High-Grade Optic Glioma in an Elderly Patient With Neurofibromatosis Type 1

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD High-Grade Optic Glioma in an Elderly Patient With Neurofibromatosis Type 1 Hidefumi Amisaki, MD, Atsushi Kambe, MD, PhD, Uno Tetsuji, MD, Makoto Sakamoto, MD, PhD, Atsushi Yamasaki, MD, PhD, Masamichi Kurosaki, MD, PhD H igh-grade optic gliomas are rare, invasive neoplasms first described by Hoyt et al in 1973 (1). These tumors can arise along the entire optic pathway: in the optic nerve, optic chiasm, or optic tract. They are pathologically classified as either anaplastic astrocytoma (WHO Grade 3) or glioblastoma (WHO Grade 4). Patients with high-grade optic glioma usually have bilateral visual loss within a few weeks and die within 1–2 years of diagnosis. Based on initial clinical and radiological evaluation, they are frequently misdiagnosed with optic neuritis, anterior ischemic optic neuropathy, or primary retinal vascular occlusion, which delays proper treatment planning. Tissue biopsy is essential to confirm the diagnosis. Optic gliomas are mostly low-grade tumors that frequently occur in children with neurofibromatosis type 1 (NF1). High-grade optic gliomas often occur in adults, but they have never been reported in adult patients with NF1. In this study, we report the first case of high-grade optic glioma in an elderly patient with NF1. The patient was disease-free for 18 months after total resection but developed dementia due to radiation-induced leukoencephalopathy. A 66-year-old man presented with a 1-week history of visual failure in his right eye. He had no other neurological symptoms. Visual acuity in the right eye was at the hand movement level at another hospital, but when he visited our ophthalmology unit 2 days later, it had deteriorated to light perception. Funduscopic examination revealed severe right optic disc edema with hemorrhage (Fig. 1A). He had café-au-lait spots and neurofibromas on the skin and was diagnosed with NF1 by a dermatologist at our institution. He had no history of malignancy and had never received chemotherapy or radiotherapy for cancer treatment. His sister had similar skin findings but had not been diagnosed with NF1. Department of Brain and Neurosciences (HA, AK, UT, MS, MK), Division of Neurosurgery, Faculty of Medicine, Tottori University, Yonago, Tottori, Japan; and Department of Ophthalmology (AY), Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan. The authors report no conflicts of interest. Address correspondence to Atsushi Kambe, MD, PhD, Department of Brain and Neurosciences, Division of Neurosurgery, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago, Tottori 6838504, Japan; E-mail: [e-mail] Amisaki et al: J Neuro-Ophthalmol 2023; 43: e221-e223 Head MRI revealed that the intraorbital portion of the right optic nerve had high signal intensity on T2 imaging (Fig. 1B). It had heterogeneous enhancement on T1 imaging with gadolinium (Fig. 1C, D). We diagnosed optic neuritis and performed pulse therapy with methylprednisolone (1,000 mg/day intravenously for 3 consecutive days). However, the patient’s visual acuity continued to deteriorate. Tumor biopsy through right pterional craniotomy and orbitotomy was performed to determine the pathological diagnosis. Pathological examination revealed the presence of a diffusely proliferated atypical glial neoplasm composed of short spindle-shaped cells (Fig. 2A, B). Immunohistochemical staining demonstrated positive reactivity for GFAP (Fig. 2C), MGMT (Fig. 2D), Olig2, and S-100, but negative for p53. The maximum MIB-1 labeling index was 30% (Fig. 2E). Rosenthal fibers or a biphasic pattern was not observed. Direct DNA sequencing with paraffinembedded specimens (item code: R617 O, SRL, Inc., Japan) showed no IDH-1/2 mutations. The pathological diagnosis was IDH wild-type WHO grade 3 anaplastic astrocytoma. We performed total resection of the right optic nerve and ophthalmectomy with the patient’s consent. Intraoperative pathological findings included tumor cells infiltrating the stump on the eyeball side. However, tumor cells were not found in the stump on the optic chiasm side. After gross total removal, he received focal radiotherapy (50 Gy in 25 fractions) plus concomitant oral temozolomide (TMZ) chemotherapy (75 mg/m2 daily), followed by 12 courses of adjuvant chemotherapy with oral TMZ (200 mg/m2 on Days 1–5 every 28 days). However, he developed dementia due to leukoencephalopathy, and his general condition worsened. He passed away from pneumonia 18 months after surgery. Most of the NF1-associated optic gliomas are pilocytic astrocytomas. Reports of high-grade optic glioma in patients with NF1 are rare. To date, only 2 pediatric patients with NF1 have been reported (2,3), but one of these cases involved malignant transformation from pilocytic astrocytoma after relapse (3). In the present case, we could not detect typical pathological findings for pilocytic astrocytoma e221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Funduscopic examination revealed severe right optic disc edema with hemorrhage (A). MRI of the head revealed that the right intraorbital optic nerve had high signal intensity (white double arrows) on T2 axial (B) and coronal (C) imaging and heterogeneous enhancement (white double arrows) on T1 axial (D) and coronal (E) imaging with gadolinium. such as Rosenthal fibers or a biphasic pattern, which may indicate that the present patient did not have malignant transformation from pilocytic astrocytoma. NF1-associated optic gliomas arise during childhood. They occur in approximately 15%–20% of pediatric patients with NF1 (4). Most of the patients are younger than 7 years (mean, 4.5 years) (4). Cases arising in adulthood are rare. High-grade optic gliomas usually arise in adulthood, but there have been no reports of an association with NF1 in adult patients. However, patients with NF1 have a 50-fold higher risk of developing high-grade cerebral glioma than the general population. In the present case, we cannot rule out the possibility that the tumor arose sporadically as opposed to being a complication of NF1. More than 70 cases have been previously described in the literature. However, the optimal treatment for FIG. 2. Pathological examination revealed the presence of a diffusely proliferated atypical glial neoplasm composed of short spindle-shaped cells (A: ·100, B: ·400). The tumor cells were immunohistochemically positive for GFAP (C: ·400) and MGMT (D: ·400). The maximum MIB-1 labeling index was 30% (E: ·400). e222 Amisaki et al: J Neuro-Ophthalmol 2023; 43: e221-e223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence high-grade optic glioma has not yet been established. There are a limited number of reports related to the effects of molecular-targeted agents such as MEK or BRAF inhibitors for NF1-associated high-grade cerebral glioma and many fewer reports for high-grade optic glioma. For high-grade cerebral glioma, focal radiotherapy plus concomitant and adjuvant TMZ chemotherapy (the Stupp regimen) after maximal tumor resection is the established standard treatment. In recent years, highgrade optic glioma has also been treated with the Stupp regimen after surgery or biopsy. Alireza et al reported that radiotherapy plus chemotherapy significantly increases median overall survival (11.0 months) compared with radiotherapy alone (10.3 months) in patients with highgrade optic glioma (5), but the prognosis seems poorer than for cerebral glioblastoma treated with the Stupp regimen, which has a median overall survival of 14.6 months. In the present case, we were able to achieve gross total resection because of limited tumor extension within the right intraorbital area, which might have been the main factor associated with longer survival (18 months) and no tumor recurrence. Gross total resection is performed much less often for high-grade optic glioma than for high-grade cerebral glioma, which may be a reason for the worse prognosis of high-grade glioma. The patient developed dementia due to radiation-induced leukoencephalopathy and died. We think that it is better to con- Amisaki et al: J Neuro-Ophthalmol 2023; 43: e221-e223 sider reduced-dose radiotherapy in elderly patients if total tumor resection is achieved with surgery. STATEMENT OF AUTHORSHIP Conception and design: A. Kambe, H. Amisaki; Acquisition of data: A. Kambe, H. Amisaki, U. Tetsuji, A. Yamasaki. Analysis and interpretation of data: A. Kambe, H. Amisaki, M. Sakamoto, M. Kurosaki. Drafting the manuscript: A. Kambe, H. Amisaki; Revising it for intellectual content: A. Kambe, H. Amisaki, U. Tetsuji, M. Sakamoto, A. Yamasaki, M. Kurosaki. Final approval of the completed manuscript: A. Kambe, H. Amisaki, U. Tetsuji, M. Sakamoto, A. Yamasaki, M. Kurosaki. REFERENCES 1. Hoyt WF, Meshel LG, Lessell S, Schats NJ, Suckling RD. Malignant optic glioma of adulthood. Brain 1973;96:121–132. 2. de Keizer RJ, de Wolff-Rouendaal D, Bots GT, Thomeer RT, Brouwer OF, Vielvoye GJ. Optic glioma with intraocular tumor and seeding in a child with neurofibromatosis. Am J Opthalmol 1989;108:717–725. 3. Zoeller GK, Brathwaite CD, Sandberg DI. Malignant transformation of an optic pathway glioma without prior radiation therapy. J Neurosurg Pediatr. 2010;5:507–510. 4. Campen CJ, Gutmann DH. Optic pathway gliomas in neurofibromatosis type 1. J Child Neurol. 2018;33:73–81. 5. Alireza M, Amelot A, Chauvet D, Terrier LM, Lot G, Bekaert O. Poor prognosis and challenging treatment of optic nerve malignant gliomas: literature review and case report series. World Neurosurg. 2017;97:751.E1–751.E6. e223 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.