Mismatch Repair “Null” Immunophenotype in Endometrial Endometrioid Carcinoma: MLH1 Promoter Hypermethylation With Somatic Inactivation of MSH2

Up to 3% of endometrial cancers may be associated with Lynch syndrome (LS). For endometrial cancer, the preferred approach to universal LS screening is immunohistochemical staining for the mismatch repair proteins MLH1, PMS2, MSH2, and MSH6, with about one-third of endometrial cancers showing abnormal results. We describe the case of a 57-year-old woman with an endometrial endometrioid carcinoma that demonstrated a rare “null” mismatch repair protein immunohistochemical profile with complete loss of MLH1, PMS2, MSH2, and MSH6 expression, with positive staining in the internal and external controls. Subsequent MLH1 methylation testing, genetic counseling, and somatic tumor tissue testing revealed MLH1 promoter methylation, no germline alterations, a somatic frameshift mutation in MLH1 and 2 somatic nonsense mutations in MSH2 , a high tumor mutational burden (68.8 mut/Mb), and microsatellite instability in 55 of 104 microsatellite sites assessed. Although the patient had a family history of colon cancer, the MMR-null immunophenotype is attributed to a combination of methylation and somatic events. However, in gastrointestinal cancer cases, the MMR-null immunophenotype has been associated with LS, and therefore, in gynecologic cases, we recommend MLH1 promoter methylation testing and germline genetic counseling and testing for cases demonstrating this rare finding.