Tutorial 12: Colorectal Cancer

Colorectal cancer (CRC) is the third most common cancer worldwide. The vast majority (>95%) are adenocarcinomas arising from the mucosal glandular epithelium of the colon and rectum. CRC incidence rises sharply after the age of 50; risk factors include low dietary fibre intake, high red and processed meat consumption, obesity, physical inactivity, type 2 diabetes, alcohol, and smoking. Chronic inflammatory bowel disease (especially ulcerative colitis) also confers significantly increased risk.

The adenoma-carcinoma sequence is the dominant pathway in sporadic CRC. An adenomatous polyp (adenoma) is a premalignant lesion characterised histologically by dysplastic epithelium — cells with enlarged hyperchromatic nuclei, increased mitoses, and loss of normal glandular architecture. Adenomas may be pedunculated (on a stalk) or sessile (flat, higher malignant risk). The lifetime risk of malignant transformation in a single adenoma is 5%; risk increases with size, degree of dysplasia (high-grade > low-grade), and villous architecture. The underlying molecular event is mutation of the APC tumour suppressor gene (chromosome 5q21), which encodes a negative regulator of the Wnt/β-catenin signalling pathway; loss of APC leads to nuclear accumulation of β-catenin, driving proliferation.

Familial adenomatous polyposis (FAP) is caused by germline APC mutations (autosomal dominant). Hundreds to thousands of adenomatous polyps develop throughout the colon from adolescence onwards; malignant transformation to CRC is virtually inevitable by the fourth decade without prophylactic colectomy.

The mismatch repair (MMR) pathway corrects replication errors in microsatellite sequences (short tandem repeats). Loss-of-function mutations in MMR genes (MLH1, MSH2, MSH6, PMS2) result in microsatellite instability (MSI) — the accumulation of mutations in microsatellite sequences throughout the genome. Hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) is caused by germline MMR gene mutations (autosomal dominant); it accounts for approximately 2–5% of all CRC. Lynch syndrome predisposes to right-sided colon cancers, as well as endometrial, ovarian, gastric, pancreatic, and urothelial cancers. MLH1 is silenced by promoter methylation (an epigenetic mechanism) in approximately 15% of sporadic MSI-high CRC.

Clinical presentation differs by tumour location. Right-sided (ascending) colon cancers grow as polypoid masses into the wide lumen and bleed occultly, causing iron deficiency anaemia (fatigue, pallor). They rarely cause obstruction. In older men and postmenopausal women, iron deficiency anaemia should be considered GI cancer until proven otherwise. Left-sided (descending/sigmoid/rectal) cancers grow as annular constricting lesions ("apple-core" appearance on barium enema) in the narrower lumen, causing change in bowel habit (alternating constipation and diarrhoea), rectal bleeding (fresh blood), and bowel obstruction. Rectal cancers may also cause tenesmus.

Investigation: colonoscopy (gold standard — visualises and biopsies lesions); CT colonography; faecal immunochemical test (FIT) for occult blood (population screening); CEA (carcinoembryonic antigen) is not diagnostic but useful for monitoring recurrence post-resection. TNM staging determines resectability and prognosis: stage I–II (localised) have >80% 5-year survival; stage IV (distant metastasis — liver and lung most common) have <15% 5-year survival. Treatment is surgical resection (hemicolectomy or anterior resection for rectal cancer) with adjuvant chemotherapy for stage III (node-positive) disease.