Clinicopathological significance of multiple molecular features in undifferentiated and dedifferentiated endometrial carcinomas

Abstract

We investigated the clinicopathological significance of multiple molecular features in undifferentiated and dedifferentiated endometrial carcinomas (UDECs). Eighteen dedifferentiated endometrial carcinomas (DDECs) and three undifferentiated endometrial carcinomas (UECs) were collected. Polymerase-ε exonuclease domain mutations (POLE-EDM) were analysed by Sanger sequencing. SWI/SNF complex subunits, mismatch repair (MMR) proteins, p53, and PD-L1 were evaluated by immunohistochemistry. The SWI/SNF complex was inactivated in half of the UDECs; variably combined with deficient MMR (dMMR), POLE-EDM, or p53 aberrance. Deficiencies in BRG1 and ARID1A were mutually exclusive (p<0.05) in DDECs. ARID1A defects were mostly (8/9) associated with dMMR and typically occurred simultaneously in both endometrioid and dedifferentiated components, whereas BRG1 defects were less frequently (3/7) combined with dMMR and were only observed in dedifferentiated cells. Two-thirds of the UDECs displayed dMMR, mainly caused by the MLH1 promotor methylation. Mutant p53 immunostaining was detected in accordant or subclonal patterns. All three POLE-EDM UDEC patients had stage IA disease with either dMMR or p53 abnormality. Strong positive signals for PD-L1 were mainly detected in dMMR samples. BRG1 defects may likely trigger the progression of dedifferentiation in UDECs by superimposing the pre-existing driver events or by initiating UECs de novo, whereas ARID1A inactivation is subordinate and may likely be secondary to dMMR. The biological behaviours of BRG1-intact UDECs were evaluated according to The Cancer Genome Atlas molecular classification; their driver events require further analysis. Exact molecular subtypes can be helpful for clinical management and treatment decisions for patients with UDEC.