With no more than two dozen cases reported in the literature, malignant peripheral nerve sheath tumor (MPNST) is a rare primary mesenchymal neoplasm arising in the female genital tract. Most cases occurred in middle‐aged adults with high grade histology, unfavorable clinical outcome, and no history of neurofibromatosis type 1. Its extreme rarity in this site no doubt poses a diagnostic challenge during routine clinical practice. In the following, we report an additional case of uterine MPNST occurring in a 49‐year‐old Chinese woman, which was initially misdiagnosed as a leiomyosarcoma. The primary tumor showed two distinctive components—a high‐grade poorly differentiated component with markedly pleomorphic spindle cells arranged in a peritheliomatous pattern; and a leiomyosarcoma‐like (LMS‐like) component with tumor cells displaying obvious myoid differentiation. The patient suffered a recurrence less than 2 years later with the recurrent tumor demonstrating similar features to the high‐grade component of the primary tumor. The patient eventually succumbed 46 months later after developing another recurrence despite receiving targeted therapy and chemotherapy. On retrospective molecular analysis, no clinically relevant fusion transcript was detected on RNA sequencing. Interestingly instead, DNA methylation analysis showed the tumor clustered with the “MPNST” group in the German Cancer Research Center (DKFZ) sarcoma classifier. The tumor was also found to have EED gene homozygous deletion, multiple copy number alterations and loss of H3K27me3 expression in both high‐grade and LMS‐like components. Combining histology with all the ancillary tests results, the diagnosis was most consistent with MPNST. Our case highlights the diagnostic pitfalls for MPNST arising in the female genital tract and the potential clinical utility of DNA methylation analysis.
