ACTIN::MITF-rearranged tumor: a distinctive entity or a cutaneous PEComa with MITF alterations? A clinicopathological and molecular study of additional 5 cases.

actinMITF-rearranged tumors represent a poorly defined subset within the expanding spectrum of MITF pathway-activated cutaneous mesenchymal neoplasms. These tumors are of uncertain lineage, with ongoing debate as to whether they are of melanocytic or, more likely, non-melanocytic origin. They are characterized by recurrent genomic rearrangements that activate the MITF signaling axis and result in MITF overexpression. To date, only ten cases have been reported, and their nosologic classification-as well as their relationship to other entities, particularly primary cutaneous perivascular epithelioid cell tumors (pcPEComas)-remains uncertain. To further characterize this entity, we identified five additional cases (3 females, 2 males; mean age 55.8 years, median 61, range 22-81), all arising on the lower extremities and measuring 0.8-3 cm. Follow-up (n = 2) revealed one local recurrence with survival at 122 months (disease status unknown) and one patient alive at 14 months with indeterminate but likely benign pulmonary nodules. Histologically, tumors were non-circumscribed dermal nodules extending to the dermoepidermal junction without epidermal involvement and displaying infiltrative and/or expansile borders. They consisted predominantly of solid sheets of epithelioid cells with focal spindle areas dissecting collagen in a characteristic "checkerboard-like" pattern. Paraganglioma-like and perivascular architectures were observed. Cytologic atypia was mild; a single mitotic figure was identified in one case; necrosis, lymphovascular, and perineural invasion were absent. All tumors showed diffuse MITF and multifocal HMB-45 expression. GPNMB and PRAME were positive in both tested cases. RNA-based sequencing demonstrated in-frame ACTG1::MITF fusions in four tumors and an ACTB::MITF fusion in one; MITF rearrangement was confirmed by break-apart FISH in two. We additionally reviewed the literature on primary cutaneous PEComas and compared their clinicopathologic features with those of ACTIN::MITF-rearranged tumors. This study expands the clinicopathologic and molecular spectrum of ACTIN::MITF-rearranged tumors and further explores their relationship to cutaneous PEComas.