L14 Colorectal Cancer

• Colorectal Cancer (CRC)


  Cancers of the colon and rectum

  
• Colorectal Cancer (CRC)


  • Also known as bowel cancer
  • Risk factors include colon polyps, long-standing ulcerative colitis, and genetic family history
  • Most colorectal cancers develop from polyps

  
• Colorectal cancer is the most commonly reported cancer in New Zealand, with around 3000 new cases and 1200 deaths each year

  
• Colorectal cancer is the second highest cause of cancer death in New Zealand

  
• Peak age for colorectal cancer is 60-79 years; <20% below 50

  
• Risk Factors for CRC

  • Older age
  • Obesity
  • Type 2 diabetes
  • Smoking
  • Alcohol
  • Physical inactivity
  • Ulcerative colitis or Crohn's disease
  • Polyposis syndromes (hereditary)
  • Family history of colorectal neoplasia
  • Diet
  • High levels of red, processed and grilled meats
• 1 in 3 women and 1 in 2 men will develop cancer in their lifetime

  
• Signs and Symptoms of CRC

  • Right side: Projecting into the lumen, leading to diffuse thickening of the wall and narrowing of the lumen
  • Left side: Eroding the surface epithelium and variable amounts of subepithelial tissue
• Pathogenesis of colorectal carcinoma (CRC)


  • Tumours develop due to changes in growth regulation resulting from modification of genes that control that growth
  • The number of genetic changes is multiple and involves an accumulation of these changes which is seen grossly and histologically with the development firstly of adenomas and then carcinomas
  • This is known as the adenoma-carcinoma sequence
  • In hereditary cases some genetic changes are present at birth

  
• Pathogenesis of CRC


  • APC, β-catenin, K-RAS and p53 are important genes in this pathway
  • Dysregulation of the APC-β-catenin pathway leads to the Chromosomal Instability (CIN) phenotype
  • Dysregulation of the mismatch repair pathway leads to microsatellite instability (MSI) phenotype
  • Epigenetic input to CRC: Global genome hypermethylation of DNA causes tumour suppressors to be switched off, leading to the CpG island phenotype (CIMP)
• Aberrant Crypt Formation (ACF) in CRC

  • Clusters of abnormal tube-like glands in the lining of the colon and rectum
  • Form before colorectal polyps
  • One of the earliest changes seen in the colon that may lead to cancer
  • ACF are, as opposed to normal epithelial cells, apoptosis resistant

  
• Polyps - adenomas


  • Due to localised epithelial proliferation
  • May be pedunculated - on a stalk or sessile - flat
• Followed for 20 years, the risk of cancer at the site of the adenoma is 25%, much higher than that expected in the normal population

  
• Removal of adenomatous polyps is associated with reduced colorectal cancer incidence

  
• Adenoma to carcinoma


  • Predominantly left-sided: APC-β-catenin (WNT) pathway
  • Predominantly right-sided: Mismatch repair (microsatellite instability pathway)

  
• Histology shows glands (arrow) in the tumour that was surgically removed
• Genomic Technology: A Revolutionary Medical Breakthrough


  Profiling cancer genomes allows targeting known vulnerabilities for personalized treatment
• Secondary cancer - metastatic spread can occur via the blood (haematogenous), portal vein, lymphatic system, or by direct contact