NTRK-Rearranged soft tissue neoplasms: A review of evolving diagnostic entities and algorithmic detection methods

  • Author Footnotes
    1 Authors contributed equally to this work.
    Lea F. Surrey
    Correspondence
    Corresponding author at: 3401 Civic Center Blvd., Children's Hospital of Philadelphia, 5NW-26 Main, Philadelphia, PA 19104.
    Footnotes
    1 Authors contributed equally to this work.
    Affiliations
    Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, USA
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally to this work.
    Jessica L. Davis
    Footnotes
    1 Authors contributed equally to this work.
    Affiliations
    Department of Pathology, Oregon Health & Science University, Portland, OR, USA
    Search for articles by this author
  • Author Footnotes
    1 Authors contributed equally to this work.

      Abstract

      The spectrum of tumors with NTRK1/2/3 rearrangements has expanded with widespread use of next generation sequencing (NGS) technology. For many years it was known that a majority of infantile fibrosarcomas (IFS), and their counterpart in the kidney, cellular congenital mesoblastic nephroma, contain the recurrent ETV6-NTRK3 fusion. Sequencing RNA transcripts from IFS and their morphologically similar counterparts in older children and adults has shown rearrangements with other 5′ partners combined with NTRK1, NTRK2, and NTRK3 can also occur. For those tumors occurring outside of the infant age group, this has resulted in a proposed new diagnostic entity of “NTRK-rearranged spindle cell neoplasm.” The clinical behavior of NTRK rearranged soft tissue tumors varies, though most show localized disease with rare metastases. The pathology of NTRK rearranged tumors exists on a spectrum, with overlapping features of classic infantile fibrosarcoma, lipofibromatosis, and malignant peripheral nerve sheath tumor. In this tumor spectrum, clinical and pathologic predictive factors are largely still to be determined, with no clear association between histologic grade and severity of disease. Of critical importance is detection of the NTRK rearrangement in order to guide treatment in patients with unresectable and metastatic disease. While resection is the definitive treatment, these tumors do show response to targeted TRK kinase inhibitors. Multiple detection methods are available, including immunohistochemistry, FISH, and next generation sequencing, which each have their merits and potential pitfalls. We aim to review the clinical characteristics and histomorphology of mesenchymal tumors with NTRK rearrangements as well as discuss molecular detection methods and diagnostic algorithms specific for soft tissue tumors.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Cancer Genetics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pulciani S.
        • Santos E.
        • Lauver A.V.
        • Long L.K.
        • Aaronson S.A.
        • Barbacid M.
        Oncogenes in solid human tumours.
        Nature. 1982; 300: 539-542
        • Wiesner T.
        • He J.
        • Yelensky R.
        • Esteve-Puig R.
        • Botton T.
        • Yeh I.
        • et al.
        Kinase fusions are frequent in Spitz tumours and spitzoid melanomas.
        Nat Commun. 2014; 5: 3116
        • Torre M.
        • Vasudevaraja V.
        • Serrano J.
        • DeLorenzo M.
        • Malinowski S.
        • Blandin A.F.
        • et al.
        Molecular and clinicopathologic features of gliomas harboring NTRK fusions.
        Acta Neuropathol Commun. 2020; 8: 107
        • Cocco E.
        • Scaltriti M.
        • Drilon A.
        NTRK fusion-positive cancers and TRK inhibitor therapy.
        Nat Rev Clin Oncol. 2018; 15: 731-747
        • Chu Y.H.
        • Dias-Santagata D.
        • Farahani A.A.
        • Boyraz B.
        • Faquin W.C.
        • Nose V.
        • et al.
        Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC).
        Mod Pathol. 2020; 33: 2186-2197
        • Skalova A.
        • Vanecek T.
        • Sima R.
        • Laco J.
        • Weinreb I.
        • Perez-Ordonez B.
        • et al.
        Mammary analogue secretory carcinoma of salivary glands, containing the ETV6-NTRK3 fusion gene: a hitherto undescribed salivary gland tumor entity.
        Am J Surg Pathol. 2010; 34: 599-608
        • Knezevich S.R.
        • Garnett M.J.
        • Pysher T.J.
        • Beckwith J.B.
        • Grundy P.E.
        • Sorensen P.H.
        ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma.
        Cancer Res. 1998; 58: 5046-5048
        • Rubin B.P.
        • Chen C.J.
        • Morgan T.W.
        • Xiao S.
        • Grier H.E.
        • Kozakewich H.P.
        • et al.
        Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma.
        Am J Pathol. 1998; 153: 1451-1458
        • Schram A.M.
        • Chang M.T.
        • Jonsson P.
        • Drilon A.
        Fusions in solid tumours: diagnostic strategies, targeted therapy, and acquired resistance.
        Nat Rev Clin Oncol. 2017; 14: 735-748
        • Doebele R.C.
        • Drilon A.
        • Paz-Ares L.
        • Siena S.
        • Shaw A.T.
        • Farago A.F.
        • et al.
        Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials.
        Lancet Oncol. 2020; 21: 271-282
        • Laetsch T.W.
        • DuBois S.G.
        • Mascarenhas L.
        • Turpin B.
        • Federman N.
        • Albert C.M.
        • et al.
        Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study.
        Lancet Oncol. 2018; 19: 705-714
        • Drilon A.
        • Laetsch T.W.
        • Kummar S.
        • DuBois S.G.
        • Lassen U.N.
        • Demetri G.D.
        • et al.
        Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.
        N Engl J Med. 2018; 378: 731-739
        • Davis J.L.A.C.
        • Bahrami A.
        Infantile fibrosarcoma.
        in: WHO classification of tumours of soft tissue and bone WHO Classification of Tumours Editorial Board. 5th ed. IARC, Lyon2020: 119-121
        • Suurmeijer A.J.H.A.C.
        NTRK-rearranged spindle cell neoplasm (emerging).
        WHO classification of tumours editorial board, editor who classification of tumours of soft tissue and bone. 5th ed. IARC, Lyon2020: 287-289
        • Alassiri A.H.
        • Ali R.H.
        • Shen Y.
        • Lum A.
        • Strahlendorf C.
        • Deyell R.
        • et al.
        ETV6-NTRK3 is expressed in a subset of ALK-negative inflammatory myofibroblastic tumors.
        Am J Surg Pathol. 2016; 40: 1051-1061
        • Antonescu C.R.
        • Suurmeijer A.J.
        • Zhang L.
        • Sung Y.S.
        • Jungbluth A.A.
        • Travis W.D.
        • et al.
        Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement.
        Am J Surg Pathol. 2015; 39: 957-967
        • Yamamoto H.
        • Yoshida A.
        • Taguchi K.
        • Kohashi K.
        • Hatanaka Y.
        • Yamashita A.
        • et al.
        ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours.
        Histopathology. 2016; 69: 72-83
        • Brenca M.
        • Rossi S.
        • Polano M.
        • Gasparotto D.
        • Zanatta L.
        • Racanelli D.
        • et al.
        Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST.
        J Pathol. 2016; 238: 543-549
        • Atiq M.A.
        • Davis J.L.
        • Hornick J.L.
        • Dickson B.C.
        • Fletcher C.D.M.
        • Fletcher J.A.
        • et al.
        Mesenchymal tumors of the gastrointestinal tract with NTRK rearrangements: a clinicopathological, immunophenotypic, and molecular study of eight cases, emphasizing their distinction from gastrointestinal stromal tumor (GIST).
        Mod Pathol. 2021; 34: 95-103
        • Hung Y.P.
        • Fletcher C.D.M.
        • Hornick J.L.
        Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics.
        Histopathology. 2018; 73: 634-644
        • Ogura K.
        • Somwar R.
        • Hmeljak J.
        • Magnan H.
        • Benayed R.
        • Momeni Boroujeni A.
        Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor.
        Clin Cancer Res. 2021; 27: 1184-1194
        • Davis J.L.
        • Lockwood C.M.
        • Stohr B.
        • Boecking C.
        • Al-Ibraheemi A.
        • DuBois S.G.
        • et al.
        Expanding the Spectrum of Pediatric NTRK-rearranged Mesenchymal Tumors.
        Am J Surg Pathol. 2019; 43: 435-445
        • Agaram N.P.
        • Zhang L.
        • Sung Y.S.
        • Chen C.L.
        • Chung C.T.
        • Antonescu C.R.
        • et al.
        Recurrent NTRK1 gene fusions define a novel subset of locally aggressive lipofibromatosis-like neural tumors.
        Am J Surg Pathol. 2016; 40: 1407-1416
        • Yamazaki F.
        • Nakatani F.
        • Asano N.
        • Wakai S.
        • Sekimizu M.
        • Mitani S.
        • et al.
        Novel NTRK3 fusions in fibrosarcomas of adults.
        Am J Surg Pathol. 2019; 43: 523-530
        • Kao Y.C.
        • Fletcher C.D.M.
        • Alaggio R.
        • Wexler L.
        • Zhang L.
        • Sung Y.S.
        • et al.
        Recurrent BRAF gene fusions in a subset of pediatric spindle cell sarcomas: expanding the genetic spectrum of tumors with overlapping features with infantile fibrosarcoma.
        Am J Surg Pathol. 2018; 42: 28-38
        • Penning A.J.
        • Al-Ibraheemi A.
        • Michal M.
        • Larsen B.T.
        • Cho S.J.
        • Lockwood C.M.
        • et al.
        Novel BRAF gene fusions and activating point mutations in spindle cell sarcomas with histologic overlap with infantile fibrosarcoma.
        Mod Pathol. 2021;
        • Gupta A.
        • Belsky J.A.
        • Schieffer K.M.
        • Leraas K.
        • Varga E.
        • McGrath S.D.
        • et al.
        Infantile fibrosarcoma-like tumor driven by novel RBPMS-MET fusion consolidated with cabozantinib.
        Cold Spring Harb Mol Case Stud. 2020; 6
        • Antonescu C.R.
        • Dickson B.C.
        • Swanson D.
        • Zhang L.
        • Sung Y.S.
        • Kao Y.C.
        • et al.
        Spindle cell tumors with RET gene fusions exhibit a morphologic spectrum akin to tumors with NTRK gene fusions.
        Am J Surg Pathol. 2019; 43: 1384-1391
        • Davis J.L.
        • Vargas S.O.
        • Rudzinski E.R.
        • Lopez Marti J.M.
        • Janeway K.
        • Forrest S.
        • et al.
        Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms.
        Histopathology. 2020; 76: 1032-1041
        • Suurmeijer A.J.H.
        • Dickson B.C.
        • Swanson D.
        • Zhang L.
        • Sung Y.S.
        • Cotzia P.
        • et al.
        A novel group of spindle cell tumors defined by S100 and CD34 co-expression shows recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes.
        Genes Chromosomes Cancer. 2018; 57: 611-621
        • Abs D.
        • Landman S.
        • Osio A.
        • Lepesant P.
        • Schneider P.
        • Obadia D.
        • et al.
        Spindle cell tumor with CD34 and S100 co-expression and distinctive stromal and perivascular hyalinization showing EML4-ALK fusion.
        J Cutan Pathol. 2021; 48: 896-901
        • Coffin C.M.B.C.
        • Neff T.
        • Corless C.L.
        • Davis J.L.
        Infantile fibrosarcoma with a novel RAF1 rearrangement: the contemporary challenge of reconciling classic morphology with novel molecular genetics.
        Human Pathology: Case Reports. 2020; 22200434
        • Lopez-Nunez O.
        • Surrey L.F.
        • Alaggio R.
        • Fritchie K.J.
        • John I.
        Novel PPP1CB-ALK fusion in spindle cell tumor defined by S100 and CD34 coexpression and distinctive stromal and perivascular hyalinization.
        Genes Chromosomes Cancer. 2020; 59: 495-499
        • Chung E.B.
        • Enzinger F.M.
        Infantile fibrosarcoma.
        Cancer. 1976; 38: 729-739
        • Stout A.P.
        Fibrosarcoma in infants and children.
        Cancer. 1962; 15: 1028-1040
        • Soule E.H.
        • Pritchard D.J.
        Fibrosarcoma in infants and children: a review of 110 cases.
        Cancer. 1977; 40: 1711-1721
        • Coffin C.M.
        • Jaszcz W.
        • O'Shea P.A.
        • Dehner L.P.
        So-called congenital-infantile fibrosarcoma: does it exist and what is it?.
        Pediatr Pathol. 1994; 14: 133-150
        • Orbach D.
        • Sparber-Sauer M.
        • Laetsch T.W.
        • Minard-Colin V.
        • Bielack S.S.
        • Casanova M.
        • et al.
        Spotlight on the treatment of infantile fibrosarcoma in the era of neurotrophic tropomyosin receptor kinase inhibitors: international consensus and remaining controversies.
        Eur J Cancer. 2020; 137: 183-192
        • Schofield D.E.
        • Yunis E.J.
        • Fletcher J.A.
        Chromosome aberrations in mesoblastic nephroma.
        Am J Pathol. 1993; 143: 714-724
        • van den Heuvel-Eibrink M.M.
        • Grundy P.
        • Graf N.
        • Pritchard-Jones K.
        • Bergeron C.
        • Patte C.
        • et al.
        Characteristics and survival of 750 children diagnosed with a renal tumor in the first seven months of life: a collaborative study by the SIOP/GPOH/SFOP, NWTSG, and UKCCSG Wilms tumor study groups.
        Pediatr Blood Cancer. 2008; 50: 1130-1134
        • Gooskens S.L.
        • Houwing M.E.
        • Vujanic G.M.
        • Dome J.S.
        • Diertens T.
        • Coulomb-l’Hermine A.
        • et al.
        Congenital mesoblastic nephroma 50 years after its recognition: a narrative review.
        Pediatr Blood Cancer. 2017; 64
        • Leclair M.D.
        • El-Ghoneimi A.
        • Audry G.
        • Ravasse P.
        • Moscovici J.
        • Heloury Y.
        • et al.
        The outcome of prenatally diagnosed renal tumors.
        J Urol. 2005; 173: 186-189
        • Vokuhl C.
        • Nourkami-Tutdibi N.
        • Furtwangler R.
        • Gessler M.
        • Graf N.
        • Leuschner I.
        ETV6-NTRK3 in congenital mesoblastic nephroma: a report of the SIOP/GPOH nephroblastoma study.
        Pediatr Blood Cancer. 2018; 65
        • Kao Y.C.
        • Suurmeijer A.J.H.
        • Argani P.
        • Dickson B.C.
        • Zhang L.
        • Sung Y.S.
        • et al.
        Soft tissue tumors characterized by a wide spectrum of kinase fusions share a lipofibromatosis-like neural tumor pattern.
        Genes Chromosomes Cancer. 2020; 59: 575-583
        • Antonescu C.R.
        Emerging soft tissue tumors with kinase fusions: an overview of the recent literature with an emphasis on diagnostic criteria.
        Genes Chromosomes Cancer. 2020; 59: 437-444
        • Suurmeijer A.J.
        • Dickson B.C.
        • Swanson D.
        • Zhang L.
        • Sung Y.S.
        • Huang H.Y.
        • et al.
        The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements.
        Genes Chromosomes Cancer. 2019; 58: 739-746
        • Croce S.
        • Hostein I.
        • Longacre T.A.
        • Mills A.M.
        • Perot G.
        • Devouassoux-Shisheboran M.
        • et al.
        Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms.
        Mod Pathol. 2019; 32: 1008-1022
        • Rabban J.T.
        • Devine W.P.
        • Sangoi A.R.
        • Poder L.
        • Alvarez E.
        • Davis J.L.
        • et al.
        NTRK fusion cervical sarcoma: a report of three cases, emphasising morphological and immunohistochemical distinction from other uterine sarcomas, including adenosarcoma.
        Histopathology. 2020; 77: 100-111
        • Alaggio R.
        • Barisani D.
        • Ninfo V.
        • Rosolen A.
        • Coffin C.M.
        Morphologic overlap between infantile myofibromatosis and infantile fibrosarcoma: a pitfall in diagnosis.
        Pediatr Dev Pathol. 2008; 11: 355-362
        • Dahl I.
        • Save-Soderbergh J.
        • Angervall L.
        Fibrosarcoma in early infancy.
        Pathol Eur. 1973; 8: 193-209
        • Michal M.
        • Ptakova N.
        • Martinek P.
        • Gatalica Z.
        • Kazakov D.V.
        • Michalova K.
        • et al.
        S100 and CD34 positive spindle cell tumor with prominent perivascular hyalinization and a novel NCOA4-RET fusion.
        Genes Chromosomes Cancer. 2019; 58: 680-685
        • Rudzinski E.R.
        • Lockwood C.M.
        • Stohr B.A.
        • Vargas S.O.
        • Sheridan R.
        • Black J.O.
        • et al.
        Pan-Trk immunohistochemistry Identifies NTRK rearrangements in pediatric mesenchymal tumors.
        Am J Surg Pathol. 2018; 42: 927-935
        • Bourgeois J.M.
        • Knezevich S.R.
        • Mathers J.A.
        • Sorensen P.H.
        Molecular detection of the ETV6-NTRK3 gene fusion differentiates congenital fibrosarcoma from other childhood spindle cell tumors.
        Am J Surg Pathol. 2000; 24: 937-946
        • Orbach D.
        • Rey A.
        • Cecchetto G.
        • Oberlin O.
        • Casanova M.
        • Thebaud E.
        • et al.
        Infantile fibrosarcoma: management based on the European experience.
        J Clin Oncol. 2010; 28: 318-323
        • Wegert J.
        • Vokuhl C.
        • Collord G.
        • Del Castillo Velasco-Herrera M.
        • Farndon S.J.
        • Guzzo C.
        • et al.
        Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants.
        Nat Commun. 2018; 9: 2378
        • Zhao M.
        • Yin M.
        • Kuick C.H.
        • Chen H.
        • Aw S.J.
        • Merchant K.
        • et al.
        Congenital mesoblastic nephroma is characterised by kinase mutations including EGFR internal tandem duplications, the ETV6-NTRK3 fusion, and the rare KLHL7-BRAF fusion.
        Histopathology. 2020; 77: 611-621
        • Gatalica Z.
        • Xiu J.
        • Swensen J.
        • Vranic S.
        Molecular characterization of cancers with NTRK gene fusions.
        Mod Pathol. 2019; 32: 147-153
        • Solomon J.P.
        • Linkov I.
        • Rosado A.
        • Mullaney K.
        • Rosen E.Y.
        • Frosina D.
        • et al.
        NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls.
        Mod Pathol. 2020; 33: 38-46
        • Demetri G.D.
        • Antonescu C.R.
        • Bjerkehagen B.
        • Bovee J.
        • Boye K.
        • Chacon M.
        • et al.
        Diagnosis and management of tropomyosin receptor kinase (TRK) fusion sarcomas: expert recommendations from the World Sarcoma Network.
        Ann Oncol. 2020; 31: 1506-1517
        • Kirchner M.
        • Glade J.
        • Lehmann U.
        • Merkelbach-Bruse S.
        • Hummel M.
        • Lehmann A.
        • et al.
        NTRK testing: first results of the QuiP-EQA scheme and a comprehensive map of NTRK fusion variants and their diagnostic coverage by targeted RNA-based NGS assays.
        Genes Chromosomes Cancer. 2020; 59: 445-453
        • Church A.J.
        • Calicchio M.L.
        • Nardi V.
        • Skalova A.
        • Pinto A.
        • Dillon D.A.
        • et al.
        Recurrent EML4-NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy.
        Mod Pathol. 2018; 31: 463-473
        • Vaishnavi A.
        • Capelletti M.
        • Le A.T.
        • Kako S.
        • Butaney M.
        • Ercan D.
        • et al.
        Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.
        Nat Med. 2013; 19: 1469-1472
        • Marchio C.
        • Scaltriti M.
        • Ladanyi M.
        • Iafrate A.J.
        • Bibeau F.
        • Dietel M.
        • et al.
        ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research.
        Ann Oncol. 2019; 30: 1417-1427
        • Skalova A.
        • Vanecek T.
        • Simpson R.H.
        • Laco J.
        • Majewska H.
        • Baneckova M.
        • et al.
        Mammary analogue secretory carcinoma of salivary glands: molecular analysis of 25 ETV6 gene rearranged tumors with lack of detection of classical ETV6-NTRK3 fusion transcript by standard RT-PCR: report of 4 cases harboring ETV6-X gene fusion.
        Am J Surg Pathol. 2016; 40: 3-13
        • Beadling C.
        • Wald A.I.
        • Warrick A.
        • Neff T.L.
        • Zhong S.
        • Nikiforov Y.E.
        • et al.
        A multiplexed amplicon approach for detecting gene fusions by next-generation sequencing.
        J Mol Diagn. 2016; 18: 165-175
        • Kim J.
        • Kim S.
        • Ko S.
        • In Y.H.
        • Moon H.G.
        • Ahn S.K.
        • et al.
        Recurrent fusion transcripts detected by whole-transcriptome sequencing of 120 primary breast cancer samples.
        Genes Chromosomes Cancer. 2015; 54: 681-691
        • Reeser J.W.
        • Martin D.
        • Miya J.
        • Kautto E.A.
        • Lyon E.
        • Zhu E.
        • et al.
        Validation of a Targeted RNA Sequencing Assay for Kinase Fusion Detection in Solid Tumors.
        J Mol Diagn. 2017; 19: 682-696
        • Sheng S.J.
        • Li J.M.
        • Zou Y.F.
        • Peng X.J.
        • Wang Q.Y.
        • Fang H.S.
        • et al.
        A low-grade malignant soft tissue tumor with S100 and CD34 co-expression showing novel CDC42SE2-BRAF fusion with distinct features.
        Genes Chromosomes Cancer. 2020; 59: 595-600
        • Choo F.
        • Rakheja D.
        • Davis L.E.
        • Davare M.
        • Park J.Y.
        • Timmons C.F.
        • et al.
        GAB1-ABL1 fusions in tumors that have histologic overlap with NTRK-rearranged spindle cell tumors.
        Genes Chromosomes Cancer. 2021;
        • Perreault S.
        • Chami R.
        • Deyell R.J.
        • El Demellawy D.
        • Ellezam B.
        • Jabado N.
        • et al.
        Canadian consensus for biomarker testing and treatment of TRK fusion cancer in pediatric patients.
        Curr Oncol. 2021; 28: 346-366
        • Bebb D.G.
        • Banerji S.
        • Blais N.
        • Desmeules P.
        • Gill S.
        • Grin A.
        • et al.
        Canadian consensus for biomarker testing and treatment of TRK fusion cancer in adults.
        Curr Oncol. 2021; 28: 523-548
        • Garrido P.
        • Hladun R.
        • de Alava E.
        • Alvarez R.
        • Bautista F.
        • Lopez-Rios F.
        • et al.
        Multidisciplinary consensus on optimising the detection of NTRK gene alterations in tumours.
        Clin Transl Oncol. 2021;
        • Pfarr N.
        • Kirchner M.
        • Lehmann U.
        • Leichsenring J.
        • Merkelbach-Bruse S.
        • Glade J.
        • et al.
        Testing NTRK testing: wet-lab and in silico comparison of RNA-based targeted sequencing assays.
        Genes Chromosomes Cancer. 2020; 59: 178-188