Gene fusion-driven cutaneous mesenchymal neoplasms: An updated review emphasizing the emerging entities

The advent of next-generation sequencing (NGS) has significantly advanced the classification of mesenchymal neoplasms, allowing for the identification of novel gene fusion-driven entities, also in the cutaneous setting. These molecular discoveries are redefining diagnostic criteria and shedding light on tumors previously misclassified or poorly understood. This review aims to provide an updated overview of cutaneous mesenchymal neoplasms characterized by recurrent gene fusions, with special attention to recently described and emerging entities. Following a molecularly oriented classification, we examine the histopathologic, immunohistochemical, and genetic profiles of key entities, including MITF pathway-activated tumors (e.g., CRTC1::TRIM11, MITF::CREM, ACTIN::MITF), small round blue cell sarcomas (e.g., EWSR1::ETS, CIC::DUX4, BCOR-fused tumors), and several distinctive fibroblastic and spindle cell neoplasms (e.g., EWSR1::SMAD3, ALK-rearranged tumors, NTRK-rearranged spindle cell neoplasms, and keratin-positive giant cell tumor). For each, we highlight diagnostic challenges, relevant differential diagnoses, and prognostic implications. The integration of molecular diagnostics into routine dermatopathology practice is essential for the accurate classification and clinical management of cutaneous mesenchymal tumors. Recognition of gene fusion signatures not only enhances diagnostic precision but also opens avenues for targeted therapy in selected cases. Continued molecular investigation and case accumulation are necessary to validate the biological behavior and therapeutic implications of many of these newly recognized entities.