RAF1-rearranged spindle cell tumour: report of two additional cases with identification of a novel FMR1-RAF1 fusion

A subset of spindle cell tumours have been recently identified to harbor recurrent fusion genes, involving NTRK1/2/3 , BRAF , RAF1 , and RET . The precise classification of these fusion-positive tumours relies essentially on genomic profiling. Herein, we present our experience with two cases of spindle cell tumour which showed RAF1 rearrangement. Both tumours occurred in children with one in the left cheek (case 1) and the other one in the left buttock (case 2). Histologically, case 1 was a low-grade neoplasm characterized by uniform ovoid to short spindle cells showing “patternless” architecture with stromal hyalinization. Case 2 had an overtly malignant phenotype composed of long intersecting fascicles with increased cellularity and mitotic activity. By immunohistochemistry, tumour cells in case 1 showed co-expression of CD34 and S100 protein whereas in case 2 there was only focal staining of CD34 with no expression of S100 protein. Fluorescence in situ hybridization tests using NTRK1/2/3 (case 1 and case 2), ETV6 , SS18 , BRAF , ROS1 , and ALK (case 2) break-apart probes were performed but yielded negative results. Subsequent next-generation sequencing (NGS) demonstrated PDZRN3-RAF1 fusion in case 1 and FMR1-RAF1 fusion in case 2, respectively, which were confirmed by FISH using RAF1 break-apart probe. This study further emphasizes the importance of molecular diagnostics in fusion-positive spindle cell tumours. In addition, we expand the genetic spectrum of RAF1 -rearranged spindle cell tumour by describing a novel FMR1-RAF1 fusion gene.