2A gene is mutated in ~4b melanoma cases.
of familiat
o CDKN2A is commonly mutated in sporadie melanomas, leading to increased
melanocytic proliferation and escape from senescence.
Activate Pro-Growth Signaling Pathways:
O
BRAF mutations (40-50%): Downsteam of RAS, promoting cell growth and
Survival.
O RAS mutations (15-20%): Aberrant RAS signaling.
o PTEN Ioss: Often accompanies BRAF mutations, heightening PI3K/AKT pathway
activation.
O KIT mutations: In non-sun-exposed melanomas, upstream of RAS and PI3K/AKT.
o NE1 loss-of-function mutations: Another mechanism for RASsignaling activation.
Activate Telomerase:
o Telomerase reactivation preserves telomeres, protecting cells from senescence.
O
TERT promoter mutations are found in ~70% of sporadic melanomas.
Rare mnelanoma -prone families have germline TERT promoter mutations.
o

o These mutations increase TERT expression, counteracting senescence.

Morphology:

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 Skin

o Melanomas display diverse colors: black, brown, red, blue, gray, and may show
zOnes of hypopigmentation.
o Their borders are irregular and notched, unlike the smooth, round borders of
benign nevi.
o Melanomas progress through radial and vertical growth phases.
o Radial growthis confined to the epidermis and superficial dermis, lacking metastatic
capacity.
o In
the vertical growth phase, melanoma cells invade deeply into the dermis, often
marked by the appearance of a nodule.
o This phase correlates with the emergence of metastatic potential and lacks
maturation.
o Melanoma cells are larger than normal melanocytes or cells in nevi.
o They have enlarged nuclei with irregular contours, clumped chromatin at the
nuclear membrane periphery, and prominent red nucleoli.
Pathologic Evaluation and Prognostie Factors:
o Pathologic features used to gauge metastatic risk and prognosis include tumor
depth (Breslow thickness), mitotic count, tumor regression, ulceration, lymphocyte
infiltration, and location.
o Favorable prognostic factors include thinner tumor depth, low mitotic count,
strong lymphocyte response, absence of vegression, and no ulceration.
o Sentinel lymph node biopsy can provide additional prognostic information;
microscopic involvement of sentinel nodes by melanoma cells is associated with a
worse prognosis.
These are the signs indicative of the development of malignancy in a pre-existing
skin lesion (ABCDE rule):
O Asymmetry: One half of the lesion doesn't match the other half.

o Border irregularity: The edges of the lesion are ragged, notched, or blurred.
o Color variation: Pigmentation is uneven and may include shades of tan, brown, or
black. White, reddish, or blue discoloration is of particular concern.
Diameter: Lesions with a diameter greater than o mm are characteristic, although
O

some melanomas may have smaller diameters. Any growth in a nevus should be
evaluated.
O
Evolving: Changes in the lesion over time are characteristic.
Reference.: Pathologic Basis of Disease, Robbins and Cotran, 10th Edition, Page No. 1139

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JaiShreeRam

260