Uveal Melanoma: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Uveal melanoma is the most common primary intraocular malignancy in adults, arising from melanocytes of the uveal tract — comprising the choroid (innermost vascular layer), ciliary body, and iris — of the eye. The choroid is the predominant site of origin (approximately 85% of cases), followed by the ciliary body (approximately 10%) and iris (approximately 5%), which carries a distinctly better prognosis due to earlier detection and lower metastatic potential. Approximately 2,500 new cases occur per year in the United States. Uveal melanoma is a biologically and molecularly distinct entity from cutaneous melanoma despite sharing the melanocyte as the cell of origin: it is driven by activating mutations in GNAQ or GNA11 G-protein alpha subunit genes (present in approximately 90% of cases) rather than the BRAF V600E or NRAS mutations characteristic of cutaneous melanoma, rendering BRAF-targeted therapies ineffective. The most concerning feature of uveal melanoma is its propensity to metastasise predominantly — and almost exclusively — to the liver in approximately 25-50% of patients, a process that can occur even decades after successful local control of the primary ocular tumour. Metastatic uveal melanoma historically carried a median OS of only 6-9 months; the approval of tebentafusp has markedly improved this outlook for eligible HLA-A*02:01-positive patients.

Established phenotypic risk factors for uveal melanoma include fair skin complexion, light-coloured (blue, grey, or green) irises, and Caucasian ancestry — reflecting the lower melanin content of the uveal tract that reduces protection against mutagenic exposures. Oculodermal melanocytosis (nevus of Ota) — a congenital hyperpigmentation of the periorbital skin and ipsilateral uvea — confers a 1-in-400 lifetime risk of uveal melanoma and is the strongest single identifiable risk factor. Dysplastic nevus syndrome (familial atypical mole and melanoma syndrome, FAMM) and BAP1 tumour predisposition syndrome (germline BAP1 mutations causing uveal melanoma, mesothelioma, renal cell carcinoma, and cutaneous melanoma clusters) represent hereditary risk pathways. Unlike cutaneous melanoma, UV radiation from sunlight does not have a clearly established causal role in uveal melanoma pathogenesis; however, welding arc exposure and intense UV light exposure in outdoor occupations may modestly increase risk. The dominant oncogenic events in uveal melanoma are somatic mutations. GNAQ or GNA11 mutations (mutually exclusive, present in approximately 90% of uveal melanomas) constitutively activate downstream MAPK and Gq/11 protein signalling pathways driving tumour growth. Secondary mutations determine metastatic potential: BAP1 (BRCA-associated protein 1) loss on chromosome 3q21 (often from monosomy 3 or somatic mutation) is the single most important prognostic biomarker, conferring high metastatic risk; SF3B1 mutations (splicing factor) are associated with delayed but eventual metastasis; EIF1AX mutations confer very low metastatic risk; chromosome 8q gain (often concurrent with BAP1 loss) further worsens prognosis.

The clinical presentation of uveal melanoma varies by location within the uveal tract and tumour size. Choroidal melanomas are frequently asymptomatic until significant tumour growth impinges on the macula (central retina responsible for fine vision) or optic disc. When symptoms develop, they include progressive visual disturbance — blurring, visual field defects (scotoma), metamorphopsia (distortion of straight lines), and photopsia (flashing lights) — resulting from exudative retinal detachment overlying the tumour or direct macular involvement. Visual acuity loss is a late symptom indicating advanced macular or disc involvement. Floaters may result from vitreous seeding in rare cases. Many choroidal melanomas, particularly smaller tumours, are detected incidentally during routine fundoscopic examination, diabetic eye screening, or ophthalmic assessment for unrelated visual symptoms; this accounts for the relatively high proportion of small tumours diagnosed in contemporary series. Ciliary body melanomas may cause lens displacement, uniocular astigmatism, and — if large — a visible dark mass behind the iris in the pars plana region. Iris melanomas are the most visible: they present as a growing pigmented nodule or sector-shaped change in iris colour (heterochromia iridis), pupil irregularity, secondary angle closure glaucoma with raised intraocular pressure, and spontaneous hyphaema (blood in the anterior chamber). Secondary glaucoma causing ocular pain and redness may be the presenting feature of advanced ciliary body or iris melanomas. Sentinel vessels (dilated episcleral vessels overlying the tumour) may be visible on external examination.

Uveal melanoma is unique among solid tumours in that it is commonly diagnosed clinically without tissue biopsy, based on characteristic ophthalmoscopic features identified by experienced ocular oncologists. Fundoscopic examination with indirect ophthalmoscopy and slit-lamp biomicroscopy provides the primary diagnostic visualisation of choroidal and ciliary body tumours. B-scan ultrasonography confirms the solid intraocular mass with characteristic features: acoustic hollowness, choroidal excavation, intrinsic vascularity, and a dome or mushroom-shaped growth pattern with collar stud configuration in larger tumours. CT and MRI of the orbits are used to exclude extraocular extension and assess optic nerve involvement. For systemic staging, CT of the chest and liver MRI are the key investigations given the predominance of hepatic metastases in uveal melanoma; PET/CT has lower sensitivity for liver involvement. Fine needle aspiration biopsy (FNAB) of the choroidal mass is recommended for molecular prognostic profiling in patients where tissue can be safely obtained: cytological specimens are used for BAP1 immunohistochemistry (surrogate for BAP1 mutation), chromosome 3 monosomy and chromosome 8q gain by fluorescence in situ hybridisation (FISH) or SNP array, SF3B1 mutation testing, EIF1AX mutation testing, and gene expression profiling (GEP, DecisionDx-UM) classifying tumours into Class 1A (lowest risk), Class 1B (low-intermediate risk), and Class 2 (high metastatic risk, approximately 70-80% 5-year metastatic rate). HLA-A*02:01 typing is required to determine eligibility for tebentafusp treatment.

Local tumour treatment is highly effective for primary ocular tumour control in the majority of patients and encompasses multiple modalities. Plaque brachytherapy (episcleral plaque radiotherapy) using iodine-125 or ruthenium-106 seeds is the most widely used globe-conserving treatment, delivering targeted radiation to the tumour while preserving the eye; the Collaborative Ocular Melanoma Study (COMS) demonstrated equivalence of I-125 brachytherapy and enucleation for medium-sized tumours in terms of overall survival. Proton beam radiotherapy delivers precisely targeted Bragg-peak radiation to larger tumours or anteriorly located tumours not amenable to plaque. Stereotactic radiosurgery (Gamma Knife, CyberKnife, Leksell Stereotactic Radiotherapy) achieves equivalent local control for medium and large tumours with single or hypofractionated high-dose delivery. Transpupillary thermotherapy (TTT) is used as adjuvant therapy with plaque brachytherapy for small tumours. Enucleation (surgical removal of the globe) remains the treatment of choice for very large tumours (greater than 18 mm basal diameter), blind and painful eyes from tumour complications, extensive extrascleral extension, or failure of radiotherapy. For metastatic uveal melanoma: tebentafusp — a gp100xCD3 bispecific ImmTAC T-cell engager — is the first systemic therapy to demonstrate overall survival benefit in metastatic uveal melanoma, achieving a 1-year OS of 73% versus 59% for investigator's choice comparator (ipilimumab, pembrolizumab, or dacarbazine) in the pivotal IMCgp100-202 Phase III trial (NEJM 2021); tebentafusp is restricted to HLA-A*02:01-positive patients (approximately 50% of Caucasian patients). Ipilimumab plus nivolumab is an alternative for HLA-A*02:01-negative patients. Clinical trial enrolment is strongly encouraged given the still-limited efficacy of available systemic options. Liver-directed therapies (TACE, radioembolisation with Y-90) provide hepatic disease control in selected patients with predominant liver-limited metastases.

There are no established and proven prevention strategies for sporadic uveal melanoma, and the absence of a clearly defined causal role for UV radiation means sunscreen and sun-avoidance recommendations do not have the same evidence base as for cutaneous melanoma. However, several risk-management strategies are clinically relevant. Individuals with oculodermal melanocytosis (nevus of Ota) — who have a lifetime risk of approximately 1 in 400 of developing uveal melanoma — should undergo annual dilated fundoscopic examination by an ophthalmologist from adolescence. Carriers of germline BAP1 mutations (BAP1 tumour predisposition syndrome) should enroll in structured multi-organ surveillance including annual dilated fundoscopic examination, skin examination, chest CT or MRI, and renal ultrasound. Choroidal naevi — common pigmented choroidal lesions affecting approximately 5-10% of Caucasian adults — require fundoscopic surveillance by an ophthalmologist every 1-2 years; risk factors for malignant transformation include acoustic hollowness on ultrasound, orange pigment overlying the naevus, subretinal fluid, visual symptoms, proximity to the optic disc, and tumour thickness greater than 2 mm. Protection against intense welding arc UV exposure using appropriate eye protection may reduce occupational risk. Welding goggles and arc flash-protective lenses with complete UV filtration should be worn consistently. Any perceived change in vision, new floaters, or a previously noticed pigmented iris lesion enlarging should prompt ophthalmological review without delay, as early-stage iris melanoma has an excellent prognosis and the goal is detection before choroidal invasion.

Seek prompt ophthalmological evaluation — ideally within 1-2 weeks — for any of the following ocular symptoms that may indicate uveal melanoma or require exclusion of serious intraocular pathology. New-onset or worsening visual disturbance in one eye — including blurring, visual field defects, shadows or curtains in peripheral vision, or flashing lights (photopsia) — without an obvious refractive explanation warrants fundoscopic examination. New floaters in the visual field of one eye, particularly if associated with visual field change, require urgent ophthalmic assessment to exclude vitreous haemorrhage or retinal detachment associated with an intraocular tumour. Any change in iris colour in one eye (new pigmented lesion on the iris or sector heterochromia), unilateral pupil irregularity, or a visible dark mass at the pupillary margin requires slit-lamp assessment by an ophthalmologist. Eye pain, redness, and decreased vision not attributable to anterior segment infection or trauma — particularly if associated with raised intraocular pressure — require dilated fundoscopy to exclude an occult ciliary body or choroidal melanoma. Patients with known high-risk features — oculodermal melanocytosis, BAP1 syndrome, family history of uveal melanoma — should attend regular annual ophthalmological surveillance even without symptoms and should not delay their scheduled appointments. Patients who have had previous uveal melanoma with locally treated primary tumour must attend their liver surveillance (MRI or contrast-enhanced ultrasound) on schedule — metastatic disease can emerge 5-20 years after primary treatment.

Local treatment achieves primary tumour control in over 95% of patients. However, 25-50% develop distant metastasis, almost exclusively to the liver. Class 2 GEP or monosomy 3 tumours: 5-year metastatic risk approximately 70-80%. Metastatic uveal melanoma: historically median OS 6-9 months; tebentafusp improved median OS to approximately 21.7 months in HLA-A*02:01-positive patients in the IMCgp100-202 trial, representing the first OS benefit from systemic therapy in this disease. The prognosis for Uveal Melanoma: Causes, Symptoms, Diagnosis and Treatment varies depending on severity at diagnosis, the patient's overall health, and how promptly treatment is initiated. With early diagnosis and appropriate management, many patients achieve good outcomes and maintain quality of life. Regular follow-up with healthcare providers is essential to monitor progress, adjust treatment as needed, and detect any complications early. Adherence to prescribed treatments and lifestyle modifications significantly improves long-term prognosis.