The Presence of ALK Alterations and Clinical Relevance of Crizotinib Treatment in Pediatric Solid Tumors
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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.
KeywordsALK Crizotinib Soft tissue sarcoma Neuroblastoma Inflammatory myofibroblastic tumor
List of Abbreviations
akt murine thymoma viral oncogene
anaplasticlarge cell lymphoma
anaplastic lymphoma kinase
alveolarsoft part sarcoma
Cooperative Weichteilsarkom Studiengruppe
c mesenchymal epithelial transition growth factor
diffuselarge B-cell lymphoma
diffusion-weighted whole-body imaging with background body signal suppression
Food and Drug Administration
fluorescent in situ hybridization
inflammatory myofibroblastic tumor
mammalian target of rapamiycin
non-small cell lung carcinoma
receptor originated from nantes
real-time polymerase chain reaction
International Society of Pediatric Oncology Europe Neuroblastoma
saline sodium citrate
signal transducer and activator of transcription
soft tissue sarcoma
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.
Compliance with Ethical Standards
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.
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