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.