Mismatch Repair Proficient Colorectal Adenocarcinoma in Two Patients With Lynch Syndrome

Screening for Lynch syndrome (LS) is essential in colorectal carcinoma (CRC) diagnosis. The hallmark of CRC in LS is mismatch repair (MMR) deficiency, a vital biomarkers assessed by microsatellite instability (MSI) analysis and/or immunohistochemistry (IHC) staining of the MMR proteins in the tumor, that also predict response to immune checkpoint inhibitors. We report two LS patients who developed MMR proficient CRCs. Patient A, with a pathogenic MSH6 germline variant, presented with two MMR discordant CRCs: a rectal MMRd/MSI adenocarcinoma, and a sigmoid MMR proficient (MMRp) and microsatellite stable (MSS) adenocarcinoma, leading to metastasis. While the MMRd/MSI carcinoma was recognized early and showed complete pathologic response after pembrolizumab treatment, the MMRp/MSS adenocarcinoma was underrecognized and poorly responsive to treatment. A second patient, with a pathogenic PMS2 variant, also developed a MMRp CRC. These cases highlight the complex biological pathways in CRC development and the impact of molecular classification on treatment.