<i>TFG‐MET</i> fusion in an infantile spindle cell sarcoma with neural features

Flucke, Uta; Noesel, Max M. van; Wijnen, Marc H. W. A.; Zhang, Lei; Chen, Chun-Liang; Sung, Yun Shao; Antonescu, Cristina R.

doi:10.1002/gcc.22470

Cited by 59 publications

(77 citation statements)

References 16 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Antonescu

2020

Genes Chromosomes & Cancer

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109

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A recent breakthrough in the classification of soft tissue tumors (STT) has been a significant expansion in the number of neoplasms associated with NTRK and other kinase related fusions. This is important not only for diagnostic purposes, but also because it opens new avenues for targeted therapy. Indeed, recent clincal trials have shown significant benefit across multiple tumor-types, prompting approval of NTRK inhibitors for clinical use in the setting of advanced/metastatic NTRK-rearranged neoplasms. Despite these therapeutic oportunities, diagnostic challenges have transpired in recognizing these emerging new histologic subtypes of kinase fusions positive-STT prospectively. This, in part, is attributable to their wide morphologic spectrum, variable risk of malignancy, and non-specific immunoprofile. As such, recommendations for pathologic criteria and immunohistochemical testing are needed to improve classification and streamline the small subset of potential candidates for further molecular validation. This overview summarizes the key histologic features of various STT associated with NTRK and other kinase fusions, which appear to share a similar morphologic spectrum. Immunohistochemically, many of these tumors, regardless of the kinase fusion type, notably show co-expression of S100 and CD34; issues related to the utility of pan-NTRK and NTRK1 immunostaining are therefore summarized. Finally, I discuss the role of confirmatory molecular testing and how, in some instances, this may also be of prognostic value. This review is intended as a critical summary of the current literature to emphasize pathologic criteria for improving recognition of this emerging and complex group of kinase fusion associated STT. K E Y W O R D S

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Section: Discussionmentioning

confidence: 99%

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

Antonescu

2020

Genes Chromosomes & Cancer

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109

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“…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 …”

Section: Introductionmentioning

confidence: 99%

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms*

et al. 2020

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Aims: The classification of paediatric spindle mesenchymal tumours is evolving, and the spectrum of socalled 'infantile fibrosarcoma' has expanded to include tumours with NTRK, BRAF and MET gene fusions. RETrearranged paediatric spindle cell neoplasms are an emerging group; there is sparse literature on their clinical, pathological and genetic features, and their nosological place in the canon of soft tissue tumours is uncertain. In this study, we report five RET-rearranged paediatric spindle cell tumours with fusion partners MYH10, KIAA1217 and CLIP2. Methods and results: The tumours occurred in the pelvic region, paraspinal region, kidney and subcutaneous tissue of hand and abdomen. The patients' ages ranged from 6 months to 13 years (median 1 year). The tumours were composed of monomorphic spindle cells arranged in a fascicular pattern. Lesional cells had minimally atypical ovoid or tapered nuclei and pale cytoplasm with indistinct borders. Necrosis was not identified. Mitoses numbered three to 12 per 10 high-power field. Cases showed inconsistent and variable expression of S100, CD34 and SMA. Clinical behaviour ranged from small lesions potentially cured by simple resection to large lesions exhibiting metastasis, but responsive to kinase inhibitor therapy. Conclusions: Our findings help to define RET-rearranged spindle cell tumours. Although it is likely that these tumours comprise part of the morphological and clinical spectrum of infantile fibrosarcoma (IFS), identification of RET gene alteration is important for its unique therapeutic implications.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Michal

Ptáková

Martínek

et al. 2019

Genes Chromosomes & Cancer

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We report a case of a 35-year old male patient with a tumor located in the deep dermis on his forearm. The lesion was completely excised but recurred 4 years later.The patient showed no signs of neurofibromatosis type 1. The morphology and immunophenotype of the tumor corresponded to the recently characterized group of soft tissue spindle cell lesions defined by a relatively uniform cytomorphology, patternless architecture, conspicuous stromal and perivascular hyalinization, S100 and CD34 coexpression and recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes.Using a 592-gene panel and massively parallel next-generation sequencing platform, we initially detected only NF1 gene mutation in our case. However, further molecular testing with Archer fusion assay revealed a novel NCOA4-RET gene fusion, adding it to the list of multiple kinase fusions originally reported in these tumors. Although break-apart FISH showed false negative result due to the presence of intrachromosomal rearrangement, RT-PCR confirmed the fusion transcript. Knowing the exact fusion is of great clinical importance especially for patients within the aggressive subset of these neoplasms that could be treated with selective kinase inhibitors.The presented case underscores the benefits of massively parallel sequencing as the types and number of gene fusions these tumors can potentially harbor render singlegene assays such as FISH impractical, and in this particular case, also insensitive. K E Y W O R D Sinfantile fibrosarcoma, kinase fusions, NCOA4-RET, NF1 gene mutation, S100 and CD34 positive spindle cell tumor, soft tissues

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

Cited by 59 publications

References 16 publications

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

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

Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms*

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

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