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Most common primary malignancy arising within the adult eye.
Represents 3-5% of all melanomas.
It is very different from cutaneous melanoma.
Arises from melanocytes of the choroid plexus, ciliary body, and the iris of the eye.
It is associated with a SOX10 gene mutation.
It is distinct from cutaneous melanoma with different molecular drivers and metastatic patterns and a different tumor-immune microenvironment.
Have characterisitc cytogenetic changes, ocnogenic mutations in GNAQ or GNA11, and a predilection to aggressively metastasize to the liver, resulting in a dismal prognosis.
Metastasis develop in approximately half of the patients, after which the prognosis is poor, with the historical median overall survival of approximately one year.
GNAQ or GNA11 mutations are seen in nearly all uveal melanomas.
GNAQ mutation is found in uveal melanomas, but not in conjunctival melanoma.
BRAF nor NRAS mutations never occur in uveal melanoma.
Somewhere between 10 and 100 times fewer mutations are present in uveal melanoma than in cutaneous melanoma.
Spread hematogenously while cutaneous melanoma is spread by lymphatics or hematogenously.
Overall chance of metastases is approximately 50%.
Rare, accounts for 3-5% of melanomas.
Metastasis occur to the liver predominantly.
Other sites of metastasis include lung, bone and skin
Up to 50% of patients will die with metastases after the treatment of the primary tumor.
Uveal melanoma maybe more aggressive upon metastatic disease than cutaneous melanoma.
Approximately 2500 people are diagnosed annually in the US, a rare form of melanoma rising in the iris, ciliary body, and choroid layer of the eye.
Annual incidence of 6 per million in the US.
More common in Caucasians and individuals with light eye coloration.
Treatment of the primary tumor requires removal of the eye in about 30% of patients.
Most patients can be treated with brachytherapy in which a radioactive plaque is implanted and remains in place for 2-4 days, depending upon the tumor size.
Brachytherapy can achieve local control in approximately 90% of cases in whom iodine 125 is the most commonly used isotope.
Ruthenium 106 isotope provides similar local control as iodine 125 but his fewer toxic effects.
Ruthenium 106 especially beneficial for smaller lesions.
It is not known whether early treatment decreases the patients chance of developing metastatic disease.
Metastases develop many years after initial eye treatment.
Almost 80% of patients with class 2 tumors, as determined by gene expression, develop metastasis by five years after diagnosis.
In the setting of metastatic disease, treatment options are limited and prognosis is poor.
Melanoma associated mortality depends on gene expression profiling class and tumor size.
The probability of death from metastatic melanoma by five years is as low as 10% for patients with small tumors less than 12 mm, and as high as 70% of patients with 12 mm basal diameter tumors or larger.
Metastases occur to the liver in 90% of cases of metastatic disease.
Diagnosis is usually a clinical one but with the recent information provided by biological analysis with gene expression providing prognosis information needle biopsy is being encouraged.
Metastatic disease occurs in about 25% of patients within five years and 50% at some point in their lives.
Median survival with liver metastases is 2 months without treatment and 5-9 months with treatment.
Advanced uveal melanoma has a one-year overall survival rate of approximately 40%, and no cytotoxic, targeted, or immunologic therapy has been identifiedto meaningfully to improve outcomes.
One-year survival with metastases 13% to 40%.
Median disease free interval 25 months and the initial site of metastases is the liver.
Unlike cutaneous, it is relatively resistant to immunotherapeutic agents.
Anti-CLA-4 blockade has achieved minimal efficacy in advanced uveal melanoma, with only 0-7% of patients achieving a response, and no overall survival benefits.
With blockade of the PD-1/PD-L axis response rates are 4% and disease control greater than 6 months in 9% of patients.
Studies of the improved effectiveness using adoptive transfer of TILs is promising.
The most common intraocular cancer.
Mutations in the gene GNAQ, encoding an alpha subunit of heterotrimetric G proteins, are found in 40% of uveal and melanomas.
83% of uveal melanomas have somatic mutations in GNAQ or GNA11(Van Raamsdonk CD et al).
Unlike cutaneous melanoma this lesion lacks mutations in BRAF, NRAS, or KIT.
Genetic differences translate into immunologic differences and cutaneous melanoma tends to have highly immune infiltrated and immunotherapy sensitive cells, where as the reverse is seen with uveal melanoma.
Patients with metastatic uveal disease have very little immune response against the tumor.
Associated with chromosome 3 monosomy.
Patients with an extremely high likelihood of metastatic disease include those with gene expression profile class 2 or BAP1 negative primary tumors.
The nevus of Ota, a bluish gray hyperpigmentation in the sclera and periorbital dermis is a risk factor.
Enucleation was the treatment primarily in the past, it is much less common now as radiation using proton therapy or brachytherapy is more predominant.
Enucleation may be required in cases of primary disease progression or recurrence.
One year overall survival of 73% reported with experimental agent IMCGP100 agent.
Liver metastases is still treated with hepatic tumor embolization with chemotherapy or radio therapy directly to liver tumors.
Objective response rates in metastatic disease range from 5-10% of the anti-PD-1 monotherapy and approximately 15% from combination Ipilimubab and nivolumab.
Bispecific T cell-engaging tebentafusp reduces survival hazard by 50%:
A bispecific protein significantly improved overall survival (OS) in metastatic uveal melanoma as compared with investigator’s choice of treatment, including checkpoint inhibitors.
Patients treated with tebentafusp had a median OS of 21.7 months versus 16.0 months for the control group.
In a study of tebentafusp treatment of patients with metastatic uveal melanomas resulting in longer overall survival than the control therapy with a survival of 73% at one year versus 59% in the control group.
Grade 3/4 treatment-related adverse events occurred infrequently, including a 1% incidence
The hepatic artery infusion of melphalan has been approved with a 36% response rate.