Microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) represents an important molecular alteration with diagnostic, prognostic, and predictive value. The increasing interest toward this genetic alteration is given to the high response rate of MSI/dMMR
tumors to
immunotherapy. There are different
cancers in the periampullary region that can harbor MSI/dMMR, and significant morphological-molecular correlates should be acknowledged in this district: (1) pancreatic ductal
adenocarcinoma (PDAC): in this
tumor category, the prevalence of MSI/dMMR is about 1-2%, and medullary and
colloid variants are the most typically involved; (2) ampullary
adenocarcinoma: here the prevalence of MSI/dMMR is up to 18%, and in this neoplastic group, MSI/dMMR is more commonly found in the intestinal subtype; (3) pancreatic
acinar cell carcinoma: here the prevalence of MSI/dMMR is up to 14%; and (4) pancreatic and ampullary
neuroendocrine carcinoma: in this
tumor category, the prevalence of MSI/dMMR is up to 5-8%, and this molecular alteration should be assessed also in cases of mixed neuroendocrine-non-neuroendocrine
neoplasms. Given the clinical importance of MSI/dMMR and its not-negligible prevalence among the different
carcinomas arising in this district, its assessment should become part of the routine diagnostic workflow at least for the most typical histotypes. The test of choice is represented by immunohistochemistry for PDAC and ampullary
carcinomas, and by direct molecular analyses including MSI-based polymerase chain reaction and next-generation sequencing for acinar cell and
neuroendocrine carcinomas.