Uveal melanoma C69.3; C69.4;

A rare malignant neuroectodermal tumor of the uveal melanocytes. Uveal melanoma includes melanomas of the choroid, ciliary body, and iris. It is the most common primary intraocular malignant tumor in adults and is biologically distinct from cutaneous melanoma.

Classification and Distribution by Location:

• Chorioidea (approximately 85–90%): the most common form
• Ciliary body (approximately 5–10%): often diagnosed later; poorer prognosis
• Iris (approximately 3–5%): usually detected earlier; often a more favorable prognosis

The incidence of uveal melanoma in Europe and North America is approximately 4–8 new cases per 1 million inhabitants per year. The peak incidence occurs between the ages of 55 and 70. People of European descent with fair skin and light-colored irises are significantly more likely to be affected. Cases in children are extremely rare. The incidence increases from southern to northern Europe. Men are slightly more likely to be affected than women.

Uveal melanoma develops through a gradual accumulation of genetic changes. It is characterized by a two-stage molecular progression:

• Early initiator mutations primarily activate the Gαq signaling pathway.
• Secondary progression mutations determine differentiation, metastasis risk, and disease progression.

In contrast to cutaneous melanoma, classic uveal melanoma typically does not exhibit the high mutation burden characteristic of UV-induced melanomas. Mutations in BRAF, NRAS, and KIT—which play a significant role in cutaneous melanoma subtypes—are rare in posterior uveal melanoma. In iris melanomas, UV-associated changes or changes similar to those seen in cutaneous melanomas are more frequently detected.

Risk Factors and Predispositions: Establishedor probable risk factors include:

• light iris color,
• fair skin,
• ocular or oculodermal melanocytosis, particularly Ota’s nevus,
• choroidal nevus,
• BAP1 tumor predisposition syndrome,
• less commonly: family history.

The role of natural or artificial UV exposure in posterior uveal melanoma has not been conclusively established. In iris melanoma, UV-associated mutation signatures are more frequently detected.

Molecular Pathogenesis: Activating mutations in the GNAQ or GNA11 genes—and, less commonly, in the CYSLTR2 or PLCB4 genes—lead to the constitutive activation of the following signaling pathways:

• PKC–RAF–MEK–ERK
• YAP/TAZ–Hippo
• PI3K–AKT–mTOR
• Trio–Rho/Rac

These early changes (initiator mutations) are thought to be essential for the development of uveal melanoma, but do not alone determine its metastatic potential. This is primarily shaped by subsequent changes in BAP1, SF3B1, or EIF1AX. Activating mutations are also found in GNAQ (59%) and, to a lesser extent, in GNA11 (16%) in most blue nevi (Möller I et al. 2017). 

Early initiator mutations and their frequencies:

• GNAQ (approximately 40–50%): Activating hotspot mutations, mostly at codon Q209, less commonly R183; constitutive activation of Gαq
• GNA11 (approximately 30–45%): Functionally largely analogous to GNAQ; Q209 or R183 mutations
• CYSLTR2 (approximately 2–4%): Most commonly an activating L129Q mutation; activates Gαq/Gα11
• PLCB4 (approximately 2–4%): Activating D630 mutation; located in the same signaling pathway distal to GNAQ/GNA11

Mutations in these genes are largely mutually exclusive. Additionally, other progression mutations play a role in the pathogenesis of uveal melanoma:

• BAP1 ( approximately 35–45% of primary tumors): This mutation type is detected in up to 80% of highly metastatic tumors. The BAP1 protein it encodes acts as a tumor suppressor and as a nuclear deubiquitinase. Mutations in BAP1 lead to early metastasis.
• SF3B1 (approximately 15–25%): The encoded protein is a component of the spliceosome. R625 mutations are associated with an intermediate risk and often late metastasis.
• EIF1AX (approximately 8–15%): The encoded protein is a translation initiation factor; mutations in EIF1AX usually occur in exon 1 or 2. They are associated with a low risk of metastasis.
• Other very rare progression-associated mutations have been identified in the SRSF2 and MBD4 genes. MBD4 encodes a DNA glycosylase. The loss of base excision repair can lead to a hypermutated tumor phenotype.

BAP1, SF3B1, and EIF1AX mutations are generally mutually exclusive. They characterize three distinct clinical courses:

• EIF1AX: tumors with a favorable prognosis
• SF3B1: intermediate risk, with metastases often occurring only after many years
• BAP1: aggressive phenotype with an early risk of hematogenous metastasis

Note: BAP1 Tumor Predisposition Syndrome: In addition to somatic mutations, pathogenic germline variants in BAP1 also occur. They cause the autosomal dominant BAP1 Tumor Predisposition Syndrome. This syndrome includes, in particular: uveal melanoma, cutaneous melanoma, BAP1-inactivated melanocytic tumors, malignant mesothelioma, andclear-cell renal cell carcinoma.

Many small tumors are discovered incidentally during ophthalmological examinations. Possible symptoms include:

• decreased vision in one eye,
• blurred vision,
• visual field defects,
• photopsia,
• “floaters,”
• metamorphopsia,
• secondary retinal detachment,
• visible pigmented iris lesion,
• pupillary distortion,
• secondary glaucoma,
• rarely pain.
• Due to their peripheral location, ciliary body melanomas often remain clinically silent for a long time.

Metastasis: Metastasis of uveal melanoma occurs almost exclusively via the bloodstream, as the uvea lacks classic lymphatic vessels. Approximately 40–50% of patients develop distant metastases over the long term. The following pattern of involvement is expected in cases of metastasis:

• Liver: in approximately 85–95% of cases with metastasis
• Lungs, bones, skin, and subcutaneous tissue
• Other organs: Micrometastases may already be present years before treatment of the primary tumor. Therefore, even after successful local tumor control, a lifelong risk of metastasis persists.

Human genetic counseling should be considered in particular in cases of:

• a young age at onset,
• bilateral or multifocal uveal melanoma,
• a positive family history,
• additional BAP1-associated tumors.

Histologically, the following distinctions are made:

• Spindle cell type: predominantly spindle-shaped, relatively well-differentiated tumor cells; more favorable prognosis.
• Epithelioid cell type: large pleomorphic cells with prominent nucleoli; poor prognosis.
• Mixed type: a combination of both cell types.

Adverse histological findings include:

• high mitotic activity,
• extrascleral spread,
• lymphocytic infiltrates,
• vascular loops or closed vascular networks,
• loss of nuclear BAP1 expression.

The diagnosis is usually made based on clinical findings and imaging:

• indirect ophthalmoscopy,
• slit-lamp examination,
• fundus photography,
• ocular ultrasound,
• optical coherence tomography,
• fundus autofluorescence,
• Fluorescein or indocyanine green angiography,
• orbital MRI if necessary.

A fine-needle aspiration biopsy or tumor biopsy may be performed for definitive diagnosis and molecular risk stratification. The following are examined in particular:

• Chromosomes 3 and 8q,
• BAP1, SF3B1, EIF1AX,
• gene expression class,
• PRAME expression(Preferentially Expressed Antigenin Melanoma) (Salzano S et al. 2025; Turner N et al. 2024). 

Choroidal nevus

Congenital hypertrophy of the retinal pigment epithelium

Melanocytoma

Choroidal hemangioma

Metastasis of an extraocular tumor

Retinal or choroidal hemorrhage

Age-related macular degeneration

Pigmented lesions of the iris pigment epithelium

Leiomyoma or medulloepithelioma of the ciliary body

Localized disease. 

Depending on the size, location, visual function, and patient factors, the following options may be considered:

• Plaque brachytherapy,
• proton or other particle radiation therapy,
• stereotactic radiation therapy,
• local tumor resection,
• enucleation for large or complex tumors,
• transpupillary thermotherapy in selected cases,
• close monitoring of small lesions with an unclear diagnosis.

Local treatment achieves good control of the primary tumor in most patients, but does not reliably prevent the development of micrometastases that have already formed.

Metastatic uveal melanoma: 

On average, the efficacy of conventional checkpoint inhibitors is lower in uveal melanoma than in cutaneous melanoma, which is related, among other factors, to the low mutation burden and the immunoprivileged nature of the organ of origin. MBD4-deficient, hypermutated tumors may represent a rare exception.

In HLA-A*02:01-positive patients, tebentafusp—a bispecific T-cell receptor fusion protein targeting gp100 and CD3—is an established systemic therapy. Tebentafusp is the first drug to demonstrate a survival benefit in a randomized controlled trial involving patients with metastatic UM (Wespiser M et al. 2023; Schank TE et al. 2022). Despite the survival benefit and regulatory approval, the restriction of tebentafusp to HLA-A*02:01-positive patients, as well as the low objective response rate, suggest that there remains a need for additional therapies. These include immune checkpoint inhibition, particularly nivolumab plus ipilimumab.

Local liver-targeted therapies for tumor control are used for liver metastases. These include: resection, ablation, transarterial procedures, or isolated hepatic perfusion. They represent a central pillar of the daily management of liver-dominant disease.

Recent data on targeted therapies that are independent of MEK inhibitors—such as the combination of darovasertib and crizotinib—represent potential additional options for metastatic UM (Koch EAT et al. 2024).

Experimental: It remains to be seen to what extent the cyclic depepsipeptide FR-900359, derived from the evergreen plant Ardisia crenata, represents an option for metastatic uveal melanoma (Gaffal E 2020).   

The prognosis is largely determined by (Jager MJ et al. 2020):

• tumor size and thickness,
• ciliary body involvement,
• extrascleral extension,
• epithelioid morphology,
• monosomy 3,
• 8q gain,
• BAP1 loss,
• Gene expression class 2,
• PRAME expression.

Small iris melanomas usually have a more favorable prognosis. Large ciliary body and choroidal melanomas with monosomy 3, 8q gain, and BAP1 loss have the highest risk of metastasis.

Follow-up care includes local ophthalmological monitoring and risk-adapted screening for distant metastases. Due to the marked tendency for liver metastases, the focus is on:

• Ultrasound or MRI of the liver,
• CT of the thorax and abdomen, if necessary,
• liver function tests,
• lifelong monitoring in cases of high-risk molecular profiles.

Measuring liver enzymes alone is not sufficient for the early detection of small liver metastases.

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2. ESMO–EURACAN Guidelines on Uveal Melanoma, NCI: Intraocular Melanoma.
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