Colorectal Cancer

 

Clinical Background

Colorectal cancer is second only to lung cancer as a cause of cancer-related deaths in the U.S.

Epidemiology

  • Incidence – 34/100,000, according to U.S. SEER (Surveillance Epidemiology and End Results) database
  • Age – usually ≥50 years
  • Sex – M>F

Inheritance

  • Microsatellite instability (MSI) (the expansion or contraction of short nucleotide repeats) is seen in tumors associated with Lynch syndrome (HNPCC) as well as in 10-15% of sporadic colorectal cancers
    • MSI can be determined directly by PCR or indirectly by immunohistochemistry (IHC) for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2)
      • Hypermethylation of the MLH1 promoter is the cause of instability in most sporadic microsatellite-unstable colorectal cancers
        • The most common IHC profile for a sporadic microsatellite-unstable cancer will be abnormal MLH1/PMS2 immunostaining
        • Lynch-associated tumors will also show this IHC profile due to a germline mutation in MLH1
        • IHC can also be used as a guide for subsequent germline mismatch repair gene evaluation
    • Most sporadic microsatellite-unstable colorectal cancers also harbor mutations in the oncogene BRAF
      • Because the BRAF V600E mutation and MLH1 methylation are commonly seen in sporadic microsatellite-unstable colorectal cancers, and are only rarely seen in Lynch syndrome, these two features can be used to help distinguish between sporadic and Lynch-associated tumors with the IHC profile of abnormal MLH1/PMS2
        • BRAF V600E mutations can also be used to evaluate the effectiveness of therapy with epidermal growth factor receptor (EGFR) inhibitors
      • BRAF V600E mutations are also seen in papillary carcinoma of the thyroid

Risk Factors

  • Diet high in animal fats (Western diet)
  • Patients with metabolic syndrome
  • Genetics – hereditary syndromes (autosomal dominant transmission)
    • Familial adenomatous polyposis (FAP)
      • Autosomal dominant syndrome in which affected persons develop hundreds to thousands of colon polyps and subsequent colorectal cancer
      • Occurs in 1/20,000 live births and accounts for <1% of total colon cancers
      • Usually caused by mutations in the APC gene, a tumor-suppressor gene on chromosome 5
      • Can also be associated with brain tumors (Turcot syndrome) and other extraintestinal manifestations
        • May develop periampullary carcinomas, osteomas, gastric polyps, small intestinal polyps, and tumors of the adrenal gland, liver, and thyroid
        • Extraintestinal manifestations in FAP, formerly called Gardner syndrome
    • Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome
      • Most common form of inherited colorectal cancer
        • Accounts for 2-3% of colon cancer cases in the U.S.
        • Autosomal dominant; 80% will develop colorectal cancer
      • Patients are also at risk for developing tumors in the uterus (endometrial cancer – 20-60% risk), ovaries (12% risk), stomach, small bowel, hepatobiliary system, pancreas, renal pelvis and ureter
      • Associated with underlying germline mutations in DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2
        • 1-2% of colorectal cancer due to mutations in mismatch repair genes
    • Hamartomatous polyps
      • Peutz-Jeghers syndrome
      • Juvenile polyposis
      • Cowden syndrome
  • Other risks
    • Ureterosigmoidostomy – carcinoma can develop ≥15 years post procedure

Pathophysiology

  • Most colorectal cancers arise from adenomatous polyps
    • Villous adenomas transform into adenocarcinomas three times more frequently than tubular adenomas
    • Subset of adenocarcinomas develop from hyperplastic-appearing polyps, especially large, right-sided polyps
    • Adenocarcinoma arising in a polyp is considered malignant when it penetrates into the submucosa 
  • Other, less-common tumors can occur (lymphomas, endocrine and mesenchymal tumors)

Clinical Presentation

  • Symptoms vary with tumor location – most are located in sigmoid colon and rectum
    • Cecum and ascending colon – tumors may be very large without obstructing
      • Anemia is a common presenting symptom
    • Descending and transverse colon – tumors tend to obstruct and cause annular lesions (apple core or napkin ring) with abdominal pain and bloating
    • Rectosigmoid – hematochezia, tenesmus and narrowing of stool caliber

Prevention

  • Aspirin and other NSAIDs
    • Suppress cell proliferation by inhibiting prostaglandin synthesis
    • Effects increase with duration of use
  • Diets rich in fruit and vegetables
    • Reduce risk
    • Do not reduce incidence of subsequent adenomas in a patient with prior adenoma removal
  • Estrogens
    • 20-30% reported reduction in colorectal cancer incidence in women who used hormone therapy
    • No mainstream studies proving estrogen therapy is preventative