Colorectal Cancer _ ___________________________________________________________________________
genetic predisposition, each child has a 50% chance of inheriting the predisposition regardless of sex • Other clinical characteristics: - Cancers with an earlier age of onset than sporadic (non-genetic) cases - Predisposition to other cancers, such as endometrial cancer - Two or more primary cancers in a single individual, including multiple primary cancers of the same type (e.g., two separate primary colorectal cancers) or primary cancer of different types (e.g., colorectal and endometrial cancer) - Presence of non-neoplastic extracolonic features, as with congenital retinal pigment epithelium hypertrophy and desmoids in FAP - Uncommon tumors such as adren-ocortical, sebaceous carcinoma, ampullary, and small bowel - The presence of multiple polyps, even when family history appears negative Oligopolyposis (i.e., polyp count greater than expected) can involve as few as 10 to 15 polyps, and the diverse pathology of polyps requires careful attention to polyp count and histology to determine whether genetic testing and/or further clinical evaluation is appropriate [111]. Genetic Testing As discussed, many genes associated with inherited colorectal cancer syndromes have been identified, and genetic testing is available for diagnosis and is the accepted standard of clinical care. Genetic testing of asymptomatic persons without colorectal cancer symptoms or precursors (adenomatous polyps) is performed to identify increased probability of developing colorectal cancer. Positive findings should lead to diagnostic testing to investigate the presence of occult cancer, followed by treatment if cancer or precursors are found. The intent is to prevent the development of colorectal cancer or increase the likelihood of curative outcome afforded by early detection. Patients can also use this information for decisions related to family planning, work, or retirement. Disease-causing mutations can be found in most families affected by one of the inherited syndromes, and once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near-100% accuracy. Cancer screening and management is then based on the genetic testing results [117]. Clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing. Genetic screening for inherited colorectal cancer syndromes can be hampered by patient or proband resistance, but consent to testing is greatly improved with coordination between the pathologist, referring surgeon or oncologist, and a cancer genetics counselor [98; 117].
Clinical criteria used to identify candidates for genetic testing to determine the presence of an inherited susceptibility to colorectal cancer include [90; 96; 103]: • A strong family history of colorectal cancer and/or polyps • Multiple primary cancers in a patient with colorectal cancer • Family history of other cancers consistent with known inherited syndromes causing a high risk of colorectal cancer • Early age at colorectal cancer diagnosis Screening/Surveillance Recommendations for Hereditary Colorectal Cancer Patients diagnosed with a hereditary colorectal cancer syndrome or with a highly suggestive family or personal history require a more intensive and frequent screening and surveillance protocol than patients with average risk because of their high risk for colorectal and extracolonic malignancies. Table 3 provides a summary of recommendations for patients with specific hereditary colorectal cancer syndromes [111]. For each hereditary colorectal cancer syndrome, the left column lists malignancies associated with the syndrome, and the corresponding right column describes screening or surveillance approach specific to the at-risk malignancy. Inflammatory Bowel Disease as Colorectal Cancer Risk Factor Patients with inflammatory bowel disease, which includes ulcerative colitis and Crohn disease, have an elevated risk of developing colorectal cancer. The extent that colorectal cancer risk is elevated depends on the extent and duration of disease, but earlier age at onset is not associated with greater risk. Older estimates of colorectal cancer risk in patients with ulcerative colitis indicated a 2% greater risk after 10 years, 7.7% to 8% after 20 years, and 15.8% to 18% after 30 years of disease [118]. More recent estimates are somewhat lower, the result of more widespread prescribing of chemoprotective aminosalicylates, earlier and more liberal use of colectomy for medically refractory disease, and higher rates of surveillance colonoscopy. Studies involving patients with either ulcerative colitis or Crohn disease have shown comparable risk in both diseases [118]. The extent of inflammatory bowel syndrome is defined as the point in time when histologically identified disease is most extensive. Most colorectal cancers develop in patients with pancolitis, and disease extent is a major risk factor for colorectal cancer in patients with inflammatory bowel syndrome [118]. Patients with left-sided disease (up to the splenic flexure) have an intermediate risk level, while proctitis, ulcerative proctosigmoiditis, and backwash ileitis have little to no influence on risk level. A family history of sporadic colorectal cancer in a first-degree relative doubles the risk of colorectal cancer, and risk increases nine-fold if the first-degree relative was younger than 50 years of age when first diagnosed with colorectal cancer.
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