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

Intraocular (uveal) melanoma is the most common primary malignant tumor of the eye in adults, arising from melanocytes within the uveal tract — the pigmented vascular layer comprising the choroid (85% of cases), ciliary body (5–10%), and iris (3–5%). Approximately 2,500 new US cases occur annually, with an incidence of approximately 5 per million per year. Uveal melanoma is biologically distinct from cutaneous melanoma: it virtually never harbors BRAF V600E mutations (which are the therapeutic target in skin melanoma), does not respond to BRAF/MEK inhibitors, and disseminates exclusively hematogenously without lymphatic spread — the liver is the dominant metastatic site in 90% of cases. Despite excellent local tumor control achievable with eye-conserving radiation, approximately 50% of patients with uveal melanoma develop metastatic disease within 10–15 years, representing the greatest clinical challenge. Gene expression profiling (GEP) and chromosome 3 monosomy testing accurately stratify metastatic risk, enabling risk-adapted surveillance. BAP1 germline mutations cause the BAP1 tumor predisposition syndrome with markedly elevated risk.

Risk factors for uveal melanoma include host characteristics related to low-melanin phenotype: fair skin, blue, gray, or green iris color, light hair color, and tendency to sunburn. Cumulative UV and visible light exposure — particularly occupational (welding without appropriate eye protection) and recreational exposure — may contribute to choroidal melanoma risk, though the evidence is less established than for cutaneous melanoma. The presence of choroidal nevi (estimated prevalence 5% in the white adult population) represents the primary precursor lesion; risk of malignant transformation of a choroidal nevus is approximately 1 in 5,000 to 1 in 9,000 per year, with transformation linked to larger size, subretinal fluid, orange pigment, and visual symptoms. Ocular melanocytosis (nevus of Ota, or oculodermal melanocytosis) — a congenital pigmented lesion of the iris, sclera, and periorbital skin — confers an elevated lifetime uveal melanoma risk of approximately 1 in 400. BAP1 germline mutations (BRCA1-associated protein 1) define the BAP1 tumor predisposition syndrome, associated with uveal melanoma, mesothelioma, clear cell renal carcinoma, and cutaneous melanoma.

Many uveal melanomas — particularly small choroidal tumors — are asymptomatic and detected incidentally during dilated fundus examination performed for unrelated reasons (refraction, cataract surgery screening, or routine ophthalmic assessment). Symptomatic presentation depends on tumor location and the extent of associated complications. Posterior pole choroidal tumors cause blurred central vision, metamorphopsia (distorted vision), photopsia (flashing lights), and monocular visual field defects when the tumor induces secondary exudative retinal detachment. New floaters from vitreous hemorrhage secondary to tumor vascularity may occur. Iris melanoma presents as a visible dark pigmented lesion on the iris surface, heterochromia iridis (difference in iris color), pupil distortion, or secondary glaucoma. Large choroidal or ciliary body melanomas may cause painful secondary glaucoma from angle closure. Extraocular extension is rare but may present as a visible subconjunctival pigmented mass or proptosis.

Clinical diagnosis in an experienced ocular oncology center is typically accurate without biopsy for posterior uveal melanoma. Indirect ophthalmoscopy reveals a dome-shaped pigmented (or amelanotic) choroidal mass, often with orange lipofuscin deposits on the surface. Standardized A/B-scan ultrasonography is the diagnostic cornerstone, demonstrating low internal reflectivity, acoustic hollowness, choroidal excavation, and orbital shadow — all characteristic of melanoma. Measurement of tumor largest basal diameter and thickness guides AJCC 8th edition T-staging (T1: ≤3mm thick, T4: >15mm or extraocular extension). MRI of the orbits with gadolinium characterizes intraocular extent and excludes orbital involvement. Fine-needle aspiration biopsy (FNAB) at the time of plaque brachytherapy allows gene expression profiling (GEP: Class 1A/1B/2) and chromosome 3 status testing, critical for metastatic risk stratification and surveillance intensity. HLA-A*02:01 genotyping is performed for metastatic disease to determine tebentafusp eligibility. Systemic staging with abdominal ultrasound or MRI liver every 6–12 months is recommended for all patients given the liver-predominant metastatic pattern.

Episcleral plaque brachytherapy using iodine-125 seeds is the gold-standard eye-conserving treatment for tumors with largest basal diameter up to 16 mm and thickness up to 10 mm, delivering 80–100 Gy to the tumor apex over 5–7 days. Local tumor control exceeds 90% at 5 years. Proton beam irradiation (60–70 Cobalt-Gray-Equivalent in 4–5 fractions) treats larger and anteriorly situated tumors, achieving comparable local control. Stereotactic radiosurgery (Gamma Knife or CyberKnife) may be used for selected cases. Transpupillary thermotherapy (TTT) with an infrared diode laser effectively treats very small tumors (less than 2.5 mm thickness) and is used as adjunct to reduce plaque radiation dose. Enucleation (surgical eye removal) is indicated for very large tumors (thickness greater than 18 mm), blind painful eyes, lack of useful vision with orbital extension, or failed radiation. Ongoing liver surveillance is required after all primary treatments given the high metastatic rate. For metastatic uveal melanoma, tebentafusp (ImmTAC bispecific T-cell engager targeting gp100 peptide/HLA-A*02:01 and CD3) is FDA-approved for HLA-A*02:01-positive patients (approximately 50% of European ancestry patients), demonstrating improved median OS of 21.7 versus 16.0 months in the IMCgp100-202 phase 3 trial.

Local tumor control with plaque brachytherapy exceeds 90% at 5 and 10 years. Five-year overall survival for localized uveal melanoma is approximately 80%, reflecting that many patients with small favorable-class tumors remain metastasis-free. Metastatic risk by GEP class: Class 1A greater than 95% 5-year metastasis-free survival; Class 1B approximately 70%; Class 2 approximately 25%. Monosomy 3 confers a risk approaching Class 2. Once liver metastases develop, historical median OS was 6–12 months without effective treatment; tebentafusp extends median OS to 21.7 months in eligible patients. Approximately 50% of all uveal melanoma patients develop metastases within 10–15 years despite successful local therapy — emphasizing the systemic nature of this disease.

UV and blue-light protective wrap-around sunglasses may reduce cumulative ocular radiation exposure, though the causal link to uveal melanoma is less established than for skin cancer. Patients with BAP1 germline mutations require enrollment in a structured multidisciplinary BAP1 tumor predisposition syndrome surveillance program, including annual dilated eye examination by an ocular oncologist, annual dermatological skin examination, kidney imaging for clear cell RCC, and respiratory assessment for mesothelioma risk. Individuals with uveal or choroidal nevi require annual fundus photography and OCT monitoring to detect growth or high-risk features (greater than 2 mm thickness, subretinal fluid, visual symptoms, overlying lipofuscin). Patients with ocular melanocytosis (nevus of Ota) benefit from annual ocular oncology review. Welders should use appropriate high-quality UV-opaque and infrared-protective lenses during all work to minimize occupational ocular radiation exposure.

Seek urgent ophthalmology evaluation for sudden onset of new floaters, flashing lights, or a shadow or curtain in the peripheral visual field — these symptoms may indicate secondary retinal detachment adjacent to a choroidal tumor and require same-day examination. Blurred or distorted central vision (metamorphopsia) that is new, particularly when affecting only one eye, requires prompt fundus examination. Any new dark or pigmented spot noticed on the iris surface, change in iris color, or visible alteration in pupil shape warrants evaluation. Parents who notice a white reflex in a child's eye (leukocoria) or a new squint should seek immediate pediatric ophthalmology evaluation. All adults with risk factors — light eye color, choroidal nevus, BAP1 syndrome, ocular melanocytosis — should have annual dilated fundus examinations. Patients with known uveal melanoma who develop right upper quadrant discomfort, new-onset jaundice, progressive fatigue, or unintentional weight loss should be evaluated urgently for liver metastases, even years or decades after successful primary treatment.