Uveal Melanoma

Malignant melanoma of the uveal tract (iris, ciliary body, choroid), the commonest primary intraocular malignancy in adults. Incidence is about 5 to 6 per million per year in white populations and 0.2 to 0.5 per million in people of African and Asian descent. Peak age 55 to 65 years.

• Sites: choroid about 90 percent, ciliary body about 6 percent, iris about 4 percent. Iris tumours are smaller at presentation and have a better prognosis.
• Risk factors: fair skin, blue or light irides, ocular and oculodermal melanocytosis (naevus of Ota), choroidal naevus, dysplastic naevus syndrome, germline BAP1 mutation (tumour predisposition syndrome with cutaneous melanocytic tumours, mesothelioma, renal cell carcinoma), and white ancestry. Ultraviolet exposure is less clearly linked than in skin melanoma.
• Molecular features: early activating mutations in GNAQ or GNA11 (about 90 percent); prognostic changes include monosomy 3, gain of chromosome 8q, loss of BAP1 (with metastasis), and SF3B1 or EIF1AX mutations (lower risk). Gene expression profiling classifies tumours into class 1 (low risk, 5-year metastasis about 2 percent) and class 2 (high risk, about 70 percent); PRAME expression adds risk.
• Metastasis occurs in about 50 percent over 10 to 20 years, to the liver in about 90 percent (also lung, bone, skin), usually without lymphatic spread, and is often fatal within about 1 year of diagnosis of metastasis.

• Many are asymptomatic and found at routine examination. Symptoms: blurred vision, floaters, photopsia, visual field defect, distortion, and pain from secondary glaucoma.
• Choroidal: dome shaped or mushroom shaped (collar stud, breaking through Bruch membrane) elevated brown or amelanotic mass, orange pigment (lipofuscin) on the surface, overlying subretinal fluid, exudative retinal detachment, and vitreous haemorrhage.
• Ciliary body: sentinel (dilated episcleral) vessels, lens subluxation or cataract, shallow anterior chamber, raised pressure, and a dark mass behind the iris seen on dilation.
• Iris: pigmented nodule, increasing in size, distortion of the pupil, ectropion uveae, secondary glaucoma, hyphaema, tapioca like nodules in diffuse tumours.
• Risk features of a small melanocytic lesion that is growing: thickness above 2 mm, subretinal fluid, symptoms, orange pigment, margin within 3 mm of the disc, acoustic hollowness, and absence of a halo and drusen.
• Extraocular extension: proptosis and a visible epibulbar mass.

• Clinical diagnosis by an ocular oncology specialist in more than 95 percent of cases.
• Ultrasound: B-scan shows a dome or mushroom shaped mass with low internal reflectivity (acoustic hollowness) and choroidal excavation; A-scan shows low-to-medium reflectivity with internal vascularity. Measure largest basal diameter and apical height.
• Optical coherence tomography (including enhanced depth imaging), fundus autofluorescence (orange pigment hyperautofluorescent), fluorescein angiography (double circulation), and widefield photography for documentation and growth.
• Ultrasound biomicroscopy for iris and ciliary body tumours; MRI orbits (hyperintense on T1, hypointense on T2) when the view is poor or extension suspected.
• Fine needle aspiration or transscleral or transvitreal biopsy for prognostic testing (gene expression profile, chromosome 3 status, BAP1) and in atypical cases.
• Staging: liver function tests (alkaline phosphatase, gamma glutamyl transferase, lactate dehydrogenase), liver MRI or ultrasound, and chest imaging at diagnosis; metastatic disease is present in under 3 percent at diagnosis.
• Size categories: small (apical height 1 to 3 mm, basal diameter 5 to 16 mm), medium (height 3.1 to 8 mm, basal diameter 16 mm or less), large (height above 8 mm or basal diameter above 16 mm).

• Referral to a specialist ocular oncology centre. Observation for small lesions with no growth and low risk features (photograph and measure every 3 to 6 months).
• Local therapy to control the eye, with options depending on size and location:
  • Plaque brachytherapy (ruthenium-106 for tumours up to 5 to 6 mm in apical height, iodine-125 or palladium-103 for up to 10 mm or more): apex dose 70 to 85 Gy delivered over 3 to 7 days, plaque removed in a second operation.
  • Proton beam radiotherapy or stereotactic radiotherapy: 50 to 60 Gy (cobalt Gray equivalent) in 4 fractions for tumours too large or too near the disc or macula for plaque.
  • Transpupillary thermotherapy or photodynamic therapy as an adjunct for small residual tumours.
  • Local resection (iridectomy, iridocyclectomy, endoresection) for selected anterior or small tumours.
  • Enucleation for very large tumours, painful blind eyes, extensive extraocular extension (with or without orbital implant and later prosthesis), and failed conservation.
• Radiation complications: radiation retinopathy and maculopathy (treat with intravitreal anti-VEGF, bevacizumab 1.25 mg or aflibercept 2 mg, and triamcinolone), radiation optic neuropathy, cataract, neovascular glaucoma, dry eye, and scleral necrosis. Prophylactic anti-VEGF or steroid after plaque for juxtapapillary tumours reduces risk.
• Prognostic stratification by tumour size, ciliary body involvement, extraocular extension, chromosome 3 and 8q status, and gene expression class guides surveillance.
• Systemic surveillance for metastasis: liver MRI or ultrasound with liver function tests every 3 to 6 months for at least 5 to 10 years, tailored to risk (every 3 to 4 months for high risk).
• Metastatic disease: tebentafusp 20 micrograms IV on day 1, 30 micrograms on day 8, then 68 micrograms weekly (for HLA-A*02:01 positive patients, with monitoring for cytokine release syndrome); liver directed therapy (percutaneous hepatic perfusion with melphalan 3 mg/kg, hepatic arterial chemoembolisation, radioembolisation, surgical resection or ablation of isolated lesions); immune checkpoint blockade (ipilimumab 3 mg/kg with nivolumab 1 mg/kg every 3 weeks for 4 doses then nivolumab maintenance) with modest response rates; clinical trials.
• Supportive: genetic counselling for germline BAP1 mutations, psychological support, rehabilitation with prosthesis, and monitoring of the fellow eye.