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.

This case report describes an endometrial carcinoma with concurrent loss of all four mismatch repair (MMR) proteins, the first such "null phenotype" reported in endometrial cancer. The authors sought to explain the mechanism behind this rare immunohistochemical pattern, and found MLH1 promoter hypermethylation together with somatic MSH2 mutations, with no pathogenic germline variants, suggesting multiple somatic mechanisms can coexist within one tumor. The authors emphasize that recognizing such unusual MMR profiles matters clinically, since MMR-deficient tumors are typically microsatellite instability-high and may be eligible for immune checkpoint inhibitor therapy.