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Colorectal Carcinoma

Epidemiology

Distribution by Site

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Aetiology and Risk Factors

Adenoma-Carcinoma Sequence

• Distribution of adenomas mirrors that of cancers (70% left-sided)
• Larger adenomas are more likely to be dysplastic
• Most early cancers have adjacent adenomatous tissue
• Adenomas are found in one-third of CRC resection specimens
• Incidence drops within colonoscopy-based screening programmes

Three Major Molecular Pathways

Consensus Molecular Subtypes (CMS)

• CMS1: MSI-high, immune activation (right-sided, sporadic MSI)
• CMS2: WNT and MYC signalling activation
• CMS3: Metabolic dysregulation
• CMS4: TGF-beta activation - Bailey and Love's

Environmental/Lifestyle Risk Factors

• Red and processed meat (haem iron, N-nitroso compounds) - strong association worldwide
• Dietary fibre - protective (reduced colonic transit time, altered microbiota)
• Obesity, alcohol, smoking - increased risk
• Inflammatory bowel disease (IBD) - significant risk factor
• High calcium and magnesium intake - potentially protective
• Aspirin/NSAIDs (COX-2 inhibitors) - strong epidemiological evidence for protection
• Cholecystectomy may marginally increase right-sided colon cancer risk

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Hereditary Syndromes

Familial Adenomatous Polyposis (FAP)

• Autosomal dominant; APC gene mutation on chromosome 5q (identified in 75% of FAP cases)
• Accounts for ~1% of all CRC
• Hundreds to thousands of polyps develop after puberty
• Lifetime risk approaches 100% by age 50 without intervention
• Extraintestinal: congenital hypertrophy of retinal pigmented epithelium, desmoid tumors, epidermoid cysts, mandibular osteomas (Gardner's syndrome), CNS tumors (Turcot's syndrome)
• Screening: Flexible sigmoidoscopy or APC gene testing from age 10-15 years
• Treatment: Surgical (total proctocolectomy + IPAA preferred; total abdominal colectomy + ileorectal anastomosis as alternative); COX-2 inhibitors (celecoxib, sulindac) may slow polyp development

HNPCC / Lynch Syndrome

• Autosomal dominant; mutations in mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2)
• Accounts for ~3% of CRC; lifetime CRC risk up to 80%
• Right-sided predominance; tends to be poorly differentiated but better prognosis than stage-matched sporadic CRC
• Associated with endometrial, ovarian, gastric, small bowel, urological tumors
• Diagnosed using Amsterdam criteria or Bethesda guidelines; confirmed by germline testing

Familial (Non-Syndromic)

• Accounts for 10-15% of CRC
• Average lifetime risk 6% (no family history) rises to 12% (one first-degree relative), 35% (two first-degree relatives)
• Diagnosis before age 50 in a relative significantly increases risk

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Pathology

• Annular/constricting - obstructive symptoms predominant
• Ulcerating - bleeding predominant
• Polypoid/fungating - especially right colon
• Diffusely infiltrating

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Spread

1. Direct/local: Longitudinal or radial extension into adjacent structures (ureter, duodenum, posterior abdominal wall, anterior abdominal wall)
2. Lymphatic: Progressive from pericolic to intermediate to central nodes; orderly but not always predictable
3. Haematogenous: Via the portal vein to the liver (most common; one-third of patients have liver metastases at diagnosis; 50% will eventually develop them). Lung is the next most common site. Ovaries, brain, kidney, bone less common
4. Transcoelomic (peritoneal): To peritoneum, ovary (Krukenberg tumour), omentum

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Staging

Dukes' Classification (Historical, Still Used)

TNM Staging (International Standard)

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Clinical Presentation

• Occult blood loss → iron-deficiency anaemia
• Vague abdominal discomfort
• Palpable mass (tumours can grow large before obstruction)

• Change in bowel habit (alternating constipation and diarrhoea)
• Rectal bleeding (bright red or dark)
• Tenesmus (especially rectal)
• Colicky abdominal pain
• Obstruction (more common than right-sided due to narrower lumen)

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Investigations

Tumour Markers

• CEA (Carcinoembryonic Antigen): Not useful for diagnosis but important for monitoring after treatment and detecting recurrence. CEA >5 ng/mL post-resection suggests residual disease or recurrence. - Quick Compendium of Clinical Pathology

Endoscopy

• Colonoscopy is the investigation of choice: secures histological diagnosis, detects synchronous polyps or carcinomas (present in 3-5% of cases). Small risk of perforation (1:1000). - Bailey and Love's

Radiology

• CT colonography (virtual colonoscopy): Highly sensitive for polyps ≥6mm; less invasive but cannot biopsy
• CT chest/abdomen/pelvis: Standard for staging CRC
• MRI pelvis: Mandatory for rectal cancer local staging (assessing circumferential resection margin, mesorectal fascia involvement)

Molecular Testing

• MSI/MMR status: Predicts Lynch syndrome; also predicts response to immune checkpoint inhibitor (ICI) therapy; MSI-H tumours respond well to pembrolizumab
• KRAS/NRAS mutation testing: Predicts resistance to EGFR inhibitors (cetuximab, panitumumab) - wild-type RAS required for benefit
• BRAF V600E mutation: Poor prognosis in metastatic CRC; predictive of response to specific therapies
• Tumour Mutation Burden (TMB): High TMB predicts ICI response
• NTRK fusion: Rare (<1% CRC), usually MSI-H; specific tyrosine kinase inhibitor therapy available

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Screening

• Annual FOBT/FIT (reduces CRC mortality by 33%, metastatic disease by 50%; specificity low - 90% of positives are false positives; must be followed by colonoscopy if positive)
• Stool DNA (e.g., Cologuard: 92% sensitive for CRC, 74% specific; every 1-3 years)
• Flexible sigmoidoscopy every 5 years (60-70% reduction in mortality)
• CT colonography every 5 years
• Colonoscopy every 10 years (gold standard) - Schwartz's

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Surgical Treatment

Colon Cancer

• Right hemicolectomy: Caecum, ascending colon, hepatic flexure tumours (with ileocolic, right colic, right branch of middle colic vessels)
• Extended right hemicolectomy: Transverse/hepatic flexure cancers
• Left hemicolectomy: Descending colon
• Sigmoid colectomy / high anterior resection: Sigmoid and upper rectum
• Minimum of 12 lymph nodes required in resection specimen for adequate staging
• Laparoscopic approach is oncologically equivalent to open surgery with faster recovery

Preoperative Preparation

• Mechanical bowel preparation combined with oral antibiotics reduces surgical site infections, anastomotic leak, ileus, reoperation, and mortality (used with ERAS protocols). - Bailey and Love's

Rectal Cancer

• Anterior resection: Upper rectum (above peritoneal reflection)
• Low anterior resection (LAR): Mid/lower rectum with total mesorectal excision (TME)
• Abdominoperineal resection (APR): Very low rectal cancers where sphincter preservation is not possible (permanent colostomy)
• TME is the standard for rectal cancer surgery - reduces local recurrence from ~30% to <10%
• Neoadjuvant (chemo)radiotherapy: For T3/T4 or node-positive rectal cancer prior to surgery

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Systemic Treatment

Adjuvant Chemotherapy

• Stage III (node-positive) CRC: FOLFOX (5-FU/leucovorin + oxaliplatin) or CAPOX (capecitabine + oxaliplatin) - standard of care
• Stage II: Adjuvant chemotherapy reserved for high-risk features (T4, obstruction, perforation, inadequate node sampling, poor differentiation)
• FOLFIRI (5-FU + irinotecan): Alternative regimen for metastatic disease

Targeted Therapy in Metastatic CRC

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Prognosis

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Post-Treatment Surveillance

• CEA every 3 months for 2 years, then every 6 months to 5 years
• Colonoscopy at 1 year post-resection; if normal, every 3-5 years
• CT chest/abdomen/pelvis annually for 3-5 years (for high-risk stage II and stage III)
• Clinical assessment at each visit

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• Bailey and Love's Short Practice of Surgery, 28th Ed.
• Schwartz's Principles of Surgery, 11th Ed.
• Quick Compendium of Clinical Pathology, 5th Ed.