Makindo Medical Notes

🧬 Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also called Lynch Syndrome, is caused by defective DNA mismatch repair → leading to early-onset colorectal cancer and increased risk of multiple extracolonic malignancies. 💡 Hallmark = microsatellite instability (MSI).

📖 About

• Autosomal dominant with incomplete penetrance (not all carriers develop cancer).
• Accounts for ~2–4% of all colorectal cancers.
• Distinct from FAP: cancers develop with few adenomas (not hundreds).
• Typically presents with proximal (right-sided) colorectal cancers at a younger age (~45 years).

🧬 Aetiology

• Mutations in DNA mismatch repair (MMR) genes → failure of DNA proofreading.
• 95% due to hMLH1 (chromosome 3) and hMSH2 (chromosome 2).
• Others: MSH6, PMS2 (lower penetrance, later onset).
• Loss of MMR → microsatellite instability (MSI) → ↑ mutation rate → malignant transformation.

🩺 Clinical Features

• 🧭 Proximal (right-sided) colon cancers are typical.
• Mean age of onset ~45 years (vs ~65 in sporadic CRC).
• <100 adenomas (contrast: hundreds in FAP).
• Symptoms vary by site: – Rectal bleeding – Change in bowel habit – Iron-deficiency anaemia (esp. right-sided lesions) – Abdominal pain or obstruction

🎯 Associated Malignancy Risks

• ♀️ Endometrial cancer – 2nd most common cancer, esp. <50 years.
• ♀️ Ovarian cancer – increased lifetime risk.
• 🍽️ Gastric & small bowel cancer.
• 💧 Urinary tract cancers (ureter, renal pelvis).
• 🧠 Brain tumours (gliomas – “Turcot’s syndrome” association).
• 📍 Biliary tract & pancreatic cancer also increased.

🔎 Investigations

• 📆 Colonoscopy: every 1–2 years from age 20–25 (or 2–5 years before earliest family case).
• 🧬 Genetic testing: detect germline MMR mutations (hMLH1, hMSH2, MSH6, PMS2).
• ⚡ MSI testing and IHC staining on tumour tissue → check for MMR deficiency.

📋 Modified Amsterdam Criteria (for HNPCC diagnosis)

• At least two successive generations affected by Lynch-associated cancers.
• One must be a first-degree relative of another affected individual.
• ≥1 case diagnosed before age 50.
• Associated cancers = colorectal, endometrial, small bowel, ureter, or renal pelvis.
• FAP excluded.
• All tumours histologically confirmed.

⚕️ Management

• 🔪 Colectomy: indicated for CRC or high-risk adenomas. Extended colectomy may be considered to reduce risk of metachronous cancers.
• 📆 Surveillance: – Colonoscopy every 1–2 years. – Annual gynaecological screening (TVUS, endometrial sampling) for women.
• 💊 Aspirin chemoprevention: daily low-dose aspirin shown to ↓ CRC incidence (CAPP2 trial). Use after risk-benefit discussion.
• ♀️ Risk-reducing surgery: prophylactic hysterectomy + bilateral salpingo-oophorectomy may be considered after childbearing.
• 👨‍👩‍👧 Family screening & genetic counselling essential.

💡 Teaching Pearls:
– Lynch = MMR defect + MSI + right-sided CRC + extracolonic cancers.
– Think of Lynch if: young age, proximal CRC, family history, endometrial/ovarian cancers.
– Always contrast with FAP: Lynch = few polyps, FAP = hundreds.
– Surveillance saves lives → colonoscopy is cornerstone.

📚 References

• National Cancer Institute – Lynch Syndrome
• NICE Guideline – Colorectal Cancer