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

Abstract

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.

Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria

“…A few cases were reported to express S100 protein; And in the GYN tract they may entrap glands, thereby mimicking adenosarcoma 15 . At the molecular level, STT with a fibrosarcoma‐like morphology and ostensibly null immunoprofile have been reported with NTRK3 14 and RET gene fusions 4 . Similar lesions have also been described in the uterine cervix, as uterine sarcomas with features of fibrosarcoma 16,17 .…”

“…A subset of kinase fusion‐positive spindle cell sarcomas, with a fibrosarcoma herring‐bone growth pattern, have been reported in adults with a wide age range at diagnosis and various anatomic locations including soft tissue and viscera 14 . A number of these cases have been labeled in the past as adult‐type fibrosarcomas (Figure 3).…”

NovelPPP1CB‐ALKfusion in spindle cell tumor defined by S100 and CD34 coexpression and distinctive stromal and perivascular hyalinization

“…The prognosis of these tumors varied, with those of low cellularity following an indolent course while those with high cellularity and frequent mitotic figures presenting with distant metastasis and death from disease 1 . More recently, two morphologically and immunophenotypically similar tumors harboring RET gene fusions including NCOA4‐RET 2 and TFG‐RET 3 as well as two cases harboring ETV6‐NTRK3 and TFG‐NTRK3 rearrangements 4 have been described. Herein, we report an additional soft tissue spindle neoplasm with similar morphology and immunophenotype harboring a PPP1CB‐ALK rearrangement, expanding the genetic spectrum of these tumors.…”

Precision Medicine in Soft Tissue Sarcoma Treatment

“…Inflammatory myofibroblastic tumor (IMT), which consists of rare components of STS, harbors specific fusion genes including ALK [89,90], and TKIs inhibiting ALK showed high responses to ALK-arranged IMT in prospective clinical trials [91]. NTRK rearrangement is observed at a low rate in many solid tumors [92], but in specific STS histological subtypes such as infantile fibrosarcoma, NTRK rearrangements were observed at high rates [93,94]. Solid tumors (regardless of tumor origin) showed high responses to NTRK-targeted TKIs [95,96], and the NTRK-targeted TKIs were approved for the treatment of solid tumors with NTRK rearrangements, including STS.…”