Primary Orbital Melanoma Associated With an Occult Episcleral Nevus FREE

Melanomas arising in the orbit can present diagnostic and managementchallenges to the physician. The pathogenesis of primary orbital melanomasis a matter of some debate. Primary melanomas arising in the orbit are rare,accounting for less than 1% of primary orbital tumors¹ andabout 2% of extenterations.² Most orbitalmelanomas arise from the uveal tract, conjunctiva, eyelids, or sinuses, and,infrequently, as metastases from distant primary sites.³ Approximately90% of primary orbital melanomas arise from melanocytes found in congenitalocular melanocytosis (including blue nevus and cellular blue nevus), orbitalmelanocytosis, or oculodermal melanocytosis (nevus of Ota).^{1 ,3 - 5} Thepresence of melanocytes has also been reported in the optic nerve sheath,orbital fat, extraocular muscles, and orbital periosteum, which theoreticallymay provide cells of origin for primary orbital melanomas.¹

Orbital biopsy may be required to diagnose orbital melanoma when noclinical evidence of melanocytosis of the periocular tissues or uveal tractis present. Even with an orbital biopsy, the histopathologic diagnosis canoften be difficult, especially if the tumor is amelanotic.⁶ Wedescribe a 36-year-old woman who developed a primary orbital melanoma thatapparently arose from a previously unreported focus of melanocytes, an occultnevus on the posterior sclera.

A 36-year-old woman was evaluated for right exophthalmos. The righteye had become increasingly prominent over several years, without pain, diplopia,or change in vision. No history of trauma or systemic medical problems wasreported. Magnetic resonance imaging (Figure1) and computed tomography (Figure2) revealed a well-circumscribed intraconal mass in the superiormedial quadrant of the right orbit, in apposition to the posterior surfaceof the globe. Orbital ultrasonography demonstrated irregular low internalreflectivity (Figure 3).

An examination revealed a visual acuity of 20/25 OU. The pupils wereequally reactive to light. Movements of the right inferior oblique and medialrectus muscles were restricted with a small right hypertropia and exotropia.The right eye was 4 mm more prominent than the left, with moderate resistanceto retropulsion. Eversion of the upper eyelids revealed a pink nodule in thesuperior conjunctival recess above the right eye (Figure 4). Results of an intraocular examination were unremarkable,and there was no evidence of unusual periocular or facial pigmentation.

The patient underwent exploration of the superior right orbit througha conjunctival incision above the globe. A biopsy was performed on a clinicallynonpigmented mass that was firmly adherent to the posterosuperior surfaceof the right eye. Frozen sections performed at the time of surgery were interpretedas "small blue cell tumor." Permanent histologic sections revealed a highlycellular proliferation of small, oval- to spindle-shaped cells with moderatenuclear pleomorphism and small nucleoli, arranged as nests and diffuse sheets(Figure 5C). The mitotic cell countwas low, with 1 mitosis per 100 high-power fields. Immunoperoxidase stainswere strongly positive for the melanoma cell markers MART1 (melanoma antigenrecognized by T cells) and NSE (neuron-specific enolase) antibodies, and thetumor also stained positive for HMB45 and S100 protein. The tumor cells didnot stain for cytokeratin, LCA (leukocyte common antigen), chromogranin, synaptophysin,GFAP (glial fibrillary acidic protein), EMA (epithelial membrane antigen),desmin, muscle actin, smooth muscle actin, or Myo D-1. Electron microscopicexamination confirmed melanocytic differentiation of the tumor. It revealedtightly packed cells with oval- to round-shaped nuclei with clumped chromatinand occasional nucleoli. Occasional cells contained membrane-bound structureswith features of stage III and IV melanosomes and intertwining cytoplasmicprocesses suggestive of Schwann cell differentiation. The diagnosis of malignantmelanoma was confirmed by independent reviewers at 3 different institutions.This lesion fits into a spectrum of previously reported primary melanocytictumors of the orbit and central nervous system, as it shares many histologicfeatures with meningeal melanocytomas.⁷

Serial indirect ophthalmoscopy and ultrasonography revealed no evidenceof an intraocular tumor. Extensive systemic workup, including chest radiography,abdominal imaging, liver function tests, bone scans, and thorough medical,dermatologic, and otorhinolaryngological evaluations, disclosed no evidenceof systemic malignancy.

The patient underwent subtotal exenteration of the right orbit, includingremoval of the tumor and the eye but with preservation of the eyelids. Grossly,the tumor was present as a 1.8 × 1.6 × 1.0-cm, well-circumscribedsolid mass on the posterior aspect of the eye, abutting but not invading thesclera, and surrounding the optic nerve Figure5. Microscopic examination revealed highly cellular spindled andepithelioid proliferation of predominantly amelanotic cells. In some areas,the cells were associated with pigment synthesis and were arranged in fascicles.There were 4 to 5 mitoses per 40 high-power fields. A ciliary nerve was presentin the sclera, surrounded by tumor cells, but no communication with the choroidwas identified. Extensive examination of multiple sections revealed a smallfocus of amelanotic melanocytic nevus cells in the posterior episcleral tissue(Figure 5). The nevus was composedof round to oval epithelioid cells without cytoplasmic pigmentation and withbland nuclei and inconspicuous nucleoli reminiscent of the type A melanocyticnevus cells present in cutaneous common or congenital nevi. There was no evidenceof pigmented spindled or dendritic cells characteristic of nevus of Ota orblue nevus. It was impossible to determine histologically if the melanomaarose from or in conjunction with the nevus. However, close association betweenthe nevus and melanoma suggests that the nevus may be a precursor lesion.Because the tumor microscopically extended to the surgical margins, the patientunderwent removal of additional orbital tissue 1 month later, at which timeno tumor was found in any of the surgical specimens. The patient subsequentlyreceived a full treatment cycle of radiotherapy to the right orbit and hashad no evidence of local recurrence or metastasis for 2 years.

Primary orbital melanomas may exhibit exophthalmos, distorted vision,or diplopia, and their onset may be rapid or insidious.^{3 ,8} Althoughslow growth is usually associated with a benign lesion, this case shows thatan orbital melanoma may enlarge painlessly over several years.⁹ Primaryorbital melanomas have been reported to occur in all races, with an olderage at onset in the setting of ocular or oculodermal melanocytosis (50-70years) compared with the setting of a cellular blue nevus (6-27 years).³ The demographics for primary orbital melanoma aresimilar to those for uveal melanoma.⁸

The rarity of primary orbital melanomas leads to low clinical suspicionin the differential diagnosis of orbital tumors. Intraoperative diagnosismay be difficult, especially in amelanotic tumors, as they are often mistakenfor other more common lesions. Classically, orbital melanomas are often dark,circumscribed masses with a pseudocapsule. In many instances, frozen-sectiondiagnosis will indicate a small blue cell tumor with a broad histologic differentialdiagnosis, which, in addition to melanoma, includes lymphoma, carcinoma, embryonalrhabdomyoma, and neuroendocrine tumors. Permanent histologic sections andimmunohistochemical studies using markers of melanocytic differentiation,such as S100, MART1 (melanin A), NSE, HMB45, and tyrosinase or microphthalmiatranscription factor are necessary to establish the final diagnosis. Identificationof melanosomes on electron microscopy may prove helpful.⁶ Thepotential for local invasion or metastasis varies widely, and strict prognosticindicators for orbital melanoma have not been established. Histopathologicevidence of aggressive behavior may be instrumental in guiding therapy. Owingto the small number of reported cases of primary orbital melanoma, the bestmanagement has not been clearly established.¹⁰ Relativelylow-grade tumors, such as the one described here, may be managed fairly conservatively,without the need for total exenteration.⁹ Mixedcell type and high mitotic count,⁸ neitherof which were found in this patient, were proposed as negative prognosticindicators.

Melanomas are believed to arise from cells derived from neuroectodermalorigin. In the orbit, these precursor cells are normally found in the uveaand the conjunctiva, but other orbital tissues may harbor neuroectodermalcells capable of transformation into melanoma.¹ Bluenevi and cellular blue nevi are also believed to be derived from neural crestcells migrating with developing nerves, and have been found in most primaryorbital melanomas.^{1 ,3 ,5} Itis difficult to definitively classify the nevus identified in this case becauseof its small size, but the histologic features are different from blue nevusor nevus of Ota. The histologic features of the nevus cells resemble thoseof type A nevomelanocytes of dermal common acquired or congenital nevi. Therefore,it may represent an episcleral analog of dermal common acquired or congenitalnevus. The nevus was intimately associated with the melanoma, and it is reasonableto speculate that the melanoma arose from this nevus. However, definitiveproof that the nevus is indeed a precursor lesion is lacking. To our knowledge,of the approximately 50 cases of primary orbital melanoma reported in theliterature,⁸ this is the first case suggestedto be associated with an occult nevus of non–blue nevus type.

The authors have no relevant financial interest in this article.

Corresponding author and reprints: Arthur S. Grove, Jr, MD, 50 StanifordSt, Third Floor, Boston, MA 02114 (e-mail: agrove@attbi.com).