BRAF V600E-Mutated Ganglioglioma of the Optic Pathway: A Case Report and Review of the Literature

Gangliogliomas are slow growing, benign neoplasms of the central nervous system (CNS). These lesions are rare, accounting for 1.3% of all CNS tumors in adults (1) but are more common in children, representing up to 7.6% of pediatric CNS tumors.

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD BRAF V600E-Mutated Ganglioglioma of the Optic Pathway: A Case Report and Review of the Literature Alexander M. Solomon, MD, Tao Ming T. Chia, MD, Gordana Juric-Sekhar, MD, PhD, Courtney E. Francis, MD G angliogliomas are slow growing, benign neoplasms of the central nervous system (CNS). These lesions are rare, accounting for 1.3% of all CNS tumors in adults (1) but are more common in children, representing up to 7.6% of pediatric CNS tumors (2). Seizures are the most common presenting symptom as the temporal lobe is frequently involved (3,4). Gangliogliomas are classified as World Health Organization (WHO) Grade I tumors and rarely undergo malignant transformation (5–7). Treatment for these tumors includes surgical resection, chemotherapy, and radiotherapy (8). Gangliogliomas of the optic pathway are exceedingly uncommon, with a total of 25 cases reported in the literature. When involving the optic pathway, gangliogliomas can cause progressive unilateral or bilateral vision loss and can pose challenges in treatment options. We present a case of an optic pathway ganglioglioma initially presumed to be an optic glioma seen over the course of 20 years. A 7 1/2-year-old boy presented to his endocrinologist with pubarche, the development of facial acne, and rapid linear growth consistent with precocious puberty. An MRI scan revealed a suprasellar mass involving the left optic tract. His initial ophthalmological evaluation demonstrated normal visual acuity and an unremarkable fundus examination. Visual evoked potential testing showed normal latency, borderline reduced amplitudes, and smaller overall peaks over the right hemisphere. The lesion was initially presumed to be an optic pathway glioma, and he was followed with serial MRIs that demonstrated slow tumor growth and treated with leuprolide acetate for precocious puberty. Two years after diagnosis, radiation therapy was offered but his family deferred treatment, and he was subsequently lost to follow-up. At the age of 22, he presented to the emergency room with 2 months of progressive right upper and lower extremity weakness that was confirmed on neurological examination. His ophthalmologic examination demonstrated normal visual acuity (20/20 OU) and full Ishihara color plates, but optic atrophy on fundus examination. Visual fields by confrontation technique revealed a right homonymous hemianopia which was confirmed on automated visual field (Fig. 1). An MRI revealed a partially cystic and nodular enhancing mass centered in the region of the left hypothalamus involving the left optic tract with the dominant cystic component measuring 4.2 · 2.4 cm in maximal dimensions, with significant growth compared with previous scans (Fig. 2). A biopsy was obtained, and the pathology demonstrated a ganglioglioma (WHO Grade I) (Fig. 3). OncoPlex Single Gene sequencing (Genetics and Solid Tumor Diagnostic Laboratory, University of Washington, Seattle, WA) detected BRAF V600E mutation. Treatment with proton beam radiation was initiated; however, he developed severe headaches and nausea with double vision during treatment. A repeat MRI demonstrated enlargement of the cystic component of the ganglioglioma causing hydrocephalus, requiring ventriculoperitoneal shunt placement and intensive rehabilitation therapy. His course was subsequently complicated by pyramidal tract and superior colliculus compression by the cystic components of his ganglioglioma requiring stereotactic fenestration and placement of an Ommaya reservoir. He also developed a symptomatic right Department of Ophthalmology (AMS, CEF), University of Washington School of Medicine, Seattle, Washington; Department of Ophthalmology (TMTC), Southern California Permanente Medical Group, Kern County, California; and Departments of Pathology (GJS), and Neurological Surgery (GJ-S, CEF), University of Washington School of Medicine, Seattle, Washington. Unrestricted Departmental Grant to University of Washington Department of Ophthalmology from Research to Prevent Blindness. The authors report no conflicts of interest. Address Correspondence to Courtney E. Francis, MD, Department of Ophthalmology, University of Washington School of Medicine, 325 9th Avenue Box 359608, Seattle, WA 98104; E-mail: [e-mail] Solomon et al: J Neuro-Ophthalmol 2021; 41: e723-e727 FIG. 1. Visual field demonstrating right homonymous hemianopsia. e723 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence hypertropia attributed to cystic compression, which was treated with prismatic correction. He has required intermittent taps of his reservoir for cystic growth over the following years, and his hypertropia has decreased gradually. His right homonymous hemianopia continues to remain stable, and the patient is now 27 years old, having been followed over the course of 20 years at 2 institutions. Gangliogliomas of the optic pathway represent a rare subset of all CNS gangliogliomas, with only 25 reports published in the literature, accounting for less than 1% of all gangliogliomas. We searched for all studies published with the terms “ganglioglioma” and “optic nerve,” “chiasm,” “optic tract,” or “optic pathway” in the title by means of a PubMed search. The findings of these case reports are summarized below (Table 1). The mean age at diagnosis was 22 years, with a slight predominance of male gender (68%). Visual changes were the most common presenting symptom (88%) followed by headaches, strabismus, and proptosis. A majority of cases underwent some form of surgical resection, with the most common being a biopsy for pathologic diagnosis and a small subset of cases involving a subtotal or gross resection. A total of 40% of cases were treated with radiation therapy, whereas chemotherapy was used in only 16% of cases. It is also interesting to note that progression of disease was reported as many as 22% of individuals with long-term follow-up, including 1 case where a teratoid/rhabdoid tumor is believed to have arisen from an optic pathway ganglioglioma (25). Gangliogliomas of the optic pathway can often be mistaken for optic gliomas. They can both be associated with neurofibromatosis type 1. Optic gliomas are the most common primary optic nerve tumor, and like gangliogliomas they present more commonly in childhood (30). As FIG. 3. Histopathological findings of ganglioglioma of the optic tract. A and B. Mixed glial and neuronal cell population in a background of markedly hyalinized vasculature and scattered lymphocytes; occasional dysplastic neurons with perimembranous aggregation of Nissl substance (arrowheads) and binucleated forms (black arrow) (hematoxylin and eosin); (C) immunoreactivity for glial fibrillary acidic protein highlights the neoplastic glial component; (D) strong mitogen activated protein-2 immunoreactivity in a binucleated dysplastic neuron. Scale bars: (A) 150 mm, (B and C) 120 mm, (D) 60 mm. such, many gangliogliomas are presumed to be optic nerve gliomas until they are resected or biopsied. The most common presenting symptom is a unilateral change in vision, with vision loss as severe as light perception (11). In rare cases, gangliogliomas can also present with bilateral vision changes, including visual field defects or cranial nerve palsies as a result of increased intracranial pressure. The most commonly involved location is the optic nerve and the optic chiasm, although the entire optic pathway can be involved (9,27,28). In cases of optic FIG. 2. MRI of ganglioglioma (A–D) (2015) (E and F) (2002). A. T2 axial postcontrast, (B) T1 axial postcontrast, (C) T1 axial noncontrast, (D) T1 coronal postcontrast, (E) T2 coronal postcontrast, (F) T1 axial fluid-attenuated inversion recovery image. e724 Solomon et al: J Neuro-Ophthalmol 2021; 41: e723-e727 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence TABLE 1. Summary of optic pathway ganglioglioma patients published in the literature (9–29) (1961–2016) N = 25 Mean age at diagnosis, yrs Sex Follow-up Mean duration, yrs Presenting symptoms Visual changes (including visual field loss and blindness) Proptosis/exophthalmos Headaches Strabismus/nystagmus Location (involvement) Optic nerve Chiasm Optic tract Hypothalamus Entire optic pathway involvement Bilateral involvement Surgical resection Biopsy Subtotal resection Gross total resection Radiation therapy Chemotherapy* Progression† 22.0 ± 18.2 (range 2–71) 68% male, 32% female 3.75 ± 4.44 (1 month–17 years) 88% (22/25) 8% (2/25) 12% (3/25) 12% (3/25) 56% 56% 28% 20% 16% 20% (14/25) (14/25) (7/25) (5/25) (4/25) (5/25) 40% (10/25) 36% (9/25) 24% (6/25) 40% (10/25) 16% (4/25) 22.2%‡ (4/18) *Etoposide, temozolomide, imatinib, other agents. † Radiographic evidence of progression or clinical progression in terms of symptoms not malignant transformation. ‡ 4/18 total with follow-up; 1 case of death—teratoid/rhabdoid tumor that arose from a ganglioglioma in an 11-year-old. pathway gangliogliomas, a careful neuro-ophthalmological examination is warranted. In general, MRI is the imaging modality of choice and demonstrates isodense lesions with calcifications on T1-weighted imaging, hyperintense on T2weighted imaging. The lesions occasionally can enhance after contrast administration and in younger patients often contain cystic components (7). If cystic components are noted on imaging, other cystic lesions of the optic pathways including arachnoid cysts, pilocytic astrocytomas, or lesions from previous inflammation or infection may be considered (31). Gangliogliomas, including those of the optic pathway, are typically classified as WHO Grade I tumors and histopathologically share the same features such as a combination of neuronal and glial cell elements of substantial variability. These tumors can be found anywhere throughout the CNS but over 70% are localized to the temporal lobe (6). Optic nerve gangliogliomas reported in the literature thus far have been low-grade (9–24,26–29) with the exception of 1 report of a high grade teratoid/ rhabdoid tumor arising from a recurrent extensive optic pathway ganglioglioma (25). The neuronal component is comprised of haphazardly oriented large dysplastic neurons with perimembranous aggregation of Nissle substance and occasional 2 nuclei with prominent nucleoli. The glial component is predominantly of astrocytic origin, although may rarely include oligodendrocytic cells (6). Rarely, areas of increased cellularity and mitotic activity can be found in Solomon et al: J Neuro-Ophthalmol 2021; 41: e723-e727 these tumors but have been attributed to rapid local growth rather than malignant transformation (19). An insufficient biopsy with only one element may lead to misdiagnosis (25). Immunophenotypically, these tumors exhibit neuronal proteins such as synaptophysin and MAP (mitogen activated protein)-2 among others in the neuronal component, whereas glial fibrillary acidic protein is immunoreactive in glial neoplastic cells (6,32). Malignant transformation of a ganglioglioma occurs rare, and usually involves the glial component, reclassifying as an anaplastic ganglioglioma (WHO Grade III) (6). Gangliogliomas of the CNS are slow growing and considered benign because of very mild neurological signs and symptoms. The 10-year survival ranges from 84% to 93% (5). Although clinical and radiographic evidence of progression of optic pathway gangliogliomas has been reported, true malignant transformation has not been reported in the literature in part because of its rarity, with the exception of one case report of a teratoid/rhabdoid tumor arising from an optic ganglioglioma (25). CNS gangliogliomas and optic nerve gliomas have been reported to undergo malignant transformation (33,34). High-grade gangliogliomas in adults in a recent study by Varshneya et al demonstrated a median survival of 44.4 months from diagnosis (35). Surgical intervention using a stereotactic approach provides an opportunity to biopsy and decrease tumor burden. Although gross total surgical resection would be e725 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence curative for most patients, it can lead to damage or loss of optic pathway fibers resulting in permanent vision loss. Gangliogliomas of the optic tract are supratentorial and in general more easily resectable than infratentorial and intramedullary tumors, thus they have better survival potential (36). Tumors that are incompletely resected may then undergo radiotherapy (i.e., proton beam therapy or gamma knife therapy) or chemotherapy. Radiotherapy in CNS gangliogliomas is given usually as adjuvant therapy combined with a subtotal resection. A cost-benefit analysis on CNS gangliogliomas demonstrated better local control but not overall survival for low-grade gangliogliomas (8). Possible malignant transformation after radiation is also a concern (37). More recently, several studies in molecular biology have linked BRAF gene mutations as a molecular basis for gangliogliomas. The BRAF gene is a proto-oncogene. Mutations lead to an activation of the MAP kinase pathway and the development of low-grade gliomas including pilocytic astrocytomas, pleomorphic xanthoastrocytomas, and gangliogliomas. These pathways are involved in cell signaling and cellular proliferation, differentiation, apoptosis, and survival. Specifically BRAF:V600E mutations can be present in approximately 60% of gangliogliomas (38). Vemurafenib and dabrafenib, both FDA-approved inhibitors of BRAF are used in the treatment of advanced or metastatic melanoma, where there is a high proportion of BRAF mutation (40%– 60%). Vemurafenib has been shown to be effective for treating brainstem gangliogliomas where surgical resection is difficult or conventional radiotherapy has failed (39). Some side effects of these BRAF inhibitors include arthralgias, photosensitivity, pruritis, and skin rash. Other chemotherapeutic agents that have also been tried include temozolomide, irinotecan, and bevacizumab (40). Gangliogliomas of the optic pathway are rare tumors that have the potential to cause vision loss. They are in general slow growing and often present when they are quite large resulting in compromise of the visual pathway. Managing these tumors represents a challenge, as a gross total resection can cause damage to the optic pathway, leading to significant morbidity and permanent vision loss. Radiotherapy and conventional chemotherapy have not shown to be very successful but are currently used as an adjunct to partial surgical resection for gangliogliomas in general. Newer modes of targeted molecular therapy such as the BRAF kinase inhibitors may present a more elegant way of targeting tumor tissue while sparing critical optic pathways, although their use in optic pathway gangliogliomas has not yet been described. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. E. Francis; b. Acquisition of data: T. M. Thomas Chia, A. M. Solomon, G. Juric-Sekhar, and C. E. e726 Francis; c. Analysis and interpretation of data: T. M. Thomas Chia, A. M. Solomon, G. Juric-Sekhar, and C. E. Francis. Category 2: a. Drafting the manuscript: T. M. Thomas Chia and A. M. Solomon; b. Revising it for intellectual content: C. E. Francis and G. Juric-Sekhar. Category 3: a. Final approval of the completed manuscript: C. E. Francis. REFERENCES 1. Kalyan-Raman UP, Olivero WC. 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