Skip to main content
SpringerLink
Log in

Rezeptor-Tyrosinkinase-Fusionen in spindelzelligen Tumoren des Kindesalters

Receptor tyrosine kinase- fusions in paediatric spindle cell tumors

  • Schwerpunkt: Kindliche Tumoren
  • Published:
Die Pathologie Aims and scope Submit manuscript

Zusammenfassung

Spindelzellige Tumoren des Kindesalters sind selten und bereiten diagnostisch häufig Schwierigkeiten, da sie ein morphologisch ähnliches Bild und ein uncharakteristisches immunhistochemisches Profil aufweisen. Durch die immer besser werdende genetische Charakterisierung dieser Läsionen wurden neue Subgruppen identifiziert, die zum Teil in die neueste WHO-Klassifizierung miteinbezogen wurden. Bei diesen Tumoren spielen vor allem die sog. Rezeptor-Tyrosinkinase-Fusionen eine Rolle. Hierbei handelt es sich um Fusionen mit Beteiligung der Gene NTRK1-3, ALK, RET und ROS1. Der Nachweis einer Fusion ist von diagnostischer Bedeutung und kann auch eine Option für zielgerichtete Therapien bieten. Insgesamt handelt es sich bei kindlichen spindelzelligen Tumoren mit Rezeptor-Tyrosinkinase-Fusionen überwiegend um low-grade Tumoren, welche häufig in die Gruppe der intermediär-malignen Tumoren eingeteilt werden.

Abstract

Pediatric spindle cell tumors are rare and often difficult to diagnose due to a similar morphology and a non-specific immunohistochemical profile. Genetic characterization of these lesions has been constantly improving, which has led to the identification of new subgroups that were partly included in the WHO classification. Receptor tyrosine kinase fusions play a special role in these tumors and their verification has diagnostic relevance and can be an option for target-oriented therapies. In the case of pediatric spindle cell tumors, genetic fusions form especially with NTRK1‑3, ALK, RET, and ROS1. Overall, pediatric tumors with receptor tyrosine kinase fusions are predominantly low-grade tumors, which are often subdivided into the group of intermediate-malign tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Abbreviations

ALCL:

Anaplastisches großzelliges Lymphom

ALK:

„anaplastic lymphoma kinase“

BDNF:

„brain-derived neurotrophic factor“

CISH:

Chromogene In-situ-Hybridisierung

FISH:

Fluoreszenz-in-situ-Hybridisierung

IFS:

Infantiles Fibrosarkom

IHC:

Immunohistochemie

IHG:

Hemisphärisches Gliom vom infantilen Typ

IMT:

Inflammatorischer myofibroblastischer Tumor

LPF:

Lipofibromatose

LPFNT:

Lipofibromatoseartiger neuraler Tumor

NGF:

„nerve growth factor“

NPM:

Nucleophosmin

NTRK:

„neurotrophic tyrosine receptor kinase“

RTK:

Rezeptor-Tyrosinkinase

RT-PCR:

Reverse-Transkriptase-Polymerase-Kettenreaktion

TKI:

Tyrosinkinase-Inhibitor

ZNS:

Zentrales Nervensystem

Literatur

  1. Erdmann F et al (2021) Impact of the COVID-19 pandemic on incidence, time of diagnosis and delivery of healthcare among paediatric oncology patients in Germany in 2020: Evidence from the German Childhood Cancer Registry and a qualitative survey. Lancet Reg Health 9:100188. https://doi.org/10.1016/j.lanepe.2021.100188

    Article  Google Scholar 

  2. Scheidt S et al (2019) Soft tissue sarcoma—a current review of the diagnostic and treatment strategies. Z Orthop Unfall 157:644–653. https://doi.org/10.1055/a-0820-6366

    Article  PubMed  Google Scholar 

  3. Mitelman F, Johansson B, Mertens F (2007) The impact of translocations and gene fusions on cancer causation. Nat Rev Cancer 7:233–245. https://doi.org/10.1038/nrc2091

    Article  CAS  PubMed  Google Scholar 

  4. Lawrence B et al (2000) TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 157:377–384. https://doi.org/10.1016/S0002-9440(10)64550-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cocco E, Scaltriti M, Drilon A (2018) NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 15:731–747. https://doi.org/10.1038/s41571-018-0113-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Filbin M, Monje M (2019) Developmental origins and emerging therapeutic opportunities for childhood cancer. Nat Med 25:367–376. https://doi.org/10.1038/s41591-019-0383-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. LaHaye S et al (2021) Discovery of clinically relevant fusions in pediatric cancer. BMC Genom 22:872. https://doi.org/10.1186/s12864-021-08094-z

    Article  CAS  Google Scholar 

  8. Villani A et al (2023) The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations. Nat Cancer 4:203–221. https://doi.org/10.1038/s43018-022-00474-y

    Article  CAS  PubMed  Google Scholar 

  9. Lang SS et al (2022) Neurotrophic tyrosine receptor kinase fusion in pediatric central nervous system tumors. Cancer Genet 262–263:64–70. https://doi.org/10.1016/j.cancergen.2022.01.003

    Article  CAS  PubMed  Google Scholar 

  10. Bertrand T et al (2012) The crystal structures of TrkA and TrkB suggest key regions for achieving selective inhibition. J Mol Biol 423:439–453. https://doi.org/10.1016/j.jmb.2012.08.002

    Article  CAS  PubMed  Google Scholar 

  11. Hechtman JF (2021) NTRK insights: best practices for pathologists. Mod Pathol 35:298–305. https://doi.org/10.1038/s41379-021-00913-8

    Article  PubMed Central  Google Scholar 

  12. Roosen M et al (2022) The oncogenic fusion landscape in paediatric CNS neoplasms. Acta Neuropathol 143:427–451. https://doi.org/10.1007/s00401-022-02405-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Solomon JP et al (2020) NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and pitfalls. Mod Pathol 33:38–46. https://doi.org/10.1038/s41379-019-0324-7

    Article  CAS  PubMed  Google Scholar 

  14. Chetty R (2019) Neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) genes. J Clin Pathol 72:187–190. https://doi.org/10.1136/jclinpath-2018-205672

    Article  CAS  PubMed  Google Scholar 

  15. Hung YP, Fletcher CDM, Hornick JL (2018) Evaluation of pan-TRK immunohistochemistry in infantile fibrosarcoma, lipofibromatosis-like neural tumour and histological mimics. Histopathology 73:634–644. https://doi.org/10.1111/his.13666

    Article  PubMed  Google Scholar 

  16. Bellantoni AJ, Wagner LM (2021) Pursuing precision: receptor tyrosine kinase inhibitors for treatment of pediatric solid tumors. Cancers 13:3531. https://doi.org/10.3390/cancers13143531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Carton M et al (2023) Larotrectinib versus historical standard of care in patients with infantile fibrosarcoma: protocol of EPI-VITRAKVI. Future Oncol Prepr. https://doi.org/10.2217/fon-2023-0114

    Article  Google Scholar 

  18. Kao Y et al (2020) Soft tissue tumors characterized by a wide spectrum of kinase fusions share a lipofibromatosis-like neural tumor pattern. Genes Chromosom Cancer 59:575–583. https://doi.org/10.1002/gcc.22877

    Article  CAS  PubMed  Google Scholar 

  19. Suurmeijer AJ et al (2019) The histologic spectrum of soft tissue spindle cell tumors with NTRK3 gene rearrangements. Genes Chromosomes Cancer 58:739–746. https://doi.org/10.1002/gcc.22767

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kang J et al (2020) Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors. Diagn Pathol 15:114. https://doi.org/10.1186/s13000-020-01031-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pavlick D et al (2017) Identification of NTRK fusions in pediatric mesenchymal tumors. Pediatr Blood Cancer 64:8. https://doi.org/10.1002/pbc.26433

    Article  CAS  Google Scholar 

  22. Chan JK et al (2001) Anaplastic lymphoma kinase expression in inflammatory pseudotumors. Am J Surg Pathol 25:761–768

    Article  CAS  PubMed  Google Scholar 

  23. O’Haire S et al (2023) Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours. Sci Rep 13:4116. https://doi.org/10.1038/s41598-023-31055-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lovly CM et al (2014) Inflammatory myofibroblastic tumors harbor multiple potentially actionable kinase fusions. Cancer Discov 4:889–895. https://doi.org/10.1158/2159-8290.CD-14-0377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hornick JL et al (2015) Modern Pathology 5:732–739. https://doi.org/10.1038/modpathol.2014.165

    Article  CAS  Google Scholar 

  26. Preobrazhenskaya EV et al (2020) Gene rearrangements in consecutive series of pediatric inflammatory myofibroblastic tumors. Pediatr Blood Cancer 67:e28220. https://doi.org/10.1002/pbc.28220

    Article  PubMed  Google Scholar 

  27. Siemion K et al (2022) What do we know about inflammatory myofibroblastic tumors? – A systematic review. Advances in Medical Sciences 67:129–138. https://doi.org/10.1016/j.advms.2022.02.002

    Article  CAS  PubMed  Google Scholar 

  28. Davis JL et al (2019) Expanding the spectrum of paediatric NTRK-rearranged mesenchymal tumors. Am J Surg Pathol 43:435–445. https://doi.org/10.1097/PAS.0000000000001203

    Article  PubMed  Google Scholar 

  29. Davis JL et al (2020) Recurrent RET gene fusions in paediatric spindle mesenchymal neoplasms. Histopathology 76:1032–1041

    Article  PubMed  Google Scholar 

  30. Antonescu CR et al (2015) Molecular characterization of inflammatory myofibroblastic tumors with frequent ALK and ROS1 gene fusions and rare novel RET rearrangement. Am J Surg Pathol 39:957–967. https://doi.org/10.1097/PAS.0000000000000404

    Article  PubMed  PubMed Central  Google Scholar 

  31. Antonescu CR (2020) Emerging soft tissue tumors with kinase fusions: An overview of the recent literature with an emphasis on diagnostic criteria. Genes Chromosomes Cancer 59:437–444. https://doi.org/10.1002/gcc.22846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Flucke U et al (2017) TFG-MET fusion in an infantile spindle cell sarcoma with neural features. Genes. Chromosomes & Cancer 56:663–667. https://doi.org/10.1002/gcc.22470

    Article  CAS  Google Scholar 

  33. Ulschmid CM et al (2023) Lipofibromatosis-like neural tumors: Report of a case and review of 73 reported cases. Pediatric Dermatology 40:664–668. https://doi.org/10.1111/pde.15218

    Article  PubMed  Google Scholar 

  34. Kube S et al (2018) Inflammatory myofibroblastic tumors—A retrospective analysis of the Cooperative Weichteilsarkom Studiengruppe. Pediatr Blood Cancer 65:e27012. https://doi.org/10.1002/pbc.27012

    Article  CAS  PubMed  Google Scholar 

  35. Hernández L et al (1999) TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations. Blood 94:3265–3268. https://doi.org/10.1200/JCO.2012.44.5353

    Article  CAS  PubMed  Google Scholar 

  36. Morris SW et al (1997) ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 14:2175–2188. https://doi.org/10.1038/sj.onc.1201062

    Article  CAS  PubMed  Google Scholar 

  37. Hallberg B, Palmer RH (2016) The role of the ALK receptor in cancer biology. Ann Oncol 27:iii4–iii15. https://doi.org/10.1016/j.biopha.2022.114162

    Article  CAS  PubMed  Google Scholar 

  38. Cajaiba MM et al (2016) ALK-rearranged renal cell carcinomas in children. Genes Chromosomes Cancer 55:442–451. https://doi.org/10.1002/gcc.22346

    Article  CAS  PubMed  Google Scholar 

  39. Coffin CM, Hornick JL, Fletcher CDM (2007) Inflammatory myofibroblastic tumor comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 31:509–520. https://doi.org/10.1097/01.pas.0000213393.57322.c7

    Article  PubMed  Google Scholar 

  40. Mariño-Enriquez A et al (2011) Epithelioid inflammatory myofibroblastic sarcoma: an aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or Perinuclear ALK. Am J Surg Pathol 35:135–144. https://doi.org/10.1097/PAS.0b013e318200cfd5

    Article  PubMed  Google Scholar 

  41. Cessna MH et al (2002) Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases. Mod Pathol 15:931–938. https://doi.org/10.1097/01.MP.0000026615.04130.1F

    Article  PubMed  Google Scholar 

  42. Chen S, Lee J (2008) An inflammatory myofibroblastic tumor in liver with ALK and RANBP2 gene rearrangement: combination of distinct morphologic, immunohistochemical, and genetic features. Hum Pathol 39:1854–1858. https://doi.org/10.1016/j.humpath.2008.04.016

    Article  CAS  PubMed  Google Scholar 

  43. Gros L, Dei Tos AP, Jones RL, Digklia A (2022) Inflammatory myofibroblastic tumour: state of the art. Cancers 14:3662. https://doi.org/10.3390/cancers14153662

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brivio E, Zwaan CM (2019) ALK inhibition in two emblematic cases of pediatric inflammatory myofibroblastic tumor: efficacy and side effects. Pediatr Blood Cancer 66:e27645. https://doi.org/10.1002/pbc.27645

    Article  PubMed  Google Scholar 

  45. Birchmeier C (1986) Characterization of an Activated Human ros Gene. Mol Cell Biol 6:3109–3116. https://doi.org/10.1128/mcb.6.9.3109-3116.1986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gainor JF, Shaw AT (2013) Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist 18:865–875. https://doi.org/10.1634/theoncologist.2013-0095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chen L et al (2021) Fibroblast growth factor receptor fusions in cancer: opportunities and challenges. J Exp Clin Cancer Res 40:345. https://doi.org/10.1186/s13046-021-02156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cheek EH et al (2020) Uterine inflammatory myofibroblastic tumors in pregnant women with and without involvement of the placenta: a study of 6 cases with identification of a novel TIMP3-RET fusion. Hum Pathol 97:29–39. https://doi.org/10.1016/j.humpath.2019.12.006

    Article  CAS  PubMed  Google Scholar 

  49. Vokuhl C (2019) Kindliche Tumoren mit Spindelzellmorphologie. Pathologe 40:381–392. https://doi.org/10.1007/s00292-019-0602-7

    Article  CAS  PubMed  Google Scholar 

  50. Wardelmann E, Hartmann W (2021) Neues in der aktuellen WHO-Klassifikation (2020) für Weichgewebssarkome. Pathologe 42:281–293. https://doi.org/10.1007/s00292-021-00935-8

    Article  PubMed  Google Scholar 

  51. Antonescu CR et al (2019) Spindle cell tumors with RET gene fusions exhibit a morphologic spectrum akin to tumors with NTRK gene fusions. Am J Surg Pathol 43:1384–1391. https://doi.org/10.1097/PAS.0000000000001297

    Article  PubMed  PubMed Central  Google Scholar 

  52. Heydt C et al (2019) Comparison of in situ and extraction-based methods for the detection of ROS1 rearrangements in solid tumors. J Mol Diagn 21:971–984. https://doi.org/10.1016/j.jmoldx.2019.06.006

    Article  CAS  PubMed  Google Scholar 

  53. Stenzinger A et al (2021) Diagnostik und Therapie von Tumoren mit NTRK-Genfusionen. Pathologe 42:103–115. https://doi.org/10.1007/s00292-020-00864-y

    Article  PubMed  Google Scholar 

  54. Sorokin M et al (2022) Clinically relevant fusion oncogenes: detection and practical implications. Ther Adv Med Oncol 14:1–34. https://doi.org/10.1177/17588359221144108

    Article  CAS  Google Scholar 

  55. Gatalica Z et al (2019) Molecular characterization of cancers with NTRK gene fusions. Mod Pathol 32:147–153. https://doi.org/10.1038/s41379-018-0118-3

    Article  CAS  PubMed  Google Scholar 

  56. Hechtman JF (2017) Pan-Trk Immunohistochemistry is an efficient and reliable screen for the detection of NTRK fusions. Am J Surg Pathol 41:1547–1551. https://doi.org/10.1097/PAS.0000000000000911

    Article  PubMed  PubMed Central  Google Scholar 

  57. Rudzinski ER et al (2018) Pan-Trk Immunohistochemistry identifies NTRK rearrangements in pediatric mesenchymal tumors. Am J Surg Pathol 42:927–935. https://doi.org/10.1097/PAS.0000000000001062

    Article  PubMed  Google Scholar 

  58. Prescott JD, Zeiger MA (2015) The RET oncogene in papillary thyroid carcinoma. Cancer 121:2137–2146. https://doi.org/10.1002/cncr.29044

    Article  CAS  PubMed  Google Scholar 

  59. Belli C et al (2021) ESMO recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol 32:337–350. https://doi.org/10.1016/j.annonc.2020.11.021

    Article  CAS  PubMed  Google Scholar 

  60. Dacic S et al (2016) ALK FISH patterns and the detection of ALK fusions by next generation sequencing in lung adenocarcinoma. Oncotarget 13:82943–82952. https://doi.org/10.18632/oncotarget.12705

    Article  Google Scholar 

  61. Pekar-Zlotin M et al (2015) Fluorescence in situ hybridization, Immunohistochemistry, and next-generation sequencing for detection of EML4-ALK rearrangement in lung cancer. The Oncol 20:316–322. https://doi.org/10.1634/theoncologist.2014-0389

    Article  Google Scholar 

  62. Wynes MW (2014) An international interpretation study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators. J Thorac Oncol 9:631–638. https://doi.org/10.1097/JTO.0000000000000115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ambati SR et al (2018) Entrectinib in two pediatric patients with inflammatory myofibroblastic tumors harboring ROS1 or ALK gene fusions. JCO Precis Oncol. https://doi.org/10.1200/PO.18.00095

    Article  PubMed  PubMed Central  Google Scholar 

  64. Rangaraju S et al (2017) TRTH-10. Pediatric Phase 1/1B Study of Entrectinib in patients with primary brain tumors, neuroblastoma and NTRK, ROS1, or ALK Fusions. Neuro Oncol 19:iv53. https://doi.org/10.1093/neuonc/nox083.222

    Article  PubMed Central  Google Scholar 

  65. Mossé YP et al (2017) Targeting ALK with crizotinib in pediatric anaplastic large cell Lymphoma and inflammatory myofibroblastic tumor: a children’s oncology group study. JCO 35:3215–3221. https://doi.org/10.1200/JCO.2017.73.4830

    Article  Google Scholar 

  66. Theilen T (2018) Crizotinib in ALK+ inflammatory myofibroblastic tumors-Current experience and future perspectives. Pediatr Blood Cancer 65:e26920. https://doi.org/10.1002/pbc.26920

    Article  CAS  Google Scholar 

  67. D’Angelo A et al (2020) Focus on ROS1-Positive Non-Small Cell Lung Cancer (NSCLC): Crizotinib, Resistance Mechanisms and the Newer Generation of Targeted Therapies. Cancers 12:3293. https://doi.org/10.3390/cancers12113293

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Keino D et al (2020) Pilot study of the combination of sorafenib and fractionated irinotecan in pediatric relapse/refractory hepatic cancer (FINEX pilot study). Pediatr Blood Cancer 67:e28655. https://doi.org/10.1002/pbc.28655

    Article  CAS  PubMed  Google Scholar 

  69. Ortiz MV et al (2020) Activity of the Highly Specific RET Inhibitor Selpercatinib. LOXO, Bd. 292., S 341–347 https://doi.org/10.1200/PO.19.00401

    Book  Google Scholar 

  70. https://ema.europa.eu/en/documents/product-information/retsevmo-epar-product-information_de.pdf

  71. Laetsch TW et al (2018) The Lancet Oncology 1(8):30119–30110. https://doi.org/10.1016/S1470-2045

    Article  Google Scholar 

  72. www.dgho.de. Zugegriffen: 2. Aug. 2023

Download references

Author information

Authors and Affiliations

  1. Sektion Kinderpathologie, Institut für Pathologie, Universitätsklinikum Bonn, Venusberg-Campus 1, 53127, Bonn, Deutschland

    Christiane Brenner & Christian Vokuhl

  2. Institut für Pathologie, Universitätsklinikum Bonn, Bonn, Deutschland

    Christine Sanders

Authors
  1. Christiane Brenner
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christine Sanders
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christian Vokuhl
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christiane Brenner.

Ethics declarations

Interessenkonflikt

C. Brenner, C. Sanders und C. Vokuhl geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Additional information

Schwerpunktherausgeber

Christian Vokuhl, Bonn

figure qr

QR-Code scannen & Beitrag online lesen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brenner, C., Sanders, C. & Vokuhl, C. Rezeptor-Tyrosinkinase-Fusionen in spindelzelligen Tumoren des Kindesalters. Pathologie 44, 357–365 (2023). https://doi.org/10.1007/s00292-023-01228-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00292-023-01228-y

Schlüsselwörter

Keywords

Search

Navigation