Intracranial Pure Germinoma With Optic Nerve Infiltration

A 19-year-old man presented with a 3-year history of episodic headaches, right hemiparesis, and progressive vision loss in both eyes. Initially, extensive laboratory testing was unrevealing. MRI later demonstrated progressive enlargement and enhancement of the left optic nerve poorly correlated with the timing of his clinical manifestations. There was no clinical or radiological response to treatment with corticosteroids, mycophenolate mofetil, or rituximab administered empirically for possible inflammatory processes. Later in the disease course, he developed diabetes insipidus (DI), worsening vision to light perception bilaterally, severe cognitive decline, and spastic quadriparesis. Cerebrospinal fluid (CSF) beta human chorionic gonadotropin (β-hCG) was elevated. Eventually, a left optic nerve biopsy was performed, which was consistent with an intracranial pure germinoma with infiltration of the optic nerve and disseminated leptomeningeal disease. Although rare, intracranial germ cell tumors can primarily involve the anterior visual pathways and should be considered in the setting of DI and elevated CSF β-hCG.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD Intracranial Pure Germinoma With Optic Nerve Infiltration Devon A. Cohen, MD, M. Tariq Bhatti, MD, Caterina Giannini, MD, PhD, Laurence J. Eckel, MD, James A. Garrity, MD, John J. Chen, MD, PhD 19-year-old right-handed man presented to our institution with a 3-year history of headaches, right-sided weakness, cognitive impairment, and progressive bilateral vision loss. His symptoms first began at the age of 16 years, when he developed stepwise deterioration in vision in both eyes in association with severe episodic bifrontal-temporal headaches associated with eye strain but no pain with eye movements. Initial evaluation at an outside hospital showed visual acuity of 20/40 in the right eye and 20/50 in the left eye with bilateral optic disc pallor. Contrast MRI of the brain, orbits, and spine obtained to evaluate for inflammatory demyelinating disease was normal. Six weeks later, visual acuity worsened to 20/200 in both eyes and visual fields revealed bilateral central depression with a left homonymous hemianopia (Fig. 1). Genetic testing for Leber hereditary optic neuropathy was negative. Cerebrospinal fluid (CSF) analysis showed 1 white blood cell (WBC), protein 36 mg/d, immunoglobulin (IgG) index 0.66 (nL ,0.61), positive qualitative oligoclonal bands (present in the CSF only), negative cytology for malignancy, and negative Lyme. Because of the left homonymous hemianopsia, a CSF alphafetoprotein (AFP) was also obtained and was negative. The patient was treated with intravenous methylprednisolone 1 g/d for 3 days followed by 2 months of oral prednisone for a presumed autoimmune process. There was some reported improvement in the headaches. Three months later, the visual field deficits had improved with stable visual acuity. Attempts to taper the oral prednisone below baseline dosing resulted in worsening visual acuity. One year later, mycophenolate mofetil was started for suspected chronic relapsing inflammatory optic neuropathy (CRION) but was later discontinued as there was no improvement in the vision. He continued having frontal headaches believed to be migraines. Nearly 2 years after symptom onset, visual acuity had declined to light perception in both eyes and neurologic examination demonstrated an isolated right plantar extensor response. MRI of the brain and orbits with contrast was obtained. Departments of Neurology (DAC, MTB, JJC), Ophthalmology (MTB, JAG, JJC), Laboratory Medicine and Pathology (CG), Radiology (LJE), Mayo Clinic College of Medicine, Rochester, Minnesota. Dr. Eckel: Abstract: A 19-year-old man presented with a 3-year history of episodic headaches, right hemiparesis, and progressive vision loss in both eyes. Initially, extensive laboratory testing was unrevealing. MRI later demonstrated progressive enlargement and enhancement of the left optic nerve poorly correlated with the timing of his clinical manifestations. There was no clinical or radiological response to treatment with corticosteroids, mycophenolate mofetil, or rituximab administered empirically for possible inflammatory processes. Later in the disease course, he developed diabetes insipidus (DI), worsening vision to light perception bilaterally, severe cognitive decline, and spastic quadriparesis. Cerebrospinal fluid (CSF) beta human chorionic gonadotropin (b-hCG) was elevated. Eventually, a left optic nerve biopsy was performed, which was consistent with an intracranial pure germinoma with infiltration of the optic nerve and disseminated leptomeningeal disease. Although rare, intracranial germ cell tumors can primarily involve the anterior visual pathways and should be considered in the setting of DI and elevated CSF b-hCG. Journal of Neuro-Ophthalmology 2020;40:112–116 doi: 10.1097/WNO.0000000000000893 © 2020 by North American Neuro-Ophthalmology Society Dr. Cohen: A The authors report no conflicts of interest. Address correspondence to John J. Chen, MD, PhD, Departments of Ophthalmology and Neurology, Mayo Clinic, Mayo Clinic College of Medicine, MA 4-89E, 200 1st Street SE, Rochester, MN 55905; E-mail: [e-mail] 112 The MRI shows enlargement of the left optic nerve relative to the normal right side, with subtle abnormal T2 signal changes (not shown) and diffuse enhancement (Fig. 2A). The anatomical involvement on MRI does not correlate Cohen et al: J Neuro-Ophthalmol 2020; 40: 112-116 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Visual fields show bilateral central depression with suggestion of a left homonymous hemianopia. well with the homonymous hemianopsia or progressive bilateral vision loss. There was an additional nonenhancing T2 hyperintensity in the left cerebral peduncle (not shown), that could be suggestive of multiple sclerosis (MS) but the history is not consistent with this diagnosis. Other radiographic possibilities include acute disseminated encephalomyelitis, neuromyelitis optica, neoplasm, and infectious/ granulomatous etiologies such as Lyme disease and sarcoidosis. intensity in the right periventricular corona radiata and posterior limbs of the internal capsules bilaterally (not shown). In addition, there is enlargement, T2 hyperintensity, and diffuse enhancement of the left intraorbital and prechiasmatic optic nerve that has progressed from the prior MRI study (Fig. 2B). Given these progressive changes of the optic nerve, MS is excluded and the other entities as discussed above must be entertained. With the recent diagnosis of DI, the differential should be focused on conditions such as histiocytosis, germinoma, lymphoma, or metastasis. Dr. Cohen: He was started on rituximab for presumed CRION; however, by the fall of 2017, he became lethargic and developed right-sided weakness. At this time, he exhibited unusual behaviors, agitation, and excessive thirst that led to drinking toilet water. The laboratory results from the outside hospital were consistent with central diabetes insipidus (DI) that resolved with desmopressin. By the winter, he developed left-sided weakness and was wheelchair-bound. Repeat lumbar puncture was unremarkable. MRI of the brain and orbits was repeated. Dr. Eckel: This updated contrast MRI of the brain and orbits now shows new confluent nonenhancing abnormal T2 hyper- Dr. Cohen: Neurologic examination on presentation to our institution in the spring of 2018 demonstrated severe cognitive impairment with inability to follow commands, spastic quadriparesis (right greater than left), and hyperreflexia. Extraocular movement testing was limited by participation, but he seemed to have bilateral abduction and adduction deficits that were not overcome with vestibulo-ocular reflex. Visual acuity could not be reliably performed, pupils were minimally reactive to light, and there was severe bilateral optic disc pallor with normal retinas. CSF analysis showed 7 oligoclonal bands, an elevated IgG index of 1.0 (nL ,0.61), 2 WBCs, and mild elevation in total protein at 51 mg/d (nL ,35 mg/d). CSF cytology and autoimmune encephalopathy panel were negative. CSF FIG. 2. Postcontrast, fat-saturated, T1 coronal magnetic resonance images, the first abnormality found on MRI 1.5 years after symptom onset (A), 6 months after chemotherapy (B), and 4 months later (C) showing an enlarged and enhancing left optic nerve (arrows), progressing over time. The right optic nerve was normal. Cohen et al: J Neuro-Ophthalmol 2020; 40: 112-116 113 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study AFP was normal (,0.5 ng/mL), and beta human chorionic gonadotropin (b-hCG) was elevated at 3.5 IU/L (nL ,1 IU/L). Serum AFP (2.9 ng/mL) and b-hCG (1.2 IU/L) were normal. Free thyroxine (0.8 ng/dL, nl 1.0–1.6), total testosterone (270 ng/dL, nL 240–950), total prolactin (17.4 ng/mL; nL 4–15.2), and morning cortisol (6.4 mg/dL, nL 7–25) levels were all suggestive of secondary adrenal insufficiency due to chronic steroid use. Repeat contrast MRI brain and orbits was obtained. Dr. Eckel: This most recent contrast MRI of the brain and orbits clearly demonstrates progression of the nonenhancing white matter T2 hyperintensity, now involving the left corona radiata, bilateral corticospinal tracts, left cerebral peduncle, and right middle cerebellar peduncle (not shown). In addition, there is new enhancement of the abducens and oculomotor nerves bilaterally (not shown). The size, abnormal T2 signal, and enhancement of the left optic nerve has also progressed, now involving nearly the entire length of the prechiasmatic left optic nerve (Figs. 2C and 3). The right optic nerve remains normal. Given these progressive changes and the distribution of the lesions, a degenerative/metabolic etiology, such as adult-onset Krabbe disease/ adrenoleukodystrophy should be added to the differential. However, I would still consider the possibility of a primary neoplasm of the left optic nerve. Drs. Chen, Bhatti, and Garrity: The clinical worsening and radiologic evolution of findings despite treatment with steroids, mycophenolate mofetil, and rituximab was striking and not in keeping with CRION or an inflammatory process. Full-body positron emission tomography scan was undertaken to evaluate for any signs of systemic inflammation or malignancy. There was no evidence of fluorodeoxyglucose (FDG)-avid malignancy, but there was mild FDG activity of the left optic nerve. Following extensive discussion with the patient’s family, the left optic nerve was biopsied. Dr. Giannini: We received an 8-mm segment of the left optic nerve. Gross examination demonstrated the nerve to be enlarged (Fig. 4 A) with a diameter of 6 mm (normal 4–5 mm). Microscopic examination showed the tissue was completely replaced by a neoplastic cell population associated with a moderate lymphocytic infiltrate (Fig. 4 B). In high power (·400), the neoplastic cells had abundant pale eosinophilic cytoplasm with large nuclei and vesicular chromatin and prominent nucleoli (Fig. 4 C). Histochemical analysis showed that the cells were immunoreactive for Oct4 (nuclear and cytoplasmic) and placental alkaline phosphatase (membranous and cytoplasmic) (Fig. 4D, E respectively). The histopathological features in conjunction with the immunophenotype were diagnostic of a pure germinoma. No other germ cell components were present. Final Diagnosis Intracranial pure germinoma with infiltration of the optic nerve and disseminated leptomeningeal disease. Drs. Cohen, Chen, and Bhatti: Intracranial germ cell tumors (GCTs) are rare, representing less than 1% of intracranial tumors in the United States (1). Initial localization in the optic nerves has been seldom reported, with the majority being located in the suprasellar space (30%–40%), pineal region (48%–60%), or both (6%–10%) (2–4). Primary anterior visual pathway tumors are also uncommon, with the majority (60%) being optic pathway gliomas (OPGs) frequently associated with FIG. 3. Postcontrast, fat-saturated, T1 axial (A) and sagittal (B) magnetic resonance images showing the enlarged, enhancing left optic nerve along its entire course, from the left orbital apex to the posterior globe. There was also the presence of T2 hyperintensity within the left optic nerve (not shown). 114 Cohen et al: J Neuro-Ophthalmol 2020; 40: 112-116 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 4. A. The optic nerve is markedly enlarged. B. The nerve is completely replaced by a population of neoplastic cells with a moderate lymphocytic infiltrate. C. In high power (·400), the neoplastic cells have abundant pale eosinophilic cytoplasm with large nuclei and vesicular chromatin and prominent nucleoli. The cells express the germ cell markers (D) Oct4 and (E) placental alkaline phosphatase. neurofibromatosis Type 1 (5). A review of 6 case reports of primary, nonexophytic anterior visual pathway GCTs revealed an all-male cohort with a mean age of 21 years at the time of diagnosis (6). These patients presented with painless, progressive vision loss with endocrine abnormalities (i.e., DI), similar to our case. GCTs are grouped as germinomas and nongerminomatous GCTs (NGGCT) based on histological characteristics. NGGCT include choriocarcinomas, endodermal sinus tumors (yolk sac tumors), embryonal carcinomas, or mixed tumors if they include more than one of these histologic categories. Histological features significantly impact and predict outcome. The 10-year survival rate for pure germinoma is 92.7%, whereas the 3-year survival rate for patients with yolk sac tumors or choriocarcinomas is 27.3% (7). European studies have classified GCTs as secreting or nonsecreting. Secreting GCTs have CSF AFP positivity, CSF b-hCG elevations .50 IU/L, or elevated serum levels of b-hCG or AFP (8). Although pure germinomas do not have elevated serum tumor markers, there can be mildly elevated b-hCG in the CSF, particularly with leptomeningeal dissemination, as seen in our case (9). Cohen et al: J Neuro-Ophthalmol 2020; 40: 112-116 Germinomas are treated with focused radiation, with or without cranial-spinal irradiation to the total neuraxis in conjunction with platinum-based chemotherapy. NGGCTs are generally less responsive to radiation and require chemotherapy in addition to proton beam or stereotactic radiosurgery (10). Dr. Cohen: The patient underwent 6 weeks of cranial-spinal irradiation locally. Per his mother’s report, he was hand motion in the right eye, could follow commands, and the spasticity had improved. She conveyed that her son “woke up.” In conclusion, germinomas should be considered in patients presenting with painless, progressive vision loss with visual field deficits in association with endocrine abnormalities of the hypothalamic–pituitary–adrenal axis (i.e., DI and hypopituitarism). Both serum and CSF AFP and b-hCG levels should be obtained and if elevated are highly suggestive of a GCT. These tumors can be diffusely enhancing and infiltrative with expansion of the nerve, but are often difficult to diagnose on neuroimaging alone, 115 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study thereby requiring surgical exploration with biopsy. Our case was particularly challenging, given the poor anatomical correlation between clinical manifestations and MRI findings, and the development of DI relatively late in his disease course. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: D. A. Cohen, M. T. Bhatti, and J. J. Chen, b. Acquisition of data: D. A. Cohen, M. T. Bhatti, and J. J. Chen, c. Analysis and interpretation of data: D. A. Cohen, M. T. Bhatti, C. Giannini, L. Eckel, J. A. Garrity, and J. J. Chen. Category 2: a. Drafting the manuscript: D. A. Cohen, M. T. Bhatti, C. Giannini, L. Eckel, J. A. Garrity, and J. J. Chen, b. Revising it for intellectual content: D. A. Cohen, M. T. Bhatti, C. Giannini, L. J. Eckel, J. A. Garrity, and J. J. Chen. Category 3: a. Final approval of the completed manuscript: D. A. Cohen, M. T. Bhatti, C. Giannini, L. J. Eckel, J. A. Garrity, and J. J. Chen. REFERENCES 1. Matsutani M. Chapter 42—germ cell tumors. In: Berger MS, Prados MD, eds. Textbook of Neuro-Oncology. Philadelphia, PA: W.B. Saunders, 2005:310–320. 116 2. Bowman CB, Farris BK. Primary chiasmal germinoma: a case report and review of the literature. J Clin Neuroophthalmol. 1990;10:9–17. 3. Wilson JT, Wald SL, Aitken PA, Mastromateo J, Vieco PT. Primary diffuse chiasmatic germinomas: differentiation from optic chiasm gliomas. Pediatr Neurosurg. 1995;23:1–5; discussion 6. 4. Horowitz MB, Hall WA. Central nervous system germinomas: a review. JAMA Neurol. 1991;48:652–657. 5. Hollander MD, Fitzpatrick M, O’Connor SG, Flanders AE, Tartaglino LM. Optic gliomas. Radiol Clin North Am. 1999;37:59–71, ix. 6. DiLuna ML, Two AM, Levy GH, Patel T, Huttner AJ, Duncan CC, Piepmeier JM. Primary, non-exophytic, optic nerve germ cell tumors. J Neurooncol. 2009;95:437–443. 7. Matsutani M, Sano K, Takakura K, Fujimaki T, Nakamura O, Funata N, Seto T. Primary intracranial germ cell tumors: a clinical analysis of 153 histologically verified cases. J Neurosurg. 1997;86:446–455. 8. Calaminus G, Bamberg M, Baranzelli MC, Benoit Y, di Montezemolo LC, Fossati-Bellani F, Jürgens H, Kühl HJ, Lenard HG, Curto ML. Intracranial germ cell tumors: a comprehensive update of the European data. Neuropediatrics 1994;25:26–32. 9. Balmaceda C, Finlay J. Current advances in the diagnosis and management of intracranial germ cell tumors. Curr Neurol Neurosci Rep. 2004;4:253–262. 10. Echevarria ME, Fangusaro J, Goldman S. Pediatric central nervous system germ cell tumors: a review. Oncologist 2008;13:690–699. Cohen et al: J Neuro-Ophthalmol 2020; 40: 112-116 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.