TFG‐MET fusion in an infantile spindle cell sarcoma with neural features

Abstract

An increasing number of congenital and infantile sarcomas displaying a primitive, monomorphic spindle cell phenotype have been characterized to harbor recurrent gene fusions, including infantile fibrosarcoma and congenital spindle cell rhabdomyosarcoma. Here we report an unusual spindle cell sarcoma presenting as a large and infiltrative pelvic soft tissue mass in a 4-month-old girl, which revealed a novel TFG-MET gene fusion by whole transcriptome RNA sequencing. The tumor resembled the morphology of an infantile fibrosarcoma with both fascicular and patternless growth, however, it expressed strong S100 protein immunoreactivity, while lacking SOX10 staining and retaining H3K27me3 expression. Although this immunoprofile suggested partial neural/neuroectodermal differentiation, overall features were unusual and did not fit into any known tumor types (cellular schwannoma, MPNST), raising the possibility of a novel pathologic entity. The TFG-MET gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital spindle cell sarcomas, with yet another example of kinase oncogenic activation through chromosomal translocation. The discovery of this new fusion is significant since the resulting MET activation can potentially be inhibited by targeted therapy, as MET inhibitors are presently available in clinical trials.

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

“…Clinical outcome is less predictable, with some cases showing aggressive clinical behavior, including distant metastases. The alternate fusions may involve genes such as BRAF , NTRK1 , 10‐12 and MET 13 ; a minority of IFS‐like tumors demonstrate compound intragenic BRAF deletions associated with tandem dupplication of exon 2, which may occur with or without the cannonical ETV6‐NTRK3 fusion 12 . Their mechanism of activation is most likely similar to the BRAF ‐related fusions, resulting in loss of the N‐terminal of BRAF protein containing the negative regulatory Ras‐binding domain (BRD), with subsequent constitutive activation of BRAF.…”

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms*

“…Moreover, novel gene fusions are described with increasing frequency, particularly within the subset of fibroblastic/myofibroblastic tumours. Overlapping gene fusion events with rearrangements involving ALK , BRAF , NTRK1 , NTRK2 , NTRK3 , MET and others have recently been described as recurrent findings in these tumours 1–8 …”

S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4‐RET fusion

“…The classification of soft tissue neoplasms is significantly refined by the increasing use of powerful genomic tools such as RNA‐sequencing in routine clinical practice. Among the most significant advances in this area belongs the emerging group of monomorphic spindle cell tumors showing ambiguous line of differentiation, defined by a largely uncharacteristic spindle cell morphology along with the presence of gene fusions that cause oncogenic activation of various kinases such as NTRK1/2/3 , RAF , BRAF , ALK , PDGFRβ , ROS1 , MET , and others . Notably, a significant minority of patients within the aggressive subset of these tumors may benefit from treatment with selective kinase inhibitors.…”