Despite its rare occurrence, ganglioglioma (GG) is the most frequent mixed glial-neural tumor of the central nervous system (CNS) (1). Most develop in the temporal lobe of children and young adults who may present with a seizure disorder. Infrequently, GG may occur in other regions of the CNS, including optic nerves, chiasm, and optic tracts (2).
Neurofibromatosis type 1 (NF1) is the most common of the phakomatoses, caused by mutations of the NF1 gene on chromosome 17q11.2. It is characterized by neurofibromas, café-au-lait spots, axillary and inguinal freckling, osseous lesions, and iris hamartomas (Lisch nodules). These patients develop a variety of glial tumors, with pilocytic astrocytoma of the optic nerve being the most common (3).
GG of the intraorbital optic nerve in adults with NF1 is extremely rare (4–6). We report such a case and review the neuroimaging findings, pathology, and treatment options of this unusual neoplasm.
A 55-year-old woman reported a 1-year history of progressive and painless vision loss in her left eye. Neuro-ophthalmologic examination of the affected eye revealed visual acuity of counting fingers, uveal ectropion, Lisch nodules, 3 mm of proptosis, and optic disc pallor. Examination of the right eye was normal. Physical examination disclosed multiple café-au-lait spots and numerous cutaneous and mucosal neurofibromas. There were no abnormalities on neurologic testing. The patient's medical history included a cyst of the upper pole of the right kidney, numerous cysts of the liver, hyperlipoproteinemia type IIb, and hypothyroidism after Hashimoto thyroiditis.
Magnetic resonance imaging (MRI) of the brain showed fusiform thickening of the entire orbital portion of the left optic nerve (Fig. 1). Because of poor vision in the left eye and uncertainty of the diagnosis, the patient consented to have the tumor removed. This was accomplished by a transcranial superior orbitotomy.
Grossly, the tumor was solid, globoid in shape, 12 mm in diameter, with a smooth surface and whitish color on cross-section. Microscopically, the neoplasm was composed of well-differentiated glial and ganglion cell types (Fig. 2A). The glial component showed features of bipolar pilocytic astrocytes with Rosenthal fibers. Neuronal cells with abundant cytoplasm, round vesicular nuclei, conspicuous nucleoli, and marginated Nissl substance were dispersed among the glial elements or gathered in small groups in the central zone of the tumor. Some binuclear ganglion cells were found. There was no nuclear or cellular atypia in both tumor components, and there was no evidence of mitotic figures, necrosis, or perivascular lymphocytic cuffing. A few psammoma bodies were seen in the subcapsular region.
With immunohistochemistry, ganglion cells exposed synaptophysin, neuron-specific enolase, neurofilament, and chromogranin A in their cytoplasm (Fig. 2B, C). Some of these cells stained for membranous CD34 (Fig. 2D). Pilocytic astrocytes demonstrated glial fibrillary acidic protein positivity.
During 6 years of follow-up, there has been no evidence of tumor recurrence with clinical and neuroimaging examinations, and the patient's visual function remains normal in the right eye.
GG is a rare primary tumor of the optic nerve (7,8), and exceptional among orbital tumors (9). To the best of our knowledge, only 7 cases of GG involving intraorbital optic nerve have been reported in the literature (Table 1). Three were detected in NF1 patients (4–6), and the remaining 4 in patients without NF1 (10–13).
Pilocytic astrocytoma is the most common tumor of the optic nerve in patients with NF1, occurring in approximately 20% of affected individuals (14). While our patient met the diagnostic criteria for NF1, she had an unexpected optic nerve GG. Differentiation between optic nerve pilocytic astrocytoma and GG in NF1 patients can be challenging. Two-thirds of optic nerve gliomas in NF1 patients cause no symptoms and are detected only by neuroimaging (15). If they cause visual loss, this occurs gradually over many years. On occasions this optic nerve tumor may regress spontaneously (16). In contrast, GG of the optic nerve causes rapid, progressive visual failure. MRI findings also may distinguish GG from pilocytic astrocytoma. In our patient, GG appeared dark on T2 MRI probably because of tumoral calcification, while pilocytic astrocytoma is typically bright. Calcification of optic nerve tumor is highly suggestive of meningioma, yet meningioma is characterized by marked contrast enhancement. In our case, the tumor failed to enhance after intravenous contrast. The MRI findings in our patient raised suspicion that we were dealing with an unusual optic nerve tumor.
Histopathologic examination is definitive in distinguishing GG from pilocytic astrocytoma. The hallmark of GG is a mixture of neuronal and glial cell elements, both of which may display heterogeneity. The spectrum of GG ranges from a neuronal phenotype toward variants with a prominent glial population (1), as in our case. Findings of this neuronal component include abnormal localization, clustered appearance, perimembranous aggregate Nissl substance, and the presence of binucleated or multinucleated forms. The presence of the neuronal component is confirmed using synaptophysin and neurofilament stains. Interestingly, CD34 and chromogranin A are not present in neural cells of the adult brain but are identified in 70%–80% of cases of GG (17,18). The presence of immunohistochemical markers CD34 and chromogranin A in our patient's GG confirms the neoplastic nature of neural cells and was a unique finding in our case. The glial component in GG shows substantial variability, comprising the proliferative cell population of the tumor. Cell types may resemble fibrillary astrocytoma, oligodendroglioma, or, as in our patient, pilocytic astrocytoma. Perivascular lymphocytic cuffing is often detected within the glial elements of GG (2) but was not found in our case.
The origin of optic nerve GG remains controversial. The predominant cell types in most cases are of monoclonal origin and develop from a common precursor cell that later differentiates to form neoplastic glial and neuronal components (19). GG may also arise from ectopic neural tissue in the orbit through neoplastic transformation (20,21).
Treatment of GG and pilocytic astrocytoma differs substantially. Seven of the 8 reported patients with optic nerve GG, including ours, underwent surgical removal of the tumor (Table 1). This management decision was made primarily on the basis of progressive visual loss and potential extension of the tumor. In contrast, because of the more favorable clinical course seen in patients with pilocytic astrocytoma, surgical removal is rarely necessary (7).
In conclusion, although rare, GG may present as a tumor of the optic nerve, including in patients with NF1. While pilocytic astrocytoma is the most likely optic nerve tumor, other neoplasms such as GG must be considered in the differential diagnosis. Clinical course, neuroimaging findings, and pathologic examination help to distinguish these two neoplasms of the optic nerve.
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