BritishJournal ofOphthalmology, 1990,74,502-504

Uveal malignant melanoma and optic nerve glioma invon Recklinghausen's neurofibromatosis

C Mark Antle, Karim F Damji, Valerie A White, Jack Rootman

AbstractA case of uveal malignant melanoma andcontralateral optic nerve glioma is describedin a 53-year-old Caucasian male with multipleuveal melanocytic hamartomas and neuro-fibromatosis. The eye was enucleated, and

histologically the melanoma was found to con-sist of 70% epithelioid cells, with many bizarre,

multinucleated forms. CT scan demonstrateda non-enhancing, fusiform enlargement of thecontralateral optic nerve with enlargement ofthe optic canal and intracranial extension.This combination of tumours has not pre-viously been reported in a patient with neuro-

fibromatosis and serves to emphasise the

common neuroectodermal origin oftumours in

this autosomal dominant condition. Figure I Axial CT scan showingfusiform enlargement ofthis~~~~~~~~~~~~~~~~~~~~~L_au_:.t___soma_dominant__condtio.\ the optic nerve wnth intracranual extension (right) andlobulated uveal mass (left).

Optic nerve glioma" and uveal malignantmelanoma-"' have both been reported in vonRecklinghausen's neurofibromatosis (NF).While the incidence of optic nerve glioma variesfrom 10 to 70%,2 only 11 cases of uveal malignantmelanoma in NF are reported."' In NF uvealmalignant melanoma has been reported withacoustic schwannomal and with orbitalneuroma.' We describe the previously un-reported association of uveal malignantmelanoma and contralateral optic nerve gliomain a patient with multiple uveal melanocytichamartomas and neurofibromatosis.

Vancouver GeneralHospital and Universityof British Columbia,Vancouver, BritishColumbia, CanadaDepartment of PathologyCM AntleK F DamjiVA WhiteJ Rootman

Department ofOphthalmologyV A WhiteJ RootmanCorrespondence to:Dr J Rootman, Eye CareCentre, 2550 Willow Street,Vancouver, British Columbia,Canada V5Z 3N9.Accepted for publication8 March 1990

Case reportA 53-year-old Caucasian man with multiplecutaneous neurofibromata, cafe-au-lait spots,and a family history ofNF presented with a four-day history of spots and blurring in the left eyerapidly progressing to total grey-out of vision.The visual acuities were 20/20-3 in the right

eye and 20/400 in the left, with a left afferentpupillary defect. The interpalpebral fissures,results of exophthalmometry, and IOP measure-ments were normal and symmetrical. Neitherglobe showed displacement. Multiple Lischnodules and iris naevi were seen, particularly inthe left eye, which also had a large inferiorsentinal vessel and a cataract. There was a largeciliochoroidal tumour between 4 and 8 o'clock,with 9-10mm of elevation, a total retinal detach-ment, and anterior iris displacement between 4and 6 o'clock.

Ultrasonography showed a solid, horseshoeshaped mass in the choroid extending frominferotemporal to inferonasal quadrants.Computed tomography showed a normal left

orbit and a left globe of normal size with anenhancing lobulated uveal mass in its inferiorhalf extending bilaterally to the ora (Fig 1)

without extrascleral extension. On the right theoptic nerve had a non enhancing, fusiformenlargement, with expansion of the optic canaland intracranial extension. No cerebellopontineangle or internal auditory canal abnormality wasseen.

Malignant melanoma was suspected, and itwas confirmed on intraoperative fine needleaspiration biopsy, which showed numerousmalignant epithelioid melanocytes with largevesicular nuclei and prominent nucleoli. Thebiopsy was followed by a cryoenucleation. Theglobe was 24-25 mm in diameter with cornealmeasurements of 13 x 11 5 mm. Oblique section-ing exposed a black tumour with a 17 mm baseand a height of 7 mm. The overlying retina wasdetached.

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Figure 2 Low power view ofglobe showing lobulatedtumour arisingfrom the uveal tract and associated retinaldetachment. (Haematoxylin and eosin, x2-7.)

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Uveal malignant melanoma and optic nerve glioma in von Recklinghausen's neurofibromatosis

Histologically a poorly differentiated malig-nant melanoma arose from the uvea, abutted thelens, occupied the pars plana, and extendedthree-quarters of the way to the posterior pole(Fig 2). The densely pigmented tumour cellswere 70% epithelioid and 30% spindle, withmany bizarre, multinucleated forms (Fig 3). Thetumour stained moderately for S100 protein andstrongly with the monoclonal antibody HMB45.Large sinusoidal spaces and focal areas ofhaemorrhage and necrosis were identified. Therewas no paraemissarial extension. The detachedretina was degenerated.

In the neovascularised iris spindle to polygonalshaped cells, many with intranuclear inclusions,formed numerous S 100-positive melanocytichamartomas (Fig 4). In the choroid multiplediffuse hamartomatous aggregations of melano-cytes, some extending round the emissariaposteriorly, were present and stained stronglypositive for S100 protein and occasionally withHMB45 (Fig 5).The patient presented three months later with

diffuse metastatic disease and died 13 monthsafter enucleation.

DiscussionNeurofibromatosis, first described by von Reck-linghausen in 1882,'4 is a common autosomaldominant disorder with a prevalence of 1 in3000.15 16 It has one of the highest mutation ratesin humans.'7 Though it was previously con-sidered to be a heterogeneous disorder withvariable expression, linkage analysis in NFfamilies has recently identified a consistentmutation at a single locus on chromosomel7.'8

Melanocytic and glial lesions of NF arederived from the neural crest. The association ofoptic nerve glioma and NF is established,' 2 andan increased incidence of uveal malignantmelanoma is also noted'9 despite the smallnumber of cases (11) reported. 1'3 Uveal naevi arealso found more frequently." Concurrentmalignant melanoma and optic nerve glioma

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have not previously been reported, but theconjunction illustrates the pathogenesis ofNF asa 'complex neurocristopathy' as initially definedby Bolande.20 This concept envisages NF as adefect in development and regulation in whichtissues derived from the neural crest show anincreased incidence of benign tumours such asneurofibromas, schwannomas, neuromas, glio-mas, meningiomas, caf6-au-lait spots, other cuta-neous naevi, uveal naeviI21621 23 and malignanttumours such as malignant schwannoma,2425pheochromocytoma,2627 cutaneous malignantmelanoma,24 2130 and uveal malignant mela-noma.-'3 A predisposition to uveal malignantmelanomamay also exist because ofthe increasedincidence of choroidal naevi in NF3' and the sup-position that malignant melanoma arises fromthese naevi.32Other features of NF cannot be attributed

directly to maldeveloped neural crest but mayarise secondarily to interactions with otherdeveloping tissues, leading to additional anoma-lies'5 such as malignant tumours (rhabdomyo-sarcoma, nephroblastoma, and myelogenousleukaemia),3337 mesodermal defects (macro-cephaly, pseudoarthrosis, kyphoscoliosis, shortstature, sphenoid wing dysplasia), diminishedintellect, speech defects, and pruritus. 16The commonest ocular feature of NF is the

Lisch nodule, present in over 90% of adultpatients.2223 Additional neural crest derivedocular features include neurofibromas of eyelid,conjunctiva, and orbit, caf6-au-lait spots, promi-nent corneal nerves, uveal naevi, choroidal glialhamartomas, optic nerve gliomas, intraocularschwannomas, sphenoid wing dysplasia,'7222338and uveal malignant melanoma.3-13The average age of patients with NF-related

Figure 3 Uveal malignantmelanoma with epithelioidcells showing granularcytoplasmic SIOO positivity(arrows). (Bleachedpreparation;immunoperoxidase stainingforSIOO antigen; x800.)

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uveal malignant melanomasand our patient was 55. Twctions for uveal malignant melapopulation occur after age 50of sex predilection in NF alkpreviously reported patientsassociated with uveal malignsfemale, a distribution not see

uveal malignant melanoma. Sreported as spindle cell, threeone as epithelioid cell. The twas mixed. Four cases sAextension at enucleation, whidid not. The malignant cell tand the large size suggested a Ia five-year survival less than 4

1 Rush JA, Younge BR, Campbell F

glioma. Long term follow-up cverified cases. Ophthalmology 1982

2 Lewis RA, Gerson LP, Axelson KARP. von Recklinghousen neurofibioptic gliomata. Ophthalmology 198

3 Bair HL, Love JG. Acoustic neur

melanoepithelioma of the choroiboth tumors. Mayo Clin Proc 1937

4 Gartner S. Malignant melanomaRecklinghausen's disease. AmJ

5 Strachov VP. Recklinghausen's di

right orbit and neoplasm of the le1941; 18: 12-16 (in Russian).

6 Szekler R. Ein Uvealsarkom bei eintmit Recklinghausenscher Krankhe126: 248-51.

7 Nordmann J. Cancer de la choroidehausen. Bull Soc OphtalmolFr 196

8 Nordmann J, Brini A, Ruolt J. Temeur melanique de la*. , ~ choroide et neurinomes chez un mime suiet. Bull Soc

4 * iD i- * * Ophtalmol Fr1%3;7:551-3.9 Yanoff M, Zimmerman LE. Histogenesis of malignant

melanomas of the uvea: III. The relationship of congenitalocular melanocytosis and neurofibromatosis to uveal

,,t,* 10 C*melanomas. Arch Ophthalmol 1967; 77: 331-6.10 Cernea P. Dobrescu G. Melanome malin uveal, manifestation

de la maladie de Recklinghausen. Ophthalmologica 1973;166:161-71.11 Wiznia RA, Freedman JK, Mancini AD, Shields JA. Malig-

,.> | nant melanoma of the choroid in neurofibromatosis. Am J* - Ophthalmol 1978; 86: 864-87.

*! X * 12 Croxatto JO, Charles DE, Malbran ES. Neurofibromatosisassociated with nevus of Ota and choroidal melanoma. Am

A JOphthalmol 1981; 92: 578-80.* 0 - 13 Specht CS, Smith TW. Uveal malignant melanoma and von

W, l bRecklinghausen's neurofibromatosis. Cancer 1988; 62:812-7.

,*'_;! 14 Crump T. Translation of case reports in Ueber die multiplen*i >** } ^ ^^Fibrome der Haut und ihre Beziehung zu den multiplen

S> w ; *; Neuromen bei F.v. Recklinghausen. Adv Neurol 1981; 29:

259-76...,s%qgvgw15. To KW, Rabinowitz SM, Friedman AH, Merker C,

- gS_ 11_-< Cavanaugh CP. Neurofibromatosis and neural crest neo-'V*-so-- Splasms: primary acquired melanosis and malignant mela-

noma of the choroid. Surv Ophthalmol 1989; 33: 373-9.-*%~ 16 Riccardi VM. von Recklinghausen neurofibromatosis. N Engl

JMed1981;305: 1617-27.17 Sergeyev AS. On the mutation rate of neurofibromatosis. Hum

X _;*t %Genet 1975; 28: 129-38.18 Barker D, Wright E, Nguyen K, et al. Gene for von

rw'M~i,-t *' Recklinghausen neurofibromatosis is in the pericentromericAl

region of chromosome 17. Science 1987; 236: 1100-2.19 Font RL, Ferry AP. The phakomatoses. Int Ophthalmol Clin

1972; 12: 31-42.20 Bolande RP. The neurocristopathies: a unifying concept of

- disease arising in neural crest maldevelopment. Hum Pathol1974; 5: 409-29.

21 Huson S, Jones D, Beck L. Ophthalmic manifestations ofneurofibromatosis. BrJ Ophthalmol 1987; 71: 235-8.

;-.....22 Lewis RA, Riccardi VM. von Recklinghausen neurofibro-matosis. Incidence of iris hamartoma. Ophthalmology 1981;88:348-54.

se.tainingforS100 23 Ilgren EB, Kinnier-Wilson LM, Stiller CA. Gliomas in;e stainingforSJOO neurofibromatosis: a series of 89 cases with evidence for

enhanced malignancy in associated cerebellar astrocytomas.PatholAnnu 1985; 1: 331-58.

24 Brasfield RD, Das Gupta TK. von Recklinghausen's disease: ais reported as 47, clinico-pathologic study. Ann Surg 1972; 175: 86-104.-thirds of enuclea- 25 Sayed AK, Bernhardt B, Perez-Atayde AR, et al. Malignant

schwannoma in siblings with neurofibromatosis. Cancernoma in the general 1987; 59: 829-35.1.39 Despite the lack 26 Healy FH, Mekelatos CJ. Pheochromocytoma and neurofibro-

matosis. NEnglJMed 1958; 258: 540-3.mne, nine of the 11 27 Modlin IM, Farndon JR, Shephard A, et al. Pheochromo-s in whom it was cytoma in 72 patients: clinical and diagnostic feature,

treatment and long term results. BrJSurg 1979; 66:456-65.ant melanoma were 28 Riccardi VM, Eichner JE. Neurofibromatosis: phenotype, naturaln in other series of history and pathogenesis. Baltimore: Johns Hopkins Univer-

sity Press, 1986: 162-8.,even tumours were 29 Silverman JF, Blahove M, Collins JL, Norris HT. Cutaneousas mixed cell, and malignant melanoma in a black patient with neurofibro-

matosis. AmJ Dermatopathol 1988; 10: 536-40.tumour in our case 30 Mastrangelo MJ, Goepp CE, Patel YA, Clark WH. Cutaneousowed extrascleral melanomain a patient with neurofibromatosis. Arch Dermatolile the present case 31 1979; 115:864-5.Hle the present case 31 Hope DG, Mulvihill JJ. Malignancy in neurofibromatosis.type of our tumour Adv Neurol 1981; 29: 33-56.

32 Yanoff M, Zimmerman, LE. Histogenesis of malignantpoor outcome, with melanoma of the uvea. Arch Ophthalmol 1967; 77: 331-6.[0%.40 33 Bader JL, Miller RW. Neurofibromatosis and childhood

leukemia. JPediatr 1978; 92: 925-9.34 Bestak M, Miller DR, Mouradian JS. Juvenile chronic myelo-

tJ, MacCarthy CS. Optic genous leukemia and dermal histiocytosis. Am J Dis Childof 85 histopathologically 1979;133: 831-3.2;89:1213-9. 35 McKeen EA, Bodurtha J, Meadows AT, et al. Rhabdomyosar-i, Riccardi VM, Whitford coma complicating multiple neurofibromatosis. J Pediatrromatosis. II. Incidence of 1978; 93: 992-3.:4; 91: 929-35. 36 Stay EJ, Vawter G. The relationship between nephroblastomarofibroma associated with and neurofibromatosis. Cancer 1977; 39: 2550-5.id: successful removal of 37 Walden PAM, Johnson AG, Bagshawe KD. Wilms's tumour7;12: 481-5. and neurofibromatosis. BrMedJr 1977; i: 813.of the choroid and von 38 Freedman SF, Elner VM, Donev ID, Gunta G. Albert DM.phthalmol 1940; 23: 73-8. Intraocular neurilemmoma arising from the posterior ciliarydisease, neurinoma of the nerve in neurofibromatosis. Ophthalmology 1988; 95:ft choroid. Vestn Oftalmol 1559-64.

39 Zimmerman LE. Malignant melanoma of the uvea. In:em Mitglied einer Familie Spencer WH, ed. Ophthalmic pathology. Philadelphia:eit. Ophthalmologica 1954: Saunders, 1986: 2072-136.

40 McLean IW, Foster WD, Zimmerman LE. Uveal melanoma:e et maladie de Reckling- location, size, cell type and enucleation as risk factors in1; 5: 322-5. metastasis. Hum Pathol 1982; 13: 123-32.

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