Diagnostic Pitfalls of <i>TFE3</i> -Rearranged Perivascular Epithelioid Cell Tumor of the Kidney

<i>TFE3</i>-rearranged perivascular epithelioid cell tumors (PEComas) of the kidney are rare, with fewer than 50 examples reported in the literature. A 32-year-old man presented with an 8.2 cm right renal mass and bulky retroperitoneal lymphadenopathy, raising concern for lymphoma versus renal cell carcinoma (RCC). An initial renal biopsy performed at an outside institution was diagnosed as "RCC, favor chromophobe type," based on morphological features and KIT positivity. Due to limited tumor cells in the initial biopsy for additional studies, a repeat renal biopsy and a biopsy of a right retroperitoneal lymph node were obtained at our institution. Both specimens revealed nests and sheets of epithelioid tumor cells with abundant granular eosinophilic to clear cytoplasm and a perivascular growth pattern. Focal areas showed prominent cell membranes, and melanin pigment was identified in rare tumor cells. Immunohistochemical staining demonstrated strong, diffuse nuclear positivity for TFE3, as well as positivity for HMB45, cathepsin K, and KIT. The tumor cells were negative for pan-keratin, keratin 7, PAX8, CA9, CD10, and SMA. A next-generation sequencing-based fusion assay identified an <i>SFPQ::TFE3</i> gene fusion. The tumor was classified as a <i>TFE3</i>-rearranged PEComa. The patient underwent systemic therapy followed by radical nephrectomy. The tumor invaded the renal sinus fat and showed extensive lymphovascular invasion (ypT3aN1). Despite treatment, restaging imaging at the 16-month follow-up revealed liver metastases. Subsequent imaging demonstrated further progression, and the patient ultimately opted for supportive care at 32 months. This report highlights the diagnostic challenges of renal <i>TFE3</i>-rearranged PEComas, due to their rarity and overlapping morphologic, immunophenotypic, and molecular features with other neoplasms.