Abstract

Background: Numerous gene fusions have been described as the oncogenic driver of Spitz and non-Spitz melanocytic lesions. Lesions with fusion-driven events tend to have a monomorphic appearance and can pose a histopathological challenge. Hence, melanocytic lesions difficult to classify were sequenced.

Methods: Cases of predominantly dermal-based and/or Spitzoid melanocytic lesions encountered between July 2022 and April 2023 were prospectively sequenced using next generation sequencing-based molecular tests looking for driver mutations or gene fusions.  

Results: Four patients were found to have fusion-driven melanocytic lesions, three limited to the dermis, and one compound lesion. The compound lesion, on the leg of a 25-year-old male, was diagnosed as a severely atypical Spitzoid melanocytic proliferation, with pan-TRK positive immunohistochemistry; sequencing revealed an LMNA::NTRK1 fusion. The dermal lesions were a spindle cell melanocytic neoplasm with PWWP2A::ROS1 on the arm of a 34-year-old female, a dermal melanocytic tumor with CRTC1:TRIM11 rearrangement on the knee of a 14-year-old male and a melanoma with TECR::PKN1 fusion and a high tumor mutation burden on the shoulder of a 75-year-old female with 1 positive lymph node, treated with anti-PD-1, and with no evidence of disease after 5 months, but developed a new primary melanoma on the contralateral shoulder.

Conclusion: The spectrum of fusion-driven melanocytic lesions is rapidly expanding with the democratization of molecular testing. Tumors with CRTC1::TRIM11 are now known for their metastatic potential. Precise characterization of these entities may inform patient follow-up and management, including the opportunity for kinase inhibitor therapies.