Endometrioid Carcinoma With Malignant Squamous Differentiation: Clinicopathologic, Immunohistochemical, and Molecular...

Endometrioid carcinoma with squamous differentiation (SqD) is morphologically heterogeneous, and the clinical significance of malignant SqD remains poorly defined. This study aimed to characterize the clinicopathologic, immunophenotypic, and molecular features of endometrioid carcinoma with malignant SqD and to explore its potential implications for diagnosis and risk stratification. We retrospectively reviewed 3696 cases of endometrial endometrioid carcinoma diagnosed from January 2020 to March 2025 and identified 9 tumors with malignant SqD based on predefined histologic criteria. All cases underwent centralized slide review, an immunohistochemical panel, and targeted next-generation sequencing. Tumors were staged according to FIGO 2023 and classified into TCGA/ProMisE molecular subtypes. Malignant SqD was rare but strongly associated with adverse pathologic features, including deep myometrial invasion, extensive lymphovascular space invasion, and frequent nodal metastasis. Preoperative biopsy and curettage frequently underestimated or misclassified malignant SqD. The malignant squamous component predominantly occupied invasive fronts and metastatic deposits and showed consistent loss of hormone receptor expression. Molecular profiling revealed heterogeneity across all 4 molecular subtypes, with recurrent alterations in the PI3K/AKT pathway. Because this aggressive phenotype spans diverse molecular subtypes, conventional morphologic evaluation remains indispensable.