Prevalence of Atypical and Subclonal p53 Immunohistochemistry Expression in Mismatch Repair-deficient and/or POLE-mutant Endometrial Carcinomas with TP53 Mutation.

Abstract

p53 immunohistochemistry (IHC) is a reliable surrogate for determining TP53 mutation status in endometrial carcinomas (ECs). However, the correlation of p53 IHC patterns and TP53 mutation characteristics in mismatch repair deficiency (MMRd) and/or POLE-mutant ECs was not comprehensively investigated. In this study, we identified four p53 expression patterns in forty MMRd and/or POLE-mutant ECs with TP53 mutations. Thirteen cases (33%) displayed wild-type pattern. Nine cases (23%) showed atypical pattern, characterized by the presence of eye-catching clustered cells with strong nuclear staining or weak to moderate cytoplasmic staining, which were patchily distributed with blurred boundaries. Fourteen cases (35%) demonstrated subclonal pattern with distinct regions of wild-type and mutation-type staining, of which three cases were originally misdiagnosed as "mixed EC". Only four (10%) cases exhibited typical aberrant pattern. Tumors with wild-type and atypical patterns were predominantly associated with MMRd and POLE mutations, respectively. Among fifty-two TP53 mutations identified, 75% were missense and 25% were truncating, predominantly in DNA binding domain. Gain-of-function (GOF) missense mutations were more frequent in cases with subclonal patterns, whereas non-GOF missense mutations predominated in wild-type or atypical patterns. Concurrent mutations were present in 25% of cases and were more common in aberrant or atypical patterns. Interestingly, two POLE wild-type cases with subclonal MMR expression showed p53 overexpression across the entire tumor, complicating molecular subtyping. These findings highlight the prevalence of atypical and subclonal p53 expression patterns in MMRd and/or POLE-mutant ECs with TP53 mutations, aiding in accurate IHC interpretation and thus more precise EC histological and molecular classification.