Malignant melanoma with areas of rhabdomyosarcomatous differentiation arising in a giant congenital nevus with RAF1 gene fusion

Abstract

A girl, born with a posterior lumbosacral giant congenital nevus, developed a central nodule that expanded over a period of 14 months into a 10‐cm pedunculated mass. Histological analysis of the mass revealed melanoma of myxoid, small round‐cell type with areas of rhabdomyosarcomatous transformation confirmed by immunohistochemistry. RNA sequencing identified an in‐frame SASS6(e14)‐RAF1(e8) fusion in both components and the nevus. A RAF1 FISH break‐apart test found a balanced rearrangement pattern in the nevus and an unbalanced pattern in the malignant areas. Wild‐type status of NRAS and BRAF was confirmed by NGS techniques. The array‐CGH profile displayed copy number alterations commonly found in rhabdomyosarcomas. Despite intensive treatment, widespread metastatic evolution of the melanomatous component was observed.

NovelLRRFIP2‐RAF1fusion identified in an acral melanoma: A review of the literature on melanocytic proliferations withRAF1fusions and the potential therapeutic implications

“…In keeping with BRAF mutations and rare BRAF translocations, RAF1 fusion alone may be insufficient for malignant behavior in a melanocytic proliferation. Three of the previously reported melanocytic lesions with RAF1 fusions were giant congenital nevi with melanoma evolving in two cases 13‐15 . Two of the three had wild‐type BRAF and NRAS , suggesting the possibility that RAF1 fusion was an early driver event that preceded malignant transformation.…”

“…9,10 Less than 1% of the melanocytic neoplasms harbor a fusion involving the RAF1 gene. 11,12 Previously reported RAF1 fusion partners include CTNNA1, LRCH3, CTDSPL, PRKAR2A, SOX5, SASS6, CDH3, GOLGA4, ANO10, PAPD7, CLCN6, TRAK1, LMNA, MPRIP, AGGF1, CLCN6, and TRAK1 [6][7][8][11][12][13][14][15][16][17] All but one case were melanomas; the remaining case was a giant congenital nevus. In keeping with 98% of RAF1 fusion melanomas reported, no hotspot mutations involving BRAF, NRAS, and NF1 were detected in our case.…”

“…Three of the previously reported melanocytic lesions with RAF1 fusions were giant congenital nevi with melanoma evolving in two cases. [13][14][15] Two of the three had wild-type BRAF and NRAS, suggesting the possibility that RAF1 fusion was an early driver event that preceded malignant transformation. In our case, there was no precursor nevus identified, and a majority of the RAF1 fusion melanomas with clinical and histopathologic annotation did not arise in preexisting nevi.…”

“…6,32 Interestingly, one of the previously reported RAF1 fusion melanomas had rhabdomyosarcomatous differentiation with a consistent genomic profile and confirmation by both immunohistochemistry and electron microscopy. 15 plasms with BAP1-inactivation. 35,36 In these cases, BAP1 staining reveals dense, clumped perinuclear, and cytoplasmic aggregates accompanying a loss of nuclear expression.…”

Melanomas with activating RAF1 fusions: clinical, histopathologic, and molecular profiles

“…This congenital nevus, like that of an ALK -fused nevus in the same study, lacked comutations of NRAS and BRAF . A striking case report also showed a fusion of S ASS6–RA F1 in a giant congenital nevus that gave rise to melanoma with rhabdomyosarcomatous differentiation [ 32 ]. While a balanced translocation was found in the background congenital nevus, an unbalanced translocation was noted in the rhabdomyosarcomatous component.…”