Molecular Profiles of Mixed Endometrial Carcinoma

Abstract

Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors.

Miks endometriyal karsinomun klinik ve patolojik özelliklerinin tersiyer bir merkezde değerlendirilmesi

“…The MEC rate was found to be 2.7% at the time of the study and it is compatible with the literature. The fact that the most common MECs are endometrioid and serous is consistent with the literature [9][10][11] . We demonstrated that there was no difference among the groups in terms of clinicalpathological features and prognosis.…”

“…They showed that different components had similar molecular features and they concluded that molecular analysis of mixed endometrial carcinomas revealed clonality in most cases. In another molecular study of 8 MEC cases demonstrated that targetable mutations might be existent in only one component of mixed tumors 11 .…”

“…In clinical management, which component accompanies and its percentage are important for avoiding the undertreatment surgery and adjuvant therapy. Although there are some studies on this subject, our knowledge on the biology of MECs is limited 10,11,15,16 .…”

“…Studies conducted to define the biological and molecular origins of MECs reveal that they mainly show clonal origin and essentially similar molecular properties 10,11 . Recently, Kobel et al have reported that most of mixed endometrial carcinomas have the same molecular genetic variences in each of their histologic components, which questions whether "true" mixed epithelial carcinomas appear intermittently in the endometrium 10 .…”

New Pathological and Clinical Insights in Endometrial Cancer in View of the Updated ESGO/ESTRO/ESP Guidelines

“…A point of concern may be the possibility of different TCGA signatures in the different components of a mixed carcinoma. Matrai et al reported the presence of POLE mutation limited to the SEC component of a mixed EEC/SEC [ 47 ]. In these cases, the prognosis might be driven by the component with the worse molecular signature.…”