🔴 Colorectal Cancer
Polyps and premalignant conditions; adenoma-carcinoma sequence; molecular pathways; staging; treatment by stage; advances in systemic therapy; and anal cancer management.
Colorectal Polyps
A colonic polyp is any protrusion from the colonic mucosa into the lumen. Polyps are classified as neoplastic (adenomas and serrated lesions — true premalignant potential) or non-neoplastic (hyperplastic, inflammatory, hamartomatous — generally benign). The critical distinction drives surveillance and treatment decisions.
Polyp Classification
Tubular Adenoma
Most common — 80% of adenomas
Structure≥80% tubular architecture — round glands. Usually pedunculated (on a stalk).
MalignancyLowest malignant potential of the adenoma types: ~5% risk in >1 cm lesions.
ManagementEndoscopic polypectomy (snare diathermy). Surveillance colonoscopy (timing depends on size, number, and histology — BSG guidelines).
Villous Adenoma
10% of adenomas — highest malignancy risk
Structure≥80% villous architecture — finger-like projections. Usually sessile (flat, broad base). More common in the rectum.
MalignancyHighest malignant potential — up to 40% harbour malignancy at the time of diagnosis if large.
Clinical pearl“Secretary villous adenoma” — large rectal villous adenomas can secrete large volumes of mucus + potassium-rich fluid → secretory diarrhoea + severe hypokalaemia (McKittrick-Wheelock syndrome). Electrolyte replacement mandatory before endoscopy/surgery.
ManagementEndoscopic resection if possible (EMR/ESD). TEM/TAMIS for rectal villous adenomas. Formal resection if cancer confirmed.
Tubulovillous Adenoma
10% — intermediate risk
StructureMixed architecture — 20–80% villous component. Intermediate malignancy risk (~22%).
ManagementEndoscopic resection. Surveillance colonoscopy. Risk stratification by size, grade of dysplasia, and completeness of resection.
Serrated Lesions
The “alternative” malignancy pathway
SubtypesHyperplastic polyps (benign, <5 mm, no malignant potential), Sessile Serrated Lesions (SSL, formerly SSA) — malignant potential via the CIMP/MSI pathway, Traditional Serrated Adenoma (TSA) — rare, malignant potential.
Why importantSSLs drive the serrated (alternative) pathway to CRC — via BRAF mutation → CpG island methylator phenotype (CIMP) → microsatellite instability (MSI-H). This is distinct from the classical APC/adenoma pathway. SSLs are flat, pale, and easily missed — account for ~30% of “interval cancers” (cancers arising between surveillance colonoscopies).
ManagementComplete endoscopic resection. Annual surveillance colonoscopy for large SSLs. Serrated polyposis syndrome (multiple large/right-sided serrated polyps) = high-risk surveillance ± surgery.
Hamartomatous Polyps
Peutz-Jeghers, juvenile polyposis
Peutz-JeghersSTK11 gene mutation. Hamartomatous polyps throughout GI tract + perioral/buccal melanin pigmentation. Risk of GI cancer, breast, pancreas, ovary. Surveillance endoscopy + capsule endoscopy for small bowel.
Juvenile polyposisSMAD4 or BMPR1A mutation. Juvenile (inflammatory) polyps in colon/stomach. Increased CRC risk. Prophylactic colectomy if extensive.
Inflammatory & Hyperplastic
Non-neoplastic — generally no malignant potential
HyperplasticMost common polyp type overall. Small, pale, left-sided. Benign unless >1 cm right-sided (reclassify as SSL).
InflammatoryOccur in IBD as pseudopolyps — islands of regenerating mucosa between ulcers. Benign themselves but their presence signals chronic IBD → increased CRC surveillance frequency.
High-Risk Polyposis Syndromes
| Syndrome | Gene / Inheritance | Polyp burden | CRC risk | Management |
|---|---|---|---|---|
| Familial Adenomatous Polyposis (FAP) | APC gene (5q21). Autosomal dominant. ~25% new mutations. | Hundreds to thousands of colorectal adenomas from mid-teens. 100% colorectal cancer by age 40 if untreated. Also: duodenal adenomas (periampullary — 2nd commonest CRC in FAP), gastric fundic gland polyps, desmoid tumours (extra-abdominal), osteomas (Gardner’s variant), retinal pigmentation (CHRPE). | 100% lifetime CRC risk if untreated | Prophylactic proctocolectomy + IPAA (usually age 18–25, guided by polyp burden). Annual flexible sigmoidoscopy from age 13–15. Duodenoscopy every 1–3 years (Spigelman staging for duodenal disease). Register and genetic testing for first-degree relatives. Sulindac/celecoxib can reduce polyp burden but NOT eliminate CRC risk. |
| Attenuated FAP (AFAP) | APC gene — attenuated mutations (5′ or 3′ end of gene) | 10–100 adenomas. Later onset (30s–40s). | ~70% lifetime risk | Intensive surveillance colonoscopy or delayed prophylactic colectomy. |
| Lynch Syndrome (HNPCC) | Mismatch repair genes: MLH1, MSH2, MSH6, PMS2, EPCAM. Autosomal dominant. | Relatively few polyps but accelerated adenoma-to-carcinoma sequence (2–3 years vs 10 years in sporadic CRC). | ~70–80% lifetime CRC risk (MLH1/MSH2). Also: endometrial (40–60%), ovarian, gastric, urinary tract, small bowel cancers. | Colonoscopy every 1–2 years from age 25 (or 5 years before youngest CRC in family). Annual gynaecological surveillance. Prophylactic hysterectomy + BSO discussed in post-reproductive women. Aspirin 600 mg daily reduces CRC risk (CAPP2 trial — 63% risk reduction). Tumours are MSI-H → responsive to immunotherapy (pembrolizumab). |
| MUTYH-Associated Polyposis (MAP) | MUTYH gene. Autosomal recessive (biallelic mutations) | 15–100 adenomas. Phenotypically similar to AFAP. Also serrated polyps. | ~80% lifetime CRC risk | Intensive colonoscopy surveillance. Prophylactic colectomy when polyp burden unmanageable. |
| Gardner’s Syndrome | APC gene — a subset of FAP with extra-intestinal manifestations. Autosomal dominant. | Same as FAP — hundreds to thousands of adenomatous polyps. Extra features remembered by GARDENS: GI polyps, Abnormal dentition (supernumerary teeth), Ribs and bony abnormalities (osteomas — mandible is classic), Desmoid tumours (intra-abdominal — post-surgery trigger, associated with thyroid), Endocrine tumours (thyroid carcinoma), Nervous system tumour (medulloblastoma), Soft tissue tumours (epidermoid cysts, fibromas). | 100% lifetime CRC risk if untreated — same as FAP | Same as FAP. Desmoid tumours complicate surgery — may require imatinib or sulindac to reduce size pre-operatively. Avoid surgical scarring where possible (desmoids are triggered by surgical trauma in the mesentery). |
| Turcot’s Syndrome | Variant of either FAP or Lynch syndrome. Autosomal recessive genetics. Two subtypes depending on which syndrome it resembles. | Colonic polyps + brain tumour. The brain tumour type distinguishes the two forms: 🔵 FAP-like Turcot: APC mutation → colonic polyposis + medulloblastoma (cerebellar — children) 🔵 Lynch-like Turcot: MMR gene mutation → CRC without polyposis + glioblastoma (aggressive astrocytoma) | High CRC risk (same as underlying FAP or Lynch) | Management based on underlying syndrome. Neurosurgical involvement for the brain tumour component. Genetic testing to distinguish FAP-type vs Lynch-type is essential. |
The Amsterdam Criteria & Bethesda Guidelines — Identifying Lynch Syndrome
Amsterdam II Criteria (clinical diagnosis of Lynch):
🔵 ≥3 relatives with Lynch-associated cancers (CRC, endometrium, small bowel, ureter, renal pelvis)
🔵 One affected relative is a first-degree relative of the other two
🔵 ≥2 successive generations affected
🔵 ≥1 cancer diagnosed before age 50
🔵 FAP excluded
🔵 Tumours verified by histopathology
Universal MMR testing: All colorectal cancers diagnosed in the UK should undergo reflex MMR IHC testing (MLH1, MSH2, MSH6, PMS2 staining on the tumour) — loss of expression directs germline testing. MSI-H/MMR-deficient status is both a Lynch marker AND a predictive biomarker for immunotherapy response.
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