Rare variant of large pediatric glioneuronal tumor with novel MYO5A::NTRK3 fusion: illustrative case

David Chenoweth Department of Neurosurgery, University of Iowa Hospital and Clinics, Iowa City, Iowa

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Hashim Syed Department of Neurosurgery, University of Iowa Hospital and Clinics, Iowa City, Iowa

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Nahom Teferi Department of Neurosurgery, University of Iowa Hospital and Clinics, Iowa City, Iowa

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Meron Challa Carver College of Medicine, University of Iowa, Iowa City, Iowa

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Jane E Persons Department of Pathology, University of Iowa Hospital and Clinics, Iowa City, Iowa

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Kathryn L Eschbacher Department of Pathology, University of Iowa Hospital and Clinics, Iowa City, Iowa

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Maggie Seblani Division of Hematology/Oncology, Department of Pediatrics, University of Iowa Hospital and Clinics, Iowa City, Iowa; and

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Brian J Dlouhy Department of Neurosurgery, University of Iowa Hospital and Clinics, Iowa City, Iowa
Carver College of Medicine, University of Iowa, Iowa City, Iowa
Iowa Neuroscience Institute, Iowa City, Iowa

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BACKGROUND

Glioneuronal tumors (GNTs) comprise a rare class of central nervous system (CNS) neoplasms with varying degrees of neuronal and glial differentiation that predominately affect children and young adults. Within the current 2021 World Health Organization (WHO) classification of CNS tumors, GNTs encompass 14 distinct tumor types. Recently, the use of whole-genome DNA methylation profiling has allowed more precise classification of this tumor group.

OBSERVATIONS

A 3-year-old male presented with a 3-month history of increasing head circumference, regression of developmental milestones, and speech delay. Magnetic resonance imaging of the brain was notable for a large left hemispheric multiseptated mass with significant mass effect and midline shift that was treated with near-total resection. Histological and molecular assessment demonstrated a glioneuronal tumor harboring an MYO5A::NTRK3 fusion. By DNA methylation profiling, this tumor matched to a provisional methylation class known as “glioneuronal tumor kinase-fused” (GNT kinase-fused). The patient was later started on targeted therapy with larotrectinib.

LESSONS

This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. GNT kinase-fused is a provisional methylation class not currently included in the WHO classification of CNS tumors. This case highlights the impact of thorough molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

ABBREVIATIONS

CNS = central nervous system; CT = computed tomography; FDA = U.S. Food and Drug Administration; GNT = glioneuronal tumor; MAPK = mitogen-activated protein kinase; MRI = magnetic resonance imaging; pHGG = pediatric high-grade glioma; PI3K = phosphoinositide 3-kinase; PICU = pediatric intensive care unit; PLCγ1 = phospholipase Cγ1; WHO = World Health Organization

BACKGROUND

Glioneuronal tumors (GNTs) comprise a rare class of central nervous system (CNS) neoplasms with varying degrees of neuronal and glial differentiation that predominately affect children and young adults. Within the current 2021 World Health Organization (WHO) classification of CNS tumors, GNTs encompass 14 distinct tumor types. Recently, the use of whole-genome DNA methylation profiling has allowed more precise classification of this tumor group.

OBSERVATIONS

A 3-year-old male presented with a 3-month history of increasing head circumference, regression of developmental milestones, and speech delay. Magnetic resonance imaging of the brain was notable for a large left hemispheric multiseptated mass with significant mass effect and midline shift that was treated with near-total resection. Histological and molecular assessment demonstrated a glioneuronal tumor harboring an MYO5A::NTRK3 fusion. By DNA methylation profiling, this tumor matched to a provisional methylation class known as “glioneuronal tumor kinase-fused” (GNT kinase-fused). The patient was later started on targeted therapy with larotrectinib.

LESSONS

This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. GNT kinase-fused is a provisional methylation class not currently included in the WHO classification of CNS tumors. This case highlights the impact of thorough molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

ABBREVIATIONS

CNS = central nervous system; CT = computed tomography; FDA = U.S. Food and Drug Administration; GNT = glioneuronal tumor; MAPK = mitogen-activated protein kinase; MRI = magnetic resonance imaging; pHGG = pediatric high-grade glioma; PI3K = phosphoinositide 3-kinase; PICU = pediatric intensive care unit; PLCγ1 = phospholipase Cγ1; WHO = World Health Organization

Glioneuronal tumors (GNTs) are a diverse class of central nervous system (CNS) neoplasms characterized by varying degrees of neuronal and glial differentiation.1 These tumors are typically found in children and young adults and, along with pediatric low-grade gliomas, represent around 30% of all pediatric CNS neoplasms.2 They are predominately classified as World Health Organization (WHO) grade 1 tumors and encompass 14 distinct tumor types in the current 2021 WHO classification of CNS tumors.1

Given their low grade and well-circumscribed nature, these tumors often present with an insidious onset of symptoms, including headache, seizures, and/or focal neurological deficits, and are best managed with resection.3–7 However, a subset of these tumors has an unusually aggressive course and requires adjuvant treatment with either chemotherapy or radiation.8,9

GNTs have overlapping histological features, which can make diagnosis challenging. Advances in the molecular characterization of CNS tumors has provided a framework for more precisely classifying GNTs.9 Recent advances in next-generation sequencing and whole-genome DNA methylation analysis have improved diagnostic accuracy and led to the characterization of various GNTs based on their molecular profile.10,11 These tests have also served to uncover possible targetable mutations for therapy. A recent analysis of copy number variations derived from whole-genome DNA analysis data has identified a provisional subset of GNTs with aberrations in the genes of different targetable kinases, including BRAF, NF1, FGFR1, NTRK1, NTRK2, and NTRK3. This class of GNTs has been termed “glioneuronal tumor kinase-fused.”11 Within this group, NTRK1, NTRK2, and NTRK3 rearrangements are rare; however, mutations in these oncogenic genes can serve as targets for therapy when present. In 2018, the U.S. Food and Drug Administration (FDA) approved TRK inhibitors for solid tumors with NTRK gene fusion,12 and in particular, entrectinib and larotrectinib have demonstrated promising disease control within the CNS.9,13–17

Herein, we present a case of a 3-year-old male who presented with a large hemispheric intracerebral GNT, with genomic analysis of the tumor specimen revealing a novel MYO5A::NTRK3 fusion. This case represents the first pediatric GNT with MYO5A::NTRK3 gene fusion to be reported in the literature.

Illustrative Case

History and Examination

A 3-year-old male with no significant past medical history initially presented to his local pediatrician with concerns of increasing head circumference over the preceding 3 months as well as delay of developmental milestones, including speech. Per family report, the patient had been otherwise healthy, with an uneventful vaginal delivery at term and no prior hospitalizations. There was no significant history of focal weakness or seizures and no family history of cancer. Physical examination was notable for macrocephaly with a head circumference of 55 cm, greater than 97th percentile for the patient’s age. Routine laboratory test results were unremarkable, and head computed tomography (CT) was ordered as part of the initial work-up. The CT was notable for a large multiseptated cystic mass in the left frontoparietotemporal lobe with areas of calcification and mass effect with midline shift measuring 2 cm and ventriculomegaly (Fig. 1A–C). The patient was subsequently transferred to the University of Iowa Hospitals and Clinics for an emergent pediatric neurosurgical consultation and evaluation.

FIG. 1
FIG. 1

Preoperative axial (A), sagittal (B), and coronal (C) CT sequences showing a large multifocal cystic mass in the left frontoparietotemporooccipital lobes, with calcification. Axial brain CT also revealed midline shift measuring 2 cm. Axial (D), sagittal (E), and coronal (F) post–gadolinium-enhanced T1-weighted MRI sequences showing a large hemispheric cystic mass with septations present throughout the left frontoparietotemporooccipital lobes.

Following transfer, the patient was admitted to the pediatric intensive care unit (PICU), and magnetic resonance imaging (MRI) of the neural axis was performed with the patient under sedation. The brain MRI was notable for a large, 9.3 × 10.4–cm, left hemispheric solid-cystic mass involving the frontal, parietal, temporal, and occipital lobes. Moreover, there was peripheral rim of capsular enhancement with small foci of calcification and significant mass effect resulting in midline shift measuring 1.7 cm with uncal herniation. MRI of the spine was unremarkable with no evidence of leptomeningeal seeding or drop metastasis. The differential diagnosis based on the radiological imaging included primitive neuroectodermal tumors or other pediatric embryonal tumors (Fig. 1D–F). Subsequently, the patient was initiated on low-dose steroids for cerebral edema management, and multidisciplinary consultations with pediatric medical and radiation oncology teams were held. The patient underwent preoperative optimization and proceeded with maximal safe resection of the underlying tumor with recommendations for adjuvant therapy to be guided by final pathological analysis.

Procedure

On hospital day 2, the patient underwent a left parietotemporooccipital craniotomy with the use of intraoperative Stealth guidance for neuronavigation (Medtronic Inc.). With the patient supine, a U-shaped incision was created with the pedicled flap anterior and a horizontal cut inferiorly from the temporal to occipital region with the incision turned rostrally at the location of the inion and proceeding along the midline sagittal plane up to the level of the coronal suture. The incision was carried down to the calvaria. Care was taken to avoid iatrogenic dural tearing, because there was a small area of dehiscent bone overlying the posterior parietal region of the tumor. This was likely caused by erosion of the underlying calvaria by the indolent tumor growth.

After placing burr holes and stripping the dura, a bone flap was created and removed in one piece, exposing the underlying dura (Fig. 2). The dura was noted to be tightly adherent to the underlying cortical surface of the brain and tumor capsule, and the decision was made to decompress the cyst of the tumor to allow safe dural opening. Using Stealth navigation, a trajectory was identified from the dural surface into the larger superior cyst within the tumor. A Scoville needle was inserted into the cyst, and serosanguineous cyst fluid was drained (Fig. 2B). Subsequent brain relaxation allowed safer dural opening. The dura was then opened in a U-shaped fashion, in the same orientation as the scalp flap, and reflected anteriorly (Fig. 2C). The tumor did not appear to invade the dura, so dural resection was deemed unnecessary. Tumor resection was then performed in a piecemeal fashion from superficial to deep and from posterior to anterior with the use of a cavitron ultrasonic surgical aspirator (Integra Inc.) and bipolar cautery (Fig. 2D). The posterior inferior resection was carried all the way down to the falx, because there was no normal-appearing brain parenchyma in the region of the left occipital lobe. Anterior resection was performed all the way to the left postcentral gyri down to the body of the left lateral ventricle. Extreme caution was used to avoid any blood leaking into the lateral ventricle to avoid intraventricular blood precipitating further hydrocephalus. Ultimately, near-total resection was achieved, with a small amount of residual tumor left along the anterior-most margin in the region of the left postcentral gyri (Fig. 2E). The dura was closed in a watertight fashion using interrupted 4-0 Nurulon sutures (Fig. 2F); peripheral dural tack-up sutures were placed; and dural sealant was applied with VISTASEAL. The bone flap was then plated onto the skull using an ultralow-profile cranial plating system (KLS Martin Inc.) (Fig. 2G). The skin was closed with a simple running 4-0 nylon suture.

FIG. 2
FIG. 2

Intraoperative photographs. A: Following left frontoparietal-occipital craniotomy with underlying tense dura exposed. B: A Scoville needle is inserted under stereotactic guidance into the cystic cavity within the tumor to allow dural relaxation prior to opening of the dura. C: Following dural opening showing a dysplastic cortex overlying the tumor. D: Bipolar cautery and regulated suction are used to create a plane between tumor and normal brain tissue prior to tumor debulking with a cavitron ultrasonic surgical aspirator. E: Postresection tumor bed showing near-total resection with complete resection of tumor up to the falx medially and the middle temporal gyrus ventrally. F: Following watertight primary dural closure and application of Tisseel for dural sealant. G: Following reattachment of the bone flap with KLS Martin plates and screws.

Postoperative Course

The patient tolerated the procedure well. He was kept intubated and transferred to the PICU for continued neuromonitoring and postoperative care. Postoperative MRI of the brain revealed near-total resection of the underlying mass (Fig. 3). He subsequently completed a course of dexamethasone and postoperative antiepileptic prophylaxis. He was extubated and began a general diet on postoperative day 1. He was transferred to the floor on postoperative day 2 and was discharged to home ambulatory on postoperative day 5.

FIG. 3
FIG. 3

Postoperative axial (A), sagittal (B), and coronal (C) post–gadolinium-enhanced T1-weighted MRI sequences showing near-total resection of the large cystic mass centered in the left cerebral hemisphere with improved midline shift. Axial post–gadolinium-enhanced T1-weighted (D), sagittal T1-weighted (E), and coronal T2-weighted (F) MRI sequences obtained 5 months after surgery, showing stable postoperative changes with no evidence of disease recurrence.

The tumor was submitted to the Department of Pathology for tissue examination. Microscopic examination revealed a variably cellular, well-circumscribed tumor primarily composed of uniform, medium-sized cells arranged in sheets, rosettes, and palisades, intermixed with more poorly differentiated regions showing tumor cells with more marked nuclear atypia and numerous mitotic figures (Fig. 4A and B). The tumor showed positive staining for synaptophysin and OLIG2, particularly in poorly differentiated areas, and was predominantly negative for glial fibrillary acidic protein and vimentin, which mostly highlighted interspersed astrocytes (Fig. 4C–F). H3K27me3 and H3K27M immunohistochemical stains all showed wild-type patterns. Paraffin-embedded tissue specimens were submitted for additional cytogenetic and molecular evaluation. Cytogenetic evaluation showed a complex karyotype with multiple partial and whole chromosomal losses, including a 1p/19q-codeletion. RNA sequencing was performed, which revealed an MYO5A::NTRK3 fusion. Notably, BRAF or other mitogen-activated protein kinase (MAPK) mutations were not detected. Subsequently, tissue was submitted to the National Cancer Institute at the National Institutes of Health for whole-genome DNA methylation profiling. By DNA methylation-based tumor classification, this tumor matched with a high confidence score to a provisional methylation class, GNT kinase-fused (Fig. 5).

FIG. 4
FIG. 4

A: A region composed of uniform, medium-sized cells arranged in sheets, rosettes, and palisades. Hematoxylin and eosin (H&E), original magnification ×100. B: A poorly differentiated region showing tumor cells with more marked atypia. H&E, original magnification ×200. C: The Ki-67 proliferative index is estimated at approximately 50%. Immunohistochemical stain, original magnification ×100. D: The tumor cells showed variable OLIG2 positivity by immunohistochemistry, which was more prominent in the poorly differentiated areas. Immunohistochemical stain, original magnification ×200. E: The tumor cells were predominantly negative for vimentin, which mostly highlighted interspersed astrocytes. Immunohistochemical stain, original magnification ×200. F: The tumor cells showed synaptophysin positivity by immunohistochemistry. Immunohistochemical stain, original magnification ×100.

FIG. 5
FIG. 5

Upper: Chromosomal microarray shows a complex karyotype with multiple partial and whole chromosomal losses, including 1p/19q codeletion. Lower: Uniform Manifold Approximation and Projection plot showing methylation classifier matching to GNT, kinase-fused. DLGNT_1 = diffuse leptomeningeal glioneuronal tumor; GNT_KinF_A = glioneuronal tumor, kinase-fused.

Patient Informed Consent

The necessary patient informed consent was obtained in this study.

Discussion

GNTs are CNS neoplasms composed of both neuronal and glial cellular components and account for nearly 30% of all pediatric CNS neoplasms.2,18 GNT is a broad classification that encompasses a wide variety of tumors, including ganglioglioma; gangliocytoma; central, extraventricular, and liponeurocytomas; desmoplastic infantile astrocytoma and ganglioglioma; diffuse leptomeningeal glioneuronal tumor; dysembryoplastic neuroepithelial tumor; diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters; papillary glioneuronal tumor; rosette-forming glioneuronal tumor; myxoid glioneuronal tumor; multinodular and vacuolating neuronal tumor; and dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease).2,18 Despite the diversity in this group of tumors, there is overlap in both histological and radiographic presentations; accordingly, histology-based diagnosis has been challenging, and GNT classification has seen restructuring in recent years.2,18

Given this diverse histopathological landscape, the 2016 WHO classification of CNS tumors expanded its scheme to include molecular parameters in addition to histology.1 This change resulted in the recognition of diffuse leptomeningeal GNT as a new entity belonging to the mixed neuronal-glial group.1 Further updates in classification were made in the 2021 WHO classification of CNS tumors because of advances in molecular characterization. This time, three new additions were made: diffuse GNT with oligodendroglioma-like features and nuclear clusters, multinodular and vacuolating neuronal tumor, and myxoid GNT.1 Further advances in molecular diagnostics have identified distinct DNA epigenetic methylation profiles among tumors, resulting in improved diagnostic capabilities and novel methods of subgrouping GNTs.9–11

Sievers et al.11 recently reported a proposed provisional methylation class, GNT kinase-fused, based on epigenetic analysis of 14 cases. In that case series, these tumors demonstrated monomorphic to slightly pleomorphic neoplastic cells, with an oligodendroglia-like morphology and perivascular rosettes in approximately 50% of cases.11 Molecular analysis revealed a more consistent theme with mutations occurring in genes regulating common molecular kinases, such as the kinase-encoding BRAF, NF1, FGFR1, NTRK1, NTRK2, and NTRK3 genes.11

MYO5A::NTRK3 Fusion

The NTRK3 gene encodes for neurotrophic tyrosine kinase receptor 3, a member of the TRK family of nerve growth factor receptors. This membrane-bound receptor phosphorylates itself when bound by neurotrophin-3, and, subsequently, the TRK activates the MAPK pathway, which is an intracellular pathway that transmits signal from the cell surface to the nucleus. This can result in cell differentiation and the enhancement of cell survival, which is hypothesized to serve an oncogenic role in several tumor types, including colorectal cancers, melanocytic tumors, and, most recently, CNS tumors.19–23

TRK is primarily activated in cancers via fusion with a 5′ partner. In our patient, the 3′ sequence of the NTRK3 gene has fused to the 5′ sequence of the MYO5A gene. MYO5A encodes one of three myosin V heavy chains, which is an actin-based motor protein involved in cytoplasmic vesicle transport, spindle-pole alignment, and mRNA.24–27 MYO5A has been described in 20 tissue types; however, it is predominately expressed in nerve cells and melanocytes.28 In melanocytes specifically, MYO5A-encoded proteins participate in the protein complex responsible for melanosome transport within melanocytes.29

When fused together, MYO5A:NTRK3 can result in retention of the MYO5A dimerization domain and the NTRK3 tyrosine kinase domain, resulting in increased activation of NTRK3.29 This can further result in downstream signaling activation of various pathways, such as MAPK/ERK, phosphoinositide 3-kinase (PI3K)/Akt, and phospholipase Cγ1 (PLCγ1) pathways, promoting oncogenesis.29

MYO5A::NTRK3 gene fusions have not been described previously in pediatric GNTs; however, they have been reported in other tumor types. Isales et al.30 explored the molecular and histopathological profile of pigmented epithelioid melanocytoma, a rare melanocytic low-grade neoplasm associated with Carney complexes, and discovered a MYO5A::NTRK3 gene fusion in 1 of the 16 cases reviewed retrospectively.30 Similarly, MYO5A::NTRK3 gene fusion has been described in spitzoid neoplasms, which are another melanocytic cancer characterized by a mixed morphology similar to both benign melanocytic nevi and malignant melanoma.31,32 Yeh et al.32 demonstrated that NTRK3 fusions work specifically by activating pathways in melanocytes such as MAPK, PI3K, and PLCγ1.

Although this mutation has been described in greater detail in melanocytic tumors, it is rarely reported in CNS tumors. To date, there has been only one documented case of this fusion occurring in a CNS ganglioneuroblastoma.29 Ito et al.29 described a 4-year-old male presenting with vomiting and brain MRI revealing an enhancing supratentorial mass. After a histological diagnosis of CNS ganglioneuroblastoma was established, the patient was treated with subtotal resection and radiation, followed by another surgery achieving gross-total tumor resection. Subsequent molecular analysis revealed the MYO5A::NTRK3 gene fusion, leading to the hypothesis of a common cellular origin of oncogenesis, because both melanocytes and extracranial ganglioneuroblastomas arise from the neural crest.29 Ito et al.29 expanded on the significance of their finding, postulating that this recent and rare discovery may inform the tumorigenesis pathways within ganglioneuroblastoma and their relationship to those in melanocytic tumors.

Therapeutic Approach

Given the evolving landscape of targeted therapeutics, screening for targetable mutations including NTRK alterations is paramount. Larotrectinib is a first-in-class, oral, selective small-molecule inhibitor of all three NTRK proteins that has been shown to have marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or tumor type20,33–36 These findings have led to approval by the FDA for adult and pediatric patients with NTRK fusion–positive solid tumors, and this is the first tissue-agnostic molecularly targeted therapy approved by the FDA. Larotrectinib has also demonstrated rapid and durable responses in CNS tumors.37 Additionally, in the pediatric patient population, a limited number of cases showing the efficacy of larotrectinib in NTRK fusion–positive intracranial tumors have also been reported,13 and the approval of TRK inhibitors has marked a significant advance in targeted cancer therapy, creating a treatment option for patients with cancer with NTRK gene fusions who may not otherwise respond well to or must contend with side effects and long-term sequelae of the conventional therapies of radiation and systemic chemotherapy. Moreover, because these mutations are found in a variety of tumor types, clinicians should have a low threshold for genetic screening of tumor specimens.

More generally, in the pediatric neuro-oncology sphere, there is growing evidence that targeted chemotherapy may serve as an effective modality. In 2019, Hargrave et al.38 used molecular characterization to stratify pediatric high-grade gliomas (pHGGs) on the presence of mutated BRAF V600E genes, reporting that the mutation was detected in 5%–10% of cases. This mutation is associated with alteration to the BRAF protooncogene, a serine-threonine protein kinase that affects MAP2K mitogen-mediated cell proliferation. Identification of this mutation profile has led to the use of dabrafenib, an inhibitor of the BRAF enzyme, in combination with trametinib, a MAP2K mitogen inhibitor, in managing patients with BRAF V600E–positive pHGG. Hargrave et al.’s subsequent analysis of treatment response revealed a significant difference in outcome between patients with pHGG harboring the BRAF V600E mutation who were treated with dabrafenib plus trametinib and the general uncharacterized pHGG cohort that was managed with standard chemotherapeutic agents.38

Moreover, as molecular and genomic testing has become more accessible and affordable, traditional histopathological diagnostic methodology has been integrated with genomic data.39 Subsequently, studies have continued to demonstrate the importance of using genomic information in prognostication and treatment.39,40

In our case, following identification of an MYO5A::NTRK3 fusion, the patient was initiated on larotrectinib 100 mg/m2 orally twice daily with an anticipated duration of treatment of 2 years with serial imaging and clinical monitoring to assess response to therapy. At his most recent follow-up 5 months after surgery, the patient’s parents reported good adherence to the larotrectinib regimen and noted his continued improvement in both gross and fine motor developmental milestones. Brain MRI also revealed stable postoperative changes with no evidence of tumor recurrence and marked improvement of prior perilesional edema.

Prognosis

Neuropsychological testing will be necessary to determine what supports this pediatric patient will require following the removal of a large hemispheric intraparenchymal tumor, but his prognosis is overall encouraging. NTRK-positive GNTs have demonstrated a dramatic response to TRK inhibitors in adults.14,41 Drilon et al.33 described 55 patients with non-CNS tumors with NTRK gene fusions, 29 of which involved NTRK3, who were treated with larotrectinib. Overall, the response rate was 75%, with 13% of participants achieving a complete response. The therapy was considered well tolerated, with the most common adverse effects of anemia, an increase in liver enzymes, weight gain, and mild neutropenia.

Given the rarity of this tumor, the prognosis of pediatric patients with glioneuronal kinase-fused tumors is unclear. Furthermore, the literature on the efficacy of molecular targeted therapy in this patient population is sparse, and future large-scale, multi-institutional prospective clinical trials are warranted prior to making definitive treatment recommendations.

Observations

We report the first case of a GNT in a pediatric patient harboring an MYO5A::NTRK3 fusion. Our patient presented with progressively increasing macrocephaly as well as regression of developmental milestones with brain MRI work-up revealing a large hemispheric solid cystic mass with significant mass effect and midline shift. The patient subsequently underwent near-total resection of the underlying mass. Histopathological assessment demonstrated a GNT, with further genetic characterization identifying the presence of an NTRK3 kinase fusion. The patient was later initiated on targeted therapy with larotrectinib.

Lessons

This is the first report of an MYO5A::NTRK3 fusion in a pediatric GNT. By DNA-based methylation classification, this tumor matched to a provisional methylation class, GNT kinase-fused, the prognostic significance of which is uncertain, given that it is based on a small number of cases in the literature. However, this case highlights the significance of precise molecular characterization of CNS tumors, especially with the increasing availability of novel gene targeting therapies.

Author Contributions

Conception and design: Teferi. Acquisition of data: Chenoweth, Syed, Persons. Analysis and interpretation of data: all authors. Drafting the article: Chenoweth, Syed, Teferi, Challa, Eschbacher. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Dlouhy. Study supervision: Dlouhy.

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  • 20

    Cocco E, Scaltriti M, Drilon A NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731747.

  • 21

    Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS Targeting TRK family proteins in cancer. Pharmacol Ther. 2017;173:5866.

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    Luo Y, Kaz AM, Kanngurn S, et al. NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer. PLoS Genet. 2013;9(7):e1003552.

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    • Export Citation
  • 23

    Sayers EW, Bolton EE, Brister JR, et al. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2022;50(D1):D20-D26.

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    Balasanyan V, Arnold DB Actin and myosin-dependent localization of mRNA to dendrites. PLoS One. 2014;9(3):e92349.

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    Wagner W, Brenowitz SD, Hammer JA 3rd. Myosin-Va transports the endoplasmic reticulum into the dendritic spines of Purkinje neurons. Nat Cell Biol. 2011;13(1):4048.

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    • Search Google Scholar
    • Export Citation
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    Fagerberg L, Hallström BM, Oksvold P, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13(2):397406.

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    Ito J, Nakano Y, Shima H, et al. Central nervous system ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. Brain Tumor Pathol. 2020;37(3):105110.

  • 30

    Isales MC, Mohan LS, Quan VL, et al. Distinct genomic patterns in pigmented epithelioid melanocytoma: a molecular and histologic analysis of 16 cases. Am J Surg Pathol. 2019;43(4):480488.

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    • Export Citation
  • 31

    Wang L, Busam KJ, Benayed R, et al. Identification of NTRK3 fusions in childhood melanocytic neoplasms. J Mol Diagn. 2017;19(3):387396.

  • 32

    Yeh I, Tee MK, Botton T, et al. NTRK3 kinase fusions in Spitz tumours. J Pathol. 2016;240(3):282290.

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    Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271282.

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  • 35

    Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705714.

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  • 36

    Marcus L, Donoghue M, Aungst S, et al. FDA approval summary: entrectinib for the treatment of NTRK gene fusion solid tumors. Clin Cancer Res. 2021;27(4):928932.

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    • Export Citation
  • 37

    Doz F, van Tilburg CM, Geoerger B, et al. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol. 2022;24(6):9971007.

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    • Search Google Scholar
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  • 38

    Hargrave DR, Terashima K, Hara J, et al. Phase II trial of dabrafenib plus trametinib in relapsed/refractory BRAF V600-mutant pediatric high-grade glioma. J Clin Oncol. 2023;41(33):51745183.

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  • 39

    Ramkissoon LA, Britt N, Guevara A, et al. Precision neuro-oncology: the role of genomic testing in the management of adult and pediatric gliomas. Curr Treat Options Oncol. 2018;19(8):41.

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  • 40

    Miklja Z, Pasternak A, Stallard S, et al. Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations. Neuro Oncol. 2019;21(8):968980.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Tadipatri R, Eschbacher J, Fonkem E, Kresl J, Azadi A Larotrectinib in NTRK fusion-positive high-grade glioneuronal tumor: a case report. Cureus. 2022;14(11):e31449.

    • PubMed
    • Search Google Scholar
    • Export Citation
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  • FIG. 1

    Preoperative axial (A), sagittal (B), and coronal (C) CT sequences showing a large multifocal cystic mass in the left frontoparietotemporooccipital lobes, with calcification. Axial brain CT also revealed midline shift measuring 2 cm. Axial (D), sagittal (E), and coronal (F) post–gadolinium-enhanced T1-weighted MRI sequences showing a large hemispheric cystic mass with septations present throughout the left frontoparietotemporooccipital lobes.

  • FIG. 2

    Intraoperative photographs. A: Following left frontoparietal-occipital craniotomy with underlying tense dura exposed. B: A Scoville needle is inserted under stereotactic guidance into the cystic cavity within the tumor to allow dural relaxation prior to opening of the dura. C: Following dural opening showing a dysplastic cortex overlying the tumor. D: Bipolar cautery and regulated suction are used to create a plane between tumor and normal brain tissue prior to tumor debulking with a cavitron ultrasonic surgical aspirator. E: Postresection tumor bed showing near-total resection with complete resection of tumor up to the falx medially and the middle temporal gyrus ventrally. F: Following watertight primary dural closure and application of Tisseel for dural sealant. G: Following reattachment of the bone flap with KLS Martin plates and screws.

  • FIG. 3

    Postoperative axial (A), sagittal (B), and coronal (C) post–gadolinium-enhanced T1-weighted MRI sequences showing near-total resection of the large cystic mass centered in the left cerebral hemisphere with improved midline shift. Axial post–gadolinium-enhanced T1-weighted (D), sagittal T1-weighted (E), and coronal T2-weighted (F) MRI sequences obtained 5 months after surgery, showing stable postoperative changes with no evidence of disease recurrence.

  • FIG. 4

    A: A region composed of uniform, medium-sized cells arranged in sheets, rosettes, and palisades. Hematoxylin and eosin (H&E), original magnification ×100. B: A poorly differentiated region showing tumor cells with more marked atypia. H&E, original magnification ×200. C: The Ki-67 proliferative index is estimated at approximately 50%. Immunohistochemical stain, original magnification ×100. D: The tumor cells showed variable OLIG2 positivity by immunohistochemistry, which was more prominent in the poorly differentiated areas. Immunohistochemical stain, original magnification ×200. E: The tumor cells were predominantly negative for vimentin, which mostly highlighted interspersed astrocytes. Immunohistochemical stain, original magnification ×200. F: The tumor cells showed synaptophysin positivity by immunohistochemistry. Immunohistochemical stain, original magnification ×100.

  • FIG. 5

    Upper: Chromosomal microarray shows a complex karyotype with multiple partial and whole chromosomal losses, including 1p/19q codeletion. Lower: Uniform Manifold Approximation and Projection plot showing methylation classifier matching to GNT, kinase-fused. DLGNT_1 = diffuse leptomeningeal glioneuronal tumor; GNT_KinF_A = glioneuronal tumor, kinase-fused.

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    Cocco E, Scaltriti M, Drilon A NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731747.

  • 21

    Khotskaya YB, Holla VR, Farago AF, Mills Shaw KR, Meric-Bernstam F, Hong DS Targeting TRK family proteins in cancer. Pharmacol Ther. 2017;173:5866.

  • 22

    Luo Y, Kaz AM, Kanngurn S, et al. NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer. PLoS Genet. 2013;9(7):e1003552.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Sayers EW, Bolton EE, Brister JR, et al. Database resources of the national center for biotechnology information. Nucleic Acids Res. 2022;50(D1):D20-D26.

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    Balasanyan V, Arnold DB Actin and myosin-dependent localization of mRNA to dendrites. PLoS One. 2014;9(3):e92349.

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    Hammer JA 3rd, Sellers JR Walking to work: roles for class V myosins as cargo transporters. Nat Rev Mol Cell Biol. 2011;13(1):1326.

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    Tabb JS, Molyneaux BJ, Cohen DL, Kuznetsov SA, Langford GM Transport of ER vesicles on actin filaments in neurons by myosin V. J Cell Sci. 1998;111(Pt 21):32213234.

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    • Search Google Scholar
    • Export Citation
  • 27

    Wagner W, Brenowitz SD, Hammer JA 3rd. Myosin-Va transports the endoplasmic reticulum into the dendritic spines of Purkinje neurons. Nat Cell Biol. 2011;13(1):4048.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Fagerberg L, Hallström BM, Oksvold P, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13(2):397406.

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    • Search Google Scholar
    • Export Citation
  • 29

    Ito J, Nakano Y, Shima H, et al. Central nervous system ganglioneuroblastoma harboring MYO5A-NTRK3 fusion. Brain Tumor Pathol. 2020;37(3):105110.

  • 30

    Isales MC, Mohan LS, Quan VL, et al. Distinct genomic patterns in pigmented epithelioid melanocytoma: a molecular and histologic analysis of 16 cases. Am J Surg Pathol. 2019;43(4):480488.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Wang L, Busam KJ, Benayed R, et al. Identification of NTRK3 fusions in childhood melanocytic neoplasms. J Mol Diagn. 2017;19(3):387396.

  • 32

    Yeh I, Tee MK, Botton T, et al. NTRK3 kinase fusions in Spitz tumours. J Pathol. 2016;240(3):282290.

  • 33

    Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731739.

  • 34

    Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705714.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Marcus L, Donoghue M, Aungst S, et al. FDA approval summary: entrectinib for the treatment of NTRK gene fusion solid tumors. Clin Cancer Res. 2021;27(4):928932.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Doz F, van Tilburg CM, Geoerger B, et al. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol. 2022;24(6):9971007.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Hargrave DR, Terashima K, Hara J, et al. Phase II trial of dabrafenib plus trametinib in relapsed/refractory BRAF V600-mutant pediatric high-grade glioma. J Clin Oncol. 2023;41(33):51745183.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Ramkissoon LA, Britt N, Guevara A, et al. Precision neuro-oncology: the role of genomic testing in the management of adult and pediatric gliomas. Curr Treat Options Oncol. 2018;19(8):41.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Miklja Z, Pasternak A, Stallard S, et al. Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations. Neuro Oncol. 2019;21(8):968980.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Tadipatri R, Eschbacher J, Fonkem E, Kresl J, Azadi A Larotrectinib in NTRK fusion-positive high-grade glioneuronal tumor: a case report. Cureus. 2022;14(11):e31449.

    • PubMed
    • Search Google Scholar
    • Export Citation

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