Discussion
Neuroblastoma is the most common extracranial solid tumor in children
and presents almost exclusively in childhood [1]. Neuroblastoma
accounts for 12-15% of all childhood cancer-related deaths. The median
age at diagnosis is about 18 months with nearly all cases being
diagnosed by 10 years of age. Disease prognosis is variable, with
survival ranging from 80-90% in children with very low and intermediate
risk tumors to less than 50% in children diagnosed with high risk
tumors [2]. A unique subset of neuroblastoma patients diagnosed in
infancy may experience spontaneous tumor regression, and this group of
patients is categorized as Stage MS according to the International
Neuroblastoma Risk Group (INRG) Staging System. Diagnostic criteria for
MS disease includes age less than 18 months at the time of diagnosis and
metastatic disease limited to liver, skin and/or bone marrow
(<10%) [3]. Many children with MS disease will have tumor
regression, but approximately 10-15% of them will experience disease
progression, usually in the liver or bone [4].
Although the pathogenesis of neuroblastoma is poorly understood,
multiple genetic mutations have been found to occur frequently in
neuroblastoma. Amplification of the MYCN gene, a transcription
factor involved in cell proliferation and apoptosis, is the most common
mutation in patients with poor prognosis [5]. Other chromosomal
changes that have been linked to poor prognosis in neuroblastoma include
deletions of 1p and 11q and gain of 17q. Segmental chromosome
abnormalities such as these are more common in high risk neuroblastoma,
while whole chromosomal gains are frequently found in low risk disease
[6, 7]. The most frequently mutated gene in primary neuroblastoma is
the anaplastic lymphoma kinase (ALK ) gene, which is present in
nearly all cases of familial neuroblastoma and in 7-10% of sporadic
cases [8].
The BRAF V600E mutation is a known neoplastic producing mutation.
This mutation is a hyper-activating missense mutation in codon 600 of
exon 15 of the BRAF gene that allows BRAF to function in a Ras
dispensable manner [9, 10]. It was previously reported thatBRAF mutations are extremely rare in pediatric solid tumors and
were not thought to play a role in the development of these neoplasms
[11]. However, recent studies have identified BRAF mutations
in the pathogenesis of neuroblastoma. In one study using Sequenom-based
genetic profiling of pediatric solid tumors, investigators found that
the BRAF V600E mutation was present in 1 out of 192 neuroblastoma
cases, revealing its occurrence in less than 1% of cases. An alternateBRAF F595L mutation was discovered in another neuroblastoma
sample. BRAF mutations were identified in 1.7% of embryonal
rhabdomyosarcoma samples and 1.3% of Ewing sarcomas. The patient linked
to the neuroblastoma sample with BRAF V600E mutation in this
study was alive at the time of the review, while the child with the
reported F595L mutation died of disease. Furthermore, the patient with
embryonal rhabdomyosarcoma with BRAF V600E mutation also died of
disease [12]. These findings suggest BRAF mutations may play
an oncogenic role in a small group of pediatric sarcomas and
neuroblastomas.
As molecular profiling of tumors has evolved, cancer treatments have
followed suit. BRAF inhibitors have been developed to target tumors
harboring BRAF gene mutations. Vemurafenib (Zelboraf) was one of
the first mutant-specific BRAF inhibitors specific for BRAF V600E
mutations. Other BRAF inhibitors are now available, such as dabrafenib
(Tafinlar), and encorafenib (Braftovi) [13]. Shahid et al reported
on the use of dabrafenib with and without trametinib, a commonly used
MEK inhibitor, in two pediatric patients with BRAF -mutated high
risk neuroblastoma. In both cases, these therapeutic agents were used in
conjunction with conventional high risk therapy. The authors concluded
that this targeted therapy was compatible with conventional high risk
neuroblastoma therapy and yielded minimal additional toxicities
[14]. For the patient in the current report, BRAF inhibition was
reserved for the treatment of relapsed disease.
In conclusion, we present the rare case of an infant with Stage MS
neuroblastoma with BRAF V600E mutation, which has been reported
to occur in less than 1% of neuroblastoma cases. Furthermore, the
patient progressed from Stage MS to Stage M disease, a phenomenon that
occurs in only 10-15% of patients diagnosed with MS disease. This case
offers further evidence for BRAF mutations as an oncogenic driver
in some pediatric solid tumors, and highlights the importance of tumor
sequencing for tumors that do not respond to standard of care therapies.