NTRK fusion; NTRK fusion partner; TRK immunohistochemistry; histology; prognosis; sarcoma; Biomarkers, Tumor; Receptor, trkA; Biomarkers, Tumor/analysis; Biomarkers, Tumor/genetics; Humans; Pathology, Molecular; Receptor, trkA/genetics; Sarcoma/genetics; Soft Tissue Neoplasms/genetics; Soft Tissue Neoplasms; Pathology and Forensic Medicine; Oncology; Cancer Research; General Medicine
Abstract :
[en] Targeting molecular alterations has been proven to be an inflecting point in tumor treatment. Especially in recent years, inhibitors that target the tyrosine receptor kinase show excellent response rates and durable effects in all kind of tumors that harbor fusions of one of the three neurotrophic tyrosine receptor kinase genes (NTRK1, NTRK2 and NTRK3). Today, the therapeutic options in most metastatic sarcomas are rather limited. Therefore, identifying which sarcoma types are more likely to harbor these targetable NTRK fusions is of paramount importance. At the moment, identification of these fusions is solely based on immunohistochemistry and confirmed by molecular techniques. However, a first attempt has been made to describe the histomorphology of NTRK-fusion positive sarcomas, in order to pinpoint which of these tumors are the best candidates for testing. In this study, we investigate the immunohistochemical expression of pan-TRK in 70 soft tissue and bone sarcomas. The pan-TRK positive cases were further investigated with molecular techniques for the presence of a NTRK fusion. Seven out of the 70 cases showed positivity for pan-TRK, whereas two of these seven cases presented an NTRK3 fusion. Further analysis of the fused sarcomas revealed some unique histological, molecular and clinical findings. The goal of this study is to expand the histomorphological spectrum of the NTRK-fused sarcomas, to identify their fusion partners and to correlate these parameters with the clinical outcome of the disease. In addition, we evaluated the immunohistochemical expression pattern of the pan-TRK and its correlation with the involved NTRK gene.
Disciplines :
Oncology
Author, co-author :
Siozopoulou, Vasiliki ; Department of Pathology, Antwerp University Hospital, Edegem, Belgium ; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Marcq, Elly; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
De Winne, Koen; Department of Pathology, Antwerp University Hospital, Edegem, Belgium
Norga, Koen; Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium
Schmitz, Gertjan; Department of Orthopaedics, Hospital of Klina, Antwerp, Belgium
Duwel, Valerie; Department of Pathology, Hospital of Klina, Antwerp, Belgium
Delvenne, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'anatomie et cytologie pathologiques
Smits, Evelien; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium ; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem, Belgium
Pauwels, Patrick; Department of Pathology, Antwerp University Hospital, Edegem, Belgium ; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Wilrijk, Belgium
Language :
English
Title :
NTRK Fusions in a Sarcomas Series: Pathology, Molecular and Clinical Aspects.
Gamboa AC Gronchi A Cardona K. Soft‐tissue Sarcoma in Adults: An Update on the Current State of Histiotype‐specific Management in an Era of Personalized Medicine. CA A Cancer J Clin (2020) 70(3):200–29. 10.3322/caac.21605
Dangoor A Seddon B Gerrand C Grimer R Whelan J Judson I. UK Guidelines for the Management of Soft Tissue Sarcomas. Clin Sarcoma Res (2016) 6:20. 10.1186/s13569-016-0060-4
Gerrand C Athanasou N Athanasou N Brennan B Grimer R Judson I et al. UK Guidelines for the Management of Bone Sarcomas. Clin Sarcoma Res (2016) 6:7. 10.1186/s13569-016-0047-1
Bessen T Caughey GE Shakib S Potter JA Reid J Farshid G et al. A Population-Based Study of Soft Tissue Sarcoma Incidence and Survival in Australia: An Analysis of 26,970 Cases. Cancer Epidemiol (2019) 63:101590. 10.1016/j.canep.2019.101590
Reichardt P. The Story of Imatinib in GIST - a Journey through the Development of a Targeted Therapy. Oncol Res Treat (2018) 41(7-8):472–7. 10.1159/000487511
Drilon A. TRK Inhibitors in TRK Fusion-Positive Cancers. Ann Oncol (2019) 30(Suppl. 8):viii23–viii30. 10.1093/annonc/mdz282
Drilon A Nagasubramanian R Blake JF Ku N Tuch BB Ebata K et al. A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Cancer Discov (2017) 7(9):963–72. 10.1158/2159-8290.CD-17-0507
Drilon A Ou S-HI Cho BC Kim D-W Lee J Lin JJ et al. Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor that Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations. Cancer Discov (2018) 8(10):1227–36. 10.1158/2159-8290.CD-18-0484
Cocco E Scaltriti M Drilon A. NTRK Fusion-Positive Cancers and TRK Inhibitor Therapy. Nat Rev Clin Oncol (2018) 15(12):731–47. 10.1038/s41571-018-0113-0
Siozopoulou V Smits E De Winne K Marcq E Pauwels P. NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects. Diagnostics (2021) 11(3):478. 10.3390/diagnostics11030478
Gatalica Z Xiu J Swensen J Vranic S. Molecular Characterization of Cancers with NTRK Gene Fusions. Mod Pathol (2019) 32(1):147–53. 10.1038/s41379-018-0118-3
De Winne K Sorber L Lambin S Siozopoulou V Beniuga G Dedeurwaerdere F et al. Immunohistochemistry as a Screening Tool for NTRK Gene Fusions: Results of a First Belgian Ring Trial. Virchows Arch (2021) 478(2):283–91. 10.1007/s00428-020-02921-6
Detre S Saclani Jotti G Dowsett M. A "quickscore" Method for Immunohistochemical Semiquantitation: Validation for Oestrogen Receptor in Breast Carcinomas. J Clin Pathol (1995) 48(9):876–8. 10.1136/jcp.48.9.876
Kummar S Lassen UN. TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Targ Oncol (2018) 13(5):545–56. 10.1007/s11523-018-0590-1
Vaishnavi A Le AT Doebele RC. TRKing Down an Old Oncogene in a new era of Targeted Therapy. Cancer Discov (2015) 5(1):25–34. 10.1158/2159-8290.CD-14-0765
Hong DS Bauer TM Lee JJ Dowlati A Brose MS Farago AF et al. Larotrectinib in Adult Patients with Solid Tumours: a multi-centre, Open-Label, Phase I Dose-Escalation Study. Ann Oncol (2019) 30(2):325–31. 10.1093/annonc/mdy539
Demetri GD Antonescu CR Bjerkehagen B Bovée JVMG Boye K Chacón M et al. Diagnosis and Management of Tropomyosin Receptor Kinase (TRK) Fusion Sarcomas: Expert Recommendations from the World Sarcoma Network. Ann Oncol (2020) 31(11):1506–17. 10.1016/j.annonc.2020.08.2232
Kao YC Suurmeijer AJH Argani P Dickson BC Zhang L Sung YS 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(10):575–83. 10.1002/gcc.22877
Agaram NP Zhang L Sung Y-S Chen C-L Chung CT Antonescu CR et al. Recurrent NTRK1 Gene Fusions Define a Novel Subset of Locally Aggressive Lipofibromatosis-like Neural Tumors. Am J Surg Pathol (2016) 40(10):1407–16. 10.1097/PAS.0000000000000675
Haller F Knopf J Ackermann A Bieg M Kleinheinz K Schlesner M et al. Paediatric and Adult Soft Tissue Sarcomas withNTRK1gene Fusions: a Subset of Spindle Cell Sarcomas Unified by a Prominent Myopericytic/haemangiopericytic Pattern. J Pathol (2016) 238(5):700–10. 10.1002/path.4701
Croce S Hostein I Longacre TA Mills AM Pérot 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(7):1008–22. 10.1038/s41379-018-0184-6
Chiang S Cotzia P Hyman DM Drilon A Tap WD Zhang L et al. NTRK Fusions Define a Novel Uterine Sarcoma Subtype with Features of Fibrosarcoma. Am J Surg Pathol (2018) 42(6):791–8. 10.1097/PAS.0000000000001055
Rabban JT Devine WP Sangoi AR Poder L Alvarez E Davis JL 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(1):100–11. 10.1111/his.14069
Alassiri AH Ali RH 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(8):1051–61. 10.1097/PAS.0000000000000677
Yamamoto H Yoshida A Taguchi K Kohashi K Hatanaka Y Yamashita A et al. ALK,ROS1andNTRK3gene Rearrangements in Inflammatory Myofibroblastic Tumours. Histopathology (2016) 69(1):72–83. 10.1111/his.12910
Olson N Rouhi O Zhang L Angeles C Bridge J Lopez-Terrada D et al. A Novel Case of an Aggressive Superficial Spindle Cell Sarcoma in an Adult Resembling Fibrosarcomatous Dermatofibrosarcoma Protuberans and Harboring anEML4-NTRK3fusion. J Cutan Pathol (2018) 45(12):933–9. 10.1111/cup.13348
So YK Chow C To KF Chan JKC Cheuk W. Myxoid Spindle Cell Sarcoma with LMNA-NTRK Fusion: Expanding the Morphologic Spectrum of NTRK-Rearranged Tumors. Int J Surg Pathol (2020) 28(5):574–8. 10.1177/1066896920905888
Kao Y-C Flucke U Eijkelenboom A Zhang L Sung Y-S Suurmeijer AJH et al. Novel EWSR1-SMAD3 Gene Fusions in a Group of Acral Fibroblastic Spindle Cell Neoplasms. Am J Surg Pathol (2018) 42(4):522–8. 10.1097/PAS.0000000000001002
Brčić I Godschachner TM Bergovec M Igrec J Till H Lackner H et al. Broadening the Spectrum of NTRK Rearranged Mesenchymal Tumors and Usefulness of Pan-TRK Immunohistochemistry for Identification of NTRK Fusions. Mod Pathol (2021) 34(2):396–407. 10.1038/s41379-020-00657-x
Davis JL Lockwood CM Stohr B Boecking C Al-Ibraheemi A DuBois SG et al. Expanding the Spectrum of Pediatric NTRK-Rearranged Mesenchymal Tumors. Am J Surg Pathol (2019) 43(4):435–45. 10.1097/PAS.0000000000001203
Hechtman JF Benayed R Hyman DM Drilon A Zehir A Frosina D et al. Pan-Trk Immunohistochemistry Is an Efficient and Reliable Screen for the Detection of NTRK Fusions. Am J Surg Pathol (2017) 41(11):1547–51. 10.1097/PAS.0000000000000911
Solomon JP Benayed R Hechtman JF Ladanyi M. Identifying Patients with NTRK Fusion Cancer. Ann Oncol (2019) 30(Suppl. l_8):viii16–viii22. 10.1093/annonc/mdz384
Nozzoli F Lazar AJ Castiglione F Campanacci DA Beltrami G De Logu F et al. NTRK Fusions Detection in Paediatric Sarcomas to Expand the Morphological Spectrum and Clinical Relevance of Selected Entities. Pathol Oncol Res. 2022;28. 10.3389/pore.2022.1610237
Rudzinski ER Lockwood CM Stohr BA Vargas SO Sheridan R Black JO et al. Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors. Am J Surg Pathol (2018) 42(7):927–35. 10.1097/PAS.0000000000001062
Solomon JP Linkov I Rosado A Mullaney K Rosen EY Frosina D et al. NTRK Fusion Detection across Multiple Assays and 33,997 Cases: Diagnostic Implications and Pitfalls. Mod Pathol (2020) 33(1):38–46. 10.1038/s41379-019-0324-7
Hung YP Fletcher CDM Hornick JL. Evaluation of Pan-TRK Immunohistochemistry in Infantile Fibrosarcoma, Lipofibromatosis-like Neural Tumour and Histological Mimics. Histopathology (2018) 73(4):634–44. 10.1111/his.13666
Csanyi-Bastien M Lanic M-D Beaussire L Ferric S François A Meseure D et al. Pan-TRK Immunohistochemistry Is Highly Correlated with NTRK3 Gene Rearrangements in Salivary Gland Tumors. Am J Surg Pathol (2021) 45:1487–98. 10.1097/PAS.0000000000001718
Suurmeijer AJH Dickson BC 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(12):611–21. 10.1002/gcc.22671
Suurmeijer AJ Dickson BC Swanson D Zhang L Sung YS Huang HY et al. The Histologic Spectrum of Soft Tissue Spindle Cell Tumors with NTRK3 Gene Rearrangements. Genes Chromosomes Cancer (2019) 58(11):739–46. 10.1002/gcc.22767
