Molecular Evaluation of Endometrial Dedifferentiated Carcinoma, Endometrioid Carcinoma, Carcinosarcoma, and Serous Carcinoma Using a Custom-Made Small Cancer Panel

Abstract

It is often difficult to histologically differentiate among endometrial dedifferentiated carcinoma (DC), endometrioid carcinoma (EC), serous carcinoma (SC), and carcinosarcoma (CS) due to the presence of solid components. In this study, we aimed to categorize these carcinomas according to The Cancer Genome Atlas (TCGA) classification using a small custom-made cancer genome panel (56 genes and 17 microsatellite regions) for integrated molecular diagnosis. A total of 36 endometrial cancer cases with solid components were assessed using IHC, next-generation sequencing (NGS), and the custom-made panel. Among 19 EC cases, six were categorized as MMR-deficient (MMR-d) and eight were classified as having a nonspecific molecular profile. Three EC cases were classified as POLE mutation (POLEmut)-type, which had a very high tumor mutation burden (TMB) and low microsatellite instability (MSI). Increased TMB and MSI were observed in all three DC cases, classified as MMR-d with mutations in MLH1 and POLD1. Except for one case classified as MMR-d, all SC cases exhibited TP53 mutations and were classified as p53 mutation-type. SC cases also exhibited amplification of CCND1, CCNE1, and MYC. CS cases were classified as three TCGA types other than the POLEmut-type. The IHC results for p53 and ARID1A were almost consistent with their mutation status. NGS analysis using a small panel enables categorization of endometrial cancers with solid proliferation according to TCGA classification. As TCGA molecular classification does not consider histological findings, an integrated analytical procedure including IHC and NGS may be a practical diagnostic tool for endometrial cancers.

Pelvic Carcinosarcoma Showing a Diverse Histology and Hierarchical Gene Mutation with a Common POLE Mutation to Endometrial Endometroid Carcinoma: A Case Report

“…12,27 Moreover, the present case is TMB-high (endometrial lesion) or TMB-ultrahigh (pelvic lesion) and MSI-low in both elements, which is not consistent with MMR-deficient subtype. 32 Actually, the every tumor element in the present case was positive for MMR proteins, and therefore, the POLE p.T457del mutation is suggested to be attributable to ultramutator phenotype.…”

Endometrial carcinosarcoma

“…POLE mutated endometrial carcinosarcoma showed an excellent prognosis similar to that of POLE mutated endometrioid endometrial cancers, supporting their inclusion in the same low-risk category for treatment purposes in the current European Society of Gynecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) guidelines 9. On the other hand, the prognosis of p53-abn and non-specific molecular profile endometrial carcinosarcoma was even worse than that of their endometrioid/serous counterparts, while that of MSI-H/dMMR tumors was unclear and remains to be clarified 4 20–27 Table 1. shows the current evidence regarding the molecular/genomic profiling of endometrial carcinosarcomas.…”

“…Future trials should focus on the efficacy of pattern-specific treatments, selected based on the specific signatures of endometrial carcinosarcoma. Several molecular studies described mutations or alterations of multiple genes and pathways in endometrial carcinosarcoma, including c-KIT, TKR, VEGF, EGFR, Her2/neu, NTRK, PI3K/AKT/mTOR pathway , WEE1, KRAS, EXP, BRCA1/2 , and other genes related to cell-cycle regulation (including homologous recombination deficiency), histone modification, and chromatin remodeling, which may all represent potential targets 21–27…”

“…However, given the similarities of endometrial carcinosarcoma with the other high-risk histologies such as uterine serous carcinoma, which instead were included, it can be speculated that immunotherapy plus tyrosine kinase inhibitor might be an attractive option also for endometrial carcinosarcoma patients. Moreover, around 10% of endometrial carcinosarcomas are MSI-H, ~5% are POLE mutated, and~60% show PD-1/PD-L1 immunohistochemical expression; immunotherapy (alone or in combination with tyrosine kinase inihibitor) may be particularly promising in these molecular subgroups 3 4 21–27. Nevertheless, to date, only anecdotal evidence exists 108 109…”

“…Several molecular studies described mutations or alterations of multiple genes and pathways in endometrial carcinosarcoma, including c-KIT, TKR, VEGF, EGFR, Her2/ neu, NTRK, PI3K/AKT/mTOR pathway, WEE1, KRAS, EXP, BRCA1/2, and other genes related to cell-cycle regulation (including homologous recombination deficiency), histone modification, and chromatin remodeling, which may all represent potential targets. [21][22][23][24][25][26][27] New molecular-targeted therapies may play a pivotal role in the treatment of endometrial carcinosarcoma, especially in the recurrence/metastatic setting, and many of these are currently being investigated in prospective clinical trials (Table 5), with the most promising therapeutic agents being immune checkpoint inhibitors, HER2 targeting agents, and WEE1 inhibitors. 104…”