Endometrial Carcinomas with DNA Mismatch Repair Abnormalities: Genotypic Phenotypic Correlations.
Karuna Garg, Noah D Kauff, Robert A Soslow. MSKCC, New York
Background: Endometrial carcinomas (ECs) are commonly associated with defective DNA mismatch repair, either due to epigenetic (MLH1 promoter methylation) or genetic alterations (germline mutations in DNA mismatch repair genes resulting in HNPCC/Lynch syndrome (LS)). Correlations between genotype and morphologic phenotype are poorly understood. In this study, we describe the pathologic characteristics of ECs with DNA MMR abnormalities.
Design: ECs with abnormal DNA MMR IHC that were tested for DNA MMR mutation and/or MLH1 promoter methylation were included in the study (n=11).
Results: Of 11 samples, 7 had absent MLH1 or PMS2 expression. Of these, 4 tumors showed MLH1 promoter methylation; germline testing in the other 3 cases demonstrated a clearly deleterious germline MLH1 mutation in 1 and missence mutations of unclear significance in 2. In the four samples with loss of MSH2 or MSH6 expression, germline testing identified 3 MSH2 mutations and 1 MSH6 mutation. Two of the 11 patients had no personal or family history suggestive of LS while 4 patients met the Amsterdam II criteria for LS (including the 2 patients with MLH1 variants). Six of the 11 tumors were endometrioid (EEC), 1 was clear cell (CC), 1 mixed endometrioid and serous and 3 undifferentiated/dedifferentiated. One endometrioid ca arose in endometriosis. Peritumoral and tumor infiltrating lymphocytes were noted in 2 cases, tumor heterogeneity in 4 cases, lower uterine segment origin in 2 cases, undifferentiated/dedifferentiated histology in 3 cases and synchronous ovarian clear cell carcinoma (arising in endometriosis) in 1 case. Correlation between genotyping and tumor morphology is shown in Table 1.
|Genotype (number of patients)||Tumor morphology (patient age in yrs)|
|MLH1 methylation (4)||1 dedifferentiated ca (35), 1 FIGO 1 EEC (49), 1 FIGO 3 EEC (58), 1 CCC (59)|
|MSH2 mutation (3)||2 FIGO 2 EEC (41, 47), 1 mixed endometrioid and serous (50)|
|MSH6 mutation||FIGO 1 EEC (42)|
|MLH1 deleterious mutation (1)||Dedifferentiated ca (52)|
|MLH1 missense mutations (2)||1 undifferentiated ca (39), 1 endometrioid ca in endometriosis (55)|