Rodríguez, Julio A MD; Hedges, Thomas R III MD; Heilman, Carl B MD; Strominger, Mitchell B MD; Laver, Nora M MD
New England Eye Center (JAR, TRH, MBS), Department of Neurosurgery (CBH), and Ocular Pathology Laboratory, Department of Pathology (NML), Tufts-New England Medical Center, Boston, Massachusetts.
Address correspondence to Thomas R. Hedges III, MD, New England Eye Center, Tufts-New England Medical Center, Box 450, 750 Washington Street, Boston MA 02111; E-mail: firstname.lastname@example.org
A 17-year-old woman developed a sixth cranial nerve palsy from a malignant peripheral nerve sheath tumor of the trigeminal nerve. This case is unusual in that the principal symptom was diplopia stemming from a sixth cranial nerve palsy. Pain was mild, and trigeminal function was preserved. Imaging evidence of rapid growth of the cavernous sinus mass gave rise to an initial impression that the cause might be inflammatory. Treatment with gamma knife stereotactic radiosurgery produced some improvement in sixth cranial nerve function and reduction in tumor size over a follow-up period of 9 months.
Malignant peripheral nerve sheath tumors (MPNSTs) that involve the cranial nerves most often affect the trigeminal nerve (1-8) and present clinically with burning facial pain (2,8). We describe a patient with a biopsy-proven MPNST who presented with a sixth cranial nerve palsy, relatively mild facial pain, and preservation of trigeminal function. Imaging evidence of rapid tumor growth gave rise to the impression of an inflammatory cavernous sinus lesion or a metastatic or hematologic malignancy.
A 17-year-old woman developed sudden persistent horizontal diplopia 2 months before our initial evaluation. She also complained of occasional daily sharp pain of varying intensity over the left brow area, especially when she looked at a blackboard at school. She also noted some pain with extraocular movements but had no facial weakness or paresthesias. At the onset of diplopia, she had a throat and right ear infection treated with amoxicillin.
She reported monthly headaches with photophobia, phonophobia, nausea, and vomiting. Her last headache had occurred 4 months before her initial presentation. She also had a history of asthma and recurrent sinusitis. Medications included fluoxetine and amphetamine for attention deficit disorder. She smoked 10 cigarettes per day.
Visual acuity was 20/15 in both eyes. Visual fields by confrontation were normal. There was no ptosis or proptosis. She had a left face turn. Abduction was reduced to 10% in the left eye, producing 8 prism-diopters of esodeviation in primary gaze position that increased to 35 prism-diopters in left gaze. Pupils measured 6 mm in dim light and constricted briskly and equally to direct light and to near stimuli. There was no dilation lag.
Sensation in the three divisions of the fifth nerve was normal to pinprick and light touch. Corneal sensation could not be adequately assessed because of prior instillation of drops. Masseter strength was normal. Facial strength and hearing were normal, as was the rest of the neurologic examination.
MRI showed a left cavernous sinus mass and adjacent mucosal opacification in the left sphenoid sinus (Fig. 1). Although a neoplasm was considered most likely, the possibility of an inflammatory lesion involving the cavernous and sphenoid sinuses was raised. Therefore, a trial of 80 mg/day of prednisone was initiated.
One week later, the esodeviation was unchanged, and she still complained of brow pain. CT scanning showed improvement in the presumed sphenoid sinusitis, but the enhancing lesion now filled the left cavernous sinus, encasing the carotid artery and eroding through the roof of the sphenoid bone. Surgical exploration showed that the mass appeared to originate from the left trigeminal nerve.
Histopathologic evaluation of a biopsy of the tumor showed an anaplastic, spindle cell neoplasm infiltrating the trigeminal nerve and ganglion (Figs. 2 and 3). The tumor cells were immunoreactive for S-100 protein and glial fibrillary acidic protein (GFAP). Mitoses were easily found, and the tumor showed a high Ki-67 labeling index. Immunohistochemistry for neuron-specific enolase, chromogranin, epithelial membrane antigen (EMA), and progesterone receptors was negative. A malignant peripheral nerve sheath tumor was diagnosed. She underwent Leksell Gamma Knife stereotactic radiosurgery at a single dose of 20 Gy.
Nine months later, the patient still had occasional left brow pain. Abduction had improved to 60%, resulting in 5 prism-diopters of esodeviation in primary gaze and 20 prism-diopters in left gaze. There was now decreased corneal sensation and loss of sensitivity to light touch and sharp stimuli over the left chin. Hearing was slightly reduced on the left side. MRI showed slight shrinkage of the tumor (Fig. 1).
MPNSTs are rare malignancies (1-5) with a reported frequency in the general population of 0.001% (6). They arise in two principal forms, sporadic (50-70%) and in association with stigmata or a family history of neurofibromatosis type 1 (30-50%). They comprise about 6% of malignant soft tissue tumors in the body (3). About 50% occur on the trunk and about 20% in the head and neck region (1).
MPNSTs that involve the cranial nerves most often affect the trigeminal nerve (3). A mere 4.6% of MPNSTs of the trigeminal nerve occur in patients who have neurofibromatosis (1), but this figure remains weakly established (2).
Most MPNSTs arise de novo, although some arise through malignant transformation of benign schwannomas (1). They most often present clinically with facial pain, sensory paresthesias, diminished corneal reflex, and dysfunction of muscles of mastication. Further growth causes ophthalmoplegia and lower cranial nerve involvement (2). In our patient, the facial pain was mild and overshadowed by the diplopia. Furthermore, facial sensation was spared.
Radiologically, the differential diagnosis between schwannoma and MPNST may be difficult, although extension of tumor growth along nerve roots may indicate malignancy (2). On CT, bony erosion of the basilar foramina is another sign of malignancy. Meningioma can mimic MPNST on imaging, but our patient's age and the relative rapidity of onset of symptoms, as well as the lack of associated bone reaction near the tumor, made this an unlikely diagnosis and favored a metastatic or hematologic neoplasm or an inflammatory condition such as bacterial sinusitis, sarcoidosis, or idiopathic pachymeningitis.
Histologically, MPNSTs show plump spindle and polyhedral cells with hyperchromatic, pleomorphic nuclei, inconspicuous nucleoli, and increased mitotic figures (2,4). Immunohistochemical stains useful for diagnosis include S-100 protein, which is present in 50-70% of these tumors (1), myelin basic protein, and leucine 7.(2) The p53 mutation is frequently expressed in these tumors, and it can serve as a marker of tumor aggressiveness. Ki-67 can be used to evaluate the growth fraction of the tumor mass (1).
There is considerable variation in the management of the MPNSTs of the trigeminal nerve. Complete resection is often not possible because of their location, and radiation therapy is given either as primary or adjuvant treatment. Chemotherapy has not been effective (2). Local recurrences have been estimated to occur in 38-45% and metastases in 40-82% of cases (1).
Our patient's clinical features are instructive, not only because of the rarity of MPNST as the cause of her symptoms and signs but also because of the initial presentation as a sixth cranial nerve palsy with only mild facial pain and relatively normal trigeminal nerve function. Sixth cranial nerve palsy in young adults and children may be benign, but malignancy should be suspected, even if there few other signs or symptoms. Biopsy of a mass seen on neuroimaging should be performed without delay.
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