Molecular characterization of mixed-histology endometrial carcinoma provides prognostic and therapeutic value over morphologic findings

Abstract

We performed molecular analysis of a single-institution cohort of clinically diagnosed mixed-histology endometrial carcinoma (MEC). A gynecologic pathologist confirmed that 72 cases met diagnostic criteria for MEC based on WHO 2020 guidelines, and these were molecularly classified using both a DNA-based and histologic approach. Tumors were classified as: POLE-mutated (13.9%), microsatellite instability (MSI)-high/mismatch repair deficient (MMRd) (26.4%), TP53/p53 abnormal (p53abnl) (48.6%), no specific molecular profile (NSMP) (11.1%). Recurrence risk significantly differed based upon molecular class, but not histology. 44% of MEC cases had a HER2 IHC score of 2-3+, and this was not limited to p53abnl tumors. Transcriptional analysis demonstrated 93 differentially expressed genes between p53abnl and NSMP tumors, including many associated with the innate immune response and DNA damage repair. While p53abnl and NSMP tumors have similarly poor outcomes, transcriptome analysis revealed biologic differences that could impact targeted therapeutics in this high-risk group.

Fig. 1. Molecular classification of mixed-histology endometrial cancer.

A Hierarchical molecular classification of mixed-histology endometrial cancer based on IHC and DNA-based tumor testing. B Relationship between histology and final hierarchical molecular classification of mixed-histology endometrial cancer. *Note that tumors classified as POLE-mutated or MSI-high/MMRd (blue or green) could have also demonstrated p53/TP53 mutation/abnormality if the tumor was a multiple classifier. Of the 58 tumors with a serous component, 11 were p53/TP53 wild-type, but of those 2 were POLE-mutated and 5 were MSI-high/MMRd. Thus, only 4/58 tumors with a serous component (6.9%) were hierarchically classified as NSMP. C Progression-free survival of patients with mixed-histology endometrial cancer based on molecular class of the tumor. D Progression-free survival of patients with mixed-histology endometrial cancer based on histologic diagnosis of the tumor.

Fig. 2. Challenges to molecular classification of mixed-histology endometrial cancer.

A Representative examples of abnormal MMR and p53 immunohistochemical staining patterns, including subclonal MSH6 expression (top), heterogenous MSH6 expression (middle), and subclonal p53 expression (bottom). B Molecular class breakdown of abnormal IHC expression patterns seen in mixed-histology tumors. C Progression-free survival of patients with multiple classifier tumors harboring TP53/p53 abnormality vs p53abnl tumors.

Fig. 3. Beyond molecular classification: additional molecular and transcriptional data in mixed-histology endometrial carcinoma.

A HER2 IHC score breakdown by molecular class. B Progression-free survival of patients with mixed-histology endometrial carcinoma based on HER2 IHC score. C Differential gene expression between p53abnl and NSMP tumors demonstrated differences in themes of tumor biology, immune response, and microenvironment remodeling using the NanoString nCounter® Tumor Signaling 360™. D Volcano plot showing differential gene expression between p53abnl and NSMP tumors. Differential gene expression was determined significant if fold change (log2 ratio) was greater than ±1.5, and p-value < 0.05, and is represented by the colored dots. The 5 most significant differentially expressed genes are labeled based on log10p-value.