Colorectal Cancer & Polyps
A high-yield board review of colorectal cancer and polyps covering the adenoma–carcinoma sequence and its three molecular pathways (APC/chromosomal instability, MSI/Lynch, serrated/BRAF), polyp and hereditary-syndrome comparison tables, right- versus left-sided presentation, current screening ages, and next-best-step diagnosis, staging, and management. Written for STEP 1 and STEP 2 CK with classic vignette buzzwords.
Pathophysiology: the adenoma–carcinoma sequence
Colorectal cancer (CRC) is the 3rd most common cancer and a leading cause of cancer death; ~95% are adenocarcinomas that evolve from adenomatous polyps over 10–15 years — the adenoma–carcinoma sequence. Three molecular pathways are tested:
- Chromosomal instability (APC pathway, ~80%) — stepwise APC → KRAS → 18q loss (DCC/SMAD4) → TP53 (17p). Biallelic APC loss ("two-hit") is the gatekeeper initiating step; it stabilizes β-catenin, driving WNT signaling. Normal mucosa → adenoma → carcinoma.
- Microsatellite instability (MSI) — defective DNA mismatch repair (MLH1, MSH2, MSH6, PMS2). Germline in Lynch; sporadic via MLH1 promoter hypermethylation (typically BRAF-mutated, which argues against Lynch). Tends to be right-sided, mucinous, better prognosis, immunotherapy-responsive.
- Serrated / CIMP — BRAF V600E with CpG-island hypermethylation, arising from sessile serrated lesions.
Most tumors are left-sided (rectosigmoid), but MSI/Lynch and serrated cancers favor the right colon.
- Modifiable: high red/processed meat, low fiber, obesity, sedentary lifestyle, smoking, alcohol, type 2 diabetes.
- Inflammatory bowel disease: ulcerative colitis > Crohn; risk rises with duration and extent (pancolitis). Dysplasia arises flat, not as discrete polyps — hence surveillance biopsies, not just polypectomy.
- Hereditary syndromes: FAP, Lynch, Peutz–Jeghers, juvenile & MUTYH polyposis (see tables).
- Streptococcus gallolyticus (formerly S. bovis biotype I) bacteremia/endocarditis → do a colonoscopy to rule out CRC. *Clostridium septicum* infection is likewise associated.
- Personal/family history of CRC or advanced adenomas.
- Protective: aspirin/NSAIDs, physical activity, fiber, possibly calcium.
- Polyp malignant risk ↑ with villous histology, size >1 cm, and high-grade dysplasia — remember "villous = villain."
Polyps: histology & malignant potential
| Polyp | Class | Malignant potential |
|---|---|---|
| Tubular adenoma | Neoplastic | Low — the most common adenoma |
| Tubulovillous adenoma | Neoplastic | Intermediate |
| Villous adenoma | Neoplastic | High; large ones cause secretory K⁺-losing diarrhea |
| Sessile serrated lesion | Neoplastic | Yes (BRAF/CIMP → MSI) |
| Hyperplastic | Non-neoplastic | Negligible (small, rectosigmoid) |
| Hamartomatous | Non-neoplastic | Low alone; ↑ within syndromes |
| Inflammatory (pseudopolyp) | Non-neoplastic | None — seen in IBD |
Hereditary CRC & polyposis syndromes
| Syndrome | Gene(s) | Key features |
|---|---|---|
| FAP | APC (5q) | >100 adenomas; ~100% CRC → prophylactic colectomy; CHRPE |
| Gardner | APC | FAP + osteomas, desmoids, epidermoid cysts, dental anomalies |
| Turcot | APC or MMR | Polyposis + CNS tumors (APC → medulloblastoma; MMR → glioblastoma) |
| Lynch (HNPCC) | MMR (MLH1, MSH2…) | Few polyps, right-sided, endometrial/ovarian/urothelial |
| Peutz–Jeghers | STK11 | Hamartomas + mucocutaneous pigmentation; intussusception; ↑ GI/breast/pancreatic |
| Juvenile polyposis | SMAD4 / BMPR1A | Childhood hamartomas; ↑ CRC |
| MUTYH-associated | MUTYH | Attenuated (10s–100s) polyposis |
Case A — A 70-year-old man has 3 months of fatigue and exertional dyspnea. Labs: microcytic iron-deficiency anemia, guaiac-positive stool; bowel habits unchanged. → Dx: Right-sided (cecal/ascending) CRC. The wide lumen and liquid stool let it bleed occultly and grow large, presenting as iron-deficiency anemia, not obstruction. Any man or postmenopausal woman with unexplained IDA needs a colonoscopy.
Case B — A 62-year-old has constipation, pencil-thin stools, and hematochezia; CT shows an "apple-core" (napkin-ring) lesion. → Dx: Left-sided (descending/sigmoid) CRC. The narrow lumen and solid stool cause obstruction, change in stool caliber, and visible bleeding.
Next best step (both): colonoscopy with biopsy to evaluate the whole colon for synchronous lesions.
- Average risk: begin at age 45 (USPSTF/ACS); continue to 75, individualize 76–85.
- Options: colonoscopy q10y (gold standard), FIT annually, FIT-DNA (Cologuard) q3y, CT colonography q5y, flexible sigmoidoscopy q5y. Any positive non-invasive test → colonoscopy.
- Family history (1st-degree relative with CRC/advanced adenoma <60, or ≥2 affected 1st-degree relatives): start at 40, or 10 yr before the youngest case, then q5y.
- Lynch: colonoscopy q1–2y starting age 20–25.
- FAP: annual sigmoidoscopy/colonoscopy from age 10–12.
- IBD: surveillance colonoscopy 8 yr after diagnosis (at diagnosis if concurrent PSC), then q1–3y.
- CEA is NOT a screening test — obtain a baseline for prognosis and recurrence monitoring.
A 34-year-old woman presents with hematochezia; colonoscopy reveals a right-sided adenocarcinoma and only a few polyps. Her mother had endometrial cancer at 44 and a maternal uncle had colon cancer at 47.
- Most likely dx: Lynch syndrome (HNPCC) — the pedigree meets Amsterdam II "3-2-1" criteria (the mother is a first-degree relative of both the patient and the affected uncle).
- Next best step: tumor testing — MMR immunohistochemistry (look for loss of MLH1/MSH2/MSH6/PMS2) and/or MSI testing; if abnormal → germline genetic testing. (Universal MMR/MSI testing of all CRCs has largely superseded pedigree criteria.)
- The tumor is MSI-high, which also predicts response to PD-1 inhibitors (pembrolizumab) in advanced disease.
- Also screen for endometrial cancer — the most common extracolonic malignancy in Lynch.
Amsterdam II criteria for Lynch syndrome — "3-2-1":
- 3 relatives with a Lynch-associated cancer (colorectal, endometrial, small bowel, ureter/renal pelvis)
- 2 successive generations affected
- 1 relative diagnosed before age 50
Plus: one affected relative is a first-degree relative of the other two, and FAP is excluded.
Other genuine classics:
- "Villous = villain" — the highest-risk adenoma.
- "Strep bovis in the blood → look in the bowel" (and the heart valves).
- Diagnosis: colonoscopy with biopsy — evaluates the entire colon for synchronous tumors.
- Staging: CT chest/abdomen/pelvis; rectal cancer → pelvic MRI ± endorectal US. TNM stage (esp. nodal status) drives adjuvant therapy. Draw a baseline CEA.
- Colon cancer: surgical resection + regional lymphadenectomy; adjuvant FOLFOX for stage III (node-positive) and high-risk stage II.
- Rectal cancer: locally advanced (T3–4 or N+) → neoadjuvant chemoradiation, then total mesorectal excision.
- Metastatic: chemo (FOLFOX/FOLFIRI) + biologics — bevacizumab (anti-VEGF); anti-EGFR (cetuximab/panitumumab) only if RAS/BRAF wild-type (and better in left-sided tumors); MSI-high → pembrolizumab. Liver is the most common metastatic site (portal drainage).
- Follow-up: CEA q3–6 mo + surveillance colonoscopy at 1 year.
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