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KARPAGA VINAYAGA INSTITUTE OF MEDICAL SCIENCES

II-MBBS Pathology - Model Exam Paper II | Complete Answers

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I. ESSAY (1×10 = 10 Marks)

Q1. Clinical Scenario: 46-year-old nulliparous woman with hard fixed breast lump (6×4×3 cm), right axillary lymphadenopathy, and erythematous scaly crusting lesion over the nipple → Invasive Breast Carcinoma with Paget's Disease of the Nipple

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a) Risk Factors & Pathogenesis of Breast Carcinoma (3 marks)

Risk Factors

• Nulliparity (as in this case) - increased lifetime estrogen exposure
• Early menarche / late menopause
• First pregnancy after age 30
• Exogenous estrogen (HRT, OCP)
• Obesity (post-menopausal) - peripheral conversion of androgens to estrogens

• BRCA1 (chromosome 17q21) - lifetime risk ~60-80%; also associated with ovarian and serous carcinoma
• BRCA2 (chromosome 13q12) - lifetime risk ~40-60%
• ~12% of all breast cancers are due to germline mutations; BRCA1/2 account for half of single-gene mutation cases
• Other genes: TP53 (Li-Fraumeni), PTEN (Cowden syndrome), ATM, PALB2

• Proliferative disease with atypia (ADH/ALH) - 4-5x increased risk
• DCIS/LCIS - 8-10x increased risk (25-30% lifetime)

• Ionizing radiation (especially during adolescence)
• High-fat diet, alcohol consumption
• Dense breast tissue on mammography

Pathogenesis

1. Familial (BRCA1/BRCA2 mutations):

• BRCA1/2 are tumor suppressor genes - encode proteins involved in homologous recombination DNA repair
• Germline mutation in one allele + somatic "second hit" loss → loss of DNA repair capacity → genomic instability → accumulation of oncogenic mutations

1. Sporadic (Non-familial):

• Estrogen drives epithelial cell proliferation → increases mitotic errors
• Estrogen metabolites act as direct mutagens (hydroxylated intermediates)
• Involves sequential accumulation of mutations in genes controlling cell cycle (cyclin D1, CDK4), growth receptors (HER2/ERBB2), and tumor suppressors (p53, Rb)
• Precursor lesion pathway: Normal epithelium → Usual hyperplasia → Atypical hyperplasia → DCIS/LCIS → Invasive carcinoma

• Estrogen binds ERα → promotes transcription of genes driving proliferation (cyclin D1, c-myc)
• Increased cell divisions → greater probability of spontaneous mutations

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b) Classification and Morphological Features (4 marks)

Carcinoma In Situ

• Confined within ducts, basement membrane intact
• Most common form; frequently found as mammographic calcifications
• Architectural subtypes: Comedo, cribriform, micropapillary, papillary, solid
• Comedo type: Large cells with high nuclear grade, central necrosis with calcification; associated with HER2 overexpression
• Precursor to invasive ductal carcinoma in the same breast

• Small, uniform, loosely cohesive cells (dyscohesive - due to loss of E-cadherin) filling lobular acini
• Bilateral and multicentric
• Risk marker: when invasion occurs, 2/3 ipsilateral, 1/3 contralateral breast

Invasive Carcinoma

• Hard, irregular, stellate mass with gritty cut surface
• Firm consistency due to desmoplastic fibrous stroma
• Fixed to surrounding tissue (explains "fixed" finding in this case)

• Malignant epithelial cells arranged in nests, cords, trabeculae or glands
• Desmoplastic stroma
• Nuclear pleomorphism, hyperchromasia, increased mitoses

Biological (Molecular) Classification

• Erythematous, scaly, crusty eczematoid lesion of nipple/areola (as seen in this case)
• Due to large malignant cells (Paget cells) migrating from an underlying DCIS/invasive carcinoma along the nipple epidermis
• Paget cells: large, pale cells with prominent nucleoli within the squamous epithelium; PAS+, GCDFP-15+, HER2+
• Always associated with underlying carcinoma (DCIS or invasive)
• Differential: nipple eczema (bilateral, no underlying mass)

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c) Prognostic and Predictive Factors (3 marks)

Most Important Prognostic Factors:

• Node-negative: ~70-80% 10-year survival
• 1-3 positive nodes: ~50% 10-year survival

• 10 positive nodes: ~20-30% 10-year survival

• T1 (<2 cm) without nodal involvement: excellent prognosis
• Each centimeter increase in size worsens prognosis

• Scores tubule formation (1-3) + nuclear pleomorphism (1-3) + mitotic count (1-3)
• Grade I (3-5): well differentiated - good prognosis
• Grade II (6-7): moderately differentiated
• Grade III (8-9): poorly differentiated - worst prognosis

• Special types (tubular, mucinous, medullary): better prognosis than IDC-NST

• Luminal A: best prognosis
• Triple negative: worst prognosis, no targetable receptors

• Perineural, lymphovascular invasion - worse prognosis

• Most comprehensive prognostic system combining tumor size, nodal status, and distant metastasis

Predictive Factors (guide therapy choice):

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II. REASONING OUT SHORT NOTES (2×5 = 10 marks)

1. Emphysema Patients are called "Pink Puffers" - Reason Out

• Expiratory airflow obstruction due to loss of alveolar elastic recoil and dynamic airway collapse
• To maintain airway patency, patients breathe through pursed lips (pursed-lip breathing)
• This creates a back-pressure (auto-PEEP) that keeps small airways open during expiration
• This results in the characteristic "puffing" appearance
• Accessory muscles of respiration are used; barrel-shaped chest (due to air trapping and increased AP diameter)

• Despite severe dyspnea, patients maintain near-normal PaO2 and SaO2 (remain relatively well-oxygenated)
• This is because: (a) they hyperventilate aggressively to compensate, and (b) the V/Q mismatch is less severe than in chronic bronchitis
• There is no significant central or peripheral cyanosis, so they appear "pink"
• Contrast with chronic bronchitis patients ("Blue Bloaters") who develop early hypoxemia, CO2 retention, cyanosis, edema, and polycythemia

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2. Prostate Carcinoma Develops Osteoblastic (Osteosclerotic) Vertebral Metastasis - Reason Out

• Batson's vertebral venous plexus - a valveless plexus surrounding the spine
• Increased intra-abdominal pressure (e.g., during micturition or straining) retrograde drives tumor emboli from the prostatic venous plexus into Batson's plexus
• Directly seeds vertebral bone marrow without passing through lungs or liver

1. Endothelin-1 (ET-1): Secreted by prostate cancer cells → binds ET-A receptors on osteoblasts → promotes osteoblast proliferation and bone formation
2. PSA (Prostate Specific Antigen): Serine protease that cleaves PTHrP → inactivates the osteolytic PTHrP signal; also activates IGF-1 bound to IGFBP3, stimulating osteoblasts
3. FGF (Fibroblast Growth Factor), PDGF, BMP (Bone Morphogenetic Proteins): All secreted by prostate cancer cells → stimulate osteoblast activity
4. Wnt signaling: Prostate cancer cells activate Wnt pathway in osteoblasts → promotes bone matrix deposition
5. RANK-L inhibition: Simultaneous upregulation of OPG (osteoprotegerin) by tumor cells inhibits osteoclast activation

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III. SHORT NOTES (10×6 = 60 marks)

1. Dysgerminoma - Ovary

• ~2% of ovarian cancers; ~50% of malignant ovarian germ cell tumors
• 75% occur in 2nd and 3rd decades; occurs in children and adolescents
• Associated with gonadal dysgenesis (Turner syndrome, testicular feminization/46XY)

• Expresses stem cell markers: OCT3, OCT4, NANOG
• Isochromosome 12p (i[12p]) - characteristic cytogenetic abnormality
• KIT gene activating mutations in 30-50%; KIT amplification in 30% - useful diagnostic marker and therapeutic target
• Most are non-functional; a few produce β-hCG (from syncytiotrophoblastic giant cells)

• Usually unilateral (80-90%), bilateral in 10-15%
• Solid, yellow-white to gray-pink, fleshy cut surface
• Can be huge - filling the abdomen

• Large vesicular cells with clear cytoplasm, well-defined cell boundaries, centrally placed regular nuclei (resembling primitive germ cells)
• Cells arranged in sheets or cords separated by scant fibrous stroma
• Fibrous stroma infiltrated by lymphocytes (T-cells)
• Non-caseating granulomas may be present

• All dysgerminomas are malignant, but only ~1/3 are aggressive
• Unilateral tumor without capsular breach: >90% 10-year survival after oophorectomy
• Highly radiosensitive and chemosensitive (BEP regimen - Bleomycin, Etoposide, Cisplatin)
• Even metastatic disease is often curable

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2. Role of CSF Examination in Meningitis

• Pressure: 70-180 mmH2O; Appearance: clear; Cells: 0-5 lymphocytes; Protein: 15-45 mg/dL; Glucose: 50-80 mg/dL (>60% of blood glucose)

• Xanthochromia: Yellow discoloration from hemoglobin breakdown → suggests subarachnoid hemorrhage (SAH)
• Oligoclonal bands: Multiple sclerosis
• Malignant cells: CNS lymphoma, carcinomatous meningitis
• Beta-2 transferrin: CSF leak confirmation

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3. Complications of Myocardial Infarction

Immediate (0-24 hrs):

• Arrhythmias - most common cause of death; ventricular fibrillation (most dangerous), ventricular tachycardia
• Cardiogenic shock (large infarct >40% LV)
• Heart block (inferior MI - AV node ischemia)

Early (1-7 days):

• Myocardial rupture (3-7 days, peak at 5 days) - when coagulative necrosis is maximal, softening occurs (due to neutrophilic enzymatic digestion)
• Free wall rupture → hemopericardium → cardiac tamponade → death
• Ventricular septal defect (VSD) → left-to-right shunt → acute heart failure
• Papillary muscle rupture → acute mitral regurgitation → flash pulmonary edema (posteromedial papillary muscle more vulnerable - single blood supply)
• Pericarditis (fibrinous) - 2-3 days after transmural MI; friction rub; treated with aspirin

Intermediate (1-8 weeks):

• Ventricular aneurysm - thinned scar bulges outward; risk of mural thrombus, systemic embolism, arrhythmias, heart failure
• Mural thrombus - especially in apical aneurysm; can embolize (stroke, mesenteric ischemia)
• Dressler syndrome (autoimmune pericarditis) - 2-10 weeks post-MI; fever, pleuritis, pericarditis, elevated ESR; due to antibodies against cardiac antigens

Long-term:

• Chronic heart failure / ischemic cardiomyopathy
• Progressive LV remodeling with dilatation
• Recurrent MI

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4. Basal Cell Carcinoma (BCC)

• UV radiation (UV-B most important - induces p53 mutations, PTCH mutations)
• Fair skin (Fitzpatrick type I/II)
• PTCH1/Gorlin syndrome (Nevoid BCC syndrome) - multiple BCCs, odontogenic keratocysts, bifid ribs, falx calcification
• Arsenic exposure, ionizing radiation, chronic immunosuppression

• Hedgehog (Hh) signaling pathway dysregulation is central
• Normally: PTCH1 inhibits Smoothened (SMO) → no Hh signaling
• UV mutation in PTCH1 → SMO constitutively active → Gli transcription factors activated → uncontrolled cell proliferation

1. Nodular BCC (most common): Pearly, translucent papule/nodule with rolled border and central ulceration ("rodent ulcer"); telangiectasias visible; on sun-exposed face (nose, medial canthus)
2. Superficial BCC: Flat, scaly red plaque with raised border; trunk and extremities
3. Morpheaform/Sclerosing BCC: Firm, scar-like plaque; most aggressive; difficult to excise (indistinct borders)
4. Pigmented BCC: Brown/black pigment; may resemble melanoma

• Gross: Nodular, ulcerated, firm lesion (rodent ulcer)
• Microscopic: Nests/islands of basaloid cells with peripheral palisading, separated from stroma by clefting artifact; stroma shows myxoid degeneration; peripheral palisading is the hallmark

• Locally invasive but RARELY metastasizes (<0.1%)
• Most common on head and neck (90%)
• Recurrence common if incompletely excised

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5. Silicosis

1. Inhaled quartz particles (<10 μm) reach alveoli
2. Engulfed by alveolar macrophages
3. Silica is NOT degraded in phagolysosomes → causes lysosomal membrane disruption
4. Macrophage death → releases silica + cytokines (IL-1β, TNF-α, TGF-β)
5. Recruits more macrophages → chronic cycle of inflammation
6. TGF-β drives collagen deposition → progressive fibrosis
7. Silica also activates NLRP3 inflammasome → amplifies IL-1β release

• Silicotic nodules: 1-10 mm, pale/black-white, hard, well-circumscribed
• Upper lobe and hilar lymph nodes preferentially affected
• "Eggshell calcification" of hilar nodes - characteristic but not pathognomonic
• Progressive Massive Fibrosis (PMF): confluence of nodules forming large (>3 cm) fibrous masses in upper lobes

• Silicotic nodule: Whorled, concentric layers of collagen with hyalinization at center
• Peripheral zone of fibroblasts, macrophages, lymphocytes
• Birefringent silica particles visible under polarized light

• Chronic/Classic: >10 years exposure, nodular, slowly progressive
• Accelerated: 5-10 years, rapid progressive
• Acute: Massive exposure, months; "Silicoproteinosis" - alveoli filled with PAS+ lipid material

• Progressive dyspnea, restrictive + obstructive pattern on PFTs
• Silicotuberculosis: Silica impairs macrophage killing of mycobacteria → high TB risk (3x increased)
• Lung cancer risk (IARC Group 1 carcinogen)
• Caplan syndrome (RA + pneumoconiosis)
• Cor pulmonale

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6. Differentiate Ulcerative Colitis and Crohn's Disease

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7. Informed Consent - Components

• Nature of the proposed procedure/treatment
• Diagnosis (if known)
• Purpose and benefits of the procedure
• Material risks and complications (including rare but serious ones)
• Alternative treatments available (including no treatment option)
• Prognosis with and without treatment

• Information must be given in patient's language/terminology they understand
• Opportunity for questions and clarification
• Checking understanding (teach-back method)

• Consent must be freely given without coercion, manipulation, or undue influence
• Patient has the right to refuse

• Patient must be legally competent (adult, ≥18 years in India)
• Cognitively capable of understanding, appreciating, and communicating a decision
• If incapacitated: surrogate (next of kin) gives consent

• Written consent preferred for surgical procedures
• Verbal consent acceptable for minor procedures
• Documentation essential

• Emergency: Implied consent when patient is unconscious and life-threatening
• Minors: Parent/guardian consent required
• Therapeutic privilege: Withholding distressing information justified only if disclosure would harm the patient (narrow exception)
• Waiver: Patient can waive the right to be informed

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8. Crescentic Glomerulonephritis (RPGN)

• Severe glomerular injury causes fibrin exudation into Bowman's space
• Parietal epithelial cells (of Bowman's capsule) and infiltrating monocytes proliferate
• Forms the crescent shape compressing the glomerular tuft

• c-ANCA (anti-PR3): Granulomatosis with Polyangiitis (Wegener)
• p-ANCA (anti-MPO): Microscopic Polyangiitis, EGPA

• Gross: Large pale kidneys with petechial hemorrhages (flea-bitten appearance if hypertensive)
• Light microscopy: Cellular crescents in Bowman's space compressing the glomerular tuft; fibrin strands in crescent; glomerular necrosis
• IF: Pattern depends on type (see table above)
• EM: Ruptures in GBM (Type I); subepithelial/mesangial deposits (Type II); no deposits (Type III)

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9. Serological Markers and Significance in Chronic Hepatitis B

• Active chronic HBV: HBsAg+ > 6 months, HBeAg+, HBV DNA high, Anti-HBs negative
• Inactive carrier: HBsAg+, HBeAg-, Anti-HBe+, HBV DNA low/undetectable, normal ALT
• Occult HBV: HBsAg negative, HBV DNA detectable (anti-HBc IgG may be the only clue)
• Vaccinated: Anti-HBs+ only (no Anti-HBc)

• HBeAg-positive = highly infectious; associated with higher rates of cirrhosis/HCC
• HBV DNA >2000 IU/mL = indication for antiviral treatment (tenofovir, entecavir)
• Elevated AFP + HBV = surveillance for HCC (6-monthly USS + AFP)

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10. Causes of Hypothyroidism + Hashimoto's Thyroiditis

Causes of Hypothyroidism

• Hashimoto's thyroiditis (most common cause worldwide in iodine-sufficient areas)
• Iodine deficiency (most common cause globally - endemic goiter)
• Post-thyroidectomy (surgical removal)
• Post-radioiodine therapy
• Drugs: Antithyroid drugs (PTU, carbimazole), lithium, amiodarone, interferon-alpha
• Congenital hypothyroidism: thyroid agenesis/dysgenesis (cretinism)
• Subacute granulomatous thyroiditis (de Quervain) - transient
• Riedel thyroiditis
• Post-partum thyroiditis

• Pituitary failure → insufficient TSH (Sheehan syndrome, pituitary tumor)

• Hypothalamic failure → insufficient TRH

Hashimoto's Thyroiditis (Chronic Lymphocytic Thyroiditis)

• Organ-specific autoimmune destruction of thyroid follicular cells
• Loss of self-tolerance to thyroid antigens (molecular mimicry, bystander activation)
• Cell-mediated mechanism: CD8+ cytotoxic T cells directly kill follicular cells; CD4+ Th cells activate macrophages → macrophage-mediated killing
• Antibody-mediated: Anti-TPO antibodies (anti-thyroid peroxidase) - most sensitive marker; Anti-thyroglobulin antibodies (anti-TG)
• CTLA-4 and PTPN22 polymorphisms increase susceptibility
• Strong female predominance (7:1 F:M); peak incidence 45-65 years

• Diffuse, symmetric, rubbery enlargement of thyroid (goiter)
• Bosselated surface

• Extensive lymphocytic infiltration with formation of reactive germinal centers (lymphoid follicles with germinal centers within the thyroid)
• Follicular cell destruction
• Hürthle cell (oncocytic/oxyphilic) metaplasia - follicular cells transformed to cells with abundant granular eosinophilic cytoplasm (packed with mitochondria) - characteristic
• Follicle atrophy and fibrosis in late stages
• Residual colloid is depleted

• Gradual onset hypothyroidism (fatigue, cold intolerance, weight gain, constipation, dry skin, myxedema)
• Painless diffuse goiter (early); thyroid may shrink later (fibrosis)
• Transient hyperthyroidism possible early ("Hashitoxicosis")
• Elevated TSH, low free T4
• Anti-TPO antibodies positive in >95%

• Increased risk of B-cell lymphoma (primary thyroid lymphoma - marginal zone/MALT type)
• Other autoimmune diseases: Type 1 DM, SLE, Sjogren syndrome, Addison disease, pernicious anemia
• Rarely: Papillary thyroid carcinoma

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