Hereditary non polyposis coli (Lynch syndrome) ✅

🧬 Hereditary Non-Polyposis Colorectal Cancer (HNPCC), also called Lynch Syndrome, results from defective DNA mismatch repair (MMR) → early-onset colorectal cancer + increased extracolonic malignancy risk. 💡 Hallmark = microsatellite instability (MSI).

📖 About

• Autosomal dominant with incomplete penetrance (not all carriers develop cancer).
• Represents ~2–4% of all colorectal cancers.
• Distinct from FAP: cancers develop with few adenomas rather than 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 (chr3) and hMSH2 (chr2).
• Others: MSH6, PMS2 (lower penetrance, later onset).
• MMR loss → MSI → increased mutation rate → malignant transformation.

🩺 Clinical Features

• 🧭 Proximal colon cancers are most common.
• Mean age ~45 (vs ~65 in sporadic CRC).
• <100 adenomas (contrast: hundreds in FAP).
• Symptoms: rectal bleeding, altered bowel habit, iron-deficiency anaemia (esp. right-sided lesions), abdominal pain or obstruction.

🎯 Associated Malignancy Risks

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

🔎 Investigations

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

📋 Modified Amsterdam Criteria (HNPCC diagnosis)

• ≥2 successive generations affected by Lynch-associated cancers.
• One must be a first-degree relative of another affected individual.
• ≥1 case diagnosed <50 years.
• Associated cancers: colorectal, endometrial, small bowel, ureter, renal pelvis.
• FAP excluded; histological confirmation of tumours.

⚕️ Management 🛠️

• 🔪 Colectomy: For CRC or high-risk adenomas. Extended colectomy reduces metachronous CRC risk.
• 📆 Surveillance:
  • Colonoscopy every 1–2 years.
  • Annual gynaecological screening (TVUS, endometrial sampling) for women.
  • Consider upper GI endoscopy every 2–3 years if gastric cancer risk elevated.
• 💊 Aspirin chemoprevention: Daily low-dose aspirin may reduce CRC incidence (CAPP2 trial); discuss risks/benefits.
• ♀️ Risk-reducing surgery: Prophylactic hysterectomy + bilateral salpingo-oophorectomy post-childbearing.
• 👨‍👩‍👧 Genetic counselling & family screening essential.

📚 Key Teaching Pearls 💡

• Lynch = MMR defect + MSI → right-sided CRC + extracolonic cancers.
• Young age, family history, and few polyps = red flags.
• Contrast with FAP: Lynch = few polyps; FAP = hundreds.
• Colonoscopy surveillance saves lives; early detection is critical.

Cases - HNPCC / Lynch Syndrome

• Case 1 – Classic CRC 👨‍🦱: 42-year-old man, right-sided tumour, MLH1 loss on IHC. Family history positive. Management: Right hemicolectomy, genetic testing confirms Lynch. Family referred for counselling and colonoscopy. Outcome: Good recovery; ongoing 1–2 yearly colonoscopic surveillance.
• Case 2 – Extracolonic (Gynaecological) 👩: 39-year-old woman, endometrial cancer, strong family CRC history. MSI-high tumour; MSH2 mutation confirmed. Management: Total hysterectomy + BSO; colonoscopy revealed multiple adenomas; relatives offered genetic testing. Outcome: Recovery uneventful; enrolled in high-risk surveillance (colonoscopy, upper GI, counselling).

🧑‍⚕️ Teaching Commentary

Lynch syndrome is an autosomal dominant cancer predisposition from MMR gene mutations (MLH1, MSH2, MSH6, PMS2). 🔑 Clues: young age, right-sided CRC, extracolonic cancers, minimal polyps. Management focuses on:

• Regular colonoscopy (1–2 yearly) starting at age 20–25.
• Screening for extracolonic cancers (gynaecological, gastric, urinary tract).
• Genetic counselling for at-risk relatives.
• Prophylactic or therapeutic surgery as indicated.

References 📚

• NICE NG151 – Colorectal Cancer: Diagnosis and Management
• National Cancer Institute – Lynch Syndrome
• NICE CKS – Colorectal Cancer Genetics