Colorectal Cancer and Polyps

Hereditary syndromes (non-modifiable, high-yield)

• Familial adenomatous polyposis (FAP): autosomal dominant germline APC loss removes the gatekeeper of Wnt/β-catenin signaling → hundreds to thousands of adenomas in adolescence. Variants: Gardner syndrome (osteomas, desmoid tumors, epidermoid cysts, congenital hypertrophy of retinal pigment epithelium) and Turcot syndrome (CNS tumors).
• Lynch syndrome (HNPCC): autosomal dominant mismatch-repair mutation → microsatellite instability; few polyps but rapid adenoma-to-carcinoma progression, right-sided predominance, and extracolonic risk (endometrial is the most common non-colonic cancer).
• MUTYH-associated polyposis: autosomal recessive base-excision repair defect — suspect in oligopolyposis without an APC mutation.
• Hamartomatous syndromes: Peutz-Jeghers (STK11, mucocutaneous macules) and juvenile polyposis (SMAD4/BMPR1A) — hamartomas, not classic adenomas, yet still carry elevated CRC risk.

Chronic inflammation

• Inflammatory bowel disease: sustained mucosal injury and repair drives a dysplasia-carcinoma sequence rather than a discrete polyp sequence. Risk rises with duration, extent (pancolitis > left-sided), and coexisting primary sclerosing cholangitis; AGA and ACG recommend surveillance colonoscopy with dysplasia sampling beginning roughly 8 years after disease onset.

• Note on aspirin: chemoprevention data exist, but the USPSTF's current aspirin statement no longer endorses initiating aspirin for colorectal cancer prevention — do not choose it as a preventive strategy on a stem.
• Infectious clue: Streptococcus gallolyticus (formerly S. bovis) bacteremia or endocarditis is an association examiners plant to trigger colonoscopy.

• Adenoma-carcinoma sequence: Sequential accumulation of mutations (APC → KRAS → TP53 → loss of 18q) transforms normal epithelium → adenoma (tubular, tubulovillous, villous) → dysplasia (low-grade, high-grade) → invasive carcinoma; villous adenomas have highest malignant potential
• Microsatellite instability (MSI): Defective DNA mismatch repair (MLH1, MSH2, MSH6, PMS2) leads to hypermethylation and Lynch syndrome; associated with better response to immunotherapy but earlier onset cancers
• CpG island methylator phenotype (CIMP): Epigenetic silencing of tumor suppressors; often associated with MLH1 promoter methylation and older age at diagnosis
• Chromosomal instability (CIN): Most common pathway (~85%); involves aneuploidy and loss of chromosome 18q; associated with traditional adenomas and intermediate prognosis
• Invasion and metastasis: Through muscularis propria into submucosa and beyond; lymphatic invasion determines lymph node metastasis; liver is most common site of metastatic disease (via portal venous drainage)
• Hereditary syndromes: Lynch syndrome (3-5% of CRC; autosomal dominant mismatch repair mutations) and familial adenomatous polyposis (FAP; APC gene; ~100% CRC risk by age 50 if untreated)

• Right-sided (cecal/ascending) colon cancers: Often present late with anemia (microcytic from chronic bleeding), fatigue, and abdominal mass; may cause obstruction less commonly due to larger luminal diameter; occult blood loss more common than gross hematochezia
• Left-sided (descending/sigmoid) colon cancers: Present earlier with change in bowel habits (constipation alternating with diarrhea), narrow "pencil-like" stools, tenesmus, and visible blood per rectum; higher risk of acute obstruction due to narrower lumen
• Rectal cancers: Hematochezia with mucus, tenesmus, urgency, feeling of incomplete evacuation; locally advanced tumors may cause pelvic pain, urinary symptoms, or fecal incontinence
• Asymptomatic presentation: ~25% diagnosed on screening colonoscopy before symptoms develop—major reason for screening success
• Emergent presentations: Acute obstruction (most common surgical emergency in CRC), perforation with peritonitis, or fistulization to adjacent organs
• Systemic symptoms: Weight loss, anorexia, fatigue suggest advanced disease; fever rare unless obstruction/perforation present

• Colonoscopy: Gold standard for diagnosis and visualization; allows direct visualization, biopsy of lesions, and therapeutic polypectomy; sensitivity >95% for lesions >6mm; complete to cecum mandatory
• Histopathology: Biopsy confirms malignancy and determines adenocarcinoma type (mucinous, signet-ring cell, neuroendocrine); critical for grading (well, moderate, poorly differentiated) and prognostic assessment
• Staging investigations after diagnosis: CT abdomen/pelvis with contrast (assesses local invasion, regional lymph nodes, distant metastases); chest CT or X-ray (pulmonary metastases); elevated carcinoembryonic antigen (CEA) suggests advanced disease and useful for monitoring post-treatment
• TNM staging system: T (depth of invasion: T1 into submucosa, T2 into muscularis propria, T3 through muscularis propria, T4 into adjacent organs); N (regional lymph node involvement: N0 none, N1 1-3 nodes, N2 ≥4 nodes); M (distant metastasis: M0 absent, M1a single organ metastasis, M1b multiple organ metastases)
• Molecular testing: MSI/mismatch repair deficiency testing on all CRC (Lynch syndrome screening); KRAS, BRAF mutations predict response to targeted therapy (EGFR inhibitors ineffective if KRAS mutant); BRAF V600E mutation associated with worse prognosis
• Colonoscopy screening intervals: Negative colonoscopy = 10 years; 1-2 small adenomas = 7-10 years; ≥3 adenomas, any adenoma >1cm, high-grade dysplasia, or sessile serrated polyp = 3 years; inadequate prep = repeat in 2-4 weeks
• Fecal occult blood testing (FOBT): Detects hemoglobin in stool; annual testing for average-risk patients; lower sensitivity (~50-70%) than colonoscopy but non-invasive option

• Stage I (T1-T2N0M0): Endoscopic polypectomy for T1 lesions without poor prognostic features (high-grade dysplasia, poor differentiation, lymphovascular invasion); segmental colectomy with regional lymphadenectomy for T2 lesions or T1 with poor prognostic features; adjuvant chemotherapy generally not indicated
• Stage II (T3-T4N0M0): Segmental colectomy with adequate margins (>5cm) and lymph node harvest (≥12 nodes); adjuvant chemotherapy (5-fluorouracil/leucovorin or capecitabine ± oxaliplatin [FOLFOX, CapeOx]) considered for high-risk features (T4b, poorly differentiated, MSI-low/CIN, inadequate lymph node sampling, perineural invasion, obstruction/perforation); MSI-high tumors may not require adjuvant chemotherapy given better prognosis
• Stage III (any T, N1-N2, M0): Segmental colectomy followed by adjuvant chemotherapy (FOLFOX or CapeOx typically 6 months); high-dose leucovorin + 5-FU + oxaliplatin is standard; improves overall survival by ~10-15%
• Stage IV (any T, any N, M1): Palliative chemotherapy as first-line (FOLFOX, FOLFIRI [5-FU/leucovorin + irinotecan], or bevacizumab-containing regimens); resection of primary tumor considered only if unobstructed and limited metastases; targeted therapy: anti-EGFR monoclonal antibodies (cetuximab, panitumumab) for KRAS/NRAS wild-type tumors; anti-VEGF bevacizumab; immunotherapy (pembrolizumab, nivolumab) for MSI-high or mismatch repair-deficient tumors; TAS-102 or regorafenib for treatment-refractory disease; median survival with modern chemotherapy ~2-3 years
• Rectal cancer special considerations: Tumors within 12-15cm of anal verge often receive neoadjuvant chemoradiation (5-FU or capecitabine + radiation 50.4 Gy) to downstage tumor and improve resectability and function preservation; low rectal tumors may require abdominoperineal resection (APR) with permanent colostomy if sphincter cannot be spared; total mesorectal excision (TME) is surgical standard
• Surveillance post-resection: CEA every 3-6 months × 2-3 years if baseline elevated (expensive and not evidence-based but commonly done); colonoscopy at 1 year, then every 3-5 years; CT imaging for symptom-directed evaluation;

Disease-related

• Large bowel obstruction (emergency): annular left-sided tumors narrow an already small lumen — obstipation, distension, tympany, dilated colon with air-fluid levels on imaging; apple-core lesion on contrast study. Closed-loop physiology with a competent ileocecal valve risks cecal perforation.
• Perforation (emergency): transmural invasion or obstructive proximal distension → free intraperitoneal air, peritonitis, sepsis. Perforation also upstages risk and worsens prognosis.
• Occult bleeding: chronic right-sided blood loss produces iron deficiency anemia (low ferritin, high RDW) long before any visible bleeding.
• Fistulization: colovesical fistula causes pneumaturia and recurrent polymicrobial UTIs.
• Metastatic disease: portal drainage seeds the liver first (rising CEA, hepatomegaly, elevated alkaline phosphatase); peritoneal carcinomatosis causes malignant ascites and bowel obstruction. Rectal tumors below the dentate line drain systemically and may go to lung directly.
• Hypercoagulability: adenocarcinoma-associated Trousseau syndrome — migratory superficial thrombophlebitis or unprovoked VTE.

Treatment-related

• Post-polypectomy bleeding and perforation: delayed hematochezia or focal peritonitis after endoscopy; free air mandates urgent surgical evaluation (emergency).
• Anastomotic leak (emergency): typically postoperative days 5–7 with fever, tachycardia, ileus, and peritonitis or feculent drain output.
• Low anterior resection syndrome: urgency, clustering, incontinence after sphincter-preserving rectal surgery; APR leaves a permanent colostomy. Pelvic autonomic nerve injury causes sexual and bladder dysfunction.
• Chemotherapy toxicity: oxaliplatin — cold-triggered and cumulative sensory neuropathy; irinotecan — acute cholinergic diarrhea (treated with atropine) and delayed diarrhea (loperamide); fluoropyrimidines — mucositis, myelosuppression, and hand-foot syndrome, with severe toxicity in DPD deficiency.
• Biologic toxicity: bevacizumab causes hypertension, impaired wound healing, bleeding, and bowel perforation (emergency); anti-EGFR antibodies cause acneiform rash and hypomagnesemia; checkpoint inhibitors cause immune-mediated colitis and endocrinopathies.
• Pelvic radiation: radiation proctitis and small bowel injury/obstruction, per NCCN survivorship guidance.

• Iron deficiency anemia in a man or postmenopausal woman is colon cancer until proven otherwise: the single best next step is colonoscopy, not empiric iron or repeat fecal testing. Any positive stool-based test (FIT, FIT-DNA) must be followed by diagnostic colonoscopy — accepting a positive FIT without colonoscopy is the classic trap.
• CEA is not a screening or diagnostic test: it is a baseline and surveillance marker. A normal CEA never excludes cancer; a rising CEA after resection prompts imaging for recurrence.
• ***Streptococcus gallolyticus* (bovis) bacteremia or endocarditis → colonoscopy.** Also remember Clostridium septicum bacteremia, which points to an occult colonic malignancy.
• Villous histology, size >1 cm, and high-grade dysplasia are the features that make an adenoma "advanced." Sessile serrated lesions arise in the right colon via the *BRAF*/CIMP methylation pathway and are the ones missed on incomplete preps — hyperplastic rectosigmoid polyps, by contrast, carry negligible risk.
• FAP is managed surgically, not endoscopically: prophylactic proctocolectomy is the definitive intervention because CRC is essentially inevitable. Lynch syndrome, in contrast, is managed with early and frequent colonoscopy, and NCCN supports universal MMR immunohistochemistry or MSI testing on all colorectal cancers to detect it.
• MSI-high/dMMR tumors respond to PD-1 blockade and generally do poorly with single-agent fluoropyrimidine adjuvant therapy — this is the immunotherapy association examiners test.
• **Anti-EGFR antibodies (cetuximab, panitumumab) work only in RAS wild-type tumors.** Giving them to a KRAS-mutant patient is a favorite distractor.
• Screening begins at age 45 for average-risk adults per the USPSTF, with colonoscopy every 10 years or annual FIT among acceptable strategies; earlier and more frequent screening applies with a first-degree relative or IBD.
• Left-sided obstructive symptoms versus right-sided anemia is the laterality dichotomy stems hinge on; apple-core lesion on barium enema is the buzzword for an annular constricting left-sided tumor.