Molecular Analysis of Mixed Endometrial Carcinomas Shows Clonality in Most Cases

Abstract

Mixed endometrial carcinoma refers to a tumor that is comprised of two or more distinct histotypes. We studied 18 mixed-type endometrial carcinomas - 11 mixed serous and low-grade endometrioid carcinomas (SC/EC), 5 mixed clear cell and low-grade endometrioid carcinomas (CCC/EC), and 2 mixed clear cell and serous carcinoma (CCC/SC), using targeted next generation sequencing and immunohistochemistry to compare the molecular profiles of the different histotypes present in each case. In 16 of 18 cases there was molecular evidence that both components shared a clonal origin. Eight cases (6 EC/SC, 1 EC/CCC and 1 SC/CCC) showed a serous carcinoma molecular profile that was the same in both components. Five cases (3 CCC/EC and 2 SC/EC) showed a shared endometrioid molecular profile and identical mismatch repair protein (MMR) deficiency in both components. A single SC/EC case harbored the same POLE exonuclease domain mutation in both components. One SC/CCC and one EC/CCC case showed both shared and unique molecular features in the two histotype components, suggesting early molecular divergence from a common clonal origin. In two cases, there were no shared molecular features and these appear to be biologically unrelated synchronous tumors. Overall, these results show that the different histologic components in mixed endometrial carcinomas typically share the same molecular aberrations. Mixed endometrial carcinomas most commonly occur through morphological mimicry, whereby tumors with serous-type molecular profile show morphological features of endometrioid or clear cell carcinoma, or through underlying deficiency in DNA nucleotide repair, with resulting rapid accrual of mutations and intratumoral phenotypic heterogeneity. Less commonly, mixed endometrial carcinomas are the result of early molecular divergence from a common progenitor clone or are synchronous biologically unrelated tumors (collision tumors).

Significant frequency of MSH2/MSH6 abnormality in ovarian endometrioid carcinoma supports histotype‐specific Lynch syndrome screening in ovarian carcinomas

“…However, in our study we assigned those cases to either the endometrioid or the clear cell type, depending on the predominant morphology, assisted by IHC (see ). Similarly, we recently demonstrated that four of five ‘mixed’ endometrial clear cell–endometrioid carcinomas had dMMR . Regarding the question of which clear cell carcinomas may be selected for dMMR testing, we cannot present a reliable age cut‐off, but our patients were aged 48–55 years (perhaps <60 years).…”

Molecular classification of endometrial carcinoma on diagnostic specimens is highly concordant with final hysterectomy: Earlier prognostic information to guide treatment

“…In a single case there was failure to sample a dedifferentiated component of a tumor in the biopsy, a rare EC variant associated with mutations in chromatin remodelling genes and frequent MMR protein [34, 35]. In theory, mixed carcinomas may also pose a challenge to classify using ProMiSE, however, truly biologically mixed tumors are exceptionally rare [36] and most cases diagnosed as mixed carcinoma are actually due to morphologic ambiguity rather than admixtures of molecularly distinct clones [37]. …”

New classification of endometrial cancers: the development and potential applications of genomic-based classification in research and clinical care

“…Fundamental features of the immunophenotype for dedifferentiated, clear cell, and mixed carcinomas have been reported [50, 54, 109–111]. Assessment of mixed tumors show that despite morphologic differences/mimicry, the majority of molecular aberrations are shared across the tumor [112]. Thus the application of ProMisE or Leiden classification systems to these cancers may be of value.…”