Colorectal Cancer

Colorectal cancer (CRC) is the third commonest cancer worldwide and a perennial favourite in NEET PG GI surgery. This note ties together the molecular pathways, hereditary syndromes, the classic right-vs-left clinical split, Duke's and TNM staging, the operation for each segment, and the principles of adjuvant therapy.

Definition & Epidemiology

Colorectal cancer is a malignant neoplasm (>95% adenocarcinoma) arising from the epithelium of the colon or rectum. The sigmoid colon and rectum together account for the majority of cases. Peak incidence is in the 6th–7th decades; sporadic CRC is rare before 40 unless a hereditary syndrome is present. Men are affected slightly more often, and there is a definite Westernised-diet association.

High-yield: Over 95% of colorectal cancers are adenocarcinomas. The commonest single site overall is the rectosigmoid region.

Risk Factors

Risk factors are heavily tested, so commit them to memory in clusters.

Category	Specific risk factors
Dietary/lifestyle	Red & processed meat, low fibre, obesity, smoking, alcohol, sedentary life
Inflammatory	Ulcerative colitis (> Crohn's), >8–10 yrs duration, pancolitis, PSC
Hereditary syndromes	FAP, Gardner, Turcot, HNPCC (Lynch), MUTYH-associated polyposis, Peutz–Jeghers, juvenile polyposis
Polyps	Adenomatous polyps (villous > tubulovillous > tubular), size >2 cm, high-grade dysplasia
Others	Prior CRC, family history, Streptococcus bovis (gallolyticus) endocarditis, ureterosigmoidostomy, acromegaly, prior pelvic radiation

High-yield: Streptococcus bovis (S. gallolyticus) bacteraemia/endocarditis mandates a colonoscopy to exclude an occult colonic carcinoma.

Polyp malignant potential: villous > tubulovillous > tubular adenoma. Risk rises with size (>2 cm), sessile architecture, and high-grade dysplasia. Hyperplastic polyps are generally benign, but sessile serrated lesions can progress via the serrated pathway.

Hereditary Syndromes (must-know)

Familial Adenomatous Polyposis (FAP)

• Autosomal dominant; mutation of the APC gene on chromosome 5q21.
• Hundreds–thousands of adenomatous polyps carpet the colon by the teens/twenties.
• ~100% lifetime risk of CRC if untreated → prophylactic total proctocolectomy (or restorative proctocolectomy with ileal pouch–anal anastomosis) is recommended.
• Gardner syndrome = FAP + osteomas (mandible/skull) + epidermoid cysts + desmoid tumours + supernumerary teeth.
• Turcot syndrome = FAP/HNPCC + CNS tumours (medulloblastoma with APC; glioblastoma with mismatch-repair defects).
• CHRPE (congenital hypertrophy of retinal pigment epithelium) is an early ophthalmologic marker.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC / Lynch)

• Autosomal dominant; defective DNA mismatch-repair (MMR) genes — MLH1, MSH2, MSH6, PMS2 → microsatellite instability (MSI).
• CRC is predominantly right-sided, occurs young (~45 yrs), and is often mucinous/poorly differentiated but paradoxically has a better stage-for-stage prognosis.
• Lynch I = colon only; Lynch II = colon + extracolonic (endometrial — commonest extracolonic, ovary, stomach, urothelium, small bowel).
• Diagnosed clinically by the Amsterdam II criteria ("3-2-1" rule) and Bethesda guidelines for MSI testing.

High-yield mnemonic — Amsterdam "3-2-1-0": 3 affected relatives (one a first-degree relative of the other two), spanning 2 successive generations, with 1 diagnosed before age 50, and FAP excluded (0 polyposis).

Feature	FAP	HNPCC (Lynch)
Gene	APC (5q21)	MMR: MLH1/MSH2/MSH6/PMS2
Inheritance	Autosomal dominant	Autosomal dominant
Polyps	Hundreds–thousands	Few (non-polyposis)
Site	Diffuse, often left	Predominantly right colon
Age at CRC	20s–30s	~45
Lifetime CRC risk	~100%	~70–80%
Extracolonic	Desmoids, osteomas, CHRPE	Endometrial, ovary, gastric, urothelial
Molecular hallmark	Chromosomal instability	Microsatellite instability (MSI)

Pathophysiology — Molecular Pathways

Two principal pathways generate CRC; both are favourite single-best-answer fodder.

1. Adenoma–carcinoma (chromosomal instability, ~85%) sequence:

Normal epithelium → APC loss (5q) → hyperproliferative epithelium → KRAS activation (12p) → adenoma → DCC/SMAD4 loss (18q) → TP53 loss (17p) → carcinoma.

High-yield: The first/earliest genetic hit in the classic Vogelstein sequence is loss of the APC tumour-suppressor gene. p53 loss is a late event marking transition to invasive carcinoma.

2. Microsatellite instability (MMR) pathway (~15%): defective mismatch repair → accumulation of replication errors in microsatellites; underlies Lynch syndrome and some sporadic tumours (sporadic ones often via MLH1 promoter hypermethylation, frequently with BRAF V600E mutation). MSI-high tumours respond well to immune checkpoint inhibitors (pembrolizumab).

Gross morphology differs by side: right colon → polypoidal/fungating (wide caecal lumen, liquid stool) and left colon → annular "napkin-ring" constricting/stenosing (narrow lumen, solid stool), explaining the clinical patterns below.

Clinical Features — Right vs Left Colon

This split is one of the most repeated NEET PG concepts.

Feature	Right (caecum/ascending)	Left (descending/sigmoid)
Lumen & stool	Wide lumen, liquid stool	Narrow lumen, solid stool
Growth pattern	Polypoidal, fungating	Annular, constricting (napkin-ring)
Dominant symptom	Anaemia, fatigue, weight loss, mass	Obstruction, altered bowel habits, bleeding
Bleeding type	Occult (microcytic anaemia)	Fresh/altered blood, mixed with stool
Presentation	Late, insidious	Earlier (obstructive)
Classic exam clue	Iron-deficiency anaemia in elderly male	Change in bowel habit + tenesmus (rectal)

High-yield: Unexplained iron-deficiency anaemia in an elderly patient = right colon carcinoma until proven otherwise → colonoscopy. Left-sided tumours present early with obstruction and change in bowel habit.

Rectal carcinoma: bleeding per rectum, tenesmus, sense of incomplete evacuation, mucus discharge, and spurious diarrhoea. Digital rectal examination detects a significant proportion of rectal cancers and is mandatory.

Diagnosis & Investigation of Choice

Stepwise approach:

Suspicion → DRE → Colonoscopy + biopsy (investigation of choice) → CT chest/abdomen/pelvis for staging → CEA baseline → (rectal) MRI pelvis ± endorectal USS.

• Colonoscopy with biopsy is the gold-standard/investigation of choice — visualises the whole colon, allows biopsy and synchronous-lesion detection (3–5% synchronous tumours).
• CT colonography is an alternative when colonoscopy is incomplete/contraindicated.
• Barium enema (now largely historical) shows the classic "apple-core" / "napkin-ring" filling defect of an annular left-sided lesion.
• CEA (carcinoembryonic antigen): not for screening/diagnosis (poor sensitivity, raised in smoking, cirrhosis, pancreatitis). Its value is prognosis, baseline before surgery, and detecting recurrence on follow-up. A rising CEA after curative resection suggests recurrence.
• Rectal cancer local staging: MRI pelvis (best for T-stage, circumferential resection margin, mesorectal nodes) and endorectal ultrasound (best for early T1/T2 differentiation).
• Metastatic work-up: CT chest/abdomen/pelvis; liver is the commonest site of haematogenous spread (via portal vein). PET-CT for equivocal/recurrent disease.

High-yield: CEA is a follow-up/prognostic marker, NOT a screening or diagnostic test. It is most useful for detecting recurrence after curative resection.

Screening

• Average-risk: begin at age 45–50, colonoscopy every 10 years (or FIT/FOBT annually, flexible sigmoidoscopy 5-yearly, CT colonography 5-yearly).
• FAP: annual sigmoidoscopy/colonoscopy from 10–12 years, plus upper GI surveillance.
• HNPCC: colonoscopy every 1–2 years from 20–25 years (or 10 years younger than the youngest case).
• IBD: surveillance colonoscopy from 8–10 years after pancolitis onset.

Staging — Duke's & TNM

Modified Astler–Coller / Duke's classification:

Duke's	Extent	Approx. 5-yr survival
A	Confined to bowel wall (not through muscularis)	>90%
B	Through bowel wall, no nodes	~70%
C	Regional lymph nodes involved (C1 apical node −, C2 apical node +)	~30–60%
D (added later)	Distant metastases	<10%

TNM (AJCC) — now standard:

• T: T1 submucosa → T2 muscularis propria → T3 through into pericolic/perirectal tissue → T4 visceral peritoneum/adjacent organs.
• N: N0 none; N1 1–3 nodes; N2 ≥4 nodes.
• M: M0 / M1 (M1a single organ, M1b multiple, M1c peritoneum).

High-yield: Nodal status (N / Duke's C) is the single most important prognostic factor in non-metastatic CRC. The number of nodes harvested (≥12 for adequate staging) and the apical node status (Duke's C1 vs C2) matter for prognosis and adjuvant decisions.

Management — Surgery by Site

Surgery is the only curative modality. The operation is dictated by tumour location and its blood supply / lymphatic drainage (segmental resection with the feeding vessel ligated at origin for adequate lymphadenectomy).

Tumour site	Operation	Vessel ligated
Caecum / ascending colon	Right hemicolectomy	Ileocolic, right colic, right branch middle colic
Hepatic flexure	Extended right hemicolectomy	+ middle colic
Transverse colon	Extended right hemicolectomy (or transverse colectomy)	Middle colic
Splenic flexure / descending	Left hemicolectomy	Left colic ± IMA
Sigmoid colon	Sigmoid colectomy / high anterior resection	IMA
Upper/mid rectum	Anterior resection (AR) with TME	IMA
Low rectum (sphincter spared)	Low anterior resection (LAR)	IMA
Very low / anal-involving rectum	Abdominoperineal resection (APR) + permanent colostomy	IMA

Key surgical principles:

• Total mesorectal excision (TME) is the standard for rectal cancer — sharp dissection in the avascular mesorectal plane (Heald's plane); dramatically reduces local recurrence.
• Distal margin: ~5 cm for colon; ≥1–2 cm distal clearance acceptable for rectum (allows sphincter preservation in LAR).
• APR (Miles' operation) removes rectum + anus + sphincters → permanent end colostomy; reserved for tumours too low to preserve continence.
• Circumferential resection margin (CRM) positivity (rectum) is a strong predictor of local recurrence.
• Obstructing left-sided tumour: options include Hartmann's procedure (resection + end colostomy + closed rectal stump), primary resection–anastomosis ± defunctioning stoma, or colonic stenting as a bridge to surgery.
• Liver metastases: isolated, resectable liver mets can be treated with metastasectomy for potential cure — CRC is the classic tumour where liver resection improves survival.

High-yield: APR = permanent colostomy and is used for very low rectal cancers; Anterior resection preserves the anal sphincter. TME is the gold-standard rectal cancer surgery.

Adjuvant / Neoadjuvant Therapy

• Colon cancer: adjuvant chemotherapy for Duke's C (stage III, node-positive) and high-risk stage II. Regimen of choice = FOLFOX (5-FU + leucovorin + oxaliplatin) or CAPOX. Adjuvant radiotherapy is generally NOT used for colon cancer (mobile, small-bowel toxicity).
• Rectal cancer: neoadjuvant chemoradiotherapy (long-course CRT or short-course RT) for locally advanced (T3/T4 or node-positive) tumours to downstage, improve resectability and reduce local recurrence — radiotherapy IS valuable here because the rectum is fixed in the pelvis. Total neoadjuvant therapy (TNT) is increasingly standard.
• Metastatic disease: systemic chemo + targeted agents — anti-EGFR (cetuximab/panitumumab) only if RAS wild-type; anti-VEGF (bevacizumab). MSI-high/dMMR tumours → immunotherapy (pembrolizumab).
• 5-FU mechanism: inhibits thymidylate synthase (anti-metabolite).

High-yield: Cetuximab/panitumumab work only in KRAS/RAS wild-type tumours; RAS-mutant tumours do not respond to anti-EGFR therapy.

Complications

• Obstruction (esp. left-sided annular tumours) and perforation (caecum by Laplace's law in distal obstruction, or at tumour site) → emergency presentation.
• Bleeding → chronic anaemia or, rarely, massive lower GI bleed.
• Local invasion: fistulae (colovesical → pneumaturia/faecaluria), ureteric obstruction.
• Metastasis: liver (commonest, portal spread), then lung, peritoneum (→ malignant ascites), bone, brain. Krukenberg-type ovarian deposits can occur.
• Post-operative: anastomotic leak (most feared, esp. low rectal/colorectal anastomoses), stoma complications, sexual/urinary dysfunction after TME (pelvic autonomic nerve injury).

Key Differentials

• Benign polyps / adenomas — distinguished on biopsy.
• Diverticular disease / stricture — can mimic an annular left-sided cancer on imaging; biopsy is decisive.
• Inflammatory bowel disease — itself a risk factor; surveillance biopsies differentiate dysplasia/cancer.
• Ischaemic colitis / infective colitis — present with bleeding and altered habit.
• Caecal/appendiceal pathology — appendicular mass, caecal TB (ileocaecal), lymphoma, carcinoid.
• Other tumours: GI lymphoma, GIST, carcinoid (appendix/rectum).

Recently asked / exam angle

• "Earliest gene mutated in adenoma–carcinoma sequence?" → APC.
• "Elderly man with iron-deficiency anaemia, occult blood positive — most likely site?" → Right (caecum) colon.
• "Best investigation for colorectal cancer?" → Colonoscopy with biopsy.
• "CEA is used for?" → Follow-up/recurrence and prognosis, NOT screening.
• "Operation for low rectal cancer involving the sphincter?" → Abdominoperineal resection (APR) with permanent colostomy.
• "Gene in HNPCC / molecular hallmark?" → Mismatch-repair genes / microsatellite instability.
• "Amsterdam criteria numbers?" → 3-2-1 rule.
• "Adjuvant regimen for stage III colon cancer?" → FOLFOX.
• "Anti-EGFR antibody works only when?" → RAS/KRAS wild-type.
• "Gold-standard surgery for rectal cancer?" → Total mesorectal excision (TME).
• "Streptococcus bovis endocarditis — next step?" → Colonoscopy.

Rapid revision

1. 95% of CRC = adenocarcinoma; commonest site = rectosigmoid.

2. APC = earliest hit; p53 = late hit; nodal status = strongest prognostic factor.
3. FAP → APC gene, ~100% CRC risk → prophylactic colectomy; Gardner = FAP + osteomas/desmoids; Turcot = + brain tumour.
4. HNPCC/Lynch → MMR genes, MSI, right-sided, young, Amsterdam 3-2-1; commonest extracolonic = endometrial.
5. Right colon → anaemia/mass (fungating); left colon → obstruction/altered habit (annular napkin-ring).
6. Investigation of choice = colonoscopy + biopsy; barium shows apple-core lesion.
7. CEA = recurrence/prognosis marker, never for screening.
8. Duke's: A wall, B through wall, C nodes, D mets.
9. Right hemicolectomy (caecum→ ileocolic vessel); APR = permanent colostomy for low rectum; AR preserves sphincter; TME for rectum.
10. Adjuvant FOLFOX for stage III colon; neoadjuvant chemoradiotherapy for locally advanced rectal cancer.
11. Cetuximab/panitumumab only if RAS wild-type; pembrolizumab for MSI-high.
12. Commonest metastatic site = liver (portal spread); isolated liver mets are resectable for cure.