Characterizing Gynecological Cancers with the Uncommon dMMR/MSS Phenotype in Lynch Syndrome Patients

Background/Objectives: Lynch syndrome is an inherited autosomal dominant disease that predisposes to a broad spectrum of malignancies. This condition is driven by a germline pathogenic variant in one or more of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, PMS2, EPCAM) that results in genomic microsatellite instability (MSI-high). However, microsatellite-stable (MSS) tumors in Lynch syndrome patients may occur, but the relevant literature is scant. Our aim is to systematically identify, organize, and characterize the comprehensive available literature for Lynch syndrome-associated gynecological cancers (vulvar, vaginal, cervical, ovarian, endometrial) exhibiting a dMMR/MSS phenotype. Methods: Systematic review of the literature. Three medical databases, major related conferences and relevant oncology journals were scrutinized for relative evidence. Results: Eleven reports were identified comprising 2351 patients, 774 had confirmed Lynch syndrome (LS), of whom MSI results were available for 299 patients. In total, 130 patients developed LS-associated gynecological cancers, for whom MSI results were available. Among them, 36 tumors (27.7%) exhibited a dMMR/MSS molecular phenotype (23 endometrial, 12 ovarian, one synchronous endometrial–ovarian). No data for vulvar, vaginal, or cervical cancers were found. For dMMR/MSS endometrial cancers, the mean age at diagnosis was 50.5 years (range 36–62). dMMR/MSS tumors arose predominantly in MSH6 and, to a lesser extent, PMS2 carriers. No data on selective response to immune checkpoint inhibitors treatment were available. Conclusions: Lynch syndrome-associated gynecological cancers with dMMR/MSS phenotype are strongly underrepresented in the literature. Endometrial and ovarian cancers with dMMR/MSS phenotype are early onset and arise in a small proportion of patients. Better characterization is demanding to unearth whether response to immunotherapy treatment vary across Lynch dMMR/MSS and dMMR/MSI-High phenotypes.