Skip to main content

Advertisement

SpringerLink
Log in

The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Soft tissue sarcomas (STS) and neuroblastomas (NBL), are childhood malignancies still associated with poor prognoses despite the overall improvement in childhood tumor survival of the past decades. Anaplastic lymphoma kinase (ALK) inhibition is promising new strategy to improve the outcome of these pediatric tumors. Eighteen histologic samples of pediatric STS and 19 NBL patients were analyzed for ALK abnormalities using fluorescent in situ hybridization (FISH) with break-apart probes and immunohistochemistry (IHC). ALK alterations were presented in 20 of the 37 sections. The presence of ALK alteration in NBL samples were detected using IHC in 84,2% of all cases compared to 21,1% FISH positivity. In STS cases the results were less different (IHC 16,7% vs FISH 22,2%). The difference can be explained by the different type of molecular alterations. FISH method detected translocation and amplification, but not the point mutation of ALK gene. IHC confirmed the diagnosis by detecting the expression of ALK protein.After ALK positivity was proven, the effectiveness and safety of the crizotinib therapy was examined in 4 patients (1 alveolar rhabdomyosarcoma (RMA), 1 embryonal rhabdomyosarcoma (RME), 1 inflammatory myofibroblastic tumor (IMT), 1 NBL). We observed continuous remission of the IMT patient, all other cases the inhibitor treatment was not curative.Our findings underline the importance of screening the ALK status parallel with both IHC and FISH. Crizotinib treatment had a long-term effect in ALK positive IMT patients, however itwas only temporary efficient in relapsed, progressive STS and NBL.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AKT :

akt murine thymoma viral oncogene

ALCL :

anaplasticlarge cell lymphoma

ALK :

anaplastic lymphoma kinase

ASPS :

alveolarsoft part sarcoma

CWS :

Cooperative Weichteilsarkom Studiengruppe

cMET :

c mesenchymal epithelial transition growth factor

DAPI :

4,6-diamino-2-fenilindol

DLBCL :

diffuselarge B-cell lymphoma

DWIBS :

diffusion-weighted whole-body imaging with background body signal suppression

FDA :

Food and Drug Administration

FISH :

fluorescent in situ hybridization

HR :

high risk

IHC :

immunohistochemistry

IMT :

inflammatory myofibroblastic tumor

JAK :

Janus-kinase

mTOR :

mammalian target of rapamiycin

NBL :

neuroblastoma

NSCLC :

non-small cell lung carcinoma

PI3K :

phosphatidylinozitol 3-kinase

RMS :

rhabdomyosarcoma

RMA :

alveolar rhabdomyosarcoma

RME :

embryonal rhabdomyosarcoma

RON :

receptor originated from nantes

ROS1 :

ROS protooncogene

RTPCR :

real-time polymerase chain reaction

SIOPEN :

International Society of Pediatric Oncology Europe Neuroblastoma

SSC :

saline sodium citrate

STAT :

signal transducer and activator of transcription

STS :

soft tissue sarcoma

References

  1. Morris SW et al (1995) Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science 267:316–317

    Article  CAS  PubMed  Google Scholar 

  2. Kruczynski A, Delsol G, Laurent C, Brousset P, Lamant L (2012) Anaplastic lymphoma kinase as a therapeutic target. Expert Opin Ther Targets 16:1127–1138

    Article  CAS  PubMed  Google Scholar 

  3. Mossé YP, Wood A, Maris JM (2009) Inhibition of ALK signaling for cancer therapy. Clin Cancer Res 15:5609–5614

    Article  CAS  PubMed  Google Scholar 

  4. Palmer RH, Vernersson E, Grabbe C, Hallberg B (2009) Anaplastic lymphoma kinase: signalling in development and disease. Biochem J 420:345–361

    Article  CAS  PubMed  Google Scholar 

  5. Hallberg B, Palmer RH (2013) Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer 13:685–700

    Article  CAS  PubMed  Google Scholar 

  6. Murakami Y, Mitsudomi T, Yatabe Y, Screening Method A (2012) For the ALK fusion gene in NSCLC. Front Oncol 2:24

    Article  PubMed  PubMed Central  Google Scholar 

  7. Selinger CI et al (2013) Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization. Mod Pathol 26:1545–1553

    Article  CAS  PubMed  Google Scholar 

  8. Li XQ, Hisaoka M, Shi DR, Zhu XZ, Hashimoto H (2004) Expression of anaplastic lymphoma kinase in soft tissue tumors: an immunohistochemical and molecular study of 249 cases. Hum Pathol 35:711–721

    Article  CAS  PubMed  Google Scholar 

  9. Mino-Kenudson M et al (2010) A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res 16:1561–1571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Minca EC et al (2013) ALK status testing in non-small cell lung carcinoma: correlation between ultrasensitive IHC and FISH. J Mol Diagn 15:341–346

    Article  CAS  PubMed  Google Scholar 

  11. Murga-Zamalloa C, Lim MS (2014) ALK-driven tumors and targeted therapy: focus on crizotinib. Pharmgenomics Pers Med 7:87–94

    PubMed  PubMed Central  Google Scholar 

  12. Subramaniam MM, Piqueras M, Navarro S, Noguera R (2009) Aberrant copy numbers of ALK gene is a frequent genetic alteration in neuroblastomas. Hum Pathol 40:1638–1642

    Article  CAS  PubMed  Google Scholar 

  13. Lowe EJ, Lim MS (2013) Potential therapies for anaplastic lymphoma kinase-driven tumors in children: progress to date. Paediatr Drugs 15:163–169

    Article  PubMed  PubMed Central  Google Scholar 

  14. Griffin CA et al (1999) Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 59:2776–2780

    CAS  PubMed  Google Scholar 

  15. Christensen JG et al (2007) Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-met, in experimental models of anaplastic large-cell lymphoma. Mol Cancer Ther 6:3314–3322

    Article  CAS  PubMed  Google Scholar 

  16. Mossé YP et al (2013) Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's oncology group phase 1 consortium study. Lancet Oncol 14:472–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. De Brouwer S et al (2010) Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res 16:4353–4362

    Article  CAS  PubMed  Google Scholar 

  18. Passoni L et al (2009) Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients. Cancer Res 69:7338–7346

    Article  CAS  PubMed  Google Scholar 

  19. Peron M, Lovisa F, Poli E, Basso G, Bonvini P (2015) Understanding the interplay between expression, mutation and activity of ALK receptor in Rhabdomyosarcoma cells for clinical application of small-molecule inhibitors. PLoS One 10:e0132330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kiratli H, Uzun S, Varan A, Akyüz C, Orhan D (2016) Management of anaplastic lymphoma kinase positive orbito-conjunctival inflammatory myofibroblastic tumor with crizotinib. J AAPOS 20:260–263

    Article  PubMed  Google Scholar 

  21. Gaudichon J et al (2016) Complete and repeated response of a metastatic ALK-rearranged inflammatory Myofibroblastic tumor to Crizotinib in a teenage girl. J Pediatr Hematol Oncol 38:308–311

    Article  PubMed  Google Scholar 

  22. Lawrence B et al (2000) TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 157:377–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schönherr C et al (2012) Anaplastic lymphoma kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells. Oncogene 31:5193–5200

    Article  CAS  PubMed  Google Scholar 

  24. Moore NF et al (2014) Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget 5:8737–8749

    PubMed  PubMed Central  Google Scholar 

  25. Carpenter EL et al (2012) Antibody targeting of anaplastic lymphoma kinase induces cytotoxicity of human neuroblastoma. Oncogene 31:4859–4867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank both the coworkers of the soft tissue tumor and the molecular pathology research group, especially Zoltánné Polgár, Linda Gyurcsó-Deák and Anna Tamási for the help with the immunohistochemistry and FISH investigation. For lecturing the publication, we thank Dóra Török MD PhD.

Author information

Authors and Affiliations

  1. 2nd Department of Pediatrics, Semmelweis University, Tűzoltó u. 7-9, Budapest, H-1094, Hungary

    Luca Felkai, Rita Bánusz, Miklós Garami, Edit Varga & Monika Csóka

  2. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary

    Ilona Kovalszky, Zoltán Sápi, Gergő Papp & Katalin Karászi

Authors
  1. Luca Felkai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Bánusz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ilona Kovalszky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zoltán Sápi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Miklós Garami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gergő Papp
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Katalin Karászi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Edit Varga
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Monika Csóka
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Csóka.

Ethics declarations

Ethics Approval and Consent to Participate

Investigations were approved by the Institutional Ethical Review Board. / The study protocol was approved by the Ethics and Scientific committee of the participating institution. TUKEB 7/2006.

Consent for Publication and Competing Interests

All of the authors declare that they have no competing interests. All authors have read and approved the final manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Felkai, L., Bánusz, R., Kovalszky, I. et al. The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors. Pathol. Oncol. Res. 25, 217–224 (2019). https://doi.org/10.1007/s12253-017-0332-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-017-0332-1

Keywords

Search

Navigation