The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements

NTRK3-rearranged tumors other than infantile fibrosarcomas (IFSs) harboring the canonical ETV6-NTRK3 fusions are uncommon, and include mainly inflammatory myofibroblastic tumors and gastrointestinal stromal tumors. Herein, we describe an additional subset of seven tumors sharing NTRK3 gene rearrangements. The cohort included five females and two males (age range 1-67 years). Tumors were located in extremities, trunk, retroperitoneum, or intra-abdominal. In all tumors, fluorescence in situ hybridization (FISH) revealed rearrangements in NTRK3 accompanied by NTRK3 amplification in two cases. In three cases, RNA sequencing identified a fusion transcript composed of NTRK3 exon 14 fused to ETV6, TFG, and TPM4, respectively, retaining the NTRK3 kinase domain. All tumors were positive for pan-TRK by immunohistochemistry (IHC). Two cases showed low- to intermediate-grade histology composed of monomorphic spindle cells arranged in a patternless architecture, stromal bands, and perivascular rings of hyalinized collagen and coexpression of S100 and CD34. The remaining five cases were high-grade fascicular monomorphic spindle cell sarcomas, morphologically somewhat reminiscent of either malignant peripheral nerve sheath tumors (MPNSTs) or fibrosarcomas (FSs). Two high-grade NTRK3 sarcomas showed aggressive clinical behavior with development of lung metastases. Identification of high-grade NTRK3-rearranged sarcomas is clinically important, since the development of selective NTRK inhibitors has opened new avenues for targeted therapy. Although IHC for pan-TRK can be applied as a screening tool, molecular studies are recommended for a conclusive diagnosis of NTRK-rearranged neoplasms.