TFE3-rearranged PEComa with hepatic and pulmonary involvement: diagnostic challenges and resistance to mTOR-targeted therapy

BACKGROUND: Perivascular epithelioid cell tumors (PEComas) are rare mesenchymal neoplasms composed of epithelioid cells that co-express melanocytic and smooth muscle markers. They can arise in various anatomic sites, most commonly the uterus, retroperitoneum, gastrointestinal tract, and liver. While most PEComas are sporadic and associated with TSC1/TSC2 mutations leading to mTOR pathway activation, a distinct molecular subset harbors TFE3 gene rearrangements, often exhibiting more aggressive clinical behavior. Given their rarity, the diagnosis and management of PEComas remain challenging and largely unstandardized. CASE PRESENTATION: We report the case of a 37-year-old woman with no significant medical history who presented with fatigue, unintentional weight loss, and vomiting. Imaging revealed a large hepatic mass and pulmonary nodules. Histopathological and immunohistochemical evaluation confirmed a diagnosis of TFE3-rearranged PEComa involving the liver and left upper lung lobe. The patient underwent right partial hepatectomy with complete resection of the hepatic lesion. Subsequent disease progression was noted in the lung, lymph nodes, and bone despite treatment with an mTOR inhibitor. CONCLUSION: TFE3-rearranged PEComas represent a rare and aggressive molecular subset with limited therapeutic options. This case demonstrates resistance to mTOR inhibition, highlighting the critical importance of molecular subtyping to distinguish TFE3-rearranged from TSC1/TSC2-mutant disease and guide individualized management. Expanded molecular profiling is essential to refine treatment strategies for this uncommon entity.