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

## TL;DR

ER-negative endometrial cancers are a diverse and aggressive group that require careful classification for better diagnosis and treatment.

## Contribution

The paper emphasizes the need to integrate ER status with morphology and molecular data for accurate classification of ER-negative endometrial cancers.

## Key findings

- ER negativity alone is insufficient for tumor classification and must be combined with other diagnostic features.
- Several high-grade ER-negative tumor types show distinct clinicopathologic and molecular characteristics.
- Improved subclassification of ER-negative endometrial cancers is crucial for prognosis and treatment.

## Abstract

Estrogen receptor–negative (ER-negative) endometrial carcinomas represent a biologically aggressive and heterogeneous subset of endometrial cancers. Although ER testing has long been used in endometrial carcinoma, it has historically been applied mainly for therapeutic decision-making rather than as a diagnostic tool. Loss of ER expression is associated with poor prognosis but, by itself, is insufficient for accurate tumor classification. In this commentary, we review the evolving diagnostic significance of ER negativity using an integrated framework that incorporates tumor morphology, immunophenotypic features, and molecular heterogeneity. We highlight several high-grade ER-negative tumor types—including gastrointestinal-type adenocarcinoma, pilomatrix-like carcinoma, mesonephric-like adenocarcinoma, clear cell carcinoma, and other high-grade ER-negative carcinomas—that show distinct clinicopathologic characteristics. We propose that ER negativity should be regarded as a diagnostic signal that prompts careful subclassification, with important implications for accurate diagnosis and clinical management.

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.