ER-Negative Endometrial Cancers: An Evolving Diagnostic Category with Major Clinical Implications

Estrogen receptor-negative (ER-negative) endometrial carcinomas represent an emerging and historically underrecognized diagnostic concept encompassing a biologically aggressive and heterogeneous subset of endometrial cancers. Although loss of ER expression is increasingly recognized as an adverse prognostic indicator, ER negativity alone is insufficient for precise classification and must be interpreted within a histotype-specific and molecularly informed context. In this commentary, we review the evolving role of ER negativity in endometrial carcinoma through an integrated morphologic, immunophenotypic, and molecular framework, emphasizing both pathogenetic insights and practical diagnostic considerations. We highlight specific high-grade ER-negative tumor entities that merit particular diagnostic attention, including endometrial gastrointestinal-type adenocarcinoma, pilomatrix-like high-grade endometrial carcinoma, mesonephric-like adenocarcinoma, endometrial clear cell carcinoma, and ER-negative high-grade carcinomas not otherwise specified. These tumors exhibit distinct morphologic features and marked molecular heterogeneity that cannot be captured by hormone receptor status alone. Key diagnostic clues and common pitfalls are discussed, underscoring a practical workflow in which ER negativity serves as a diagnostic signal rather than a terminal category. Improved recognition and subclassification of ER-negative endometrial carcinomas are essential for accurate diagnosis, prognostic stratification, and optimized clinical management.