Harvey's Garden

Colorectal cancer

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aliasescolorectal carcinoma, colon cancer

6 min read

Pathophysiology

Colorectal carcinogenesis pathways (molecular pathology)

  • 1. Chromosomal Instability (CIN) Pathway (~80%)
    • The classic Adenoma-to-Carcinoma Sequence.
    • Stepwise accumulation of key mutations:
      1. APC loss (initiation, ↑β-catenin)
      2. KRAS mutation (unregulated growth)
      3. p53 loss (malignancy)
    • Clinical Association:

Mnemonic

This follows the alphabet: APC -> KRAS -> P53

  • 2. Microsatellite Instability (MSI) Pathway (~15%)
    • Caused by defective DNA Mismatch Repair (MMR).
    • Microsatellites are short, repetitive DNA sequences (e.g., CACACA…). During DNA replication, these regions are prone to errors (insertions/deletions).
    • Due to mutations in MLH1, MSH2, MSH6, PMS2.
    • Leads to errors in repetitive DNA sequences (microsatellites).
    • Associated with Lynch Syndrome (HNPCC) and right-sided tumors.
  • 3. Serrated Pathway (~5%)
    • Arises from serrated polyps.
    • Driven by BRAF mutation followed by CIMP (CpG Island Methylator Phenotype).
    • CIMP hypermethylates and silences genes, often including the MLH1 mismatch repair gene, which can lead to MSI.

  • COX-2 overexpression
    • Associated with colorectal cancer
    • Possible protective effect of long-term use of aspirin and other NSAIDs c

Epidemiology & Risk Factors

  • Age ≥ 45 (standard screening starts at 45 for average risk).
  • Inherited syndromes: FAP (APC mutation, 100% progress to CRC), Lynch syndrome (MMR gene mutation, MSI).
  • Personal/family history of CRC or adenomatous polyps.
  • IBD (UC carries higher risk than Crohn’s disease; risk increases with duration and extent of disease).
  • Pathogens: Streptococcus bovis, Clostridium septicum c
  • Modifiable: High red/processed meat diet, low fiber, obesity, smoking, alcohol. c
    • Heme iron (abundant in red meat) catalyzes the Fenton reaction, generating reactive oxygen species (ROS).
SyndromeGene MutationColon Cancer RiskOther Associated Neoplasms
Familial adenomatous polyposisAPC100%Upper gastrointestinal, Thyroid, Desmoids/osteomas
Lynch syndromeMSH2/6, MLH150%-80%Endometrial, Ovarian
Peutz-Jeghers syndromeSTK1139%Upper gastrointestinal, Pancreatic, Breast
CharacteristicsColitis-associatedSporadic
AgeYounger (age 40-55)Older (age >60)
Origin of dysplasiaFlat (nonpolypoid) lesionsPolypoid lesions
LocationProximal > distal (particularly with CD)Distal > proximal
TumorsMultifocalSingular
HistologyMucinous and/or signet ring cells, Poorly differentiatedRarely mucinous, Well differentiated
MutationsEarly p53 mutation, Late APC gene mutationEarly APC gene mutation, Late p53 mutation

Pathophysiology

Clinical features

Right-sided colon carcinomas

  • Large, bulky masses that protrude into the colonic lumen due to the relatively large caliber of the ascending colon
  • Occult bleeding or melena
  • Manifestations of iron deficiency anemia (due to chronic bleeding)

Left-sided colon carcinomas

  • Often infiltrate the wall of the colon, encircling it and narrowing the lumen
  • More likely to cause obstruction
  • Changes in bowel habits (size, consistency, frequency)
  • Blood-streaked stools
  • Colicky abdominal pain (due to obstruction) c
    • Bowel obstruction occurs earlier in left-sided colon carcinomas because the distal colon has a smaller lumen than the proximal colon and contains solid fecal matter.

Diagnostics

  • Initial/Screening Options:
    • Colonoscopy every 10 years (preferred, diagnostic & therapeutic).
    • Fecal Immunochemical Test (FIT) or Fecal Occult Blood Test (FOBT) annually.
      • A negative fecal occult blood test (guaiac-negative stool) does not rule out GI malignancy, as tumor bleeding is often intermittent. Scopes must still be performed.
    • Multi-target stool DNA (Cologuard) every 3 years.
  • Confirmatory/Gold Standard: Colonoscopy with biopsy showing adenocarcinoma.
  • Staging & Workup:
    • CT Chest/Abdomen/Pelvis to evaluate for metastatic disease.
    • Pelvic MRI or Endorectal Ultrasound (EUS) specifically for rectal cancer (assesses depth of invasion & nodal status).
  • Key Labs: Microcytic anemia (↓ Hb, ↓ MCV, ↓ ferritin).
  • Tumor Marker: CEA (Carcinoembryonic Antigen). Crucial Note: Not used for screening or diagnosis; used solely for monitoring disease recurrence and response to treatment.

Treatment

  1. Colon Cancer (Stage I-III):
    • Surgical Resection: Upfront partial colectomy (hemicolectomy) with wide margins and regional lymphadenectomy (min 12 LNs required for staging).
    • Adjuvant Chemotherapy: Indicated for Stage III (node-positive) and high-risk Stage II. Regimen: FOLFOX (5-FU, Leucovorin, Oxaliplatin) or CAPOX.
  2. Rectal Cancer (Stage II-III):
    • Neoadjuvant Therapy: Chemoradiotherapy (5-FU + radiation) to downstage tumor before surgery.
    • Surgical Resection: Total mesorectal excision (TME).
      • Low Anterior Resection (LAR): For upper/middle rectal tumors; allows sphincter preservation.
      • Abdominoperineal Resection (APR): For lower rectal tumors invading sphincter; requires permanent colostomy.
    • Adjuvant Chemotherapy: Completed post-operatively.
  3. Metastatic Disease (Stage IV):
    • If isolated resectable mets, esp liver/lung:
      • Resection or ablation + systemic chemo can be curative-intent. c
    • Unresectable/metastatic:
      • Systemic chemo: FOLFOX, FOLFIRI, or CAPOX
      • Add biologic depending on markers:
        • Bevacizumab: anti-VEGF
        • Cetuximab/panitumumab: only RAS wild-type, usually left-sided tumors
        • Pembrolizumab/nivolumab: MSI-H/dMMR metastatic CRC

Follow-up

  • Patient history, physical examination, CEA level 
    • Every 3–6 months for 2 years
    • Every 6 months for an additional 3 years
  • CT chest/abdomen/pelvis: annually for 5 years 
  • Colonoscopy
    • 1 year after preoperative colonoscopy c
    • Every 3–5 years in the further follow-up, depending on findings
  • Proctoscopy/sigmoidoscopy
    • Recommended additional follow-up modality after the treatment of rectal cancer
    • Every 6–12 months for 3–5 years 
    • May be supplemented with endorectal ultrasound
  • Recommended duration of close follow-up: 5 years following the completion of curative treatment

Screening

Average-Risk CRC Screening Guidelines

  • Screening Initiation: Begin routine screening at age 45 years (recently lowered from 50).
  • Screening Termination:
    • Ages 45–75 years: Strong recommendation for routine screening.
    • Ages 76–85 years: Individualize based on comorbidities, life expectancy (>10 years), and prior screening history.
    • Ages >85 years: Discontinue screening.
  • Screening Modalities & Standard Intervals:
    • Colonoscopy: Every 10 years (Gold standard / Tier 1 option; both diagnostic and therapeutic). c
    • Fecal Immunochemical Test (FIT): Annually (Tier 1 option).
    • High-sensitivity Guaiac FOBT (gFOBT): Annually.
    • Multi-target stool DNA (mt-sDNA / Cologuard): Every 3 years.
    • CT Colonography or Flexible Sigmoidoscopy: Every 5 years.
  • Key Step 2 CK Rule: Any positive result on a non-colonoscopy screening test (FIT, gFOBT, mt-sDNA, CT colonography) must be followed by a diagnostic colonoscopy within 6 months. c

High-Risk CRC Screening Protocols

  • Family History of CRC or Advanced Adenoma:
    • ≥1 First-Degree Relative (FDR) diagnosed at <60 years (or ≥2 FDRs at any age): Begin screening at age 40 or 10 years before the youngest relative’s diagnosis (whichever is earlier). Perform screening with colonoscopy only and repeat every 5 years. c
    • 1 FDR diagnosed at age ≥60 years: Begin screening at age 40. Screening intervals and modalities are the same as average-risk populations (e.g., colonoscopy every 10 years or annual FIT).
  • Inflammatory Bowel Disease (IBD - UC or Crohn’s with colitis):
    • Begin surveillance colonoscopy 8 years after symptom onset.
    • Repeat colonoscopy every 1–3 years with random/targeted biopsies. c
  • Lynch Syndrome (HNPCC):
    • Autosomal dominant mismatch repair (MMR) gene mutation.
    • Begin screening colonoscopy at age 20–25 years (or 2–5 years before the youngest family diagnosis).
    • Repeat colonoscopy every 1–2 years.
  • Familial Adenomatous Polyposis (FAP):
    • Autosomal dominant APC gene mutation.
    • Begin screening with annual sigmoidoscopy/colonoscopy at age 10–12 years.
    • Management: Prophylactic colectomy once carpeted polyposis is identified.
  • Prior Childhood Cancer (Radiation Therapy):
    • History of abdominopelvic or total body irradiation.
    • Begin colonoscopy starting at age 30 or 5 years after radiation (whichever is last). Repeat every 5 years.

Post-Polypectomy Surveillance Intervals

All surveillance intervals assume a complete exam, adequate bowel preparation, and complete resection of all identified polyps.

Low-Risk Polyp Findings

  • Distal hyperplastic polyps <10 mm: Regarded as normal. Repeat screening in 10 years.
  • 1–2 small (<10 mm) tubular adenomas: Repeat colonoscopy in 7–10 years (under updated guidelines).
  • 1–2 small (<10 mm) sessile serrated polyps (SSPs): Repeat colonoscopy in 5–10 years.

Intermediate/High-Risk Polyp Findings

  • 3–4 small (<10 mm) tubular adenomas or SSPs: Repeat colonoscopy in 3–5 years.
  • 5–10 tubular adenomas or SSPs: Repeat colonoscopy in 3 years.
  • Advanced Adenomas (defined as ≥10 mm, villous/tubulovillous histology, or high-grade dysplasia [HGD]): Repeat colonoscopy in 3 years.
  • High-Risk SSPs (defined as ≥10 mm or SSP with dysplasia): Repeat colonoscopy in 3 years.
  • >10 adenomatous polyps (or SSPs) in a single session: Repeat colonoscopy in 1 year (work up for underlying polyposis syndromes).

Large Polyps & Piecemeal Resection

  • Large polyps (≥2 cm) removed via piecemeal resection: High risk of local recurrence. Repeat colonoscopy in 6–12 months. If no recurrence, repeat in 1 year, then in 3 years.

Surveillance after Negative Follow-up

  • If surveillance colonoscopy is negative following prior low-risk findings: Repeat colonoscopy in 10 years.
  • If surveillance colonoscopy is negative following prior high-risk findings: Repeat colonoscopy in 5 years.

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