Colorectal Carcinoma

Overview

98% of large-bowel malignancies. Commonest visceral cancer death cause in US after lung. Avg age ~60. Rectal cancer 2:1 male; elsewhere equal.

Etiology

Geographic — high N.America/N.Europe, low S.America/Africa/Asia, correlates w/ affluence. Japan: LOW colon cancer but SIMILAR rectal cancer to US (colon≠rectal driver)
Dietary — ↓fibre→↓stool bulk→↑risk; ↑fat→cholesterol metabolites carcinogenic; ↑refined carbs→prolonged mucosal contact→altered flora→carcinogens
ADENOMA-CARCINOMA SEQUENCE — strong evidence:
- Early cancers show surrounding adenoma→hyperplasia→dysplasia→CIS→invasive sequence
- Adenoma incidence ∝ colorectal CA prevalence
- Endoscopic adenoma removal ↓ risk
- Adenoma peak precedes CA peak by yrs-decades
- Risk ↑ with: NUMBER (polyposis syndrome→near-certain CA), SIZE (larger=worse), TYPE (more villous=worse: tubular 5%, villous 30%, tubulovillous intermediate)
HNPCC/Lynch syndrome — AD, multiple 1° cancers (endometrium, ovary) + colorectal, NO polyposis. ≥2 generations, <50yrs, PROXIMAL colon predominant, BETTER prognosis than sporadic. Mismatch-repair genes hMLH2(chr2)/hMLH1(chr3) → DNA instability
Other: IBD (esp. UC), long-duration diverticular disease, smoking (younger patients)

Genetic basis — 2 mechanisms

1. APC/β-catenin mechanism — matches visible adenoma-carcinoma sequence:

APC loss (5q), 80% sporadic cases → β-catenin nuclear translocation → activates MYC+cyclin D1 → proliferation
K-RAS point mutation (after APC loss), 10-50%
DCC deletion (18q), 60-70%
p53 loss, 70-80%

2. Microsatellite instability mechanism — multiple gene mutations, NO visible morphologic sequence (contrast #1). 10-15% of cases. Basic defect = DNA repair gene loss → microsatellite instability (hallmark). Key genes: TGF-β receptor (normally inhibits proliferation), BAX (normally→apoptosis, defect→dysregulated growth)

Morphology

Distribution: rectum 60% > sigmoid/descending 25% > caecum/ileocaecal 10% > ascending/flexures 5% > transverse (rare).

Gross — RIGHT vs LEFT differ:

RIGHT: large cauliflower-like, soft, friable, FUNGATING POLYPOID — liquid content allows luminal growth
LEFT: NAPKIN-RING (annular, circumferential, fibrous, central ulcer, elevated margins) = “carcinomatous ulcer” — solid content favours wall spread
Early lesions both sides: small button-like elevations

Micro: right=left. 95% adenocarcinoma (10% mucin-secreting COLLOID/mucinous). Remaining 5%: undifferentiated, signet-ring, adenosquamous (near anus). Grade: well→mod→poor.

Spread

Direct (commonest) — circumferential + through wall to serosa/pericolic fat/±peritoneum
Lymphatic (fairly common) — regional→preaortic/internal iliac/sacral nodes
Haematogenous (LATE) — liver, lungs, brain, bones, ovary

Clinical features

Late-appearing: occult bleeding (melaena), bowel habit change (more L-sided), weight loss, anorexia, anaemia/weakness. Commonest complications: obstruction, haemorrhage. Less common: perforation, infection.

CEA: elevated 100% metastatic, 20-40% early, 60-70% advanced primary. PROGNOSTIC not diagnostic — also +ve in lung/breast/ovary/bladder/prostate CA + UC/pancreatitis/alcoholic cirrhosis.

Staging

Most important prognostic factor = STAGE at diagnosis. Systems: Dukes’ A-B-C(-D modified), Astler-Coller (most widely used, Dukes’ modification), TNM.

Other tumours

Other malignant: leiomyosarcoma, lymphoma, hindgut carcinoids (rectum/colon). Anal canal: SCC, basaloid, mucoepidermoid, adenocarcinoma, undifferentiated, malignant melanoma.

Clinical relevance

Right/left gross split explains presentation: right = silent bleeding→anaemia (liquid content masks bulky growth); left = early obstruction/habit change (annular narrowing). CEA = monitoring/prognostic marker only, NOT diagnostic/screening — low specificity, frequently tested distinction. Two genetic pathways: APC/β-catenin explains the classic VISIBLE adenoma-carcinoma sequence (majority of cases); MSI pathway explains cases where no visible precursor sequence exists — anchor both back to why adenomas are the precursor lesion.

Overview

Colorectal cancer comprises 98% of all malignant tumours of the large intestine, and is the commonest visceral cancer causing cancer deaths in the United States, second only to lung cancer. Incidence rises with age; average patient age is about 60 years. Rectal cancer is twice as common in males as females (2:1), while at other large-bowel sites the sex incidence is roughly equal.

Etiology

Geographic variation — much more common in North America and Northern Europe than South America, Africa, or Asia; correlates directly with socioeconomic affluence. Notably, Japan has much lower colon cancer incidence than the US, but similar rectal cancer incidence — showing colon and rectal cancer are not driven identically.
Dietary factors:
- Low vegetable-fibre intake → low stool bulk → higher risk.
- High fatty-food consumption → excess cholesterol and its metabolites, which may be carcinogenic.
- Excess refined carbohydrate → prolonged mucosal contact time → altered bacterial flora → carcinogenic byproducts.
Adenoma-carcinoma sequence — strong evidence that colonic adenocarcinoma evolves from pre-existing adenomas:
- Early invasive cancers often show surrounding tissue displaying the preceding evolution: adenoma → hyperplasia → dysplasia → carcinoma in situ → invasive carcinoma.
- Adenoma incidence in a population correlates directly with colorectal cancer prevalence.
- Endoscopic removal of all identified adenomas lowers subsequent cancer risk.
- Peak adenoma incidence precedes peak colorectal cancer incidence by years to decades.
- Malignancy risk rises with: number of adenomas (a syndrome with hundreds of polyps evolves to cancer almost inevitably), size of adenomas (larger = higher risk), and type (greater villous component = higher risk — tubular adenoma ~5%, villous ~30%, tubulovillous intermediate malignant potential).
Hereditary non-polyposis colonic cancer (HNPCC / Lynch syndrome) — autosomal dominant, with multiple primary cancers at different sites (endometrium, ovary) alongside colorectal cancer, but without the polyposis seen in the inherited polyp syndromes. Seen in ≥2 generations of first-degree relatives; occurs at a relatively early age (<50 years); located more often in the proximal colon; carries a better prognosis than sporadic colon cancer. Due to germline mutations in mismatch-repair genes — human mutL homologs hMLH2 (chromosome 2) and hMLH1 (chromosome 3) — resulting in DNA instability.
Other risk factors:
- Inflammatory bowel disease (especially ulcerative colitis).
- Long-duration diverticular disease (a low-fibre diet implicated in both diverticular disease and colorectal cancer pathogenesis).
- Tobacco smoking, particularly linked to earlier-onset disease in younger patients.

Genetic Basis of Colorectal Carcinogenesis

Sequential multistep mutations drive the evolution of colorectal cancer from adenomas, via one of two mechanisms:

1. APC mutation / β-catenin mechanism — generally associated with the morphologically identifiable adenoma-carcinoma sequence changes described above:

Loss of the tumour-suppressor APC gene (5q) — seen in 80% of sporadic colon cancers. APC’s function is linked to β-catenin; APC loss lets β-catenin translocate to the nucleus and activate transcription of MYC and cyclin D1, both of which drive cell proliferation.
Point mutation in K-RAS, following APC loss, in 10–50% of adenoma-carcinomas.
Deletion of DCC gene (18q, “deleted in colorectal cancer”) in 60–70% of colon cancers.
Loss of p53 tumour suppressor in 70–80% of colon cancers.

2. Microsatellite instability mechanism — multiple mutations of different genes, but without morphologically identifiable changes (unlike the APC pathway). Accounts for 10–15% of colon cancers. The basic defect is loss of a DNA repair gene, causing repetitive DNA sequences (microsatellites) to become unstable during replication — the defining hallmark of this pathway. Key DNA repair genes mutated:

TGF-β receptor gene — normally inhibits cell proliferation; mutated form permits uncontrolled colonic epithelial proliferation in adenoma.
BAX gene — normally causes apoptosis; a defect causes loss of apoptosis and dysregulated growth.

Morphology

Distribution: ~60% occur in the rectum, followed in descending order by sigmoid and descending colon (25%), caecum and ileocaecal valve (10%), ascending colon/hepatic/splenic flexures (5%), and quite uncommonly the transverse colon.

Gross — right- and left-sided growths differ distinctly:

Right-sided: large, cauliflower-like, soft, friable masses projecting into the lumen — fungating polypoid carcinoma.
Left-sided: napkin-ring configuration — encircle the bowel wall circumferentially with increased fibrous tissue forming an annular ring, central ulceration, slightly elevated margins — carcinomatous ulcers.
This right/left difference likely reflects luminal content consistency: liquid content in the ascending colon leaves room for luminal (polypoid) growth on the right, while more solid left-colon content favours spread into the bowel wall.
Early lesions on either side are small, button-like areas of elevation.

Microscopy — right- and left-sided growths look similar. About 95% of colorectal carcinomas are adenocarcinomas of varying differentiation, of which roughly 10% are mucin-secreting colloid (mucinous) carcinomas. The remaining 5% include uncommon patterns: undifferentiated carcinoma, signet-ring cell carcinoma, and adenosquamous carcinoma (more distal colon, near the anus). Histologic grade ranges well- to moderately- to poorly-differentiated.

Spread

Direct spread — commonest route; both circumferentially into the bowel wall and directly through the wall depth to serosa, pericolic fat, and sometimes the peritoneal cavity.
Lymphatic spread — occurs fairly commonly, first to regional nodes near the tumour, then to preaortic, internal iliac, and sacral nodes.
Haematogenous spread — occurs relatively late; involves liver, lungs, brain, bones, and ovary.

Clinical Features

Symptoms appear only after considerable time: occult bleeding (melaena), change in bowel habits (more marked in left-sided growths), weight loss (cachexia), loss of appetite (anorexia), anaemia, weakness, malaise. Commonest complications are obstruction and haemorrhage; perforation and secondary infection are less frequent.

Diagnostic tools: stool occult-blood test, PR examination, proctoscopy, radiographic contrast studies, CT scan. Carcinoembryonic antigen (CEA) is elevated in 100% of metastatic colorectal cancers, positive in 20–40% of early lesions and 60–70% of advanced primary lesions — but it has prognostic, not diagnostic, significance, since it is also positive in cancers of the lung, breast, ovary, urinary bladder, and prostate, as well as non-neoplastic conditions like ulcerative colitis, pancreatitis, and alcoholic cirrhosis.

Staging and Prognosis

Prognosis depends on: extent of bowel wall involvement, presence/absence of metastases, histologic grade, and tumour location — but the single most important prognostic factor is stage at diagnosis. Three staging systems are used:

Dukes’ A-B-C staging (modified Dukes’ adds stage D).
Astler-Coller staging — a further modification of Dukes’, most widely used.
TNM staging.

Other Malignant Large-Bowel and Anal Tumours

Besides colorectal carcinoma, other malignant tumours occasionally found in the large bowel are leiomyosarcoma and malignant lymphoma; hindgut carcinoids may also occur in the rectum and colon.

Anal canal epithelial tumours are uncommon and sometimes combine several histologic types. Among benign anal tumours, viral warts (condyloma acuminata) are the only tumour of note. Malignant anal canal tumours include squamous cell carcinoma, basaloid carcinoma, mucoepidermoid carcinoma, adenocarcinoma (rectal, anal gland, or anorectal fistula origin), undifferentiated carcinoma, and malignant melanoma — these resemble their morphologic counterparts elsewhere in the body.

Clinical Relevance

The right-versus-left gross morphology split (fungating polypoid vs napkin-ring/annular) is a genuinely useful clinical discriminator, since it maps onto different presenting symptoms — right-sided lesions bleed occultly and present with anaemia because the liquid luminal content lets bulky polypoid growth develop silently before obstructing; left-sided annular lesions narrow the lumen early and present with an altered bowel habit or obstruction.
CEA’s role is a frequently tested distinction: it is a monitoring/prognostic marker, not a diagnostic or screening one, because it lacks specificity for colorectal cancer and can be elevated in several non-neoplastic conditions.
The two-pathway molecular genetics (APC/β-catenin producing the classic visible adenoma-carcinoma morphologic sequence, versus microsatellite instability producing no equivalent visible sequence) is worth anchoring to the adenoma-carcinoma sequence discussion — the APC pathway is the one that actually explains why adenomas are the precursor lesion in the majority of cases.

Adenoma-carcinoma sequence with the two molecular pathways (APC/β-catenin vs microsatellite instability) branching off it
Right-sided fungating polypoid growth vs left-sided napkin-ring growth, side by side