Colorectal Cancer

• Adenoma-Carcinoma Sequence: The classical Vogelstein model describes progression from normal epithelium → small adenoma → large adenoma → carcinoma. This process involves early loss of APC (adenomatous polyposis coli) tumor suppressor function, which normally constrains Wnt/β-catenin signaling. Loss of APC leads to aberrant β-catenin accumulation in the nucleus, constitutively activating transcription of proliferative genes. Intermediate steps involve activating mutations in KRAS (oncogene promoting proliferation via MAPK/ERK pathway) and SMAD4 loss. Final transformation to carcinoma typically requires loss of TP53 function, eliminating G1/S checkpoint control and apoptotic responses. This sequential model explains why CRC typically develops over a decade, supporting the rationale for colonoscopic surveillance and adenoma resection.

• Chromosomal Instability (CIN) Pathway: Approximately 85% of sporadic CRCs develop via CIN, characterized by widespread aneuploidy, loss of heterozygosity, and chromosomal translocations. CIN results from defects in mitotic checkpoints and DNA repair, allowing accumulation of mutations at an accelerated rate. This pathway drives the classic APC → KRAS → TP53 sequence and is associated with worse prognosis than other molecular subtypes. CIN CRCs demonstrate loss of chromosome 18q containing SMAD2/SMAD4 genes, which impair TGF-β signaling tumor suppression.

• Microsatellite Instability (MSI) Pathway: MSI occurs in 15-20% of sporadic CRCs and results from mismatch repair (MMR) gene defects (MLH1, MSH2, MSH6, PMS2). Defective MMR allows accumulation of mutations in repetitive DNA sequences, creating a hypermutable phenotype. Sporadic MSI-H (high) CRC typically results from MLH1 promoter hypermethylation, while hereditary nonpolyposis colorectal cancer (HNPCC/Lynch syndrome) involves germline MMR mutations. MSI-H tumors paradoxically have better prognosis when localized but higher risk of synchronous/metachronous CRC. MSI-H status predicts immunotherapy responsiveness (checkpoint inhibitors), as high mutation burden generates immunogenic neoantigens.

• CpG Island Methylator Phenotype (CIMP): A subset of CRCs (approximately 15-20%) demonstrate widespread epigenetic silencing through methylation of promoter regions in CpG islands. CIMP typically involves MLH1 methylation and is associated with BRAF mutations (distinct from KRAS mutations in CIN pathway). CIMP tumors often arise from sessile serrated polyps and represent the "serrated pathway" to malignancy, characterized by rapid progression from precursor lesion to carcinoma.

• Inflammatory Microenvironment and Progression: The colorectal epithelium is exposed to chronic antigenic stimulation from commensal bacteria and dietary factors, creating an inflammatory milieu. Inflammatory cytokines (IL-6, TNF-α, IL-17) promote proliferation through STAT3 and NF-κB activation. Chronic inflammation (as in inflammatory bowel disease) increases CRC risk through sustained epithelial proliferation and genomic instability. Conversely, the tumor microenvironment can become immunosuppressive through recruitment of regulatory T cells and myeloid-derived suppressor cells, facilitating immune evasion.

• BRAF and PIK3CA Mutations: BRAF V600E mutations occur in 5-10% of CRCs and are mutually exclusive with KRAS mutations. BRAF mutations are associated with CIMP, MSI-H status, older age at diagnosis, and worse prognosis when occurring in MSI-L/MSS tumors. PIK3CA activating mutations in the PI3K/AKT pathway occur in 15-20% of CRCs and promote survival signaling and chemotherapy resistance.

• Age: CRC incidence increases exponentially after age 50, with median age at diagnosis of 68 years. The 10-year risk of developing CRC is approximately 5% in individuals age 50 and older. Recent cohort studies demonstrate increasing incidence in individuals under 50 (early-onset CRC, EOCRC), with rates rising 1-2% annually since the 1990s in some Western countries. The pathophysiology of EOCRC remains incompletely understood but may involve different molecular pathways and increased biological aggressiveness.

• Inflammatory Bowel Disease (IBD): Both ulcerative colitis (UC) and Crohn's disease (CD) significantly increase CRC risk, with cumulative incidence of 2-3% at 10 years, 5-10% at 20 years, and 10-15% at 30 years post-diagnosis. Risk is proportional to disease duration and extent of colonic involvement; pancolonic UC carries highest risk. Chronic inflammation drives continuous epithelial proliferation and accumulation of mutations. Dysplasia surveillance colonoscopy (every 1-2 years after 8 years of disease) is recommended, with colectomy indicated upon diagnosis of dysplasia.

• Hereditary Syndromes:
• Lynch Syndrome (HNPCC): Accounts for 2-3% of all CRCs; autosomal dominant inheritance with germline MMR gene mutations. Lifetime CRC risk is 40-80% without surveillance. Characterized by early onset (median age 45), right-sided predominance, and increased risk of synchronous/metachronous tumors. Requires colonoscopic surveillance every 1-2 years beginning at age 20-25.
• Familial Adenomatous Polyposis (FAP): Autosomal dominant APC mutations result in development of hundreds to thousands of adenomas beginning in adolescence; virtually 100% develop CRC by age 40-50 without colectomy. Genetic testing and prophylactic colectomy (proctocolectomy) are standard management.
• PTEN Hamartoma Tumor Syndrome (Cowden): Autosomal dominant PTEN mutations; increased risk of CRC and multiple extraintestinal malignancies.

• Family History: First-degree relatives of CRC patients have 2-3 fold increased risk, even without identified hereditary syndrome. Risk is higher if CRC was diagnosed before age 50, if multiple relatives are affected, or if relatives had advanced adenomas. Individuals with one affected first-degree relative should undergo colonoscopy at age 40 or 10 years before the earliest diagnosis in the family, whichever is earlier.

• Dietary and Lifestyle Factors:
• Red and Processed Meat: Consumption is associated with 20-30% increased CRC risk per 100g daily increase. Mechanisms include heme iron-induced oxidative stress, heterocyclic amines from cooking at high temperatures, and N-nitroso compound formation. Conversely, dietary fiber intake (25-35g daily) is protective through fermentation-derived butyrate production, which enhances epithelial barrier function and histone deacetylase inhibition.
• Obesity: BMI >30 kg/m² increases CRC risk by 20-30%, with stronger association in men. Obesity promotes CRC through insulin resistance, increased growth factor signaling (IGF-1), and chronic low-grade inflammation.
• Alcohol and Smoking: Alcohol >2 drinks daily increases risk 20-40%, particularly for right-sided CRC. Smoking increases risk 20% and is associated with worse outcomes.
• Protective Factors: Aspirin and NSAIDs reduce CRC incidence by 20-30% through COX-2 inhibition and β-catenin destabilization; however, cardiovascular risks typically outweigh benefits for primary prevention in average-risk individuals.

• Prior Adenomatous Polyps: History of adenomas increases CRC risk 5-fold; risk is proportional to adenoma size, degree of dysplasia, and villous histology. Adenomas with high-grade dysplasia or advanced features (≥10mm, villous component, ≥3 adenomas) confer highest risk for metachronous CRC.

• Type 2 Diabetes Mellitus: 20-30% increased CRC risk through mechanisms including hyperinsulinemia, chronic inflammation, and altered gut microbiota.

• Acromegaly: Excess growth hormone increases CRC risk 4-5 fold through IGF-1 signaling; colonoscopy screening is recommended.

• Rectal Bleeding/Hematochezia: Visible bright red blood per rectum is the most common presenting symptom, occurring in 40-50% of patients. Blood is typically bright red and observed on toilet paper, in the toilet bowl, or coating the stool surface, particularly with distal (rectal and sigmoid) tumors. The physiologic mechanism involves superficial ulceration of the tumor mucosa with exposure of submucosal vasculature. Hematochezia must never be attributed to hemorrhoids without colonoscopic evaluation, as internal hemorrhoids coexist in 40% of CRC patients and can mask the malignancy diagnosis.

• Alteration in Bowel Habits: Changes in stool frequency, caliber, or consistency occur in 30-40% of symptomatic patients. Left-sided (rectosigmoid) tumors cause pencil-thin stools, sensation of incomplete evacuation (tenesmus), and increased frequency (often 3-4 times daily). Right-sided tumors may present with less distinct changes. The mechanism involves mechanical obstruction from tumor mass and associated inflammatory response causing increased motility.

• Abdominal Pain or Cramping: Occurs in 20-30% of presentations, ranging from mild discomfort to severe colicky pain. Cramping suggests partial obstruction with increased intraluminal pressure proximal to the tumor. Location correlates with tumor site: right lower quadrant pain with cecal/ascending colon tumors, left lower quadrant with sigmoid tumors.

• Constipation: Progressive constipation or obstruction occurs in 15-20% of cases, more common with left-sided lesions. Acute presentation with severe constipation, abdominal distension, and vomiting indicates acute colonic obstruction, a surgical emergency requiring decompression and resection.

• Anemia and Fatigue: Chronic blood loss, particularly from right-sided tumors, leads to iron-deficiency anemia presenting with fatigue, dyspnea on exertion, and palpitations. Microcytic, hypochromic anemia with low serum ferritin in an adult, particularly males and postmenopausal females, warrants colonoscopy to exclude CRC.

• Unintentional Weight Loss: Occurs in 10-15% of patients, reflecting tumor-induced metabolic changes, reduced oral intake from obstruction, and cachexia from pro-inflammatory cytokines. Weight loss >10 lbs over 1-2 months in the setting of other GI symptoms is concerning for malignancy.

• Asymptomatic Presentation: 20-30% of CRCs are detected through screening in asymptomatic individuals, typically at earlier stages with improved prognosis.

• Advanced/Metastatic Presentation: Approximately 20% of patients present with stage IV disease (distant metastases). Symptoms may include hepatomegaly, abdominal distension from ascites, or specific symptoms related to metastatic sites (bone pain, neurologic symptoms, respiratory symptoms).

• Acute Presentations:
• Perforation: Occurs in 3-6% of cases, presenting with acute peritonitis, severe abdominal pain, fever, and sepsis. Represents surgical emergency with high mortality (20-30%) even with treatment.
• Obstruction: Acute or subacute presentation with abdominal distension, constipation, vomiting, and abdominal pain. More common with left-sided lesions; right-sided obstruction tends to present later due to larger luminal diameter.

• Paraneoplastic Syndromes: Rare presentations including acanthosis nigricans, dermatomyositis, hypertrophic osteoarthropathy, or venous thromboembolism.

• Clinical History and Risk Assessment: Detailed history of symptom onset, bowel habit changes, family history of CRC or polyps, and personal history of IBD or prior adenomas provides critical risk stratification. Any adult ≥50 years with rectal bleeding, iron-deficiency anemia, or persistent change in bowel habits warrants colonoscopy. For individuals with family history of CRC diagnosed before age 50, colonoscopy should begin 10 years before the earliest diagnosis in that family member or at age 40, whichever is earlier.

• Carcinoembryonic Antigen (CEA): A glycoprotein tumor marker useful for prognosis and surveillance but not recommended for screening due to low sensitivity (50-80%) and specificity (60-90%). Elevated preoperative CEA (>5 ng/mL, normal <2.5 ng/mL) indicates worse prognosis and higher recurrence risk. CEA rises with tumor burden and metastatic disease; postoperative elevation suggests recurrence. CEA monitoring every 3-6 months for 2 years post-resection can detect recurrence amenable to surgical resection, though impact on overall survival is debated.

• Colonoscopy with Biopsy: The gold standard diagnostic modality, allowing direct visualization, tissue diagnosis via biopsy, and assessment of location and extent. Sensitivity is >95% for lesions >5 mm. Findings include a polypoid, ulcerated, or stricturing mass, with surrounding edema and erythema. Biopsy demonstrates invasive adenocarcinoma with desmoplastic response. Complete colonoscopy with visualization to the cecum is mandatory to exclude synchronous lesions (present in 5% of cases) and assess distal adenomas. Colonoscopy within 3-6 months of diagnosis should examine the entire colon (if not done at diagnostic colonoscopy) to identify synchronous neoplasms.

• Computed Tomography (CT) Colonography (Virtual Colonoscopy): Offers sensitivity of 90-95% for lesions ≥10 mm and 80-85% for 6-9 mm lesions, with specificity >95%. Useful alternative for patients with incomplete colonoscopy, obstructing tumors preventing complete visualization, or who refuse colonoscopy. Lower sensitivity for sessile polyps and flat lesions compared to optical colonoscopy.

• High-Sensitivity Fecal Immunochemical Test (FIT): Detects hemoglobin in stool with sensitivity 79-98% for CRC and 24-67% for advanced adenomas; specificity >95%. FIT is superior to guaiac-based tests (sensitivity 11-25% for CRC) and forms the basis of many screening programs. A single positive FIT result warrants colonoscopy. Annual FIT screening over 10 years reduces CRC mortality by 30-40%.

• Staging Evaluation: Following diagnosis, staging studies determine extent of disease and guide treatment:
• CT Chest, Abdomen, and Pelvis: Standard imaging for metastatic disease evaluation. Assesses liver metastases (present in 20% at diagnosis), peritoneal involvement, ascites, and regional lymph node involvement. CT has ~85% sensitivity for detecting metastases >1 cm.
• MRI Pelvis: For rectal cancers, provides superior soft tissue contrast for assessing depth of invasion through rec

Immediate stabilisation (acute presentations)

• Obstructing tumor: NPO, nasogastric decompression, IV fluids, correction of electrolytes; urgent surgical consultation. Options include emergent resection with primary anastomosis or diverting colostomy, or a self-expanding metal stent as a bridge to surgery or palliation in left-sided obstruction (NCCN Colon Cancer guidelines).
• Perforation with peritonitis: broad-spectrum antibiotics covering enteric gram-negatives and anaerobes plus emergent laparotomy; oncologic resection is performed if feasible.

Definitive management of localized disease

• Colon cancer (stage I–III): en bloc segmental colectomy with regional lymphadenectomy; NCCN considers a minimum of 12 examined nodes necessary for adequate staging. Malignant polyps with favorable histology may be cured by endoscopic polypectomy alone.
• Rectal cancer: total mesorectal excision after neoadjuvant therapy for locally advanced (cT3–4 or node-positive) disease. Total neoadjuvant therapy — chemoradiation plus systemic chemotherapy before surgery — is now the NCCN-preferred approach; selected complete clinical responders may enter nonoperative watch-and-wait surveillance.

Systemic therapy

• Adjuvant chemotherapy: fluoropyrimidine plus oxaliplatin (FOLFOX or CAPOX) for stage III and high-risk stage II colon cancer (ASCO/NCCN). Duration of 3 versus 6 months is risk-adapted based on the IDEA collaboration.
• Metastatic first line: cytotoxic backbone (FOLFOX or FOLFIRI) plus a biologic — an anti-VEGF antibody (bevacizumab) or, only in RAS/BRAF wild-type left-sided primaries, an anti-EGFR antibody (cetuximab or panitumumab).
• Biomarker-directed escalation: PD-1 blockade (pembrolizumab) is first-line for dMMR/MSI-high metastatic disease; BRAF V600E–mutant disease is treated with a BRAF inhibitor plus cetuximab.
• Oligometastatic liver or lung disease: metastasectomy with perioperative chemotherapy can be curative — always assess resectability before declaring palliative intent.

Contraindicated / avoid

• Anti-EGFR antibodies in RAS-mutant tumors: downstream constitutive MAPK signaling makes them ineffective and potentially harmful.
• Bevacizumab near surgery: impaired wound healing and bowel perforation; hold for several weeks perioperatively.
• Full-dose fluoropyrimidine in DPD deficiency and standard irinotecan in UGT1A1 poor metabolizers.

Disease-related

• Large bowel obstruction (emergency): annular left-sided tumor narrows the lumen where stool is solid; signals itself as distension, obstipation, feculent vomiting, and dilated colon with transition point on CT. Cecal diameter beyond roughly 12 cm predicts impending perforation.
• Perforation and feculent peritonitis (emergency): transmural tumor necrosis or closed-loop obstruction against a competent ileocecal valve; rigid abdomen, free air under the diaphragm, septic shock.
• Iron-deficiency anemia: chronic occult loss from a friable right-sided mass; microcytosis with low ferritin, sometimes with high-output heart failure.
• Hepatic metastases: portal venous drainage seeds the liver first; hepatomegaly, RUQ pain, cholestatic LFTs. Distal rectal tumors draining via the middle/inferior rectal veins into the IVC can metastasize to lung without liver involvement.
• Peritoneal carcinomatosis and malignant ascites; colovesical fistula (pneumaturia, fecaluria); venous thromboembolism from tumor-associated hypercoagulability (PE is an emergency).

Treatment-related

• Anastomotic leak (emergency): typically postoperative day 5–7 with fever, tachycardia, leukocytosis, and peritonitis or purulent drain output; confirm with CT and reoperate/divert.
• Oxaliplatin neurotoxicity: acute cold-triggered dysesthesias and a cumulative, dose-limiting sensory neuropathy.
• Irinotecan diarrhea: acute cholinergic diarrhea with cramping and diaphoresis, treated with atropine; delayed diarrhea treated with loperamide.
• Fluoropyrimidine toxicity: mucositis, myelosuppression, palmar-plantar erythrodysesthesia, and coronary vasospasm causing chest pain; catastrophic toxicity in DPD deficiency.
• Anti-EGFR antibodies: acneiform papulopustular rash (correlates with response) and hypomagnesemia from blocked tubular Mg reabsorption.
• Bevacizumab: hypertension, proteinuria, impaired wound healing, arterial thrombosis, and bowel perforation.
• Checkpoint inhibitors: immune-related colitis, hepatitis, thyroiditis, hypophysitis — high-grade colitis requires corticosteroids.
• Neutropenic fever (emergency): empiric antipseudomonal beta-lactam without delay.
• Pelvic radiation: radiation proctitis, strictures, and low anterior resection syndrome with urgency and clustering of stools.

• ***Streptococcus gallolyticus* (formerly S. bovis) bacteremia or endocarditis**: the single association examiners test most. Best next step is colonoscopy, not simply completing antibiotics — occult colonic neoplasia is present in a large fraction of cases. Clostridium septicum bacteremia carries the same implication.
• Iron-deficiency anemia in a man or postmenopausal woman: assume GI malignancy until proven otherwise; the next step is bidirectional endoscopy, not empiric iron alone.
• Sidedness drives the stem: right-sided (cecal/ascending) tumors are exophytic and bleed occultly into liquid stool → anemia and fatigue; left-sided tumors are annular and constricting → apple-core lesion on barium enema, pencil-thin stools, obstruction.
• Screening starts at 45 for average-risk adults and continues to 75 (USPSTF, with selective screening 76–85). Any positive noninvasive test — FIT, stool DNA, or CT colonography — mandates diagnostic colonoscopy.
• CEA is for prognosis and post-resection surveillance only (ASCO/NCCN). A stem offering CEA as a screening test is the classic distractor.
• Molecular gatekeepers: anti-EGFR antibodies (cetuximab, panitumumab) work only in RAS/BRAF wild-type, left-sided tumors; pembrolizumab is reserved for dMMR/MSI-high disease. Giving cetuximab to a *KRAS*-mutant tumor is the trap.
• Hereditary syndromes: FAP = APC on chromosome 5q, hundreds of polyps, prophylactic proctocolectomy (Gardner adds osteomas, desmoids, and congenital hypertrophy of the retinal pigment epithelium; Turcot adds CNS tumors). Lynch = germline MMR defect, few polyps, right-sided, early onset, with endometrial cancer as the leading extracolonic malignancy.
• Never attribute hematochezia to hemorrhoids in an adult without completing colonoscopy — hemorrhoids frequently coexist with an occult carcinoma.
• Rectal cancer below the dentate line drains to the IVC and can present with pulmonary metastases sparing the liver.