Uveal melanoma is a cancer that forms in the pigmented layer of the eye, making it the most common primary eye cancer in adults. It develops from melanocytes, the same pigment-producing cells responsible for skin melanoma, but it behaves very differently. Unlike skin melanoma, uveal melanoma has a strong tendency to spread to the liver, and it responds poorly to the immunotherapy drugs that have transformed treatment for skin melanoma. About 90% of these tumors arise in the choroid (the blood vessel layer at the back of the eye), roughly 10% in the ciliary body (the ring of tissue behind the iris), and a smaller fraction in the iris itself.
How Uveal Melanoma Develops
The uvea is the middle coat of the eye, sandwiched between the white outer shell (sclera) and the retina. It contains melanocytes that give the iris its color and help protect the eye from stray light. When these melanocytes begin dividing uncontrollably, a tumor forms. Choroidal melanoma, the most common subtype, grows in the highly vascular layer that nourishes the retina. Ciliary body melanoma is rarer and harder to detect because the ciliary body sits behind the iris, out of direct view.
At the genetic level, uveal melanoma is driven by mutations in two closely related genes called GNAQ and GNA11. One or the other is mutated in roughly 80 to 90% of cases, and these mutations are thought to be early events that kick off tumor growth. What determines whether the cancer becomes dangerous is often a second genetic change: loss of one copy of chromosome 3, combined with inactivation of a gene called BAP1. About half of primary uveal melanomas carry this BAP1 change, and those tumors have a significantly higher risk of spreading to distant organs.
Risk Factors
Uveal melanoma shares some risk factors with skin melanoma. Fair skin, blue or light-colored eyes, blond or red hair, and a tendency to freckle all increase risk. It is more common in people of European descent, though it can affect individuals of any ethnicity. Unlike skin melanoma, there is no clear link to ultraviolet radiation exposure, which makes it biologically distinct despite involving the same cell type.
A small percentage of cases run in families. The strongest known genetic risk factor is an inherited mutation in the BAP1 gene, found in roughly 1.6 to 3% of uveal melanoma patients. People who carry this mutation face elevated risk not only for uveal melanoma but also for skin melanoma, mesothelioma, kidney cancer, and meningioma. The mutation follows a dominant inheritance pattern, meaning a single copy from one parent can increase cancer risk, though not everyone who carries it will develop disease.
Symptoms and How It Is Found
Many uveal melanomas cause no symptoms at all and are discovered during a routine dilated eye exam. When symptoms do appear, the most common is a gradual loss of visual sharpness. Some people notice flashing lights, a new cluster of floaters, or a shadow or dark spot in their field of vision. These symptoms happen because the tumor can push on or detach the retina, and fluid can accumulate beneath it.
On examination, an ophthalmologist typically sees a raised mass in the back of the eye. About 55% of these tumors are darkly pigmented, 15% have little or no pigment, and 30% are a mix. Orange-colored deposits on the tumor surface are a hallmark finding. An ultrasound of the eye (B-scan) is the key diagnostic tool: uveal melanoma appears as a dome-shaped or mushroom-shaped mass with a characteristic low internal reflectivity. If the tumor has broken through a membrane called Bruch’s membrane, it takes on the classic mushroom shape that is nearly diagnostic. Specialized dye tests can reveal the tumor’s own blood supply, another distinguishing feature.
Treatment Options
The goal of treatment is to destroy or remove the tumor while preserving as much vision as possible. For small and medium-sized tumors, radiation is the standard approach. Plaque brachytherapy involves surgically attaching a small radioactive disc to the outside of the eye, directly over the tumor, for several days. A landmark clinical trial (the Collaborative Ocular Melanoma Study) showed that this approach produces survival outcomes equivalent to removing the eye entirely for medium-sized tumors, making it the preferred choice when the tumor’s size and location allow it.
Proton beam therapy is an alternative form of radiation that delivers a highly focused beam of protons to the tumor. It is particularly useful for tumors thicker than 8 mm, tumors located near the optic nerve where a radioactive plaque would damage it, and anteriorly located tumors in the iris or ciliary body. Long-term studies show local tumor control rates of about 92 to 94% at 5 to 10 years with proton therapy.
Removal of the eye (enucleation) is reserved for cases where radiation is not feasible. This typically means the tumor is very large (thicker than 12 mm or wider than 18 mm at the base), has broken through the wall of the eye into the orbit, has seeded into the eye’s drainage system, or is causing uncontrollable pressure buildup inside the eye.
Survival and Prognosis
Survival depends heavily on tumor size at diagnosis. For early-stage tumors (stages T1 and T2), five-year survival exceeds 90%. At stage T3, it drops to around 80%, and at stage T4 it falls to roughly 65%. The overall five-year disease-specific survival across all stages is about 84%, but by ten years that number decreases to around 66%, reflecting the fact that uveal melanoma can metastasize years or even a decade after successful treatment of the eye tumor.
The genetic profile of the tumor matters as much as its size. Tumors with BAP1 inactivation and loss of chromosome 3 carry the highest metastatic risk. Genetic testing of the tumor, done either through a biopsy or after enucleation, is now a routine part of care because it determines how aggressively a patient needs to be monitored afterward.
Why the Liver Is the Main Concern
Up to half of uveal melanoma patients eventually develop metastatic disease, and the liver is the primary destination in the vast majority of cases. This liver tropism distinguishes uveal melanoma from most other solid tumors and has major implications for follow-up. In the United States, guidelines recommend imaging the liver every 3 to 6 months for the first five years in high-risk patients, then every 6 to 12 months out to ten years. In Europe, liver ultrasound every 6 to 12 months for 10 to 15 years is the typical protocol. Lower-risk patients are generally screened annually.
Treatment for Metastatic Disease
Once uveal melanoma spreads to the liver, it has historically been very difficult to treat. Standard checkpoint immunotherapy drugs that work well for skin melanoma have shown limited benefit here, largely because uveal melanoma creates a different immune environment around itself.
A drug called tebentafusp (sold as Kimmtrak) marked a turning point when it was approved in 2022. It works by simultaneously binding to a protein on the surface of melanoma cells and recruiting the body’s immune cells to attack them. In a phase III trial comparing it to pembrolizumab (a standard immunotherapy), tebentafusp improved one-year survival from 59% to 73% in previously untreated patients. Pooled data across multiple studies show a median overall survival of roughly 20 months, with a one-year survival rate of about 69% and a two-year rate of 42%. There is an important limitation: the drug only works in patients who carry a specific immune marker called HLA-A*02:01, which is present in roughly 40 to 50% of people of European descent. Patients who receive tebentafusp as a first treatment tend to do better than those who have already had other therapies.
Liver-directed treatments, including surgical removal of liver tumors, targeted radiation to the liver, and procedures that deliver chemotherapy directly into the liver’s blood supply, are also used depending on how widely the cancer has spread.