SIDDAGANGA MEDICAL COLLEGE - PATHOLOGY INTERNAL ASSESSMENT

Model Answers (II MBBS, 2024-25)

LONG ESSAY (1 × 10 = 10 Marks)

Q1. A 5-year-old boy with pallor, jaundice, failure to thrive; Hb 5 g%, PS - microcytic hypochromic RBCs + target cells, Reticulocyte count 7%

a) Most Probable Diagnosis (2 marks)

• Age 5, failure to thrive - chronic illness from early childhood
• Hb 5 g% - severe anemia
• Microcytic hypochromic RBCs on peripheral smear - impaired HbA synthesis
• Target cells (codocytes) - characteristic of thalassemia
• Reticulocyte count 7% (elevated) - reflects hemolysis and compensatory erythropoiesis
• Jaundice - extravascular hemolysis

b) Etiopathogenesis (4 marks)

• Autosomal codominant disorder; mutations in β-globin gene (chromosome 11)
• Over 100 mutations described; most common: point mutations causing abnormal RNA splicing
• Two allele types: β⁰ (no β-globin) and β⁺ (reduced β-globin)
• β-Thalassemia major = homozygous state (β⁰/β⁰ or β⁰/β⁺)

1. Inadequate HbA formation:
   • Reduced/absent β-globin synthesis → insufficient HbA (α₂β₂) production
   • Red cells are small (microcytic) and poorly hemoglobinized (hypochromic)
2. Toxic α-globin chain accumulation:
   • Unpaired α-globin chains (now in excess) form insoluble precipitates
   • These precipitates damage RBC membranes and erythroid precursors
   • Massive apoptosis of erythroid precursors in bone marrow = Ineffective erythropoiesis
   • The few mature RBCs produced are destroyed by splenic macrophages = Extravascular hemolysis → jaundice

• Severe anemia → tissue hypoxia → ↑ erythropoietin → marrow expansion
• Marrow expansion → skeletal deformities (thalassemic facies: bossing of skull, maxillary prominence, "hair on end" X-ray)
• Ineffective erythropoiesis → low hepcidin → ↑ iron absorption → systemic iron overload (hemosiderosis)
• Repeated transfusions worsen iron overload → deposits in heart, liver, endocrine organs

FIG: Pathophysiology of β-thalassemia major - Robbins & Kumar Basic Pathology

c) Laboratory Investigations (4 marks)

REASONING QUESTIONS / SHORT ANSWERS (5 × 3 = 15 Marks)

Q2. 35-year-old HIV-positive with oral candidiasis, CD4+ T-cell count 120/μL

Q3. 45-year-old with low serum B12, anemia, and peripheral neuropathy

1. Conversion of methylmalonyl-CoA → succinyl-CoA (via methylmalonyl-CoA mutase): Deficiency causes accumulation of methylmalonyl-CoA and its precursor propionic acid. Abnormal fatty acids are incorporated into neuronal myelin, leading to demyelination - specifically subacute combined degeneration (posterior columns + lateral corticospinal tracts), causing peripheral neuropathy and ataxia.
2. Conversion of homocysteine → methionine (via methionine synthase): Deficiency impairs thymidylate synthesis → defective DNA synthesis → megaloblastic anemia (large, immature RBCs) and hypersegmented neutrophils.

Q4. 60-year-old with homozygous α-1 antitrypsin deficiency; chest CT shows diffuse, uniform enlargement of air spaces affecting entire acini

• Uninhibited neutrophil elastase and other proteases (MMP-9, MMP-12) destroy elastin and connective tissue in alveolar walls
• This leads to permanent, irreversible dilation of airspaces distal to the terminal bronchiole
• Homozygous ZZ genotype → severe AAT deficiency (<15% of normal)
• Affects entire acinus uniformly = Panacinar (panlobular) emphysema (vs. centriacinar in smokers, which affects respiratory bronchioles)
• The lower lobes are typically more affected in AAT-deficiency emphysema
• Progressive dyspnea results from loss of elastic recoil and air trapping

Q5. Echocardiography in 25-year-old with Rheumatic Heart Disease (RHD) shows thickening and fusion of mitral valve

• Acute phase: Verrucous vegetations along valve leaflet lines of closure; Aschoff bodies (granulomatous inflammation with Anitschkow cells)
• Chronic/healed phase: Organization and fibrosis leads to leaflet thickening, commissural fusion, chordae tendineae shortening and thickening
• Result: Mitral stenosis - the classic sequela of RHD
• Mitral valve is most commonly affected (left-sided, higher pressure), followed by aortic valve
• The "fish-mouth" or "button-hole" deformity of the mitral valve results from commissural fusion and leaflet thickening seen on echo

Q6. Colorectal adenomas are considered premalignant

• Adenomas harbor dysplastic epithelium by definition
• They follow a stepwise accumulation of mutations: APC gene loss (early) → KRAS mutation → SMAD4/DPC4 loss → TP53 mutation → carcinoma
• Risk factors for malignant transformation: size >2 cm, villous architecture (tubular < tubulovillous < villous in risk), high-grade dysplasia
• Villous adenomas have ~40% risk of malignant transformation
• They are detected by colonoscopy and must be removed - this is the basis of colorectal cancer screening programs

SHORT NOTES - APPLIED ASPECT (4 × 5 = 20 Marks)

Q7. 4-year-old boy: painful swelling of right knee after minor fall; PT-Normal, aPTT-Prolonged, Factor VIII assay 2% of normal

a) Diagnosis

b) Genetic and Pathological Basis of Hemarthrosis

• Caused by mutations in F8 gene on X chromosome (Xq28)
• Males are affected (hemizygous); females are carriers
• ~45% due to intron 22 inversion; remainder from point mutations, deletions
• Severity: severe (<1% Factor VIII), moderate (1-5%), mild (5-30%)
• This case: 2% = severe hemophilia A

• Factor VIII is a critical cofactor for Factor IXa in the intrinsic coagulation pathway (tenase complex)
• Without Factor VIII, the intrinsic pathway is blocked → prolonged aPTT (intrinsic pathway) but normal PT (extrinsic pathway intact)
• Joints (knees, elbows, ankles) are susceptible because synovial vascularity is rich and minor trauma easily disrupts small vessels
• In the joint: repeated bleeding → hemosiderin deposition in synovium → synovial hypertrophy → pannus formation → cartilage and bone destruction = hemophilic arthropathy
• Acute: warm, swollen, painful joint (hemarthrosis)
• Chronic: iron-catalyzed free radical damage, inflammatory cytokines (IL-1, TNF-α) destroy cartilage

Q8. 30-year-old male: weakness, pallor, bleeding gums; TLC 1,10,000 with many blasts positive for myeloperoxidase

a) Most Likely Diagnosis

b) Classification

• M0: Undifferentiated; M1: Without maturation; M2: With maturation; M3: Acute promyelocytic (APL); M4: Myelomonocytic; M5: Monocytic; M6: Erythroleukemia; M7: Megakaryoblastic

• Replacement of normal marrow → anemia (pallor), thrombocytopenia (bleeding gums), neutropenia (infections)
• Auer rods - pathognomonic pink rod-like inclusions in myeloblasts (MPO-positive)
• MPO positive = myeloid origin (distinguishes from ALL, where MPO is negative)

Q9. 60-year-old man: weight loss, abdominal pain, anorexia; mass detected in stomach

a) Diagnosis

b) Morphology

• Intestinal type: Usually forms an ulcerated, exophytic mass with heaped-up margins (fungating/polypoid lesion), commonly in antrum/lesser curvature; associated with H. pylori, intestinal metaplasia
• Diffuse type: Infiltrating, produces a rigid, thickened "leather-bottle" stomach - linitis plastica; signet ring cells infiltrate all layers; poor prognosis
• Early gastric cancer: Confined to mucosa/submucosa regardless of node status
• Advanced gastric cancer: Invades muscularis propria and beyond

• Gland-forming adenocarcinoma
• Malignant columnar cells with nuclear pleomorphism, mitoses
• Desmoplastic stroma

• Signet ring cells - large mucin vacuole displaces nucleus to periphery
• Poorly cohesive cells due to loss of E-cadherin (CDH1 mutation)

• Direct: through gastric wall
• Lymphatic: to regional lymph nodes; Virchow node (left supraclavicular)
• Hematogenous: liver most common
• Transcoelomic: peritoneal seeding; Krukenberg tumor (bilateral ovarian metastases from signet ring cells)

Q10. 42-year-old female: recurrent right upper quadrant pain; ultrasound shows multiple gallstones

a) Diagnosis

b) Etiopathogenesis

1. Cholesterol stones (80%): Pure cholesterol or mixed
2. Pigment stones (20%): Black (hemolysis) or brown (infection)

• Liver secretes excess cholesterol relative to bile salts and lecithin
• Normal cholesterol solubility depends on the cholesterol saturation index (CSI)
• Obesity, estrogen (OCP, pregnancy), clofibrate → ↑ cholesterol secretion
• Ileal disease/resection → ↓ bile salt reabsorption → relative ↑ CSI

• Supersaturated bile forms cholesterol monohydrate crystals
• Mucin glycoproteins act as pronucleating agents
• Gallbladder stasis (fasting, pregnancy, TPN) promotes crystal aggregation

• Crystals aggregate and grow into macroscopic stones
• Reduced gallbladder motility (progesterone effect) → incomplete emptying → stone growth

SHORT NOTES (7 × 5 = 35 Marks)

Q11. Carcinoid Tumor

• Definition: Well-differentiated neuroendocrine tumor (NET) arising from enterochromaffin (Kulchitsky) cells; can occur anywhere in GI tract, bronchus, or thymus
• Common sites: Appendix (most common, rarely malignant), ileum, rectum, bronchus
• Gross: Small, yellow-tan submucosal nodule; firm due to desmoplastic reaction
• Microscopy: Nests, ribbons, or rosettes of uniform small cells with round nuclei, "salt-and-pepper" chromatin, abundant pink granular cytoplasm; mitoses rare
• Histochemistry: Silver staining positive (argyrophilic/argentaffin); Chromogranin A and Synaptophysin positive (IHC markers)
• Products secreted: Serotonin (5-HT), histamine, bradykinin, substance P, VIP
• Carcinoid syndrome (occurs with liver metastases): Episodic flushing, diarrhea, bronchospasm, right-sided cardiac fibrosis (tricuspid/pulmonary valve)
• Malignant potential: Relates to size and site - appendiceal <2 cm rarely metastasize; ileal >2 cm frequently metastasize
• Marker: Serum Chromogranin A and 24-hr urine 5-HIAA (5-hydroxyindoleacetic acid) for diagnosis/follow-up

Q12. Morphology of Myocardial Infarction

• STEMI (transmural): Full thickness; associated with plaque rupture + occlusive thrombus
• NSTEMI (subendocardial): Inner 1/3 of wall; most vulnerable zone (farthest from epicardial supply)

Q13. Morphology of Pleomorphic Adenoma

• Definition: Most common salivary gland tumor (~70%); also called "mixed tumor" - contains both epithelial and mesenchymal elements
• Site: Parotid gland (80%), then submandibular, minor salivary glands
• Gross: Encapsulated (but capsule incomplete/irregular), rubbery, lobulated, gray-white; cut surface shows myxoid/chondroid areas
• Microscopy (two components):
  • Epithelial component: Ductal cells forming gland-like structures; surrounded by myoepithelial cells (spindle/stellate shaped)
  • Stromal component: Myxoid, chondroid (cartilage-like), hyaline stroma - produced by myoepithelial cells (hence "mixed" appearance)
• Key feature: Myoepithelial cells are the key cell type - they can differentiate into both ductal epithelium AND stromal elements
• IHC: Cytokeratin (ductal), Vimentin, S-100, GFAP (myoepithelial)
• Behavior: Benign but risk of recurrence if incompletely excised (due to capsular pseudopods); 6-10% risk of malignant transformation to carcinoma ex pleomorphic adenoma over time

Q14. Classify Hodgkin Lymphoma (HL); Reed-Sternberg cells; IHC markers

• Large, binucleated or bilobed cells
• Each nucleus has a large inclusion-like eosinophilic "owl-eye" nucleolus - pathognomonic
• Mononuclear variant: Hodgkin cell
• Lacunar cell (NSCHL): RS cell with retracted cytoplasm creating empty space (lacuna)
• "Popcorn" or LP cell (NLPHL): Multi-lobated nucleus
• RS cells are derived from germinal center B-cells

• CD15 (Leu-M1) - positive (also expressed on granulocytes)
• CD30 (Ki-1) - positive (marker of activated lymphoid cells)
• CD20 - negative (classic HL); positive in NLPHL
• CD45 (LCA) - negative (distinguishes from NHL)
• PAX5 - weakly positive (B-cell transcription factor)
• EBV (LMP-1) - positive in ~40% of classic HL (especially MCCHL)

Q15. Etiopathogenesis of Atherosclerosis

• Risk factors: Hyperlipidemia (LDL), hypertension, smoking, diabetes, homocysteine
• Injured endothelium → ↑ permeability, ↑ adhesion molecule expression (VCAM-1, ICAM-1, E-selectin)

• LDL enters intima, gets oxidized (ox-LDL)
• Ox-LDL is chemotactic for monocytes and inhibits macrophage migration (traps them)

• Monocytes adhere to endothelium (via VCAM-1/MCP-1 interaction), migrate into intima
• Differentiate into macrophages → engulf ox-LDL via scavenger receptors (SR-A, CD36)
• Become foam cells → accumulate to form fatty streak (earliest visible lesion)

• Macrophages and platelets release PDGF, FGF → smooth muscle cells (SMC) migrate from media to intima
• SMC proliferate and secrete collagen, proteoglycans → fibrous cap

• Mature plaque = fibrous cap (SMC + collagen) overlying lipid core (foam cells, cholesterol crystals, necrotic debris)
• Calcification occurs in advanced plaques
• Plaque rupture → thrombosis → MI/stroke

Q16. Amebic Liver Abscess

• Causative organism: Entamoeba histolytica (protozoan)
• Route: Fecal-oral → trophozoites invade colonic mucosa → portal circulation → liver
• Site: Most commonly right lobe, posterosuperior aspect (portal blood from cecum/ascending colon)
• Gross morphology:
  • Large solitary abscess (may reach 10-15 cm)
  • Wall: shaggy, ragged inner lining (no true pyogenic wall)
  • Content: "anchovy sauce" or "chocolate brown paste" - liquefied necrotic liver (NOT true pus; acellular)
  • Composed of: necrotic hepatocytes, red blood cells, cellular debris
• Microscopy:
  • Amebic trophozoites found at the periphery/wall of abscess (not in center)
  • Trophozoites: 20-40 μm, with nucleus having central karyosome; engulf RBCs (erythrophagocytosis)
  • Surrounding liver shows inflammation and fibrosis
• Complications: Rupture into peritoneal cavity, pleural space ("anchovie-like" pleuritis), pericardium; secondary bacterial infection
• Diagnosis: Serology (anti-amebic antibodies), stool examination, ultrasound (round/oval hypoechoic lesion), needle aspiration
• Treatment: Metronidazole (drug of choice) + diloxanide furoate (luminal agent)

Q17. Classify Cirrhosis; Mention Complications

• Alcoholic cirrhosis (most common in Western countries)
• Post-viral cirrhosis (HBV, HCV - most common in India/Asia)
• Biliary cirrhosis (primary or secondary)
• Metabolic: Wilson's disease, hemochromatosis, NAFLD/NASH
• Cardiac cirrhosis (chronic right heart failure)
• Cryptogenic (unknown cause, ~10%)

1. Portal hypertension → esophageal varices (bleeding), caput medusae, splenomegaly, hemorrhoids
2. Ascites - due to portal hypertension + hypoalbuminemia + secondary hyperaldosteronism
3. Spontaneous Bacterial Peritonitis (SBP) - infective complication of ascites
4. Hepatic encephalopathy - ammonia accumulation, cerebral edema, asterixis
5. Hepatorenal syndrome - functional renal failure
6. Coagulopathy - reduced synthesis of clotting factors (I, II, V, VII, IX, X) → bleeding tendency
7. Hypoalbuminemia → edema, ascites, poor wound healing
8. Hepatocellular Carcinoma (HCC) - in ~3-5% of cirrhosis patients per year (especially HBV, HCV, hemochromatosis)
9. Hepatopulmonary syndrome - intrapulmonary shunts → hypoxemia
10. Hypersplenism - pancytopenia from splenic sequestration