Colorectal Cancer | Clinical Medicine

Right- and Left-Sided Disease Mapped by Anatomy Right-sided cancers include cecum, ascending colon, and transverse colon up to the splenic flexure, most often the ascending colon. Left-sided cancers involve the splenic flexure, descending colon, sigmoid colon, and rectum, most often at the rectosigmoid junction. This anatomical divide shapes presentation, growth patterns, and treatment choices.

Right Colon’s Wide Lumen Hides Disease The right colon’s wide lumen and liquid stool make obstruction uncommon. Tumors tend to ulcerate and bleed, the blood mixing with stool and escaping detection. Occult gastrointestinal bleeding leads to iron deficiency anemia or positive stool blood tests, while many patients remain otherwise asymptomatic.

Left Colon Obstruction Signals Trouble The left colon’s smaller lumen and solid stool promote obstructive symptoms. Strictures force stool through narrow channels, producing pencil-thin stools, tenesmus, and constipation. Small amounts of liquid stool may intermittently pass, mimicking diarrhea. Bleeding often coats the stool, making hematochezia visible.

From Mutated Epithelium to Carcinoma Colorectal cancers arise from mucosal epithelium through accumulating mutations. An initial genetic hit creates a mutated but subtle epithelium, followed by additional defects that drive unchecked proliferation. Adenomas emerge and can progress to invasive carcinoma as regulatory safeguards fail.

Serrated Pathway: BRAF and Mismatch Repair Silencing In the serrated pathway, a BRAF mutation constitutively drives proliferative signaling. Subsequent CpG methylation silences mismatch repair genes, preventing correction of replication errors. Sessile serrated adenomas form without stalks and are easily missed on colonoscopy. These lesions can progress rapidly to carcinoma and account for a minority of cases.

Microsatellite Instability: Flat, Fast, and Right-Sided Microsatellite instability stems from mutations in mismatch repair genes, inherited or sporadic. Secondary changes, such as transforming growth factor beta alterations and BAX inactivation, fuel growth and impair apoptosis. Flat adenomas arise, subtle on endoscopy yet prone to swift malignant transformation. This pathway is characteristic of right-sided disease and Lynch syndrome.

Chromosomal Instability: APC → KRAS → TP53 The chromosomal instability sequence begins with loss of APC, allowing β-catenin–mediated hyperproliferation. KRAS activation locks growth signaling and enlarges adenomas. Pedunculated tubular adenomas evolve, and TP53 loss removes tumor suppressor control, culminating in carcinoma. This is the predominant route in left-sided cancers.

Genotype Guides Targeted Therapy Molecular profiling steers therapy in advanced disease. Tumors with high mismatch repair deficiency respond to PD‑1 inhibitor therapy. KRAS or BRAF mutations render EGFR blockers ineffective, whereas wild-type status permits growth factor blockade. Testing for MMR status and KRAS/BRAF mutations directs targeted options.

Family History and Age Elevate Risk A first-degree relative diagnosed with colorectal cancer before age 60 markedly raises risk. Men over 50 are at higher risk, potentially reflecting reduced estrogen’s protective effect. These factors justify earlier and more frequent screening.

Inflammatory Bowel Disease Accelerates Dysplasia Chronic inflammation from inflammatory bowel disease fosters dysplasia and cancer, with ulcerative colitis posing greater risk than Crohn’s. Recurrent inflammation and pseudopolyps set the stage for malignant change. Early and repeated colonoscopic surveillance mitigates this danger.

Lifestyle Choices Shape Susceptibility Diets high in processed or red meats, heavy alcohol use beyond two drinks daily, and cigarette smoking elevate risk. Smoking especially increases serrated polyp formation in females. Obesity and physical inactivity further compound susceptibility.

FAP: APC Loss and Thousands of Polyps Familial adenomatous polyposis arises from APC mutation and produces hundreds to thousands of adenomas, predominantly on the left side. The lifetime risk of colorectal cancer approaches 100% by age 40. Early surveillance in childhood is mandatory and definitive colectomy is ultimately required.

Gardner Syndrome: Extraintestinal Tumors with Polyposis Gardner syndrome couples FAP’s intestinal polyps with extraintestinal bone and soft-tissue tumors. Osteomas and fibromas may develop in the jaw, hands, and skin. Colorectal cancer risk remains high alongside these manifestations.

Turcot Syndrome: CRC with Brain Tumors Turcot syndrome combines colorectal cancer with primary brain tumors. Medulloblastoma pairs with FAP, while glioma aligns with Lynch syndrome. Presentations reflect the age patterns of their associated syndromes.

Lynch Syndrome: Right-Sided CRC and “CEO” Risks Lynch syndrome features mismatch repair mutations that drive flat adenomas to rapid carcinoma, typically on the right. It heightens risks of colorectal, endometrial, and ovarian cancers—the “CEO” triad. Vigilant screening across these organs is essential.

Hamartomatous Polyps Across the GI Tract Hamartomatous polyps can arise throughout the gastrointestinal tract, including stomach, small intestine, and colon. These pedunculated, hammer-like lesions possess malignant potential, more so in the small intestine. Their presence contributes to, but does not dominate, colorectal cancer risk.

Peutz‑Jeghers: Polyps Plus Pigmented Macules Peutz‑Jeghers syndrome presents with hamartomatous polyps and hyperpigmented macules on the lips, oral mucosa, hands, and feet. Cancer risks include small intestinal, pancreatic, and breast malignancies. Colorectal cancer risk is increased but typically less than that of small bowel cancer.

Juvenile Polyposis: Early, Diffuse Polyp Burden Juvenile polyposis manifests in very young children with numerous hamartomatous polyps across the stomach, small intestine, and colon. Unlike Peutz‑Jeghers, there are no characteristic mucocutaneous lesions. The burden of polyps drives surveillance needs.

Right-Sided Clues: Occult Bleeding and Anemia Right-sided tumors bleed easily, and blood mixes with liquid stool to create occult bleeding. Chronic loss produces iron deficiency anemia with fatigue and pallor. Cytokine release suppresses appetite and causes unintentional weight loss. Older men and postmenopausal women with unexplained anemia require evaluation for colorectal cancer.

Left-Sided Clues: Pencil Stools and Hematochezia Left-sided tumors constrict the lumen, producing pencil-thin stools, tenesmus, and constipation. Partial obstruction allows occasional passage of liquid stool, creating alternating constipation and diarrhea. Bleeding often appears as bright red blood coating the stool. Weight loss can accompany these changes.

Liver Metastasis: The Commonest Destination The liver is the most common metastatic destination via portal circulation. Many patients are asymptomatic, although hepatomegaly and mild transaminase elevations may appear. Imaging frequently reveals multiple hypodense hepatic lesions.

Lung and Brain Metastases Mark Advanced Spread Venous spread can seed the lungs, leading to cough, hemoptysis, dyspnea, or pleural effusions. Brain metastases raise intracranial pressure and provoke seizures or focal neurological deficits. These sites indicate advanced disease burden.

Peritoneal Carcinomatosis and Malignant Ascites Peritoneal dissemination increases vascular permeability and produces albumin-rich ascites. A serum–ascites albumin gradient below 1.1 supports an exudative process. Imaging may reveal omental caking alongside free fluid. Diagnostic paracentesis evaluates for cytology and excludes infection.

Endocarditis Clue: Streptococcus gallolyticus Streptococcus gallolyticus (formerly under S. bovis) can translocate through ulcerated colonic mucosa and seed heart valves. Subacute endocarditis presents with fever, a new murmur, and septic emboli such as splinter hemorrhages. Positive blood cultures for this organism warrant colonoscopy to search for an underlying tumor.

From Obstruction to Perforation and Peritonitis A complete left-sided obstruction dilates the colon, compressing mural blood vessels and inducing ischemia. Persistent pressure causes necrosis, and the weakened wall perforates. Stool, air, and bacteria spill into the peritoneum, triggering peritonitis with guarding, rigidity, rebound tenderness, shock, and free subdiaphragmatic air on imaging. This scenario constitutes a surgical emergency.

Average-Risk Screening at 45 with Clear Triggers Average-risk adults begin colonoscopy at age 45, repeating every 10 years if normal. Findings of polyps or high-grade dysplasia shorten the interval to 3–5 years. Annual FIT with or without stool DNA testing and CT colonography every 5 years are acceptable alternatives that mandate colonoscopy when abnormal.

Apple-Core Sign on Barium Enema Though less commonly used, barium enema can reveal a classic apple-core narrowing. This circumferential defect strongly suggests colorectal carcinoma. Such imaging prompts definitive evaluation by colonoscopy and biopsy.

High-Risk Surveillance Tailored to Etiology High-risk profiles demand tailored schedules. Family history dictates colonoscopy at age 40 or 10 years before the earliest diagnosis, whichever comes first, with 5‑year intervals if normal. FAP requires annual flexible sigmoidoscopy or colonoscopy from ages 10–12 until prophylactic colectomy. Lynch syndrome needs colonoscopy every 1–2 years starting at 20–25. Peutz‑Jeghers begins colonoscopy every 3 years at age 8, adding pancreatic MRI every 3 years from age 30, while juvenile polyposis pairs colonoscopy with EGD every 1–3 years from age 12; IBD surveillance starts 8 years after pancolitis or 12–15 years after left-sided colitis, then every 1–3 years.

Symptomatic Evaluation and Staging Roadmap Unexplained iron deficiency anemia in older adults, persistent hematochezia with bowel habit changes, or S. gallolyticus endocarditis triggers colonoscopy with biopsy. After diagnosis, stage with CT of chest, abdomen, and pelvis to assess lungs, liver, and peritoneum. Obtain a baseline tumor marker for monitoring and perform MMR, KRAS, and BRAF testing to guide systemic therapy.

Treatment by Stage and Molecular Profile Stages I–III are treated with colectomy tailored to tumor location, often with regional lymph node removal; chemotherapy is added for stage III and select high-risk stage II. Regimens include combinations such as FOLFOX or FOLFIRI. Stage IV emphasizes palliation—stenting for obstruction and systemic therapy guided by molecular profile. PD‑1 inhibitors aid MMR‑deficient disease, EGFR blockade benefits left-sided KRAS/BRAF–wild-type tumors, VEGF inhibition supports cases with KRAS/BRAF mutations, FAP mandates prophylactic colectomy, and limited hepatic metastases may be resected with curative intent.