Pilomatrix-like High-grade Endometrial Carcinoma: An Underdiagnosed Entity With Aggressive Clinicopathologic Features

Pilomatrix-like high-grade endometrial carcinoma (PiMHEC) is a rare and aggressive variant of endometrial carcinoma often misdiagnosed due to overlapping features with other high-grade malignancies. This study characterizes its clinicopathologic, immunophenotypic, and molecular features to establish key diagnostic criteria and propose a standardized terminology. Ten tumors were analyzed using histopathologic examination, immunohistochemistry, and next-generation sequencing. All but 1 tumor exhibited both low-grade endometrioid and high-grade basaloid components, the latter characterized by either geographic or comedo-type necrosis and shadow cells. Although shadow cells are a hallmark feature, they may be focal or absent, necessitating careful evaluation. High-grade areas consistently showed ER and PR negativity with diffuse nuclear β-catenin staining, correlating with CTNNB1 exon 3 mutations in all tumors. Identical CTNNB1 mutations in spatially distinct tumor components suggest a clonal progression from a low-grade precursor. Additional mutations in ARID1A, PTEN, and PIK3CA were identified. Clinically, PiMHEC exhibited aggressive behavior, with 7 patients experiencing recurrence and 1 succumbing to the disease within 9 months. Metastatic sites included the lungs, liver, lymph nodes, and abdominal wall. PD-L1 expression in 4 tumors suggests potential responsiveness to immune checkpoint inhibitors, whereas low-level HER2 expression (1+ to 2+) in 5 tumors raises the possibility of HER2-targeted therapies. Folate receptor alpha was not expressed in any tumor. In conclusion, PiMHEC is a distinct and highly aggressive endometrial carcinoma with unique histopathologic and molecular features that differentiate it from high-grade endometrioid and other high-grade endometrial cancers including squamous cell carcinoma in rare situations. Its key diagnostic features include high-grade basaloid tumor cells associated with shadow cells, tumor necrosis, and diffuse nuclear β-catenin staining. To improve diagnostic accuracy and reduce ambiguity, we propose adopting "pilomatrix-like high-grade endometrial carcinoma" as a standardized term.