Ovarian & Colorectal Cancer: Risks, OmpathStudy

--- Q37. Discuss Ovarian Carcinoma: Risk Factors, Pathogenesis, Classification, Morphology, Staging Risk factors: Nulliparity / low parity Early menarche, late menopause (prolonged uninterrupted ovulation — "incessant ovulation" theory) Family history, BRCA1/2 mutations, Lynch syndrome (HNPC C) Infertility, endometriosis (→ endometrioid/clear cell subtype) Increasing age (peak 60s) Protective: OCP use, multiparity, breastfeeding, tubal ligation (interrupt ovulation cycle) Pathogenesis: "Incessant ovulation" theory — repeated ovulation → repeated epithelial trauma/repair at ovarian surface → accumulated mutations BRCA1/2 mutations → defective homologous recombination DNA repair → genomic instability Two-pathway model: Type I (low-grade) — slow, stepwise progression from borderline tumours; KRAS, BRAF mutations; indolent Type II (high-grade serous) — most common and aggressive; arises from fallopian tube fimbrial epithelium (STIC lesions); early, near-universal TP53 mutation; rapid, aggressive spread Endometrioid/clear cell subtypes arise from endometriosis-associated malignant transformation Classification (with examples): Surface epithelial tumours (~65-70% of all, majority of malignant) — serous, mucinous, endometrioid, clear cell, Brenner Germ cell tumours (young women) — mature teratoma (benign), dysgerminoma, yolk sac tumour, choriocarcinoma Sex cord-stromal tumours — granulosa cell (oestrogen-secreting), Sertoli-Leydig (androgen-secreting), fibroma/thecoma Metastatic — Krukenberg tumour (bilateral, signet-ring cells, usually gastric primary) Morphology: Serous cystadenocarcinoma — cystic, papillary excrescences, psammoma bodies (concentric calcifications) on histology, often bilateral Mucinous — multiloculated, mucin-filled cysts, tall columnar mucin-secreting epithelium Clear cell — hobnail cells, clear cytoplasm, "hobnail" pattern Malignant features generally: nuclear atypia, high mitotic rate, stromal invasion, necrosis Staging (FIGO, simplified): Stage I — confined to ovary/ovaries Stage II — pelvic extension (uterus, tubes, other pelvic tissue) Stage III — peritoneal spread beyond pelvis and/or retroperitoneal/inguinal lymph nodes Stage IV — distant metastasis (liver parenchyma, lung, etc.) Spread pattern: transcoelomic (peritoneal seeding) is the dominant/classic route, unlike most other cancers where haematogenous/lymphatic spread dominates early Tumour markers: CA-125 (epithelial, monitoring not screening — poor specificity), AFP (yolk sac), β-hCG (choriocarcinoma), inhibin (granulosa cell) Clinical features: vague — bloating, pelvic pain, early satiety, urinary frequency ("silent killer," usually presents late, Stage III at diagnosis) --- Q38. Discuss Colorectal Carcinoma: Risk Factors, Pathogenesis, Morphology, Staging Risk factors: Age 50 Low-fibre, high-fat/red meat diet IBD (ulcerative colitis Crohn's, risk rises with disease duration/extent) Family history — FAP, HNPCC/Lynch syndrome Smoking, alcohol, obesity, sedentary lifestyle Type 2 diabetes Pathogenesis (two distinct molecular pathways): Chromosomal instability pathway (adenoma-carcinoma sequence, ~80%) APC gene mutation (tumour suppressor) → initiates adenoma formation (loss of both alleles — "two-hit") KRAS mutation → adenoma growth/progression p53 mutation → progression to invasive carcinoma Sequence: normal mucosa → small adenoma → large/villous adenoma with high-grade dysplasia → invasive carcinoma Microsatellite instability (MSI) pathway (~15-20%) Defective DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2) Underlies Lynch syndrome (HNPCC) — autosomal dominant, right-sided predominance, earlier onset, less step-wise polyp progression FAP — germline APC mutation → hundreds to thousands of colonic polyps from adolescence → near-100% progression to cancer if colon not removed Morphology: Right-sided (caecum/ascending colon) — exophytic, polypoid, fungating masses; wider lumen tolerates growth without obstruction → presents late with occult bleeding/anaemia Left-sided (descending/sigmoid) — annular, "napkin-ring" constricting lesions; narrower lumen → presents earlier with obstruction, altered bowel habit, blood-streaked stool Microscopically: gland-forming adenocarcinoma (majority), mucinous subtype (worse prognosis), signet-ring subtype (worse prognosis) Staging (TNM, correlating with old Dukes' staging): Stage I — invades submucosa/muscularis propria, no nodal spread (Dukes A) Stage II — invades through muscularis into serosa/pericolic tissue, no nodes (Dukes B) Stage III — any depth with regional lymph node involvement (Dukes C) Stage IV — distant metastasis, classically liver (via portal venous drainage) (Dukes D) Tumour marker: CEA — used for monitoring/recurrence, not screening (low sensitivity/specificity early) Screening: colonoscopy, faecal occult blood test/FIT, starting age 45-50 (earlier if family history) --- Q39. Discuss Polycystic Ovarian Syndrome (PCOS): Aetiology, Pathogenesis, Diagnostic Criteria, Complications A