Mismatch Repair Protein Deficiency/Microsatellite Instability Is Rare in Cholangiocarcinomas and Associated With Distinctive Morphologies

OBJECTIVES: Although germline mutations of mismatch repair (MMR) genes (Lynch syndrome) are not typically associated with cholangiocarcinomas, the US Food and Drug Administration recently approved the use of pembrolizumab in patients with advanced solid tumors at all sites that show MMR deficiency or associated high microsatellite instability. METHODS: We analyzed 96 cases of intra- and extrahepatic cholangiocarcinomas for morphology using H&E and for MMR status using immunohistochemical staining. We submitted any results with MMR loss for microsatellite instability testing. RESULTS: We found that 6% of samples showed MMR deficiency. The best predictive factor was a nontypical infiltrating pattern of invasion (P < .0001). No patients with MMR deficiency had a history of a cancer typically associated with Lynch syndrome. CONCLUSIONS: Solid, mucinous, or signet-ring appearance of a cholangiocarcinoma should prompt MMR testing for immunotherapy options but should not necessarily raise concern about Lynch syndrome.