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July 10th — Paper 4: Pathology Answers

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Q1. Discuss Major Central Nervous System (CNS) Lesions in AIDS

• Direct invasion by HIV into microglia and macrophages
• Histology: microglial nodules, multinucleated giant cells (pathognomonic), myelin pallor, astrogliosis
• Clinical: progressive cognitive decline, motor dysfunction (HIV-associated neurocognitive disorder - HAND)

• Most common CNS mass lesion in AIDS (responsible for ~50% of mass lesions)
• CD4+ count typically <100 cells/μL
• Gross: multiple ring-enhancing abscesses, predilection for basal ganglia and corticomedullary junction
• Histology: tachyzoites and bradyzoites (tissue cysts) in necrotic centers
• Imaging: multiple ring-enhancing lesions on MRI/CT

• Caused by Cryptococcus neoformans
• Gross: gelatinous exudate at base of brain; "soap bubble" lesions (pseudocysts) in basal ganglia
• Histology: encapsulated yeasts, minimal inflammatory response (due to immunosuppression)
• India ink test positive; CSF: elevated opening pressure, low glucose, elevated protein

• Caused by JC virus (human polyomavirus); reactivation in immunosuppression
• Affects oligodendrocytes → demyelination
• Gross: multifocal white matter lesions
• Histology: enlarged oligodendrocyte nuclei with intranuclear inclusions, bizarre astrocytes (Creutzfeldt astrocytes), lipid-laden macrophages
• MRI: non-enhancing white matter lesions

• Cytomegalovirus reactivation
• Histology: large cells with intranuclear "owl-eye" inclusions (cytomegalic cells)
• Periventricular necrosis, ventriculoencephalitis

• B-cell non-Hodgkin lymphoma; associated with EBV reactivation
• Solitary or multiple periventricular, ring-enhancing mass lesions
• Main differential with toxoplasmosis; thallium SPECT/PET and brain biopsy differentiate
• CD4+ typically <50 cells/μL

• Less common; organisms include Listeria monocytogenes, Streptococcus pneumoniae

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Q2. Discuss Tumor-Like Lesions of Bone

• Commonest tumor-like lesion; adolescents
• Metaphysis of long bones (distal femur, proximal tibia)
• Histology: whorled storiform pattern of spindle cells (fibroblasts/histiocytes), multinucleated giant cells, hemosiderin, xanthoma cells
• Self-limiting; most regress spontaneously

• Children/adolescents; proximal humerus and femur
• Fluid-filled unilocular cyst lined by thin fibrous membrane
• Pathological fracture common ("fallen leaf" sign on X-ray)
• Histology: fibrous wall with focal reactive bone formation

• Rapidly expansile; metaphysis of long bones, posterior vertebra
• Gross: "blood-filled sponge" - multiple blood-filled spaces separated by fibrous septa
• Histology: cavernous spaces without endothelial lining, multinucleated giant cells, reactive woven bone
• May be primary or secondary (to GCT, osteoblastoma)

• Jaw bones mainly; also small bones of hands/feet
• Histology: sheets of ovoid mononuclear cells + clusters of osteoclast-like giant cells

• Monostotic (single bone) or polyostotic (multiple bones)
• Defective osteoblast differentiation due to GNAS1 mutation
• Histology: "Chinese letters" / "alphabet soup" - irregular woven bone trabeculae in cellular fibrous stroma (no osteoblastic rimming)
• Polyostotic + café-au-lait spots + precocious puberty = McCune-Albright syndrome

• Skull, ribs, femur in children
• Histology: Langerhans cells (kidney-shaped nuclei, longitudinal groove, Birbeck granules on EM), eosinophils, plasma cells
• IHC: CD1a+, S-100+

• Benign developmental anomaly; posterior distal femur in children
• Histology: fibrous tissue replacing cortical bone

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Q3. Discuss Primary Adrenocortical Insufficiency (Addison's Disease)

1. Autoimmune adrenalitis (most common in Western world, ~70-80%)
   • Autoantibodies against steroidogenic enzymes (21-hydroxylase / CYP21A2)
   • May be isolated or part of Autoimmune Polyendocrine Syndrome (APS) Type 1 or 2
2. Tuberculosis (most common cause worldwide/developing countries)
   • Bilateral adrenal destruction with caseous necrosis; often calcified adrenals
3. Other causes: histoplasmosis, CMV (in AIDS), metastatic carcinoma (lung, breast), amyloidosis, sarcoidosis, bilateral adrenal hemorrhage

• Autoimmune: Lymphocytic infiltration, cortical atrophy, destruction of all three zones; medulla preserved
• TB: Caseating granulomas, calcification; adrenal enlargement initially then atrophy

• Loss of cortisol → loss of negative feedback → ↑ ACTH/MSH (from POMC cleavage) → hyperpigmentation
• Loss of aldosterone → sodium wasting, potassium retention, volume depletion, hypotension
• Loss of androgens → decreased libido (in women), loss of axillary/pubic hair

• Chronic fatigue, weakness, weight loss
• Hyperpigmentation (skin, buccal mucosa, scars, pressure points) - due to elevated ACTH/MSH
• Hypotension, salt craving
• Nausea, vomiting, abdominal pain
• Hyponatremia, hyperkalemia, hypoglycemia
• Eosinophilia, lymphocytosis

• Triggered by stress, infection, trauma in a patient with chronic insufficiency
• Severe hypotension, vomiting, confusion, fever, hypoglycemia - life-threatening emergency
• Treatment: IV hydrocortisone + saline immediately

• Acute primary adrenocortical insufficiency
• Bilateral adrenal hemorrhage due to fulminant bacteremia (classically Neisseria meningitidis)
• DIC → hemorrhagic destruction of both adrenals → acute adrenal crisis

• Low morning cortisol, low 24-hr urine free cortisol
• High ACTH (primary vs. secondary)
• Cosyntropin (ACTH) stimulation test: inadequate cortisol rise
• Anti-21-hydroxylase antibodies (autoimmune)

• Glucocorticoid replacement: hydrocortisone
• Mineralocorticoid replacement: fludrocortisone
• Stress dosing during illness

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Q4. Discuss Infective Tubulo-Interstitial Diseases of Kidney

• Most common infective tubulointerstitial disease
• Pathogenesis: Ascending infection (most common) from bladder via ureters; hematogenous route less common
• Organisms: E. coli (most common ~80%), Proteus, Klebsiella, Enterococcus
• Risk factors: Vesicoureteral reflux, obstruction (BPH, calculi, pregnancy), catheterization, diabetes, female sex
• Pathology:
  • Gross: enlarged kidney with yellow-white microabscesses on surface and cortex, hemorrhagic streaks along medullary rays
  • Histology: neutrophilic infiltration of tubules (tubulitis), interstitial edema, tubular necrosis; glomeruli relatively spared
  • Papillary necrosis: ischemic necrosis of papillary tips - in diabetics, analgesic nephropathy, sickle cell
• Clinical: Flank pain, fever, dysuria, pyuria, bacteriuria, WBC casts (pathognomonic), nitrites positive
• Complications: Perinephric abscess, xanthogranulomatous pyelonephritis, chronic pyelonephritis, septicemia

• Result of recurrent/persistent bacterial infections, usually with reflux (reflux nephropathy)
• Pathology:
  • Gross: irregular scarring, cortical depressions overlying dilated blunted calyces (corticomedullary scarring) - "thyroid-like" appearance
  • Histology: tubular atrophy with colloid-like casts ("thyroidization of kidney"), interstitial fibrosis, lymphocytic infiltrate, periglomerular fibrosis
• Clinical: Hypertension, proteinuria, progressive renal failure

• Rare; associated with Proteus/E.coli, renal calculi
• Gross: yellow nodules replacing renal parenchyma
• Histology: lipid-laden macrophages (foam/xanthoma cells), multinucleated giant cells, plasma cells, neutrophils
• May mimic renal cell carcinoma on imaging

• Hematogenous spread from primary TB
• Upper pole predilection; caseous granulomas, cavitation
• "Putty kidney" (dystrophic calcification)
• Sterile pyuria (pus cells without bacteria on routine culture)
• Auranamine-rhodamine / Ziehl-Neelsen stain; PCR for confirmation

• Cortical abscess (hematogenous - S. aureus) or corticomedullary abscess (ascending - E. coli)

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Q5. Discuss Histogenesis and Classification of Testicular Tumors

A. Germ Cell Tumors (GCT) - 95% of all testicular tumors

1. Seminoma (most common GCT, ~50%)

• Pure Seminoma: Large cells with clear cytoplasm and central nucleus ("fried egg" appearance), fibrous septa with lymphocytic infiltrate, occasional syncytiotrophoblast giant cells
• Radiosensitive
• Markers: β-hCG (10%), LDH, PLAP+, OCT3/4+; AFP always negative

2. Nonseminomatous Germ Cell Tumors (NSGCT)

• Embryonal Carcinoma: Most aggressive; primitive epithelial cells in sheets/glands; AFP+, β-hCG+
• Yolk Sac Tumor (Endodermal Sinus Tumor): Most common in children; Schiller-Duval bodies (pathognomonic - glomeruloid structures); AFP markedly elevated
• Choriocarcinoma: Syncytiotrophoblasts + cytotrophoblasts; β-hCG markedly elevated; highly vascular, early hematogenous spread to lungs, brain, liver
• Teratoma: Tissues from all 3 germ layers (ecto, meso, endoderm); mature (benign in children, malignant potential in adults), immature (malignant)
• Mixed GCT: Contains more than one component (~40% of GCTs)

B. Sex Cord-Stromal Tumors (~5%)

1. Leydig Cell Tumor: Most common sex cord tumor; brown, yellow cut surface; Reinke crystalloids (pathognomonic rectangular/rhomboid cytoplasmic crystals); produces androgens/estrogens; gynecomastia in adults, precocious puberty in children
2. Sertoli Cell Tumor: Tubular/trabecular pattern; Call-Exner-like bodies; variable hormone production
3. Granulosa Cell Tumor: Rare; juvenile/adult types

C. Secondary Tumors

• Lymphoma (most common testicular tumor in men >50 years) - diffuse large B-cell lymphoma
• Leukemic infiltration

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Q6. Discuss the Pathology of Multi-Organ Failure Syndrome (MOFS)

• Sepsis (most common trigger - gram-negative bacteremia most frequent)
• Severe trauma, burns
• Pancreatitis
• Prolonged shock (hypovolemic, cardiogenic)
• Major surgery

1. Trigger (sepsis/trauma) → activation of macrophages, neutrophils, complement, coagulation
2. Cytokine storm: TNF-α, IL-1, IL-6, IL-8, PAF released in excess
3. Endothelial injury and activation: ↑ permeability, adhesion molecule expression (ICAM-1, E-selectin), microvascular thrombosis
4. DIC (Disseminated Intravascular Coagulation): widespread fibrin thrombi → microinfarcts in multiple organs
5. Tissue hypoxia: cellular dysfunction → organ failure
6. Neutrophil-mediated damage: ROS, proteases, lysosomal enzymes

• Widespread fibrin microthrombi in capillaries (DIC)
• Hyaline membranes in alveoli (ARDS)
• Necrosis of proximal tubular epithelium (ATN)
• Centrilobular hepatocytic necrosis
• Ischemic necrosis of gut mucosa

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Q7. Discuss the Role of MMPs (Matrix Metalloproteinases) in Diseases

• Wound healing and tissue remodeling
• Angiogenesis
• Embryonic development
• Bone resorption and remodeling

• MMP-2 and MMP-9 (gelatinases) degrade type IV collagen in basement membranes → tumor invasion
• MMP-9 promotes angiogenesis by releasing VEGF from ECM
• Overexpression correlates with poor prognosis in breast, lung, colorectal cancers
• MT1-MMP (MMP-14) activates pro-MMP-2, facilitating invasion

• MMP-1, MMP-3, MMP-8, MMP-13 degrade articular cartilage collagen
• MMP-9 mediates neutrophil migration into synovium
• ADAMTS-4, ADAMTS-5 degrade aggrecan (cartilage proteoglycan) alongside MMPs
• Synovial fibroblasts and macrophages are main sources

• MMP-13 (collagenase-3) is the predominant destructive enzyme for type II collagen in cartilage
• Imbalance between MMP and TIMP activity → progressive cartilage destruction

• MMP-2, MMP-9 degrade fibrous cap of atherosclerotic plaque → plaque instability and rupture → acute MI/stroke
• Macrophage-derived MMPs are key contributors
• MMP-9 levels elevated in unstable angina

• MMP-2 and MMP-9 degrade elastin and collagen in aortic wall → weakening → aneurysm formation
• High MMP activity in aneurysm wall tissue

• COPD/Emphysema: MMP-9, MMP-12 (macrophage elastase) degrade alveolar wall elastin → emphysema
• Pulmonary fibrosis: paradoxically, TIMPs exceed MMPs → excessive matrix deposition

• MMP-9 disrupts blood-brain barrier → cerebral edema in stroke, meningitis
• Elevated in MS (multiple sclerosis) lesions

• Chronic non-healing wounds: excess MMP activity degrades provisional matrix
• MMP-1, MMP-9 elevated in chronic ulcers
• Keloids: TIMP excess → excessive collagen deposition

• MMP inhibitors (marimastat, batimastat) - clinical trials; limited success due to lack of specificity
• TIMP gene therapy under research

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Q8. Discuss Pleomorphic Adenoma and Its Biological Behaviour

• Parotid gland (most common site, ~80%)
• Submandibular gland, minor salivary glands (palate most common for minor glands)

• Arises from myoepithelial cells and ductal reserve cells
• Chromosomal translocations: t(3;8)(p21;q12) affecting PLAG1 gene; t(8;9)(q12;p23) affecting HMGA2
• Dual cell population: luminal ductal cells + myoepithelial cells

• Well-encapsulated (though capsule may be incomplete)
• Rubbery, lobulated mass; gray-white cut surface
• May show areas of myxoid/chondroid consistency
• Size: usually 2-6 cm

1. Epithelial component: Ductal epithelial cells forming small ducts, tubules, solid nests, or sheets
2. Myoepithelial component: Spindle, plasmacytoid ("hyaline"), or stellate cells
3. Mesenchymal (stromal) component: Myxoid, chondroid (cartilage-like), osseous, or fibrous stroma

• The stroma is derived from myoepithelial cells that undergo metaplastic change (hence "pleomorphic" = "mixed")
• No cartilage is present elsewhere in salivary glands - its presence is a hallmark

1. Benign but locally aggressive:
   • Capsule is incomplete in places → finger-like pseudopodal projections penetrate the capsule
   • This is why simple enucleation leads to recurrence; total parotidectomy/superficial parotidectomy with margins is required
2. Recurrence:
   • 1-5% after adequate surgery
   • Higher if capsule ruptured or inadequate excision
   • Recurrent tumors may be multinodular and harder to excise
3. Malignant Transformation - Carcinoma ex Pleomorphic Adenoma:
   • Occurs in ~5-10% of cases, especially after long-standing (>15 years) or recurrent tumors
   • Risk increases ~10% per decade after 15 years
   • Sudden rapid enlargement in a pre-existing mass is the warning sign
   • Types of malignancy arising: adenocarcinoma NOS, salivary duct carcinoma, myoepithelial carcinoma, undifferentiated carcinoma
   • Subtypes:
     • Non-invasive (in situ)
     • Minimally invasive (<1.5 mm beyond capsule) - better prognosis
     • Widely invasive (>1.5 mm) - poor prognosis; 5-year survival ~25%
4. Metastasizing Pleomorphic Adenoma:
   • Rare phenomenon where histologically benign-appearing tumor metastasizes
   • Site: lungs, bone
5. Facial nerve preservation:
   • Parotid tumors are intimately related to the facial nerve
   • Surgery must preserve the nerve while achieving complete tumor excision

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Q9. Discuss Major Etiological Factors and Molecular Mechanisms of Lung Cancer

• Causally linked to squamous cell carcinoma, small cell carcinoma, and adenocarcinoma
• Tobacco smoke contains >60 proven carcinogens: polycyclic aromatic hydrocarbons (PAH), nitrosamines, benzene, formaldehyde, vinyl chloride
• PAHs → benzo[a]pyrene diol epoxide (BPDE) → DNA adducts → mutations in TP53 (codon 249 hotspot), KRAS
• Dose-response relationship: pack-year history
• Passive/secondhand smoke: 20-30% increased risk

• Asbestos: Synergistic with smoking (55-fold risk); causes mesothelioma + lung cancer (adenocarcinoma, squamous cell)
• Radon gas: Second leading cause of lung cancer (radioactive decay of uranium-238); α-particle radiation
• Arsenic: Smelting, pesticide workers
• Chromium, Nickel compounds: Chromate workers
• Uranium, bis-chloromethyl ether
• Silica dust: Crystalline silica classified as carcinogen

• Particulate matter (PM2.5), diesel exhaust, benzo[a]pyrene
• IARC Group 1 carcinogen (outdoor air pollution)
• Contributing factor in never-smokers

• First-degree relatives of lung cancer patients have 2-3x increased risk
• Li-Fraumeni syndrome (TP53 mutation), BRCA2 mutations
• Never-smokers: more likely to have driver mutations (EGFR, ALK)

• COPD, pulmonary fibrosis, old TB scars (scar carcinoma - adenocarcinoma)

1. KRAS mutation: Most common in lung adenocarcinoma (~25-30%); KRAS G12C mutation; confers resistance to EGFR therapy; targeted by sotorasib (KRAS G12C inhibitor)
2. EGFR (HER1) mutation: Exon 19 deletions, L858R point mutation (exon 21) - common in East Asian women, never-smokers, adenocarcinoma; targeted by gefitinib, erlotinib, osimertinib
3. ALK rearrangement: EML4-ALK fusion (~5%); young non-smokers; adenocarcinoma; targeted by crizotinib, alectinib
4. ROS1 rearrangement: ~1-2%; overlaps with ALK profile; crizotinib-sensitive
5. MET amplification/exon 14 skipping: Targeted by capmatinib
6. BRAF V600E mutation: ~2%; targeted by dabrafenib + trametinib
7. RET fusion, NTRK fusion: Targeted therapies available
8. MYC amplification: Common in small cell carcinoma

1. TP53 mutations: Present in >80% of small cell carcinoma, ~50% of NSCLC; G:C → T:A transversions at codons 157, 248, 249 caused by BPDE from smoking
2. RB1 (Retinoblastoma) deletion: Virtually 100% in small cell carcinoma; pRb loss removes cell cycle brakes
3. CDKN2A (p16/INK4A): Frequently deleted/hypermethylated in NSCLC; p16 inhibits CDK4/6 → Rb pathway
4. FHIT (3p14.2): Fragile histidine triad gene; deleted in most lung cancers; involves chromosomal region 3p
5. RASSF1A: Methylation-silenced in ~90% of SCLC; Ras effector tumor suppressor

• Loss of heterozygosity (LOH) at 3p, 9p, 13q, 17p
• Chromosome 3p deletions: found in virtually all SCLC and most NSCLC (affects FHIT, RASSF1A, ROBO1)

• CpG island hypermethylation of tumor suppressors (p16, DAPK, RASSF1A)
• Histone modifications
• miRNA dysregulation (miR-21 upregulated, miR-let7 downregulated)

• PI3K/AKT/mTOR pathway: activated in NSCLC; promotes survival and proliferation
• Wnt/β-catenin pathway
• Hedgehog signaling: especially in SCLC
• NF-κB activation by inflammation
• VEGF overexpression → angiogenesis → bevacizumab target

• PD-L1 expression on tumor cells → immune evasion → checkpoint inhibitor therapy (pembrolizumab, nivolumab)

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Q10. Discuss Features of Vegetations in Major Forms of Endocarditis

A. Rheumatic Endocarditis

• Small (1-2 mm), irregular, firm, warty vegetations
• Located along the line of valve closure (chordal side of AV valves, atrial side of semilunar valves)
• Do NOT embolize (firmly adherent, platelet-fibrin composition)
• Heal with fibrosis → scarring → thickening, calcification, fusion of valve leaflets and commissures

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B. Infective (Bacterial) Endocarditis

• Subacute IE: Viridans streptococci (most common on abnormal valves), Streptococcus bovis (colon cancer association), HACEK organisms
• Acute IE: Staphylococcus aureus (most virulent, attacks normal valves, IV drug users), group B Streptococcus
• Prosthetic valves (early): S. epidermidis, S. aureus
• IV drug users: S. aureus, right-sided (tricuspid) endocarditis

• Large (0.5-3 cm), bulky, irregular, friable, destructive masses
• Located on atrial surface of AV valves and ventricular surface of semilunar valves (low-pressure zone just distal to line of closure)
• May cover the entire leaflet or chordae tendineae
• May perforate or destroy valve leaflets → acute regurgitation
• EMBOLIZE FREELY → septic emboli to brain (abscesses), kidney (Löhlein focal nephritis/infarcts), spleen, liver, extremities
• Gross: gray-brown, necrotic, hemorrhagic
• May form ring abscesses in valve annulus

• Osler nodes (painful, subacute): immune complex vasculitis
• Janeway lesions (painless, acute): septic emboli
• Roth spots: retinal hemorrhages
• Splinter hemorrhages: subungual
• Clubbing (in subacute)
• Glomerulonephritis (focal or diffuse)

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C. Non-Bacterial Thrombotic Endocarditis (NBTE / Marantic Endocarditis)

• Small to medium, sterile, non-destructive
• Located along the line of valve closure (like rheumatic)
• Loosely attached → embolize frequently (systemic emboli causing stroke, MI, renal infarcts)
• No valve destruction

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D. Libman-Sacks Endocarditis (Systemic Lupus Erythematosus)

• Small, irregular, sterile vegetations
• Unique location: both surfaces of valve leaflets (atrial AND ventricular surfaces) - key distinguishing feature
• Mitral and tricuspid valves most affected
• May cause scarring and regurgitation

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E. Carcinoid Endocarditis

• Right-sided heart valves (tricuspid and pulmonary)
• Caused by excess serotonin from carcinoid tumors (left side protected by lungs metabolizing serotonin)
• Fibrous plaques (not true vegetations) on endocardium - "white plaques"
• Leads to tricuspid regurgitation and pulmonary stenosis

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Comparison Table: Vegetations in Endocarditis

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