MLH1 promoter hypermethylation in uterine carcinosarcoma rarely coexists with TP53 mutation

Introduction: Carcinosarcoma (CS) is an infrequent neoplasm composed of a carcinomatous and a sarcomatous element. Its molecular pathogenesis is poorly understood. In this study, we investigated the disturbances in the immunohistochemical expression of p53 and mismatch repair (MMR) proteins, as well as their molecular background.

Material and methods: The study group consisted of 20 uterine CSs. We analysed their morphology and immunohistochemical expression of hMLH1, hPMS2, hMSH2, MSH6, and p53 as well as the presence of mutations in TP53 and promoter methylation of the hMLH1. Loss of hMLH1 and PMS2 was found in 3/20 tumours. All cases were positive for hMSH2 and hMSH6. The TP53 mutation was detected in 8/19 tumours (42.1%), whereas MLH1 promoter hypermethylation in 4/19 cases (21%), and one case with synchronous aberrations (5%). Agreement between the results of the genetic and immunohistochemical study was moderate for p53 (k = 0.615, p< 0.01) and strong for MLH1 (k = 0.826, p< 0.01).

Results and conclusions: We demonstrated MLH1 promoter hypermethylation in uterine CS, leading to loss of MLH1 immunostaining. Concomitant aberrations of p53 and hMLH1 are infrequent. It is likely that uterine CS may develop in two independent molecular pathways in association with either chromosomal or microsatellite instability.