Complete loss of all mismatch repair protein expression in endometrioid carcinoma: A first case report of null phenotype induced by MLH1 hypermethylation and MSH2 somatic mutation

Background Endometrial cancer (EC) is a heterogeneous disease comprising four molecular subtypes, one of which is mismatch repair-deficient (MMRd). Immunohistochemical (IHC) evaluation of MMR proteins typically reveals the loss of paired MMR protein expression. However, concurrent loss of all four MMR proteins, known as the null phenotype, is extremely rare and has been reported only in a few colorectal, gastric, and small bowel adenocarcinomas. The mechanisms underlying this unusual MMR IHC pattern remain unclear. Case Report We describe a patient with EC showing concurrent loss of all four MMR proteins by IHC. Molecular analysis revealed hypermethylation of the MutL homolog 1 (MLH1) promoter and somatic mutations in MutS homolog 2 (MSH2). Germline genetic testing identified no pathogenic variants, suggesting that the MMR alterations were acquired somatically. To the best of our knowledge, this is the first reported case of EC with the null MMR phenotype. The coexistence of MLH1 promoter hypermethylation and MSH2 mutations suggests that multiple mechanisms of MMR disruption may occur within a single tumor. Conclusion This case highlights the importance of recognizing unusual MMR IHC profiles in EC and performing molecular analyses to clarify the underlying genetic and epigenetic alterations. Although MMR deficiency can result from different mechanisms, including MLH1 promoter hypermethylation, Lynch syndrome, and somatic mutations, multiple mechanisms may coexist in an individual tumor. Accurate characterization of MMR deficiency is clinically relevant because MMR-deficient tumors are often microsatellite instability-high and may be eligible for immune checkpoint inhibitor therapy.