Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Major Genetic Syndromes
Table 10. Clinical Practice Guidelines for Colon Surveillance of BiallelicMYH-Associated Polyposis (MAP) continued...
In the setting of known or suspected LS, the detection of one to ten adenomas is still in keeping with the diagnosis. A similar adenoma count in a young patient undergoing colonoscopy for symptoms or in a screening patient over age 50 years could raise the question of LS. In the appropriate clinical setting—early onset and positive family history—the detection of any number of adenomas may support the testing and diagnosis of a patient for underlying LS mutations, consistent with guidelines such as those offered by the NCCN. Some controversy exists over the utility of testing adenoma tissue for microsatellite instability (MSI), as the yield is lower than in invasive cancer. In general, and subject to the above caveats, LS is not routinely considered in a discussion of oligopolyposis.
One study considered a series of polyps (37 adenomas) from 21 patients with known MMR mutations, performing MSI and immunohistochemistry (IHC) for MMR protein expression. Overall, MSI-high (MSI-H) was seen in 41% and in 100% of adenomas larger than 1 cm. Adenomas measuring smaller than 1 cm yielded MSI about 30% of the time. Correlation between MSI and loss of staining on IHC was fairly high, although the discordance rate (17%) was higher than in other series that evaluated invasive cancers from known MMR mutation carriers. A higher MSI likelihood was observed in subjects older than 50 years. IHC staining in relation to mutation showed 8 of 12 MLH1 adenomas to have lost protein expression, with 10 of 20 adenomas from MSH2 patients to have loss of expression. In contrast, none (0 of 6) of the adenomas from MSH6 mutation carriers had loss of associated protein expression. The authors concluded that while normal MSI/IHC was simply not informative, abnormal MSI/IHC was as likely in larger (>8 mm) polyps as in cancers and thus a reasonable test to consider.
AFAP is found at the other end of the oligopolyposis spectrum. Most cases will have more than 100 adenomas, albeit at a later age and often with a predominance of microadenomas of the right colon and with fewer, larger polyps in the left colon. Cases with a positive family history and an APC mutation are clearly variant cases of FAP, as the term AFAP implies. However, patients with no immediate family history and a lesser adenoma burden may not be found to have an APC mutation. The lower the polyp count the lower the probability of APC mutation. Some of these cases are now known to carry biallelic MYH mutations, although even here, the lower the adenoma count the lower the mutation likelihood.