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Colorectal polyps, microsatellite instability and Lynch syndrome
Colorectal cancer has two main pathways — the classic adenoma pathway with an APC mutation, and the serrated pathway with BRAF and methylation — and a polyp is described by type, size and grade of dysplasia; MMR or MSI is tested in every colorectal cancer to identify Lynch syndrome and guide treatment.
Why it matters in the exam
The bank asks which polyps are dangerous and what characterises MSI cancer. A hyperplastic polyp — small, rectal, serrated only in the upper crypts — is almost harmless. A sessile serrated lesion — right-sided, with crypts dilated at their base and L-shaped or "boot-shaped" — carries a BRAF mutation and methylation (CIMP), and can progress to MSI cancer through silencing of MLH1. A tubular, tubulovillous or villous adenoma carries an APC mutation; risk rises with a size of 10 mm or more, a villous component and high-grade dysplasia.
MSI-high cancer tends to be right-sided, mucinous or medullary, with many lymphocytes within the tumour and a Crohn-like reaction around it; despite a "less differentiated" appearance, prognosis in early stages is better, and it responds well to immunotherapy (PD-1 inhibitors). When immunohistochemistry shows loss of MLH1 and PMS2, BRAF V600E or MLH1 promoter methylation is tested: if present, the tumour is probably sporadic; if not — Lynch syndrome should be suspected and the patient referred for genetic counselling. Loss of MSH2 and MSH6 raises suspicion of Lynch from the outset.
Hamartomatous polyps: the juvenile polyp (in children, with dilated glands and inflamed stroma) and the Peutz-Jeghers polyp (with branching smooth muscle, and lip pigmentation; STK11 mutation). Two specific findings the bank likes: diversion colitis in a defunctioned segment — lymphoid follicular hyperplasia of the mucosa; and gut GVHD — apoptosis of cells at the base of the crypts.
Key points
- Two pathways: APC in adenoma; BRAF and methylation in the serrated lesion.
- Adenoma risk: 10 mm or more, villous, high grade.
- MSI: right side, mucinous, lymphocytes, response to immunotherapy.
- MLH1 loss with BRAF or methylation — sporadic; otherwise — Lynch.
- MMR or MSI testing in every colorectal cancer.
Summary table
| Lesion | Site and appearance | Molecular change | Risk |
|---|---|---|---|
| Hyperplastic polyp | Rectum, small, serrated above | KRAS or BRAF | Very low |
| Sessile serrated lesion | Right side, crypts dilated at base | BRAF, CIMP, MLH1 silencing | MSI cancer |
| Conventional adenoma | Whole colon | APC | Rises with 10 mm, villous, high grade |
| MSI-high cancer | Right side, mucinous, lymphocytes | Defective MMR | Relatively good prognosis; immunotherapy |
| Peutz-Jeghers | Mainly small bowel | STK11 | Cancer risk in many organs |
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Sources
- WHO Classification of Tumours: Digestive System Tumours, 5th edition (2019) — Colorectal serrated lesions and adenomas
- NCCN Guidelines: Genetic/Familial High-Risk Assessment: Colorectal, 2024 — Universal tumour screening for Lynch syndrome
- Robbins and Cotran Pathologic Basis of Disease, 10th edition (2021) — The colon — polyps and carcinoma
Sources are given for further reading; the text is written afresh and not copied from them.
Reviewed by the Examqo AI Professor · 2026-11-06. The text may contain errors; when in doubt, check the source.