Angiomyolipoma/PEComa: the past, the present…and back to the future

Purpose of review: This review provides a comprehensive update on renal angiomyolipoma, a mesenchymal neoplasm within the PEComa family. It revisits its historical classification, evolving pathological understanding, and recent molecular insights, emphasizing its relevance in current diagnostic and pathogenetic contexts. Recent findings: Angiomyolipoma/PEComa has transitioned from being considered a hamartoma to a neoplasm with clonal origin and malignant potential in a few epithelioid angiomyolipoma/pure epithelioid PEComa. Advances in immunohistochemistry have identified new markers such as GPNMB, STING, and TRIM63, aiding differential diagnosis. Molecular studies highlight frequent TSC1/TSC2 mutations and mTOR pathway dysregulation. Emerging evidence suggests a noncanonical activation of TFEB via the cGAS-STING pathway in angiomyolipoma/PEComa. Summary: A thorough understanding of the histological subtypes and molecular drivers of angiomyolipoma/PEComa is essential for accurate diagnosis and risk stratification. However, the comprehension of its pathophysiological mechanisms remains not completely understood. The cGAS-STING-TFEB axis may explain the unique immunophenotype of the cellular element composing these neoplasms. Furthermore, this pathway could also be related to the unexpected presence of autophagy observed in angiomyolipoma/PEComa, with STING representing the missing piece in this intricate puzzle. Nevertheless, this proposed mechanism requires validation through further research.