Uveal melanoma
Choroidal melanoma; ciliary body melanoma; iris melanoma
Uveal melanoma is the commonest primary intraocular malignancy in adults, arising from melanocytes of the choroid (~90%), ciliary body (~7%) or iris (~3%). It is biologically distinct from cutaneous melanoma — driven by GNAQ / GNA11 mutations rather than BRAF, and metastasising preferentially to the liver. Despite excellent local control with brachytherapy or proton-beam radiotherapy, up to ~50% develop metastases (predominantly hepatic) over long-term follow-up; risk is strongly class-dependent — much higher in class 2 / monosomy-3 / BAP1-mutant tumours than class 1. Tebentafusp (a bispecific gp100 × CD3 immunotherapy) was approved by NICE (TA1027, published 9 January 2025) for HLA-A*02:01 metastatic disease — the first agent to extend overall survival in this setting. Dermatologists should know the BAP1 link (see BAP1-TPDS).
Epidemiology
- UK incidence ~6 per million per year; ~700 new cases annually.
- Median age 60; M:F roughly equal.
- Risk factors: light eye colour, fair skin, ocular/oculodermal melanocytosis (naevus of Ota), BAP1 germline mutation.
- Sun exposure is not a strongly established risk factor.
Genetics & molecular
- Driver mutations in GNAQ or GNA11 (~85%) — mutually exclusive; not seen in cutaneous melanoma.
- Loss of chromosome 3 (monosomy 3) and BAP1 mutation define a high-metastatic-risk class (Class 2).
- SF3B1 mutation — intermediate metastatic risk; EIF1AX — low risk.
- Gene-expression profiling (Class 1A/1B vs 2) used in some centres for prognostic stratification.
Diagnosis
- Diagnosed clinically by an ocular oncologist using slit lamp, indirect ophthalmoscopy, and B-scan ultrasound (high internal reflectivity).
- Fundus photography, fluorescein angiography, OCT.
- MRI of the orbit if extra-ocular extension suspected.
- Fine-needle aspirate / vitrectomy for genetic testing in selected cases.
- Biopsy is not always required — diagnosis is often made on imaging alone.
Treatment
Local (the eye)
- Plaque brachytherapy (ruthenium-106 or iodine-125) — eye-preserving, first-line for small to medium choroidal melanomas.
- Proton-beam radiotherapy — for tumours unsuitable for plaque (large, posterior, juxtapapillary).
- Enucleation — for very large tumours, total retinal detachment, painful blind eye, or extra-ocular extension.
- Adjuvant techniques: trans-scleral resection, transpupillary thermotherapy.
Metastatic
- Hepatic-predominant metastasis — liver-directed therapies (selective internal radiation therapy, hepatic intra-arterial chemotherapy, isolated hepatic perfusion in specialist centres).
- Tebentafusp (Kimmtrak) — bispecific HLA-A*02:01-restricted gp100 / CD3 T-cell engager. Approved by NICE (TA1027, published 9 January 2025) for HLA-A*02:01-positive untreated metastatic uveal melanoma. First systemic therapy to improve overall survival.
- Anti-PD-1 immunotherapy — much lower response rates than cutaneous melanoma due to low tumour mutation burden; combination ipilimumab + nivolumab modest activity.
Surveillance
- 6-monthly liver imaging (MRI or contrast ultrasound) for at least 10 years following primary treatment — particularly for high-risk (monosomy 3 / BAP1-mutant / Class 2) tumours.
- Annual ophthalmology review for the affected and fellow eye.
- Counsel for symptoms of liver metastasis.
BAP1 implications
Up to 5% of uveal melanomas occur in patients with germline BAP1 tumour predisposition syndrome, who are also at risk of cutaneous BAP1-inactivated melanocytic tumours (BAPomas), cutaneous melanoma, mesothelioma, renal cell carcinoma and others. Refer for genetic counselling if there is a family history of these tumours, multiple primaries, or onset under 30. See BAP1-TPDS.
References
- Carvajal RD et al. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol; 2017.
- Nathan P et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med; 2021.
- NICE TA1027. Tebentafusp for treating advanced uveal melanoma. Published 9 January 2025.
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