Colorectal polyps and cancer – when to refer to genetics
Universal tumor testing
Because of the limitations of relying on clinical family history, such as with the Amsterdam criteria and the Bethesda guidelines,18,19 as of 2014 the NCCN recommended universal tumor screening for DNA MMR deficiency associated with LS. This approach, also known as “universal testing,” has been shown to be cost effective and more sensitive in identifying at-risk patients than clinical criteria alone.20,21 Specifically, the NCCN recommends that tumor specimens of all patients diagnosed with CRC undergo testing for microsatellite instability (MSI) or loss of MMR proteins (MLH1, MSH2, MSH6, PMS2) expression by immunohistochemistry (IHC).5 Loss of MMR proteins or MSI-high findings should prompt a referral to genetics for counseling and consideration of testing for germline mutations. Universal testing of CRC and endometrial cancers is considered the most reliable way to screen patients for LS.
Universal testing by MSI or IHC may be performed on premalignant or malignant lesions. However, it is important to recognize that DNA MMR deficiency testing may not be as reliable when applied to colorectal polyps. Using data from three cancer registries (Dana-Farber Cancer Institute, University of Michigan, MD Anderson Cancer Center), Yurgelun and colleagues investigated the yield of MSI and IHC in colorectal polyps removed from patients with known LS.22 Overall, high-level MSI was found in only 41% of Lynch-associated adenomas and loss of MMR protein expression was evident in only 50%. While adenomas 8 mm in size or greater were more likely to have MSI-high or loss of MMR protein expression compared with those less than 8 mm in size, MMR-deficiency phenotype was less reliable in smaller adenomas. Consequently, results of MSI and/or IHC should therefore be interpreted with caution and in the context of the specimen upon which they are performed.
Considerations for clinical genetic testing
Genetic testing for cancer susceptibility should include informed consent and counseling for patients regarding potential risks and benefits. Clinicians ordering genetic testing should have the expertise necessary to interpret test results, which may be positive (pathogenic or likely pathogenic germline variant identified), or negative (no variants identified), or may yield one or more variants of uncertain clinical significance. Individuals found to carry a pathogenic or likely pathogenic germline variant associated with cancer susceptibility should be referred for additional genetic counseling and may require additional expert consultation for management of extracolonic cancer risks. It is important that individuals diagnosed with a hereditary cancer syndrome be informed that this diagnosis has implications for family members, who may also be at risk for the condition and may benefit from genetic testing.
Practical considerations
Given the difficulty in obtaining a detailed family history while in clinic or in endoscopy, several studies have investigated strategies that may be integrated into practice to identify high-risk patients without substantial burden on providers or patients. Kastrinos and colleagues identified the following three high-yield questions as part of a CRC Risk Assessment Tool that can be used while performing a precolonoscopy assessment: 1) Do you have a first-degree relative with CRC or LS-related cancer diagnosed before age 50?; 2) Have you had CRC or polyps diagnosed prior to age 50?; and 3) Do you have three or more relatives with CRC? The authors found that these three questions alone identified 77% of high-risk individuals.23 In addition, implementation of family history screening instruments using standardized surveys or self-administered risk prediction models at the time of colonoscopy have been shown to improve ascertainment of high-risk patients.24,25 Such strategies may become increasingly easier to implement with integration into patients’ electronic medical records.
