NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects

Siozopoulou, Vasiliki; Smits, Evelien; Winne, Koen De; Marcq, Elly; Pauwels, Patrick

doi:10.3390/diagnostics11030478

Cited by 39 publications

(37 citation statements)

References 57 publications

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“…In our study we did not detect Ewing sarcoma with distinct NTRK and EWSR1 fusions. By the clinical point of view, ETV6-NTRK3 fused sarcomas were reported as aggressive tumours, regardless of the grade of cytological atypia ( 18 , 25 ); we described two neoplasms with ETV6-NTRK3 fusion showing an indolent course, chemosensitive and without any signs of recurrence or metastatic spread, in contrast with what previously reported, so that the fusion partner does not seem a potential marker to predict prognosis. Further studies are needed to explore the significance of NTRK in this setting.…”

Section: Discussioncontrasting

confidence: 84%

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities

Nozzoli¹,

Lazar

Castiglione³

et al. 2022

Pathol. Oncol. Res.

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Undifferentiated round cell sarcomas (URCS) of soft tissue and bone and tumours of uncertain differentiation (TUD) are commonly ascribed to a subset of neoplasms with low frequency of NTRK gene fusions. However, more recently NTRK-rearranged round and spindle cell tumours have been noted in case reports and in limited or heterogeneous cohorts. The aim of our study was to investigate the presence of NTRK gene fusions in a large retrospective cohort of paediatric URCS and TUD after a systematic review of the diagnosis, according to the recently updated WHO classification scheme. One-hundred and five patients with diagnosis of URCS or TUD, involving the bone or soft tissue, were retrospectively evaluated. After the case selection and the histopathological review of the case cohort, pan-Trk immunohistochemistry (IHC) testing was performed on formalin-fixed paraffin-embedded (FFPE) tissues. Tumour RNA was extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation, using a 10-gene NGS fusion panel, sequenced on an Illumina MiSeq. The NGS-positive cases were further confirmed by real-time PCR. On immunohistochemical screening, 12/105 (11.4%) cases were positive using the pan-Trk antibody, showing three different staining patterns with the cytoplasmic distribution being most common. Molecular analysis using NGS and confirmed by the real-rime PCR detected two positive cases for the ETV6-NTRK3 fusion. The histological pattern of the two positive cases, together with the demonstration of the NTRK rearrangement, leaded to re-classify these previously not otherwise specified sarcomas with uncertain differentiation into the emerging category of NTRK-rearranged neoplasms. In addition, we found the two NTRK fused neoplasms showing a clinical indolent course, in contrast with literature.

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Section: Discussioncontrasting

confidence: 84%

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities

Nozzoli¹,

Lazar

Castiglione³

et al. 2022

Pathol. Oncol. Res.

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“…These neoplasms are characterized by a wide spectrum of morphologies, relative non‐specific immunoprofiles, and variable clinical courses 1‐6 . Because these tumors are potential candidates for targeted therapies, it is critical to better define their histopathologic spectrum and diagnostic criteria in order to facilitate the recognition of these tumors in routine diagnostic practice 2,8,9 . BRAF gene, located at 7q34, is a serine/threonine‐protein kinase proto‐oncogene.…”

Section: Discussionmentioning

confidence: 99%

BRAF‐rearranged spindle cell mesenchymal neoplasm with a predominant lipofibromatosis‐like neural tumor pattern and co‐expression of CD34, S100 protein, and markers associated with perineurial differentiation: A rare case with potential diagnostic pitfall

Sun

Zhao

2021

J Cutan Pathol

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Recently, a distinctive group of S100 protein/CD34‐positive spindle cell mesenchymal neoplasms characterized by a predominant lipofibromatosis‐like neural pattern harboring recurrent gene rearrangements involving NTRK1‐3, RAF1, RET, ROS1, ALK, and MET has been identified. BRAF rearrangements have been rarely documented in this group of neoplasms. Herein, we report a 54‐year‐old man with a 1.3‐cm painless mass located in the subcutis of left back. The tumor was composed of mildly atypical, short‐spindle shaped to ovoid cells with fascicles and whorls intervening between and admixed with the subcutaneous adipose tissues and nerve bundles. Focally abundant thick, band‐like stromal hyalinization was also noted. The neoplastic cells showed diffuse reactivity for S100 protein and CD34 and multifocal immunopositivity for markers associated with perineurial differentiation including epithelial membrane antigen, GLUT1, and claudin‐1. Fluorescence in situ hybridization analyses showed positive for BRAF rearrangement and negative for rearrangements involving NTRK1, RET, and ROS1. The tumor was narrowly excised and recurred after 24 months of follow‐up. To our knowledge, we report the second case of BRAF‐rearranged spindle cell mesenchymal tumor with predominant lipofibromatosis‐like neural tumor pattern. Expression of markers associated with perineurial differentiation is exceptional and represents a potential diagnostic pitfall, which may cause significant diagnostic confusion with a peripheral nerve sheath tumor.

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“…Inflammatory myofibroblastic tumors often carry ALK rearrangements or, less frequently, gene fusions involving other receptor tyrosine kinases [63]. NTRK1/2/3 translocations are particularly characteristic for infantile fibrosarcomas and occur at some frequency in other sarcoma types [64]. A small subset of clear-cell sarcomas carries the BRAF V600E mutation [65].…”

Section: Other Cancer Typesmentioning

confidence: 99%

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

Aleksakhina

Imyanitov

2021

IJMS

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The administration of many cancer drugs is tailored to genetic tests. Some genomic events, e.g., alterations of EGFR or BRAF oncogenes, result in the conformational change of the corresponding proteins and call for the use of mutation-specific compounds. Other genetic perturbations, e.g., HER2 amplifications, ALK translocations or MET exon 14 skipping mutations, cause overproduction of the entire protein or its kinase domain. There are multilocus assays that provide integrative characteristics of the tumor genome, such as the analysis of tumor mutation burden or deficiency of DNA repair. Treatment planning for non-small cell lung cancer requires testing for EGFR, ALK, ROS1, BRAF, MET, RET and KRAS gene alterations. Colorectal cancer patients need to undergo KRAS, NRAS, BRAF, HER2 and microsatellite instability analysis. The genomic examination of breast cancer includes testing for HER2 amplification and PIK3CA activation. Melanomas are currently subjected to BRAF and, in some instances, KIT genetic analysis. Predictive DNA assays have also been developed for thyroid cancers, cholangiocarcinomas and urinary bladder tumors. There is an increasing utilization of agnostic testing which involves the analysis of all potentially actionable genes across all tumor types. The invention of genomically tailored treatment has resulted in a spectacular improvement in disease outcomes for a significant portion of cancer patients.

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NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects

Cited by 39 publications

References 57 publications

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities

NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities

BRAF‐rearranged spindle cell mesenchymal neoplasm with a predominant lipofibromatosis‐like neural tumor pattern and co‐expression of CD34, S100 protein, and markers associated with perineurial differentiation: A rare case with potential diagnostic pitfall

Cancer Therapy Guided by Mutation Tests: Current Status and Perspectives

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