High-grade endometrial stromal sarcoma is closely related to BCOR-altered sarcomas of the soft tissue and kidney rather than to other uterine sarcomas: implications for uterine sarcoma classification

High-grade endometrial stromal sarcoma (HGESS), which was not recognized as a distinct entity in the third edition of the World Health Organization (WHO) classification and was therefore included in the undifferentiated uterine sarcoma (UUS) category, was reestablished as a separate entity in the fourth edition. HGESS shares BCL-6 corepressor (BCOR) alterations with undifferentiated small round-cell sarcoma (USRCS) of the soft tissue and clear cell sarcoma of the kidney (CCSK). This study aims to perform a comparative morphological, immunohistochemical, and molecular analysis of HGESS, UUS, USRCS, and CCSK. Consecutive uterine sarcomas diagnosed as HGESS or UUS were reviewed and compared to BCOR-altered USRCS (n = 28) and CCSK (n = 10) (including both previously published and new cases). Molecular, DNA methylome (DNAm), and copy number variation (CNV) analyses were performed. DNAm data of 93 previously analyzed uterine and round-cell tumors of several different types were used for clustering analysis. Twenty-five uterine sarcomas (six HGESS and 19 UUS) were included; five of six HGESS cases showed fusions associated with BCOR alterations (YWHAE::NUTM2A/B, EPC1::KDM2B, ZC3H7B::BCOR); UUS showed no fusions (n = 15) or fusions unrelated to BCOR alterations (n = 4). All USRCS and CCSK cases showed either BCOR-ITD or BCOR alteration-related fusions. BCOR-altered HGESS showed broad morphological and immunophenotypic overlap with USRCS and CCSK. DNAm analysis showed that BCOR-altered HGESS, USRCS, and CCSK clustered together, separately from all other tumor types. The non-BCOR-altered HGESS showed a JAZF1::SUZ12 fusion and arose from a low-grade endometrial stromal sarcoma component. CNVs were found in 15/16 uterine sarcomas and in 16/36 USRCS/CCSK cases. BCOR-altered HGESS appeared to be closely related to BCOR-altered USRCS and CCSK rather than to other uterine sarcomas. We suggest that HGESS with BCOR alterations may warrant reclassification as ‘BCOR-altered uterine sarcomas’. © 2026 The Pathological Society of Great Britain and Ireland.