Journal of Neuro-Ophthalmology, March 1990, Volume 10, Issue 1

Progressive cranial polyneuropathy caused by primary central nervous system melanoma.

Primary malignant melanoma of the central nervous system (CNS) is exceedingly rare. The earliest description by Virchow in 1859 has been followed by approximately 50 autopsy-proven cases reported in the literature. These tumors are considered to arise from leptomeningeal melanocytes whose embryonic origin is neural crest tissue. Given the rarity of primary CNS melanoma, the diagnosis requires a thorough search to exclude a dermatologic, ocular, or visceral site of tumor origin. We report an unusual case of primary CNS melanoma in a patient with painful, progressive cranial polyneuropathy that eluded antemortem diagnosis despite extensive clinical, radiographical, and laboratory investigations.

! ounull of Clinical Neuro- ophthalmology 10( 1): 41- 44, 1990. © 1990 Raven Press, Ltd., New York Progressive Cranial Polyneuropathy Caused by Primary Central Nervous System Melanoma Larry A. Fish, M. D., Ph. D., Deborah 1. Friedman, M. D., and Alfredo A. Sadun, M. D., ph. D. Primary malignant melanoma of the central nervous sys­tem ( CNS) is exceedingly rare. The earliest description by Virchow in 1859 has been followed by - 50 autopsy­proven cases reported in the literature. These tumors are considered to arise from leptomeningeal melanocytes whose embryonic origin is neural crest tissue. Given the rarity of primary CNS melanoma, the diagnosis requires a thorough search to exclude a dermatologic, ocular, or visceral site of tumor origin. We report an unusual case of primary CNS melanoma in a patient with painful, progressive cranial polyneuropathy that eluded ante­mortem diagnosis despite extensive clinical, radiograph­ical, and laboratory investigations. Key Words: Progressive cranial polyneuropathy­Primary central nervous system melanoma. From the Doheny Eye Institute and Department of Op~ thal­mology, University of Southern California School of Medlone, Los Angeles, California. Address correspondence and reprint requests to Dr. A. A. Sadun, Estelle Doheny Eye Institute, 1355 San Pablo Street, Los Angeles, CA 90033, U. S. A. 41 CASE REPORT In July 1986, a 44- year- old white man presented with a I- year history of progressive painful oph­thalmoplegia of the left eye. He initially experi­enced severe burning pain in the left upper face that progressed to involve the entire left face. He developed left facial and oral cavity numbness as­sociated with a 2- month history of left facial weak­ness and diplopia. Initial neuroophthalmic exami­nation revealed the following: Cranial nerve I was normal. Cranial nerve II had a visual acuity of 20/ 20 in each eye with recognition of 8/ 8 American Optical color plates. There was 4 mm of proptosis on the left; orbital repositus was normal bilaterally. The right pupil was 4 mm, round, and briskly re­active. The left pupil was 7 mm with no light re­sponse and no afferent pupillary defect. Intraocu­lar pressure measured 14 mm Hg in each eye. Am­sler grid and tangent screen perimetry were normal for both eyes, as were slit- lamp biomicros­copy and dilated fundus exam. There was a 60 prism diopter exotropia in primary gaze and com­plete III and IV cranial nerve palsies on the left. Motility was normal on the right. Cranial nerve V had decreased sensation to pinprick in VI and V2 on the left. Cranial nerve VI appeared normal. Cra­nial nerve VII had left hemifacial weakness. Cra­nial nerve VIII had subjective decreased hearing on the left. Cranial nerves IX- XII were normal as was the remainder of the neurologic and physical examinations. Computed tomography of the head and orbits suggested a subtle diffuse mass lesion along the left orbital apex with evidence of ipsilateral cavern­ous sinus enlargement ( Fig. 1). Prednisone ( 60 mg daily) was begun with symptomatic pain relief, but no improvement of the ophthalmoplegia. Craniotomy performed in July 1986 revealed only slight thickening of the arachnoid in the cli- 42 L. A. FISH ET AL. FIG. 1. Contrast- enhanced computed tomographic scan suggestive of diffuse mass in left orbital apex, extending to left cavernous sinus ( arrowheads). vus region; histopathological examination of bi­opsy tissue from this region showed reactive meningeal hyperplasia. Protein S- 100 staining of this tissue was negative. The posterior orbital apex specimen revealed chronic inflammatory changes. Magnetic resonance imaging ( MRI) performed 1 month postoperatively was normal. The facial pain worsened over the next several months. A left VI nerve palsy developed, along with left corneal numbness and right facial numb­ness. In addition, left posterior pharyngeal numb­ness occurred. There was no dysphagia. Repeat MRI scan failed to disclose any abnormality. Lum­bar puncture revealed a mildly elevated protein ( 54 mg/ ml) and no malignant cells on cytospin. Cere­brospinal fluid bacteriological, viral, acid fast ba­cilli, and fungal cultures were negative on several occasions. Antinuclear antibody was 1: 80 ( nucleo­lar) and Wintrobe sedimentation rate was 19. Syphilis serology and Lyme disease antibody were negative. Serum chemistries and complete blood counts were normal except for a persistently ele­vated white blood cell count ( range, 18,900­41,400). Epstein- Barr virus ( EBV) titers were ele­vated ( Epstein- Barr nuclear antigen, 1: 16; EBV an­tibody, 1: 160), suggesting a recent infection. On findings from thorough systemic and oncologic evaluations, including chest roentgenogram, liver function tests, computed tomography of the abdo­men, bone marrow biopsy, and gallium scan were normal. Six months after surgery, a neurotropic corneal ' 1' 1 " 1; 1.1"",,, ," ulcer developed on the left, despite complete pto­sis. The ulcer resolved with intensive topical anti­bacterial therapy. However, visual acuity in that eye decreased to hand motions coincident with the appearance of a marked afferent pupillary defect and left papillitis. The patient was admitted to an outside hospital in June 1987 with altered mental status. He suffered cardiopulmonary arrest during intubation for ventricular shunt placement. He died on July 7, 1987, following a protracted hospi­tal course complicated by seizures and pneumo­nia. RESULTS: HISTOPATHOLOGIC FINDINGS The brain exhibited small foci of parenchymal cystic degeneration infiltrated by lymphocytes, few plasma cells, and polymorphonuclear leuko­cytes. Bordering these areas were zones of reactive gliosis and capillary proliferation. Perivascular cuffing by lymphocytes was seen. Sections of the medulla at the level of the olive exhibited diffuse infiltration of the leptomeninges, nerves, and blood vessels by tumor cells and lym­phocytes ( Fig. 2). Some tumor cells demonstrated enlarged bizarre nuclei while others were oval to spindle- shaped with eosinophilic nuclei. Cyto­plasm was abundant and pale pink. Sections at the level of the pons showed meningeal perivascular and perineural infiltration by tumor cells. The op­tic nerves were unavailable for examination. The optic tracts were examined using the paraphe­nylene diamine ( PPD) technique that stains degen­erated axons ( 1). The left optic tract showed marked degeneration in fascicles representing un­crossed fibers originating from the left optic nerve, FIG. 2. Malignant cells are seen in the brainstem me­ninges. These cells are characterized by a large nu­cleus and prominent nucleolus. ( Hematoxylin- eosin). eNS MELANOMA 43 confirming the patient's clinical optic neuropathy ( Fig. 3). Pathologic diagnosis was primary malig­nant CNS melanoma deriving from the meninges. Exhaustive gross and histopathologic examination failed to reveal evidence of cutaneous or visceral tumor. COMMENT Primary melanoma of the central nervous sys­tem ( CNS) typically exhibits one of two patterns of growth and development. Tumors may take the form of a discrete lesion or alternatively may arise as a diffusely infiltrative melanosis that shows a predilection for cranial nerve roots and perivascu­lar spaces ( 2- 4). Extracranial extension occurs rarely ( 5). Discrete tumor masses occur predominantly in the spinal cord ( 6). Solitary lesions have also been FIG. 3. Left optic tract. ( A' SunaTes or degene~ ai. ed axons from the left optic nerve are clearly dt~ tln­guished from normal decussating fibers of the right optic nerve ( PPD x55). ( 8) Each dark profile ( arrow) represents degen'erated axons from the ipsilateral left optic nerve ( x828). described as ansIng in the pituitary, choroid plexus, and dura ( 7- 10). The majority ofintracranial cases are diffuse lesions. However, Bojsen- Moller described a series of six cases in which four pa­tients were found to have solitary brain tumors. These patients had a relatively long survival as compared to other reported cases ( 4). In their extensive review of CNS melanoma, Savitz and Anderson compiled autopsy results from a number of published case reports ( 2). Based on histopathologic sectioning, most cases demon­strated extensive infiltration of the subarachnoid space with perivascular cuffing and cranial nerve root involvement. Most cases presented in the third or fourth decades of life, and the majority died of complications from CNS melanoma within 1- 2 years of presentation. Although it is now well accepted that melanoma can originate in the CNS, such was not always the case. In 1897, Ribbert [ cited by Savitz and Anderson ( 2)] maintained that all pigmented tumors of the brain, spinal cord, and meninges were metastatic. Lubarsch [ cited by Savitz and Anderson ( 2)] in 1920 likewise felt that the presence of even one pigmented cutaneous ne­vus precluded the diagnosis of primary CNS mel­anoma. In 1948, Rawles studied the migration of neural crest cells to the epidermis, iris and choroid of the eye, and leptomeninges. She conclusively demonstrated that, when neural crest was deleted from transplants, skin and hair were structurally normal but were devoid of pigment ( 11). This con­clusively established the embryologic origin of me­lanocytes and thus permitted the diagnostic possi­bility of primary CNS melanoma. The neural crest origin of melanocytes may account for the reported clinical association of CNS melanoma, a neuroec­todermal dysplasia, with a variety of phacoma­toses, including neurofibromatosis and hemangi­omatosis ( 2). Therapeutic intervention in CNS melanoma has been disappointing. With the exception of local­ized spinal cord tumors, surgical resection is un­successful, and these tumors are resistant to both radio- and chemotherapy ( 2,4,6). Novel therapeu­tic efforts are aimed at in vitro enhancement of cytotoxic activity of autologous lymphocytes iso­lated from a tumor specimen, with subsequent re­introduction of these activated cells into the host ( 12). Our patient manifested two frequently seen clin­ical features of primary CNS melanoma: a relent­less deteriorating course and failure to establish antemortem diagnosis. His clinical presentation with unilateral involvement of cranial nerves III, IV, V, and VI suggested a cavernous sinus syn- 1elin Neuro- ophthalmol, Vol. 10, No. 1, 1990 44 L. A. FISH ET AL. drome or orbital apex lesion. Failure to improve dramatically on steroids mitigated against Tolosa­Hunt syndrome, and tissue biopsy performed at orbitotomy was nondiagnostic. Progressive in­volvement of cranial nerves VII ( bilateral), VIII, and IX suggested brainstem involvement; how­ever, high- quality radiographic studies and nu­merous lumbar punctures failed to disclose any ab­normality. Oncologic consultation and workup were unrevealing. In the present case, it appears that a primary leptomeningeal melanoma arose at the level of the pons and affected both an ascending course that eventually involved the left optic tract via the cav­ernous sinus, and a descending course encom­passing the medulla. In addition to rapidly pro­gressive cranial nerve dysfunction, the disease course was characterized by severe pain. These clinical features correspond with the diffusely in­filtrative tumor growth pattern found on histo­pathologic examination, in which parenchymal, perivascular, and perineural invasion was seen. Unfortunately, our orbital biopsy failed to detect malignancy, although a tissue diagnosis at that time would not have altered the clinical course, management, or outcome. J '-"" ",,, REFERENCES 1. Sadun AA, Smith LEH, Kenyon KR. Paraphenylenedi­amine: a new method for tracing human visual pathways. JNeuropathol Exp Neurol 1983; 42: 200- 6. 2. Savitz MH, Anderson PJ. Primary melanoma of the lepto­meninges: a review. Mt Sinai J Med NY 1974; 41: 774- 91. 3. Hardman JM. Nonglial tumors of the nervous system. In: Rosenberg RN, ed: The clinical neurosciences: neuropathology. New York: Churchill Livingstone, 1983; 170- 1. 4. Bojsen- Moller M. 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