DISCUSSION
In this case of PNET arising from an immature teratoma, multiomic analysis allowed for targeted treatment when traditional chemotherapeutic approaches lost efficacy. This is the first report of a PNET treated with targeted tyrosine kinase inhibitor (TKI) therapy. Treatment with crizotinib has shown efficacy in a variety of ALK mutant and rearranged tumors including non-small cell lung cancer (NSCLC), inflammatory myofibroblastic tumors, and neuroblastoma [7-9] and, now there is emerging evidence of the effectiveness of ALK-inhibitors in the treatment of tumors with ALK overexpression without mutation or fusion [10, 11]. While PNET is a distinct entity from neuroblastoma, there are shared biologic and molecular characteristics that make the finding of oncogenic ALK expression less surprising in the case presented here. It has been shown that embryonic neuroblasts and neural crest cells rely on ALK and MYC pathway activation to maintain differentiation during embryonic development [12,13]. ALK mutation and even ALK-wt overexpression have significant impact on MYC-pathway activation and tumorigenesis based on in vitro assessment [14]. Specifically, in central-type PNET, the pathologic appearance of neuroglial phenotype suggests similar pathway activation for neuroglial-type differentiation as in neuroblastoma. Thus, a theory that ALK overexpression may be common in PNET tumors and simply has yet to be studied aligns with the known paucity of multiomic data for this tumor type. In addition to these biologic features, ALK overexpression is an attractive target because of the tolerability of crizotinib and its ability to be combined with standard chemotherapy as in current chemotherapeutic trials for pediatric solid tumors.
As this case demonstrates, screening for targeted therapy options is vital when standard treatment options fail or are limited based on toxicity. This case demonstrates the clear benefit of targeted therapy in salvage scenarios as a sustained response was produced given the dependence of our patient’s tumor on ALK-pathway signaling. This case highlights the possibility that oncogenic protein upregulation via transcriptome or proteome analysis is underassessed in many clinical scenarios and can lead to valuable treatment options. Interestingly in our case, prolonged use of crizotinib did not lead to TKI-specific resistance despite frequent emergence of resistance mechanisms with long-term crizotinib therapy reported in both NSCLC and neuroblastoma [15-18]. As more ALK-targeted TKIs such as lorlatinib which is being utilized in neuroblastoma clinical trials currently become available, moving from one ALK-targeted TKI to another when resistance emerges could become easier similar to multiple-tiered TKI use in chronic myelogenous leukemia (CML) [19,20]. Given the rarity of this case, having further treatment options in the event of recurrence is helpful as crizotinib therapy may lose effectiveness. In summary, this case represents the first known use of crizotinib to target oncogenic ALK overexpression in central-type PNET arising from an immature teratoma and highlights the importance of obtaining early molecular analyses in these rare tumor entities to determine novel treatment options.
AUTHOR CONTRIBUTIONS : BS, AL, MM, MF all have made substantial contributions to conception and design, acquisition of data, and analysis of the data. BS, AL, AH, MM, and MF all have been involved in drafting the manuscript or revising it critically for important intellectual content, given final approval of the version to be published, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
ACKNOWLEDGMENT : We acknowledge the care provided by members of the pediatric general surgery, radiology, and radiation oncology teams involved in this patient’s care.
CONFLICT OF INTEREST : We have no conflicts of interest to declare.
DATA AVAILABILITY : Data pertaining to the case report is available upon request.
ETHICAL APPROVAL : MM and MF were co-investigators on P50HD090215 NICHD grant that expired in June 2022. Authors with no other current funding for this research. The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Ethics approval was not required as this is a case report.
CONSENT : Written informed consent was obtained from the patient’s father to publish this report in accordance with the journal’s patient consent policy.