🧬 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

Cases — Hereditary Non-Polyposis Colorectal Cancer (HNPCC / Lynch Syndrome)

Case 1 (Classic colorectal presentation): 👨‍🦱 A 42-year-old man presents with altered bowel habit and intermittent rectal bleeding. He reports that his father died of colon cancer at 48, and his sister had endometrial cancer at 46. Colonoscopy shows an ascending colon tumour; biopsy confirms adenocarcinoma. Immunohistochemistry of the tumour shows loss of MLH1 expression. Management: Right hemicolectomy with curative intent. Genetic testing confirms Lynch syndrome. Family referred for genetic counselling and surveillance colonoscopy. Outcome: Good surgical recovery. Patient remains under 1–2 yearly colonoscopic surveillance and referred for screening of extracolonic cancers.
Case 2 (Extracolonic presentation — gynaecological): 👩 A 39-year-old woman with strong family history of colorectal cancer presents with abnormal uterine bleeding. Endometrial biopsy shows endometrioid adenocarcinoma. Her brother was diagnosed with colon cancer at 41. Tumour shows microsatellite instability (MSI-high). Management: Total hysterectomy with bilateral salpingo-oophorectomy performed. Colonoscopy arranged, which reveals multiple adenomas. Genetic testing confirms MSH2 mutation. Outcome: Recovery from surgery uneventful. Enrolled in high-risk surveillance: annual colonoscopy, upper GI endoscopy every 2–3 years, and counselling for relatives.

🧑‍⚕️ Teaching Commentary

Lynch syndrome is an autosomal dominant cancer predisposition due to mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). It causes microsatellite instability and a high risk of colorectal cancer (particularly right-sided) and extracolonic cancers (endometrial, ovarian, gastric, urinary tract). 🔑 Clues: young age at diagnosis, family clustering, and absence of polyposis (unlike FAP). Management involves: • Early and regular colonoscopy (1–2 yearly) starting at 20–25. • Screening for extracolonic cancers (gynaecological, gastric, urinary). • Genetic counselling for relatives. Early detection is crucial: prognosis improves markedly with surveillance and prophylactic surgery in selected cases.

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Hereditary non polyposis coli (Lynch syndrome)