Third Nerve Palsy Due to a Malignant Oculomotor Nerve Sheath Tumor

Malignant peripheral nerve sheath tumors (MPNSTs) affecting the cranial nerves are very rare. They may arise from benign neurofibromas or schwannomas or appear de novo from the peripheral nerve sheath. They can be associated with systemic syndromes such as neurofibromatosis (NF) I or result from previous radiotherapy (1). The largest case series of intracranial MPNSTs to date included 17 patients with involvement of vestibular nerves (n = 7), vagal nerves (n = 4), facial nerves (n = 3), unspecified nerves in the posterior fossa (n = 2), and the optic chiasm (n = 1) (2). Five patients met the criteria for NFI, and 4 patients had lesions that were radiation-induced. Additional literature on this topic is limited to individual case reports describing MPNSTs involving the oculomotor (3,4), trigeminal (5–8), vestibular (9), acoustic (10–12), vagus (13), facial (14), cerebellopontine angle (15), and lateral skull base nerves (13). We present a unique case of a primary MPNST of the oculomotor nerve in an otherwise healthy man who had progressive visual symptoms due to the aggressive nature of the lesion. CASE REPORT A 40-year-old healthy man presented with a 1-month history of left ptosis and horizontal binocular diplopia. He had normal afferent visual function and left ptosis with limitation of elevation, depression, and adduction of the left eye. The left pupil was dilated and was poorly reactive to light. Computed tomography (CT) angiography was normal, and MRI revealed a T1-hypointense, T2-hyperintense enhancing mass along the course of the left oculomotor nerve (Fig. 1A and B). Chest x-ray and lumbar puncture were normal; neurosurgery advised against biopsy due to the associated risks of surgery in that location. The patient also declined biopsy. Bloodwork was performed and included a normal serum angiotensin converting enzyme, antineutrophil cytoplasmic antibody, and quantiferon-gold. The lesion was believed to be consistent with an oculomotor nerve schwannoma, and he was treated with fractionated radiotherapy (50.4 Gy in 28 fractions) and a short course of dexamethasone. Two weeks after treatment, his left ptosis and diplopia started to improve; repeat MRI 6 months after treatment showed a substantial reduction in size of the mass (Fig. 1C).FIG. 1.: MRI T1-weighted gadolinium-enhanced image demonstrating an enhancing mass (A). The mass was hyperintense on T2-weighted images (B) along the course of the left oculomotor nerve. Six months after treatment, there was a significant reduction in size of the oculomotor nerve mass (C). Eighteen months after treatment, there was an increase in the size of the cavernous and intraorbital portions of the oculomotor nerve mass (D).Eighteen months after treatment, the patient's double vision recurred and repeat MRI showed an increase in the size of the cavernous and intraorbital portions of the oculomotor nerve mass (Fig. 1D). Since he had experienced relatively rapid improvement after the initial radiation and dexamethasone, an inflammatory lesion was considered. The patient underwent repeat lumbar puncture and CT of the chest, abdomen, and pelvis, which were all normal. He was treated with mycophenolate mofetil since he had experienced significant side-effects previously with oral corticosteroids. One month later, the patient developed sudden loss of vision in the left eye. Repeat examination revealed visual acuities of 20/20 in the right eye and hand motions in the left eye with a left relative afferent pupillary defect. The optic nerves appeared normal, and he had left ptosis and complete left external and internal ophthalmoplegia (Fig. 2). Repeat MRI demonstrated increased tumor size and compression of the left optic nerve at the orbital apex (Fig. 3). The patient's vision worsened to no light perception despite treatment with methylprednisolone 1 g intravenously daily. Biopsy of the mass revealed a high-grade spindle cell tumor with numerous mitoses, a fascicular pattern of growth and cartilaginous differentiation, diagnostic of a high-grade MPNST (Fig. 4). He underwent intracranial resection of the tumor through a left cranio-orbital zygomatic craniotomy with extradural clinoidectomy and exenteration of the frontal and ethmoidal sinuses and orbit. Because the tumor surrounded the carotid artery, extracapsular dissection was not possible. Because of continued tumor growth, he underwent repeat fractionated radiotherapy (66 Gy in 33 fractions) and received 2 doses of cisplatin. A follow-up MRI 6 months after surgery showed stability in the size of the lesion.FIG. 2.: Nineteen months after radiotherapy, he had recurrent left ptosis and complete left ophthalmoplegia with a dilated, nonreactive pupil.FIG. 3.: Axial (A) and coronal (B) MRI T1-weighted gadolinium-enhanced image 19 months after radiotherapy demonstrating an enlarged oculomotor nerve mass with compression of the left optic nerve at the orbital apex.FIG. 4.: Hematoxylin and eosin stain of the oculomotor nerve mass demonstrating a high-grade spindle cell tumor with fascicular pattern of growth and numerous mitoses. This was most consistent with a malignant peripheral nerve sheath tumor.DISCUSSION Primary MPNSTs of the oculomotor nerve are extremely rare and posed a diagnostic dilemma in our patient with a new-onset third nerve palsy. The differential diagnosis of enlarged cranial nerves include infectious (mycobacterium, fungal, and Lyme), inflammatory (sarcoidosis, granulomatosis with polyangiitis, systemic lupus erythematosus, and Sjogren's), infiltrative (lymphoma, leukemia, and amyloidosis) and neoplastic etiologies (neurofibroma, perineuroma, schwannoma, metastases, and perineural invasion) (16). There were no initial findings or symptoms in our patient to suggest an infectious or inflammatory cause, and his initial MRI was believed to be consistent with an oculomotor nerve schwannoma. He therefore underwent radiotherapy due to the considerable risks of surgical resection and biopsy in that region and the patient's personal preference to avoid surgery. The dramatically positive response to radiation initially was more than expected for a benign tumor such as a schwannoma, likely indicating that the tumor was already high-grade at the time of presentation. The patient's symptoms also developed rapidly, also unlike those expected for a schwannoma. The substantial amount of shrinkage over such a short period argues against radiation-induced malignant transformation, which typically takes several years to occur (17). The 2 previously reported cases of oculomotor MPNSTs are not directly comparable with our patient. Kozic et al (3) described a 9-year-old boy with a left oculomotor MPNST who also had benign schwannomas of the trigeminal nerve and within the internal auditory canal. The patient had surgical resection of the third nerve lesion because of rapid increase in size of the tumor and mass effect on the brainstem. Fard et al (4) reported a 72-year-old man with a left complete, pupil-sparing third nerve palsy, and a multilobulated mass centered in the sphenoid sinus. Gross total resection showed an intermediate-grade MPNST, and the patient's third nerve palsy resolved after 7 months. This led the authors to conclude that the symptomatic oculomotor nerve palsy was potentially ischemic or inflammatory in etiology. Other reported cases of intracranial MPNSTs were mostly treated with initial neurosurgical resection due to their aggressive nature, (5–8,10,11,13–15) although fractionated radiation treatment in one case resulted in stabilization of a MPNST of the right cerebral peduncle for 18 months until rapid neurological deterioration and death ensued (9). Malignant transformation of an initially benign peripheral nerve sheath tumor may occur even without adjunctive radiotherapy, emphasizing the importance of continued surveillance (11). In summary, MPNSTs are rare but should be included in the differential diagnosis of enlarged cranial nerves, especially if there is an aggressive clinical course or an exaggerated positive response to radiotherapy. Obtaining tissue for histopathological analysis is important in establishing this diagnosis to allow for earlier and more aggressive treatment. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: J. A. Micieli, H.-K. G. Shu, and N. J. Newman; b. acquisition of data: J. A. Micieli, H.-K. G. Shu, and N. J. Newman; c. analysis and interpretation of data: J. A. Micieli, H.-K. G. Shu, and N. J. Newman. Category 2: a. drafting the manuscript: J. A. Micieli; b. revising it for intellectual content: H.-K. G. Shu and N. J. Newman. Category 3: a. final approval of the completed manuscript: J. A. Micieli, H.-K. G. Shu, and N. J. Newman.

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