Colorectal Carcinoma & Polyps

Colorectal carcinoma (CRC) is the prototype of the adenoma–carcinoma sequence, where a benign neoplastic polyp accumulates stepwise genetic hits and turns malignant. This topic links surgical pathology, molecular genetics (APC, KRAS, p53, mismatch-repair genes) and staging — a perennial NEET PG favourite. Read it as one continuum: polyp → dysplasia → invasive carcinoma → metastasis.

Classification of Colorectal Polyps

A polyp is any mass projecting into the gut lumen. The single most important distinction is neoplastic vs non-neoplastic, because only neoplastic (adenomatous) polyps carry malignant potential.

Polyp type	Nature	Malignant potential	Key facts
Hyperplastic polyp	Non-neoplastic	Nil (classic)	Commonest polyp overall; serrated "saw-tooth" crypts; usually rectosigmoid, <5 mm
Sessile serrated lesion (SSL/SSA)	Neoplastic (serrated pathway)	Yes	Right colon, BRAF mutation, CpG methylation (CIMP), MSI-high
Inflammatory / pseudopolyp	Non-neoplastic	Nil	Regenerating mucosa in ulcerative colitis
Hamartomatous (juvenile, Peutz-Jeghers)	Non-neoplastic (mostly)	Low but real in syndromes	Juvenile = commonest polyp in children
Adenoma (tubular/villous/tubulovillous)	Neoplastic	Yes — premalignant	Defined by epithelial dysplasia

High-yield: All adenomas are by definition dysplastic. The presence of dysplasia is what makes an adenoma neoplastic and premalignant.

Adenomatous Polyps — Subtypes & Malignant Potential

Adenomas are subtyped by architecture:

Subtype	Architecture	Frequency	Malignant potential
Tubular adenoma	>75% tubular glands; usually pedunculated	~80% (commonest)	Lowest
Tubulovillous	Mixed 25–75% villous	~10–15%	Intermediate
Villous adenoma	>50% finger-like villous fronds; sessile, large, often rectosigmoid	~5–10% (least common)	Highest

Three factors increase the risk of malignancy in an adenoma — remember "SVD" → Size, Villous architecture, Degree of dysplasia:

1. Size → >4 cm carries the greatest risk; <1 cm is low risk.
2. Villous histology → villous > tubulovillous > tubular.
3. High-grade dysplasia present.

High-yield: A villous adenoma has the highest malignant potential and is classically associated with secretory diarrhoea causing hypokalaemia (loss of potassium-rich mucus) — a repeatedly tested clinical pearl.

High-yield: Sessile polyps are more likely to be malignant than pedunculated ones; the stalk in a pedunculated polyp acts as a barrier delaying invasion.

The Adenoma–Carcinoma Sequence (Molecular Pathways)

CRC arises through two principal molecular routes. The classic chromosomal instability (CIN / APC) pathway accounts for ~80%; the microsatellite instability (MSI) pathway accounts for ~15%.

APC/β-catenin (CIN) pathway flow:

Normal mucosa → loss of APC (5q21; "gatekeeper", first hit) → at-risk mucosa → DNA hypomethylation + KRAS mutation (12p) → adenoma → loss of 18q (DCC/SMAD) → → TP53 (17p) loss → invasive carcinoma.

Mnemonic for the order: "APC → KRAS → DCC → p53" = "A K D P" ("All Kids Dislike Pathology").

High-yield: APC is the earliest and most important mutation in sporadic CRC and the gatekeeper for the CIN pathway. TP53 loss marks the transition from adenoma to invasive carcinoma.

MSI (mismatch-repair / microsatellite instability) pathway:

Defective DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2) → failure to correct replication errors → accumulation of mutations in microsatellite (repeat) regions → MSI-high tumours. Sporadic MSI is usually due to MLH1 promoter hypermethylation (often with BRAF V600E mutation). Hereditary MSI = Lynch syndrome.

High-yield: MSI-high CRC tends to be right-sided, poorly differentiated/mucinous, with tumour-infiltrating lymphocytes (Crohn-like reaction), yet carries a better prognosis and responds to immune checkpoint inhibitors (pembrolizumab). However, MSI-high tumours are resistant to 5-FU.

Hereditary CRC Syndromes

Familial Adenomatous Polyposis (FAP)

• Autosomal dominant, germline mutation of APC gene (chromosome 5q21).
• Hundreds to thousands (>100, often >1000) of colonic adenomas appearing in teens.
• Virtually 100% lifetime risk of CRC → prophylactic total proctocolectomy is standard.
• Variants:
  • Gardner syndrome = FAP + osteomas (mandible/skull), epidermoid cysts, desmoid tumours, supernumerary teeth, CHRPE (congenital hypertrophy of retinal pigment epithelium).
  • Turcot syndrome = colonic polyposis + CNS tumours (medulloblastoma with APC; glioblastoma with MMR genes).
• Attenuated FAP = fewer polyps (<100), later onset, proximal colon.

High-yield: FAP = APC gene, chromosome 5q21, autosomal dominant, ~100% progression to carcinoma. Gardner = osteomas + soft-tissue tumours; Turcot = brain tumours.

Lynch Syndrome (HNPCC — Hereditary Non-Polyposis Colorectal Cancer)

• Autosomal dominant, germline mutation of MMR genes — MSH2 (most common overall via large deletions) and MLH1 are the principal players; also MSH6, PMS2.
• Few or no polyps, but rapid progression of the few adenomas present.
• Right-sided (proximal) predominance, younger age, often synchronous/metachronous tumours.
• Increased risk of extracolonic cancers — endometrial (commonest extracolonic; ~2nd overall in women), ovarian, gastric, small bowel, urothelial (ureter/renal pelvis), and sebaceous tumours (Muir-Torre variant).

Amsterdam II criteria (the "3-2-1 rule") for clinical diagnosis:

• 3 relatives with Lynch-associated cancer (one a first-degree relative of the other two).
• 2 successive generations affected.
• 1 diagnosed before age 50.
• FAP excluded; tumours verified.

The Bethesda guidelines are used to select tumours for MSI testing.

High-yield: Lynch syndrome — MLH1/MSH2 mutation, microsatellite instability, few polyps but high cancer risk, right colon, and endometrial carcinoma as the leading extracolonic malignancy. Diagnose clinically with Amsterdam II (3-2-1) criteria.

Feature	FAP	Lynch (HNPCC)
Gene	APC (5q21)	MMR — MLH1, MSH2, MSH6, PMS2
Mechanism	Chromosomal instability	Microsatellite instability
No. of polyps	Hundreds–thousands	Few / none
Site	Left colon predominant	Right colon predominant
Onset	Teens	~45 years
Extracolonic	Osteomas, desmoids, CHRPE (Gardner)	Endometrial, ovarian, urothelial, gastric
CRC risk	~100%	~80%

Clinical Features of Colorectal Carcinoma

CRC presentation depends strongly on site, a classic exam discriminator:

Right (caecum/ascending) colon	Left (descending/sigmoid) colon
Wide lumen, liquid stool	Narrow lumen, semisolid/solid stool
Polypoidal / fungating lesion	Annular "napkin-ring" / constricting lesion
Iron-deficiency anaemia, fatigue, occult bleeding	Obstruction, change in bowel habit, alternating constipation/diarrhoea
Mass may be palpable	Pencil-thin stools, fresh blood (haematochezia)

High-yield: Right-sided CRC bleeds (anaemia); left-sided CRC obstructs. An elderly patient with unexplained iron-deficiency anaemia must be evaluated for a right colon carcinoma until proven otherwise.

Rectal carcinoma presents with bleeding per rectum, tenesmus, and a sense of incomplete evacuation.

Diagnosis & Investigation of Choice

Diagnostic flow:

Suspicion (symptoms / positive screening) → Colonoscopy + biopsy (investigation of choice; allows visualisation, biopsy and polypectomy) → histopathology confirms adenocarcinoma → staging with CT chest/abdomen/pelvis (± MRI pelvis for rectal CA, endorectal USG for T-stage) → baseline CEA.

• Screening: average-risk adults from 45 years — colonoscopy every 10 years, or annual FIT (faecal immunochemical test)/FOBT, or CT colonography. Colonoscopy is the gold-standard screening + diagnostic tool.
• Histology: ~95% are adenocarcinomas. Mucinous (colloid) and signet-ring subtypes carry a worse prognosis.
• CEA (carcinoembryonic antigen): NOT for screening or diagnosis. Used for prognosis, monitoring response, and detecting recurrence during follow-up. A rising CEA post-resection suggests recurrence.

High-yield: Colonoscopy with biopsy is the investigation of choice. CEA is a follow-up/recurrence marker, not a screening test. Screening now begins at age 45.

Staging — Dukes & TNM

The original Dukes staging (and Astler-Coller modification) is still examined:

Dukes stage	Extent	Approx. 5-yr survival
A	Limited to bowel wall (not through muscularis propria)	>90%
B	Through muscularis propria into serosa/pericolic tissue, no nodes	~70%
C	Regional lymph node involvement	~30–50%
D (added later)	Distant metastasis (commonest = liver)	<10%

AJCC TNM (current standard):

• T — depth: Tis (in situ) → T1 submucosa → T2 muscularis propria → T3 through into pericolorectal tissue → T4 visceral peritoneum/adjacent organs.
• N — N0 none; N1 (1–3 nodes); N2 (≥4 nodes).
• M — M0 none; M1 distant metastasis.

High-yield: Lymph node status (N) is the single most important prognostic factor; depth of invasion (T) is next. The liver is the commonest site of distant (haematogenous) metastasis via the portal vein; lung is next.

Management & Drug of Choice

• Localised colon cancer → surgical resection (segmental colectomy with regional lymphadenectomy) is the mainstay and only curative modality.
• Adjuvant chemotherapy for node-positive (Stage III) disease: FOLFOX = 5-Fluorouracil + Leucovorin + Oxaliplatin. 5-FU is the backbone cytotoxic drug.
• Rectal cancer: neoadjuvant chemoradiation followed by total mesorectal excision (TME) — radiotherapy has a defined role in rectum (not in colon, due to small-bowel toxicity).
• Metastatic disease — targeted agents:
  • Anti-VEGF: bevacizumab.
  • Anti-EGFR: cetuximab / panitumumab — effective only in KRAS/RAS wild-type tumours (RAS mutation predicts non-response).
  • MSI-high/dMMR tumours → immunotherapy (pembrolizumab/nivolumab).

High-yield: 5-FU is the backbone chemotherapeutic; anti-EGFR (cetuximab) works only in RAS wild-type tumours; MSI-high tumours respond to checkpoint inhibitors but are resistant to 5-FU.

Complications

• Intestinal obstruction (left-sided annular tumours) — may present as acute large-bowel obstruction.
• Perforation → peritonitis; or contained perforation forming an abscess.
• Iron-deficiency anaemia from chronic occult blood loss (right-sided).
• Liver metastasis — commonest distant spread; raised alkaline phosphatase, hepatomegaly.
• Streptococcus bovis (S. gallolyticus) endocarditis / bacteraemia — classic association demanding colonoscopy to exclude an underlying colonic carcinoma.
• Clostridium septicum infection also associated with occult CRC.

High-yield: Streptococcus bovis endocarditis → look for colon cancer. A heavily tested association.

Key Differentials

• Diverticular disease / diverticulitis — can mimic a constricting sigmoid carcinoma on imaging; both cause altered bowel habit and bleeding.
• Inflammatory bowel disease (ulcerative colitis) — long-standing pancolitis is itself a CRC risk factor; pseudopolyps must not be mistaken for adenomas. UC-associated dysplasia is flat and arises without an adenoma precursor.
• Ischaemic colitis — bloody diarrhoea, "thumb-printing" at splenic flexure.
• Infective colitis / amoebic colitis — amoeboma can mimic a caecal mass.
• Other colonic tumours — carcinoid (rectum), GIST, lymphoma.

High-yield: In ulcerative colitis, cancer arises from flat dysplasia, NOT through the adenoma–carcinoma sequence; risk rises with duration (>8–10 yrs), extent (pancolitis), and co-existing primary sclerosing cholangitis.

Recently asked / exam angle

• "Villous adenoma is associated with which electrolyte abnormality?" → Hypokalaemia (secretory diarrhoea).
• "Earliest genetic event in colorectal carcinogenesis (sporadic)?" → APC mutation.
• "Gene defective in Lynch syndrome?" → MMR genes — MLH1 / MSH2; mechanism = microsatellite instability.
• "FAP gene and chromosome?" → APC on 5q21, autosomal dominant.
• "Commonest site of distant metastasis in CRC?" → Liver.
• "Tumour marker for follow-up of CRC?" → CEA (not screening).
• "Which side of colon presents with anaemia?" → Right; obstruction → left.
• "Most important prognostic factor?" → Lymph node status (TNM N stage).
• "Streptococcus bovis endocarditis points to?" → Colon carcinoma.
• "MSI-high tumour — prognosis and drug response?" → Better prognosis, responds to immunotherapy, resistant to 5-FU.
• Image-based: serrated "saw-tooth" crypts (hyperplastic/SSL) vs villous fronds (villous adenoma).

Rapid revision

1. Only adenomatous (and serrated) polyps are premalignant; all adenomas are dysplastic by definition.
2. Tubular = commonest, lowest risk; villous = highest malignant potential + hypokalaemia.
3. Malignant risk ↑ with size >4 cm, villous architecture, high-grade dysplasia (SVD).
4. Sporadic CRC = APC → KRAS → DCC → TP53 (CIN pathway); APC is the gatekeeper, p53 marks invasion.
5. FAP = APC (5q21), AD, >100 polyps, ~100% cancer risk → prophylactic colectomy.
6. Gardner = osteomas/desmoids/CHRPE; Turcot = brain tumours.
7. Lynch = MLH1/MSH2, MSI, few polyps, right colon, endometrial cancer; diagnose by Amsterdam II (3-2-1).
8. Right colon → anaemia/fungating; left colon → obstruction/napkin-ring.
9. Colonoscopy + biopsy = investigation of choice; CEA = recurrence marker; screen from age 45.
10. Dukes C / TNM N = nodes; liver = commonest metastasis; nodal status = top prognostic factor.
11. Treatment: surgery + FOLFOX (5-FU based); cetuximab only in RAS wild-type; MSI-high → pembrolizumab.
12. Streptococcus bovis endocarditis → hunt for colorectal carcinoma.