To the editor,
Gangliocytomas are WHO grade I neuroepithelial tumors consisting of
mature ganglion cells intermixed with normal glial cells (1). They
usually present between 10-30 years of age and comprise less than 0.5 %
of the CNS tumors (1). The most common sites for presentation are
temporal lobe, cerebral hemispheres, cerebellum (Lhermitte-Duclos
disease), floor of the 3rd ventricle and spinal cord
(1). Spinal gangliocytomas are exceedingly rare, comprising less than
10% of all gangliocytomas (1). Maximal safe resection is the mainstay
of treatment, as this tumor does not respond to irradiation or
traditional chemotherapy (1). Very little is known about the molecular
makeup or the role of targeted therapy in this tumor. We present a novel
molecular finding, BCR-NTRK2 fusion and overexpression of BRAF, in a
pediatric patient with spinal gangliocytoma.
A 7-year-old male child with no significant past medical history
presented with scoliosis, prompting work-up with magnetic resonance
imaging (MRI) of the spine. He had no back pain or neurologic deficits.
MRI of the spine revealed a heterogeneously enhancing, expansile solid
and cystic intradural, intramedullary, T2 hyperintense infiltrating mass
extending from T6 to L2 with associated cranial and caudal syrinx
formation (Fig 1). Patient underwent T6-T12 laminectomy and near total
resection of the intramedullary intradural spinal cord tumor.
Postoperatively, patient had mild sensory and proprioception deficits
that resolved within a few weeks. Histopathology demonstrated moderately
cellular, abnormal neural tissue composed of irregular clusters and
cords of mature appearing tumor neurons in a coarse neutrophil
background, without microvascular proliferation or necrosis, diagnostic
of gangliocytoma of the spinal cord (Fig 1). MRI brain did not show any
intracranial mass. Patient remains neurologically stable and has been
monitored with serial MRIs of the spine over 2 years with no growth or
new recurrence of tumor (Fig 1). Molecular sequencing of the tissue
demonstrated somatic BCR-NTRK2 fusion and overexpression of BRAF. No
germ line mutations were noted.
Gangliocytomas are not radiosensitive or chemo sensitive tumors;
therefore, the goals of surgical treatment gross total or maximal safe
resection in order to optimize long-term outcomes. Molecular analysis
was performed to identify any targetable gene mutations for future
therapy, revealing a BCR-NTRK2 fusion. This mutation has not previously
been reported in gangliocytomas.
NTRK fusion genes have been reported in a number of adult and pediatric
malignancies. They are reported with high frequency in rare adult
malignancies like secretory breast carcinoma, mammary analog secretory
carcinoma (MASC) and with low frequency in common adult malignancies
like breast, lung, colorectal cancers, melanoma, ALL and AML (2). NTRK2
fusions have also been described in adult low grade gliomas (2). In
pediatric malignancies, these fusions are fairly common in infantile
fibrosarcoma, congenital mesoblastic nephroma, papillary thyroid cancer
and soft tissue sarcomas/mesenchymal tumors (2). NTRK fusions have also
been reported in non-brainstem high grade gliomas in infants (2).
Tropomyosin receptor kinase (Trk) family of receptors Trk A, B and C are
encoded by NTRK1, NTRK2 and NTRK3 genes respectively (3). Ras-ERK,
PI3K-AKT and PLC are the three pathways involved in TRK signaling. The
ligand NGF (nerve growth factor) binds to TrkA, BDGF (brain derived
growth factor) binds to Trk B and NT3 (neurotrophin-3) binds with TrkC
but also with lower affinity to the other two receptors. (3). Binding of
the respective ligands with TrkA and B receptors activates all three
pathways while TrkC activates the Pi3-AKT pathway (3). The activation of
these pathways is responsible for cell differentiation and proliferation
(3). The genetic fusions involving NTRK1, 2 and 3 genes result in
constitutively active or overexpressed receptor tyrosine kinases,
resulting in oncogenesis (3).
Larotrectinib received FDA approval in November 2018 for a wide array of
pediatric and adult solid tumors with NTRK fusions. Entrectinib is
another pan Trk inhibitor with activity against ROS1 and ALK (2) as
well. In the event of future disease progression, molecularly targeted
therapy with Larotrectinib or Entrectinib may be an option for this
particular patient..
Molecular testing of rare tumors like spinal gangliocytomas provides
insights into oncologic transformation, allowing for a precision
medicine approach to treatment. Viable molecularly targetable treatment
options can be identified and implemented at the time of recurrence or
progression in low-grade tumors like gangliocytoma, potentially
minimizing the need for repeat surgical resection when traditional
treatment options like chemotherapy or radiation have been exhausted or
are not applicable.
Funding Source : No funding was secured for this study.
Conflicts of interest : The authors have no conflicts of
interest to disclose.
Author‘s contribution : All authors contributed significantly to
this manuscript, reviewed and agreed upon its content.