Genomic Profiling of Pediatric Mycosis Fungoides, Lymphomatoid Papulosis, and Primary Cutaneous Anaplastic Large Cell Lymphoma Identifies Recurrent Tyrosine Kinase Gene Fusions.

Pediatric cutaneous T-cell lymphoproliferative disorders encompass a diagnostically complex set of rare diseases of undefined pathogenesis, including mycosis fungoides (MF), lymphomatoid papulosis (LyP), and primary cutaneous anaplastic large cell lymphoma (pcALCL). In the pediatric population, these disorders are much less common than in adults, which has precluded systematic evaluation of their molecular pathogenesis. We report the clinicopathologic and molecular features of pediatric MF (n = 14, ages 5-17 years at diagnosis), LyP (n = 8, ages 4-17 years), and pcALCL (n = 2). Next-generation sequencing analysis (targeted 72-gene fusion panel, targeted 447-gene exome sequencing panel, and/or FoundationOneHeme) was performed. JAK2 fusions were detected in 64% (7/11) MF (PCM1::JAK2, ILF3::JAK2 [n = 2], ATXN2L::JAK2 [n = 2], and NUP214::JAK2 [n = 2]) by next-generation sequencing of available cases. TYK2 fusions were identified in 1 of 11 MF (novel LMNA::TYK2), 3 of 5 LyP (NPM1::TYK2 [n = 2], and novel RAN::TYK2), and 1 of 2 pcALCL (RAN::TYK2) cases tested. A novel NUP214::FRK fusion was observed in the other pcALCL. Fusions were in-frame and retained the kinase domain of the 3' partner in all cases. MF cases demonstrated clonal TCR gene rearrangements (12/12 tested). Treatment was heterogeneous, although it usually included narrowband ultraviolet B phototherapy for MF and topical steroids for MF and LyP. We demonstrate that pediatric MF, LyP, and pcALCL harbor frequent tyrosine kinase gene fusions with enrichment of JAK2 and TYK2 fusions, genomic alterations that are diagnostically useful and may be amenable to targeted therapy.