Clinicopathologic and molecular characteristics of acral melanomas harboring RARA fusions

Unlike in hematologic malignancies like acute promyelocytic leukemia (APL), the tumorigenic role of RARA fusions in solid tumors, including melanomas, remains largely unknown. Here, we present a comprehensive clinicopathologic and molecular analysis of two cutaneous melanomas harboring RARA fusions. Both melanomas were of the acral subtype, affecting the feet of adults (median age: 60.5 years) without sex predilection. At diagnosis, Breslow thickness ranged from 1.2 to 5.5 mm, ulceration was present in one case, and the median mitotic rate was 4/mm². Tumor cells exhibited variable cytomorphology, including spindled and epithelioid features, with occasional rhabdoid morphology. Molecular analysis revealed a consistently low tumor mutational burden (median: 4.5 mutations/Mb). One acral melanoma was triple wild-type (lacking mutations in BRAF, NRAS, and NF1) and showed no gene amplifications, but harbored a LOC107984974::RARA fusion. The other acral melanoma carried an NF1 loss-of-function mutation and multiple gene amplifications involving 11q13.3 (CCND1, FGF3, FGF4, FGF19), 11q13.5-q14.1 (PAK1), 12q15 (MDM2), and 6q24.3 (SHPRH), along with two RARA fusions: RARA::LRP5 and RARA::RNF169. Over a median follow-up of 23 months, one patient developed a distant metastasis involving the brain approximately 20 months after the initial diagnosis. At last follow-up, one patient was alive with disease, while the other remained alive without clinical or radiological evidence of recurrence. These findings expand the current understanding of the molecular landscape of acral melanomas and may provide insights into the potential utility of targeted therapies against RARA fusions in a subset of melanomas, analogous to their therapeutic role in APL.