Orbital melanoma is a malignant tumor derived from melanocytes that occurs within the orbit. It is broadly classified into primary and secondary types.
Primary
Definition: Malignant transformation of ectopic melanocytes within the orbit.
Frequency: Extremely rare, accounting for less than 1% of all orbital tumors.
Predisposing factors: 90% are associated with pigmented lesions such as blue nevus, nevus of Ota, and orbital melanocytosis.
Secondary
Definition: Orbital involvement due to invasion from surrounding tissues or distant metastasis.
Frequency: Accounts for 5–20% of all metastatic orbital tumors. Metastatic orbital tumors constitute 2–7% of all orbital tumors.
Primary sites: Choroid 51%, conjunctiva 17%, skin 12%, sinonasal cavity 3%, eyelid 2%.
Epidemiological data for primary orbital melanoma are as follows. Based on a pooled analysis of 88 cases from a literature review 1).
The diagnostic interval for secondary orbital melanoma ranges widely from 0 months to 34 years after diagnosis of the primary melanoma. In adults, cutaneous malignant melanoma can also be a primary source of orbital metastasis.
Primary orbital melanoma originates from ectopic melanocytes within the orbit and is extremely rare, accounting for less than 1% of all orbital tumors. Secondary orbital melanoma results from invasion or distant metastasis of uveal, conjunctival, or cutaneous melanoma, comprising 5–20% of all metastatic orbital tumors. The prognosis is worse for secondary orbital melanoma, with a median survival of 24 months.
The frequencies of major subjective symptoms are shown below (from a literature review of 88 cases) 1).
| Symptom | Frequency |
|---|---|
| Unilateral proptosis | 73% |
| Decreased vision | 32% |
| Diplopia | 15% |
| Periorbital pain | 14% |
| Palpable mass | 9% |
Other symptoms may include ptosis, eyelid swelling, relative afferent pupillary defect (RAPD), and poliosis1).
Restriction of eye movement due to malignant tumor orbital invasion progresses relatively rapidly.
The following findings and tests should be evaluated during an ophthalmologic examination:
Primary orbital melanoma arises from malignant transformation of ectopic deep mesenchymal neurotropic melanocytes within the orbit. Melanocytes are derived from the neural crest and can form tumors in neural crest migration sites other than the skin, such as the brain and gastrointestinal tract.
Pigmented precursor lesions are present in 90% of primary cases 1).
In a literature review of 88 cases, 24% had associated ocular melanocytosis or nevus of Ota 1).
Risk factors include family history, exposure to ultraviolet A radiation, blue eyes, red or blond hair, fair skin, numerous nevi, and immunosuppression.
In 90% of primary orbital melanomas, predisposing pigmented lesions exist, and nevus of Ota (oculodermal melanocytosis) is one of the representative predisposing factors 1). However, not all nevi of Ota become malignant; malignant transformation is rare. Regular ophthalmologic follow-up is important.
Definitive diagnosis is made by biopsy and pathological examination. It cannot be confirmed by imaging alone. In patients with ocular melanocytosis, biopsy should be avoided to prevent dissemination.
A comparison of CT and MRI findings is shown below.
| Feature | CT | MRI |
|---|---|---|
| Morphology | Well-defined homogeneous mass | Enhancement with gadolinium contrast |
| Signal Characteristics | Useful for detecting bone destruction | T1 hyperintensity, T2 hypointensity (melanin paramagnetic property) |
| Limitations | May be misdiagnosed as benign tumor | Choroidal melanoma also shows similar signals |
On MRI, melanin’s paramagnetic properties cause high signal on T1-weighted images (compared to vitreous) and low signal on T2-weighted images (compared to vitreous). It enhances with gadolinium and signal increases on fat-suppressed sequences.
The tumor is depicted within the muscle cone or along the extraocular muscles, and may show invasion into the orbital roof, retrobulbar fat, or cavernous sinus.
The histological subtypes are as follows:
Immunohistochemical stains used for confirmation are S100, HMB-45, and Melan-A 1). SOX-10 is also positive 1).
Because imaging findings are well-defined, misdiagnosis with benign tumors (schwannoma, fibrous histiocytoma, arteriovenous malformation, cavernous hemangioma) can occur 1). Differentiation from orbital melanocytoma is also important.
Surgery is the mainstay of treatment 1). The surgical options are local excision (excision/debulking) and orbital exenteration.
Local Excision
Indications: Cases where the tumor location and size are resectable.
Features: Preserves function and cosmesis.
Outcomes: Selected in 38% of 88 cases in a literature review. No significant difference in survival or recurrence rates compared to orbital exenteration (p=.16) 1).
Orbital Exenteration
Indications: When radical resection is difficult and adjuvant therapy is not expected to be effective.
Features: High curability but involves significant psychosocial and functional impairment.
Outcomes: Selected in 57% of 88 cases in a literature review. No difference in survival compared to local excision (p=.16) 1).
Major complications of orbital exenteration include sino-orbital fistula (15/64 cases), skin graft failure, chronic discharge, and cerebrospinal fluid leakage. Reconstruction methods range from spontaneous granulation to free flaps. Reconstruction of the closed cavity with a temporalis muscle flap is considered useful for restoring orbital volume and improving tolerance to adjuvant radiotherapy 2).
Addition of adjuvant radiotherapy significantly improves the hazard ratio for death compared to surgery alone (HR 0.2, 95% CI 0.06–0.69, p=.01) 1).
For small tumors, radiation therapy alone is also an option.
Late complications after radiotherapy include radiation retinopathy, optic neuropathy, and corneal scarring, which require attention.
Although used for metastatic melanoma, evidence specific to orbital melanoma is limited. For metastatic tumors, treatment is performed in collaboration with other departments (dermatology, medical oncology, etc.) that manage the primary lesion.
There is a case report of complete remission with no recurrence for 2 years in a patient with uveal melanoma orbital invasion (including intraperitoneal metastasis) after 9 cycles of pembrolizumab2).
Analysis of 88 cases in a literature review showed no significant difference in survival or recurrence rates between orbital exenteration and local resection (p=.16)1). On the other hand, adding adjuvant radiotherapy to surgery significantly improves the hazard ratio for death (HR 0.2, p=.01). The choice of surgical procedure is made considering tumor location, size, and general condition.
Primary orbital melanoma originates from melanocytes of the leptomeninges, ciliary nerves, or ectopic melanocyte nests within the orbit 1). Melanocytes are neural crest-derived cells, and tumors can arise at their migration sites (including the brain and gastrointestinal tract, in addition to the skin). 60–80% of cutaneous melanomas arise de novo, while 20–40% result from malignant transformation of benign nevi.
Two genetic subgroups of primary orbital melanoma have been reported 1).
Regarding prognosis, SF3B1 and EIF1AX mutations suggest a favorable prognosis 1). Loss of BAP-1 expression is associated with metastasis in uveal melanoma but is not necessarily linked to poor prognosis in primary orbital melanoma 1).
Two groups have been reported: the uveal melanoma type (GNAQ/GNA11/SF3B1 mutations) and the conjunctival melanoma type (NRAS/TERTp mutations) 1). It has been suggested that the location of the tumor within the orbit may correspond to the genetic type, and this may be used in the future to predict response to immunotherapy.
In a literature review by Adetunji et al. (2021), the first use of ipilimumab plus nivolumab combination therapy for primary orbital melanoma was reported 1). After two cycles, immune-related aseptic meningitis and autoimmune hepatitis developed, leading to discontinuation, and no tumor shrinkage was achieved.
The response rate of immune checkpoint inhibitors for uveal melanoma is lower than for cutaneous melanoma. Low tumor mutational burden is considered one of the contributing factors 1).
On the other hand, a case of complete remission with pembrolizumab in a patient with orbital invasion of uveal melanoma (including intraperitoneal metastasis) has been reported 2), and predicting immunotherapy response through genetic testing is cited as a future challenge 1).
