Colorectal Neoplasia
APC to KRAS to p53, the polyposis syndromes, and left vs right tumors
Molecular pathways to colorectal cancer
Chromosomal instability (adenoma-carcinoma sequence). Most sporadic colorectal cancers follow a stepwise accumulation of mutations. Loss of the APC tumor suppressor (both alleles, per the two-hit model) decreases intercellular adhesion and increases proliferation, because APC normally helps degrade β-catenin in the Wnt pathway. An activating KRAS mutation then drives unregulated growth signaling, and finally p53 loss plus increased COX expression completes the transformation to carcinoma. Remember AK-53: APC, KRAS, p53. The COX step is one reason aspirin and NSAIDs lower colorectal cancer risk.
- Normal mucosaAPC loss (two hits)
- AdenomaKRAS mutation
- Advanced adenomap53 loss, increased COX
- CarcinomaInvasion
Microsatellite instability (MSI). A separate pathway driven by defective DNA mismatch repair (MLH1, MSH2). Without repair, replication errors pile up in short repetitive sequences (microsatellites), which become unstable, the molecular hallmark of Lynch syndrome. MSI also underlies about 15% of sporadic cancers, through MLH1 promoter hypermethylation. MSI tumors tend to be right-sided.
Serrated pathway. Sessile serrated lesions progress through BRAF mutation, often with MLH1 silencing, which is how many sporadic right-sided MSI cancers arise.
Colorectal polyps
Non-neoplastic vs premalignant. Hyperplastic polyps are the most common colonic polyps and are benign: small, usually rectosigmoid, with sawtooth (serrated) glands and no dysplasia. Adenomatous polyps (tubular, tubulovillous, villous) are dysplastic by definition and premalignant. Sessile serrated lesions resemble hyperplastic polyps but carry malignant risk via the serrated/BRAF pathway.
Villous is villainous. Among adenomas, cancer risk rises with size (>1 cm), villous histology, and high-grade dysplasia. Villous adenomas carry the highest risk and can rarely cause secretory diarrhea with hypokalemia.
| Polyp | Features | Malignant potential |
|---|---|---|
| Hyperplastic | Most common; small, rectosigmoid; sawtooth glands, no dysplasia | Essentially none (small) |
| Sessile serrated lesion | Serrated architecture; often right-sided | Yes: serrated/BRAF pathway |
| Tubular adenoma | Dysplastic tubular glands, often pedunculated | Yes: lowest among adenomas |
| Villous adenoma | Fingerlike projections, often large and sessile | Highest; may cause hypokalemic secretory diarrhea |
| Hamartomatous (juvenile, Peutz-Jeghers) | Disorganized normal tissue | Sporadic single polyp benign; syndromic polyposis raises risk |
Hereditary polyposis and cancer syndromes
Familial adenomatous polyposis (FAP). Autosomal dominant germline loss of APC (chromosome 5q21), so every colonocyte already carries the first hit. Hundreds to thousands of adenomatous polyps carpet the colon by adolescence, and progression to colorectal cancer approaches 100%, so prophylactic colectomy is required. Duodenal and periampullary adenomas also occur.
FAP variants. Gardner syndrome adds osteomas (e.g., mandibular), dental anomalies, soft-tissue tumors (desmoids, epidermoid cysts), and congenital hypertrophy of the retinal pigment epithelium. Turcot syndrome adds CNS tumors, medulloblastoma or glioma ("Turcot = Turban").
Lynch syndrome (HNPCC). Autosomal dominant germline mismatch-repair mutation (MLH1, MSH2) producing MSI. There are few polyps, but each progresses rapidly, giving proximal (right-sided) colon cancer at a young age. Endometrial cancer is the second most common Lynch cancer; others include gastric, small bowel, urothelial, ovarian and hepatobiliary cancers, plus sebaceous skin tumors (Muir-Torre variant). Suspect it when colorectal and endometrial cancers cluster across three relatives in two generations, with one diagnosed before age 50.
Hamartomatous syndromes. Peutz-Jeghers syndrome (autosomal dominant STK11/LKB1) combines hamartomatous GI polyps with mucocutaneous hyperpigmentation of the lips, oral mucosa, hands, and genitals; polyps can act as lead points for intussusception, and risk rises for GI, breast, pancreatic, and other cancers. Juvenile polyposis syndrome (autosomal dominant SMAD4/BMPR1A) causes numerous juvenile polyps in children under 5, with GI bleeding and increased colorectal cancer risk; a single sporadic juvenile polyp is benign.
| Syndrome | Gene (all AD) | Polyps | Extracolonic clues |
|---|---|---|---|
| FAP | APC (5q21) | Hundreds to thousands of adenomas | Gardner: osteomas, desmoids, dental anomalies; Turcot: CNS tumors |
| Lynch (HNPCC) | MLH1, MSH2 (mismatch repair) | Few adenomas, rapid progression | Endometrial, gastric, small bowel, urothelial, ovarian; sebaceous skin tumors |
| Peutz-Jeghers | STK11 (LKB1) | Hamartomas throughout GI tract | Lip and oral pigmentation; intussusception; breast, pancreatic cancer |
| Juvenile polyposis | SMAD4, BMPR1A | Numerous juvenile hamartomas (age <5) | GI bleeding |
Presentation, markers, and screening
Left vs right. Tumor location changes the presentation. The left colon (descending, sigmoid, rectum) has a narrow lumen and semisolid stool, so tumors grow circumferentially and obstruct: apple-core lesions, change in stool caliber, and hematochezia. The right colon (cecum, ascending) has a wide lumen and liquid stool, so exophytic tumors grow large and bleed occultly, presenting as iron-deficiency anemia and fatigue.
Iron-deficiency anemia in an older man (or postmenopausal woman) is colorectal cancer, classically right-sided, until proven otherwise.
Markers. CEA is used to monitor for recurrence and treatment response after resection, not for screening, because it is nonspecific. Streptococcus gallolyticus (formerly S. bovis) bacteremia or endocarditis is a red flag for occult colorectal cancer and should prompt colonoscopy.
Screening. Average-risk screening begins at age 45 with colonoscopy every 10 years, or alternatives: FIT yearly, FIT-DNA every 3 years, or CT colonography every 5 years. Higher-risk groups start earlier:
- FAP: around age 10–12.
- Lynch syndrome: around age 20–25.
- IBD: 8 years after diagnosis.