To the Editor:
We report the rare finding of a MS neuroblastoma harboring a mutation inBRAF . Briefly, a healthy 5 month old female presented with fever,
tachycardia and Escherichia coli bacteremia. Imaging evaluation revealed
a right-sided adrenal mass and liver lesions (Fig. 1A). Homovanillic
acid (HVA) was mildly elevated to 34.1 mg/g creatinine and
vanillylmandelic acid (VMA) was increased to 82.2 mg/g creatinine. She
underwent right adrenalectomy, liver biopsy, and bone marrow aspirates.
Pathology of the adrenal mass was consistent with poorly differentiated
neuroblastoma with favorable histology, liver biopsy revealed metastatic
neuroblastoma, and bone marrow aspirates revealed minimal marrow
involvement (Fig. 1B). She was diagnosed with Stage MS neuroblastoma and
was managed with observation. Six months later, follow-up imaging
revealed a left adrenal mass, stable liver lesions, and bony disease
(Fig. 2A). Bone marrow aspirates showed increased marrow disease (5%,
previously <1%) (Fig. 2B), Curie score was 7 and HVA and VMA
were elevated (59.6 and 90.6 mg/g creatinine, respectively). Molecular
genetic testing revealed BRAF V600E mutation and loss of
heterozygosity (LOH) at 1p and copy number gain at 17q. She was treated
with 6 cycles of intermediate-risk therapy per Children’s Oncology
Group, ANBL0531. End of therapy disease evaluation showed resolution of
the adrenal mass, decreased liver lesions, negative bone marrows, normal
VMA and HVA, and Curie score of 0. She is currently fifteen months out
from therapy without evidence of recurrence.
A unique subset of neuroblastoma patients diagnosed in infancy is
categorized as Stage MS according to the International Neuroblastoma
Risk Group (INRG) Staging System using diagnostic criteria that include
age less than 18 months at the time of diagnosis and metastatic disease
confined to liver, skin and/or bone marrow (<10%) [1].
Most children with MS disease will have spontaneous regression, but
10-15% will experience disease progression [2].
Multiple genetic mutations occur in neuroblastoma. Amplification of theMYCN gene is the most common mutation in patients with poor
prognosis [3]. Segmental chromosome abnormalities including
deletions of 1p and 11q and gain of 17q are common in high-risk
neuroblastoma, while whole chromosomal gains are found in low-risk
disease [4, 5]. The most frequently mutated gene is anaplastic
lymphoma kinase (ALK ) [6].
The BRAF V600E 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 [7, 8]. BRAF mutations
are rare in pediatric solid tumors and are not thought to play a role in
the development of these neoplasms [9]. Recent studies have
identified BRAF mutations in neuroblastoma. Shahid et al.
identified BRAF V600E mutations in two patients with high-risk
neuroblastoma that developed vasoactive intestinal peptide (VIP)-induced
diarrhea during induction therapy [10]. In another study,
investigators found a BRAF V600E mutation to be present in 1 of
192 neuroblastoma cases, revealing its occurrence in less than 1% of
cases [11]. An alternate BRAF 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 [11]. These findings suggest BRAF mutations may play
an oncogenic role in a small group of neuroblastomas pediatric sarcomas.
BRAF inhibitors have been developed to target tumors harboringBRAF mutations. Vemurafenib was one of the first inhibitors
specific for BRAF V600E mutations. Other BRAF inhibitors are now
available [12]. Shahid et al. combined dabrafenib with trametinib, a
MEK inhibitor, as an adjunct to conventional high-risk therapy to treat
VIP-induced diarrhea in two children with BRAF V600E mutations.
They concluded that this targeted therapy was compatible with
conventional high-risk neuroblastoma therapy and yielded minimal
additional toxicities [10]. For the patient in the current report,
BRAF inhibition was reserved for the treatment of relapsed disease.
We present a case of an infant with Stage MS neuroblastoma withBRAF V600E mutation, which, to our knowledge has not been
reported previously in the literature. 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 oncogenic drivers in some
pediatric tumors, and highlights the importance of sequencing for tumors
that do not respond to standard therapies.
Fig 1: CT and MIBG scans and bone marrow aspirates at
presentation. (A ) CT scan demonstrating right adrenal mass
(open arrow, left panel ) with MIBG avidity (closed arrow,
right panel ). (B ) Immunohistochemistry of right (left
panel ) and left (right panel ) iliac bone marrow aspirates
demonstrating large atypical cells (star ) and clumps of atypical
cells (star ), consistent with neuroblastoma constituting
less than 10% of the specimen. Scale bars represent 10 µm.
Fig 2: MIBG scan and bone marrow aspirates at relapse.(A ) MIBG scan showing left adrenal mass (open arrows )
and bilateral pelvic and femur bony disease (closed arrows ).
(B ) Bilateral right (left panel ) and left (right
panel ) iliac bone marrow aspirates with large atypical cells(star ) consistent with neuroblastoma. Scale bars represent 10 µm.
The authors have nothing to disclose.