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.