Endometrial Mixed and Mixed-Feature Carcinomas: Small Cohort Clinicopathologic and Molecular Studies

TL;DR

This study explores rare mixed endometrial cancers, finding they have unique genetic mutations that could guide better treatment strategies.

Contribution

The study identifies molecular features of mixed endometrial carcinomas, suggesting a clonal origin and distinct mutations compared to pure subtypes.

Findings

Mixed carcinomas show TP53 and PIK3CA mutations in both histologic components, indicating a clonal origin.

ERBB2 amplifications are more frequent in mixed carcinomas compared to pure subtypes.

FBXW7 mutations are unique to mixed carcinomas and not found in pure endometrioid or serous carcinomas.

Abstract

Endometrial cancer is a prevalent disease worldwide. There are different kinds of endometrial cancers and their treatment is based on the specific type of cancer—termed the histologic type, and the extent of disease spread—termed stage. The pathology diagnosis of the specific type of endometrial cancer is improving because of our ability to identify specific gene mutations that are unique to the different histologic groups of endometrial cancer. Discovering more about these gene mutations will enable us to design better, more personalized treatment, and avoid having patients try medicines that may not be effective at eliminating their tumor cells. In this current research investigation, we studied a rare sub group of endometrial cancers called mixed carcinomas. There are currently no treatment guidelines for this particular group, and we wanted to learn more about their gene mutations in order to better guide future therapy.

Objectives: To examine the clinical, pathologic, and molecular features of mixed and mixed feature endometrial carcinomas and compare them to pure serous carcinoma and pure endometrioid carcinoma. Methods: The study analyzed the clinical characteristics, histologic composition, and molecular genetic profiles of mixed and mixed feature endometrial cancers, with a focus on shared and distinct mutations. Patient demographics, disease-free survival, and molecular alterations, including in TP53, PIK3CA, TERT, MAP2K1 genes, and ERBB2 gene amplifications, were assessed and compared to pure serous and pure endometrioid carcinomas. Results: Patients with mixed and mixed-feature carcinomas were older (median age: 73 years) and had worse disease-free survival (median: 23 months) than those with pure endometrioid carcinoma (median: 48 months). Mixed and mixed-feature carcinomas were histologically high-grade, most commonly comprising serous and endometrioid components. Molecular profiling supported a clonal origin of these tumors, with identical TP53 and PIK3CA gene mutations between the two histologic components in each case. There were additional gene mutations (e.g., TERT and MAP2K1) found in higher-grade components. ERBB2 amplifications were more frequent in the mixed carcinomas groups (33%) compared to pure serous (11%) and pure endometrioid carcinomas (0%). Some of the mixed and mixed-feature carcinomas also showed FBXW7 mutations, not seen in either the pure endometrioid or pure serous carcinomas. Conclusions: Mixed and mixed-feature carcinomas share origins with pure endometrial serous and endometrioid carcinoma subtypes but exhibit distinct molecular alterations. These findings highlight the importance of molecular subtyping for diagnosis and treatment planning. Future research could focus on larger cohorts and targeted sequencing to better understand the pathogenesis of mixed and mixed-feature carcinomas in order to refine therapeutic strategies.

Figures