Melanoma is a malignancy of melanocytes and can present as a primary malignancy, secondary malignancy due to local extension, or metastatic lesion from a distant primary lesion . Primary orbital melanoma is exceedingly rare, accounting 1% of all orbital tumors and less than 1% of all primary orbital tumors . Secondary orbital melanoma accounts for 5-15% of all metastatic orbital tumors, and is therefore more common than primary orbital melanoma, but relatively uncommon as a whole .
Orbital melanoma can be broadly categorized as a primary or secondary malignancy. Secondary orbital melanoma can then be further classified based on local or distant metastasis. Primary orbital melanoma frequently arises in pre-existing pigmentary lesions, however this is not always the case . Rose et al conducted a study on 89 patients and found that the choroid (51%), was the most common primary location followed by the conjunctiva (17%) for secondary orbital melanoma. Additional documented sites of primary origin include the skin (12%), eyelid (2%), and nose/sinuses (3%) .
The origin of primary orbital melanoma is thought to be deep mesenchyme-neurotropic melanocytes, which undergo malignant transformation . These are considered ectopic melanocytes, as this cell type is typically absent in the orbit . Uveal melanoma is the most common primary intraocular malignancy in adults with approximately 85-90% arising from choroidal melanocytes. Melanomas may also arise from the iris (3%-5%) or ciliary body (5%-8%) . Extrascleral spread of these two entities can lead to orbital melanoma.
Melanocytes are neural crest derived and despite usually occurring in skin, they can also arise wherever neural crest cells migrate (i.e. the brain or GI tract) . Cutaneous or skin melanoma is most often associated with de novo melanoma formation (60-80%). Conversely, benign nevi can turn malignant (20%-40% of cases) .
Secondary orbital melanoma by local extension from the conjunctiva, is a result of metastatic transformation of melanocytes from the basal layer of the conjunctival epithelium. These atypical melanocytes then invade the substantia propria; a similar origin is present in cutaneous and eyelid melanomas . Distant cutaneous melanomas can metastasize to the orbit through lymphatic or hematogenous spread .
Secondary orbital melanoma is often seen in extrascleral extension of intraocular melanoma, orbital extension of conjunctival and eyelid melanomas, recurrence after surgical treatment of an ocular melanoma, or as a metastasis of the orbit from a distal cutaneous melanoma .
Risk Factors and Pathophysiology
Primary orbital melanoma is commonly associated with a predisposing pigmented lesion, such as oculodermal melanocytosis, congenital ocular melanocytosis, blue cellular nevus, and orbital melanocytosis. 90% of patients with primary orbital melanoma have an associated history of predisposing lesion . In a retrospective study of 21 cases of primary orbital melanoma, Tellada et al found that 90% of patients had an associated blue nevus, and 47.5% had some form of congenital melanosis .
Neither primary nor secondary orbital melanoma has a strong predilection for either sex . Most patients presenting with either primary or secondary lesions are of white northern European descent.
Given that orbital melanoma may represent metastatic disease from a distant site, risk factors for cutaneous melanoma should be considered. These include family history, excessive exposure to UV-A radiation, having blue eyes and red/fair hair, fair complexion, large number of benign and/or dysplastic nevi, and immunosuppression .
Imaging aids in the diagnosis of orbital melanoma, however a definitive diagnosis requires biopsy with confirmatory pathological examination. Biopsy should be avoided in those with ocular melanocytosis to prevent potential spread .
For primary orbital melanoma, patients with pre-existing pigmented lesions should be monitored, as primary orbital melanoma frequently arises within pre-existing lesions . Given that secondary orbital melanoma is not seen infrequently, there should be a high clinical index of suspicion in a patient with a history of melanoma diagnosed elsewhere. The mean-time-to-diagnosis following primary melanoma for a patient with secondary orbital melanoma varies greatly, ranging from 0 months, diagnosed at the time of primary melanoma, to 34 years .
Proptosis, particularly unilateral proptosis, is often seen on exam . Additional exam findings include ptosis, abnormal eye movements, chemosis, and conjunctival injection . Optic nerve compression can result in advanced cases, and optic disc edema may be noted on exam.
Suggested Exam findings to note:
- Hertel exophthalmometry
- Color vision testing (red-desaturation, color plates, etc.)
- Extraocular muscle motility
- Visual acuity and intraocular pressure
- Anterior and posterior segment examination
- Visual field testing
- Macula and optic nerve OCT
In those with pre-existing nevi, signs associated with malignant transformation include color variation, increased nodularity, and bleeding .
Both primary and metastatic tumors present with diplopia due to involvement of the extraocular muscles . Patients may also experience pain, which may be periorbital or retro-orbital, however some patients may be pain-free .
CT findings are nonspecific, demonstrating a well-defined homogenous mass located intraconally or along extraocular muscles (5). Evidence of invasion of the orbital roof, retrobulbar fat, or cavernous sinus may be seen . Due to its well-defined appearance, orbital melanoma can be mistakenly identified as benign .
Magnetic Resonance Imaging
The paramagnetic properties of melanin shorten T1 and T2 relaxation, which in turn causes a hyperintense appearance in comparison to vitreous and hypointense appearance in comparison to fat on T1-weighted imaging. On T2-weighted imaging, lesions are hyperintense to fat and muscle and hypointense to vitreous . Orbital melanoma enhances with gadolinium and an increased signal is seen with fat saturation sequences.
A study of 129 patients with primary orbital melanoma conducted by Caplan et al found that the most common histological category was melanoma not otherwise specified (86.6%), followed by epithelioid melanoma (8.5)% . Additional histologic categories reported included mixed epithelioid and spindle (1.6%), amelanotic (0.8%), spindle type A (0.8%), and spindle type B (1.6%).
Features associated with metastatic melanoma include polygonal or spindle-shaped cells; large, round to oval nucleoli; and mitotic figures . Cutaneous metastatic melanoma often presents with epithelioid cell subtype. Confirmatory staining for melanoma can be done with S100, HMB-45, or melan-A.
Orbital melanoma can be misdiagnosed as a benign tumor due its radiographic appearance . Potentially benign etiologies include tumors and vascular malformations such as schwannoma, fibrous histiocytoma, arteriovenous malformations, and cavernous hemangiomas.
Management consists of surgical options, including exenteration, local excision, and debulking, as well as systemic medical therapy with chemotherapeutic or immunologic agents. Localized radiotherapy is another treatment modality.
Systemic medical treatment has specifically been used in the setting of metastatic melanoma . Previously, cytotoxic chemotherapy was the mainstay of treatment, however newer immunotherapy agents are available and have demonstrated success in improving overall survival in malignant melanoma . Specific agents include PD-1 inhibitors nivolumab and pembrolizumab, and CTLA-4 inhibitor ipilimumab. The benefit of immunotherapy over chemotherapy is the lower side effect profile, thus these drugs may be better tolerated. Treatment outcomes for the use of immunotherapy specifically in metastatic orbital melanoma have not been well-documented.
Medical follow up
Those receiving immunological agents should be monitored by the treating oncologist for adverse outcomes, which can be broadly classified into dermatologic, gastrointestinal/hepatic, and endocrinologic . With the exception of endocrinopathy, most adverse effects are responsive to corticosteroids and paucity of immunotherapy use. Ocular side effects have been noted with immune checkpoint inhibitor s (ipilimumab, pembrolizumab and nivolumab), most commonly these are uveitis and dry eye .
Surgery and Radiotherapy
Surgery plays a role in both local disease management and palliation of symptoms, it is particularly useful in tumors at a mean size of 6 cm . Surgical debulking or complete excision is dependent on the tumor characteristics. Determining whether the tumor is diffuse, well-defined, and infiltrative are all important characteristics. Rose et al, did not routinely perform orbital exenteration as there is proven survival benefit and tumor debulking or complete resection was effective in addressing the immediate consequences of an intraorbital mass..
Radiation therapy may be offered prior to surgery to reduce tumor size, or as an adjuvant following debulking or exenteration . In smaller tumors, radiotherapy may be offered as monotherapy .
Orbital exenteration is a radical and disfiguring procedure that is associated with significant psychosocial disability and functional impairment . Exenteration involves removal of orbital and/or periorbital contents—including the globe, adnexa, and part of the bony orbit as well as the periorbita and surrounding face. It is infrequently performed and is only considered in the case of improving the chance of survival for the patient . In one study conducted over 13 years by Rahman et al, complications and comorbidities were detailed for 64 patients undergoing orbital exenteration. 15 patients had a Sino-orbital fistula, 4 failed skin graft requiring regrafting, 3 failed skin graft allowed to granulate, 1 chronic discharge, 1 cerebrospinal fluid leak . Some studies suggest that exenteration for melanoma has no impact on survival and might even be detrimental . Rendahl et al. proposed that exenteration in cases of extrascleral extension from a uveal melanoma might disseminate tumor cells further . Due to morbidity with outcomes associated with exenteration and radiotherapy associated skin graft failing, patients require careful counseling to make an informed decision .
Surgical follow up
Patients require regular follow-up to monitor for disease progression or recurrence following surgical management as well as long-term effects of radiation therapy if received, such as radiation retinopathy and optic neuropathy .
Primary orbital melanoma has been known to metastasis to the liver and lung, with a 5-year prevalence of 38% . Additional complications include those associated with the various treatment modalities and include postoperative complications and the potential need for additional surgery; radiation retinopathy, optic neuropathy, and corneal scarring following radiation treatment; and systemic adverse effects of chemotherapeutic or immunologic agents.
Median overall survival in a study conducted by Caplan et al on 129 patients with primary orbital melanoma was 36.9 months, with mean 5-year survival of 42% . Secondary orbital melanoma median survival was 24 months in a study on 89 patients conducted by Rose et al, and those with a cutaneous primary had the worst outcomes .
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