Definition

Cancer of the colon or rectum

TypeFrequencyCellular origin
Adenocarcinoma95%Glandular epithelium
Lymphoma1%Extranodal lymphatic system
Carcinoid0.5%Neuroendocrine cells
Sarcoma0.3%Blood vessels, muscle, connective tissue
Squamous cellrareSquamous cells
StromalrareInterstitial cell of Cajal

Adenocarcinoma

  • By far the most common
  • "Colorectal adenocarcinoma"
    used interchangeably with
    "colorectal cancer"

Lifetime Incidence

  • 1 in 20 will develop in lifetime
  • 1 in 50 will die from in lifetime

Prevalence

  • 3rd most common cancer worldwide
    (10% of total cancers)

  • Steadily increasing incidence
    • ↑ 30% among males since 1975
    • Ageing population?
    • Westernised diet?

Morbidity

Mortality

  • 40% overall
  • 2nd-3rd most responsible for cancer-related mortality

Data: O'Connell et al.

Cost

Ireland, 2008 (Ref: Tilson et al.)
  • Average healthcare cost per case = ~€40,000
  • More for rectal cancers
  • More for advanced stages

Pathogenesis

  • 5-10% single gene disorders
    • HNPCC (MLH1, MSH2 genes)
    • FAP (APC gene)

  • 30% complex genetic causes

  • 60% sporadic
    • age-associated
    • Western diet
    • chronic inflammation
    • abdominal radiation
    • immunosuppression

Polyps

Small growths from mucous membranes
Kd4ttc [CC-BY-2.5], via Wikimedia Commons
Gilo1969 [CC-BY-SA-3.0 or GFDL], via Wikimedia Commons

Pedunculated polyp


Ed Uthman [Public domain], via Wikimedia Commons

Polyps

  • Neoplastic polyps
    • Adenomatous polyps (adenomas)
    • 10% of all polyps
    • Potential for malignant change, but most do not

  • Non-neoplastic polyps
    • Inflammatory, hamartomatous, hyperplastic
    • 90% of all polyps
    • Generally no malignant change
    • A sign of greater risk of adenoma (carcinoma)

Adenomas

  • 0.3 to 10 cm diameter
  • Velvety, raspberry-like texture of irregular epithelium
  • Sessile or pedunculated

Ed Uthman [CC-BY-SA-2.0], via Wikimedia Commons

Adenoma Architectures

  1. Tubular: small, peduncular, tubular glands
  2. Tubulovillous
  3. Villous: larger, sessile, villous surface
Nephron [CC-BY-SA-3.0 or GFDL], via Wikimedia Commons
The Juan Rosai Collection [CC0], via Wikimedia Commons

Malignant Transformation

  • Risk factors:
    • Large size
    • Sessile shape
    • Villous architecture
    • Multiple adenomas

  • 90% of malignancies develop from pedunculated adenomas
    • 33% of Western people have benign adenomas
    • 1% of adenomas undergo malignant change

  • 10% of malignancies develop from sessile adenomas
    • more difficult to detect

Familial Colorectal Cancer Syndromes

  • Heritable genetic syndromes predisposing to polyps
  • Greatly increased lifetime risks of colorectal carcinoma
  • Both autosomal dominant
Syndrome Gene Gene type
Familial Adenomatous Polyposis (FAP) APC Tumour suppressor
Hereditary Non-Polyposis Colorectal Cancer (HNPCC)
 MLH1, MSH2 Mismatch repair

Familial Adenomatous Polyposis (FAP)

  • 3% of all colorectal carcinoma
  • Develop 100s-1000s of polyps by teens
  • 100% risk of carcinoma <30y if not treated by prophylactic colectomy

Samir [GFDLor CC-BY-SA-3.0], from Wikimedia Commons

Familial Adenomatous Polyposis (FAP)

  • Adenomatous polyposis coli ( APC ) gene
    • Tumour suppressor gene
    • Two-hit mutation/silencing

  • Specific mutation variants :
    • Gardner syndrome
      • Osteomas of skull and long bones
      • Epidermal cysts
      • Desmoid, thyroid tumours
      • Supernumerary and unerupted teeth
    • Turcot syndrome
      • CNS medulloblastomas and glioblastomas

Hereditary Non-Polyposis Colorectal Cancer (HNPCC)

  • Also called Lynch syndrome
  • Cancers: colorectal, gastric, endometrial, ovarian, uterine
  • Colorectal carcinoma in the young

  • Inherited mutations in DNA mismatch repair genes:
    • MLH1, MSH2, others (rarer)
    • Two-hit mutation/silencing
    • Accumulation of mutations in short, repeating microsatellite regions

Gatekeeper/Caretaker Genes

  • 'Gatekeeper' genes 'control the gate' to tumour mutation
  • 'Caretaker' genes 'weed the garden' of tumours

Gatekeeper

 Control cell growth Tumour suppressor genes Many tumours, but less aggressive FAP
Caretaker

 Stabilise genome, prevent mutations Mismatch repair genes Few tumours, but more agressive HNPCC

Molecular Pathways

  • Identified pathways of colorectal carcinoma development
  • Genetic and epigenetic abnormalities
  • Stepwise accumulation of mutations

Pathway Gene Gene type Downstream effects
APC/β-catenin APC Tumour suppressor WNT, KRAS, p53, LOH, SMAD2/4
Microsatellite instability MLH1, MSH2 Mismatch repair TGF-β, BAX, BRAF

APC/β-catenin pathway

      Normal APC function:
  • APC binds β-catenin, marks for degradation

    Loss of APC function:
  • APC cannot bind, β-catenin accumulates
  • β-catenin upregulates gene transcription in nucleus:
    • WNT signalling pathway
    • genes promoting proliferation (e.g. MYC, cyclin D1)
  • Activating mutations in KRAS:
    • promote growth, prevent apoptosis
  • Chromosomal instability, further mutations:
    • p53, LOH, SMAD2, SMAD4, gross chromosomal alterations, telomerase expansions

APC/β-catenin pathway

Microsatellite Instability Pathway

  • Defects in mismatch repair genes
    • MLH1, MSH2, others (rarer)
  • Mutations accumulate in short, repeating microsatellite regions
  • Regions are mostly non-coding, but contain some promoters for genes of cell growth regulation
    • TGF-β: inhibits colonic epithelial cell proliferation
    • BAX: pro-apoptotic for abnormal clones
    • BRAF: oncogene

Microsatellite Instability Pathway

Symptoms

Signs

Risk Factors

  • History, genes:
    • Family or personal history
    • Polyps, adenomas, cancers, FAP, HNPCC

  • Chronic inflammation: ulcerative colitis, Crohn's disease
  • Lifestyle: obesity, sedentary, smoking

  • Diet:
    • risk: fat, red meat, alcohol, refined carbs
    • protective: fibre, antioxidants, NSAIDs

Age

  • Strongly related, 95% of cases are >50y

Ethnicity

  • Higher incidence in West than Africa/Asia
  • Increasing incidence in Asia with Westernising diet

Labs

  • Carcinoembryonic antigen (CEA)
    • Serial measurements for follow-up
    • Rising = recurrence
    • Not useful for primary Dx

  • Faecal occult blood
    • Can detect in early stages
    • Populations screening, GP, hospital

  • Liver function tests (mets)
  • Haemoglobin (blood loss)

Histology

Nephron [CC-BY-SA-3.0 or GFDL], via Wikimedia Commons
  • Indicators of malignant change:
    • large size
    • villous architecture
    • severe dysplasia

  • 'Signet ring' cells (pictured →)
    • Glandular cells producing mucin
    • Mucin displaces nucleus to edge
    • Poorer prognosis

Colonoscopy

  • 'Gold-standard' diagnosis
  • 70% of carcinomas in distal distal 1/3 of colon, easily visualised
  • Can biopsy and remove polyps



Gilo1969 [CC-BY-SA-3.0 or GFDL], via Wikimedia Commons

CT Colonography

  • 'Virtual colonoscopy'
  • Assess size, spread, metastasis

Imaging

  • Ultrasound
    • staging

  • PET
    • suspicious small lesions not confirmed by CT

  • MRI
    • staging, suspicious small lesions
  • Double-contrast barium enema
    • when CT or colonoscopy not possible

Acute Complications

Chronic Complications

Treated

  • Potential for early detection with screening
  • Removal of adenomas during endoscopy
  • Most have surgery, <50% survive 5yr
    • variable type, depending site
    • most: resection with restorative anastomosis
  • Adjuvant chemotherapy
  • Biologics:
    • Bevacizumab: anti-VEGF
    • Cetuximab: anti-EGFR, KRAS mutation resistance

Follow-Up

  • Regular colonoscopy
  • Annual CT for liver metastases
  • Serial CEA, rise = recurrence
James Heilman [CC-BY-SA-3.0 or GFDL], via Wikimedia Commons

Untreated


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