Ocular Tumours — Retinoblastoma and Uveal Melanoma: Genetics, Features, Staging and Treatment

Two malignant tumours dominate exam questions on the eye's interior: retinoblastoma in infants and young children, and uveal melanoma in adults. Retinoblastoma is the commonest primary intraocular cancer of childhood, accounting for about 3% of paediatric malignancies, and uveal melanoma is the commonest primary intraocular malignancy in adults.

Retinoblastoma arises from mutation of the RB1 tumour suppressor gene on chromosome 13q14, which encodes the retinoblastoma protein (pRB). Normally pRB blocks the G1 to S transition by restraining the E2F transcription factor; when both alleles are lost, E2F is unchecked and immature retinal cells proliferate.

Knudson's two-hit hypothesis explains both forms. In hereditary disease the first hit is a germline RB1 mutation present in every cell, and a second somatic hit in a retinal cell triggers the tumour. In sporadic disease both hits occur in a single retinal cell. About 2% of cases are RB1-independent, for example through MYCN amplification.

• In bilateral retinoblastoma, the mutation is germline in about 98%, although only about 5% have a family history because most arise as new mutations.
• Nearly 90% of unilateral retinoblastomas are non-heritable.
• Overall second-malignancy risk in hereditary disease is about 6%, and it rises about fivefold after external beam radiotherapy, one reason radiotherapy is avoided.
• Genetic testing of RB1 confirms hereditary disease and guides screening of relatives.

The hallmark is leukocoria, a white pupillary reflex that parents notice as a 'white spot' in the eye or in flash photographs. It occurs in 60–80% of cases. Strabismus occurs in 20–30% because of vision loss in the affected eye. Less common presentations are a red painful eye, poor vision, and, in advanced disease, proptosis, orbital inflammation or secondary glaucoma.

• Gold standard: examination under anaesthesia with indirect ophthalmoscopy.
• Ultrasound and CT or MRI confirm the tumour. Calcification is a hallmark and is detected on CT; MRI is best for optic nerve invasion, a key prognostic factor.
• Diagnosis relies on clinical examination, imaging and molecular testing.
• Genetic analysis of RB1 and counselling for the family.

Grossly, retinoblastoma is a white, friable intraocular mass with areas of necrosis, haemorrhage and calcification. Microscopically the cells are small, round, blue, with hyperchromatic nuclei and scanty cytoplasm. Growth patterns are endophytic (into the vitreous, causing vitreous seeding), exophytic (into the subretinal space, causing retinal detachment) or mixed.

The International Intraocular Retinoblastoma Classification (IIRC) groups intraocular disease from A to E. It has largely replaced the older Reese–Ellsworth system, which predicted eye salvage after external beam radiotherapy. Extraocular disease is staged with TNM.

• Chemoreduction (intravenous vincristine, carboplatin, etoposide) shrinks larger tumours before focal treatment and has reduced the need for enucleation and radiotherapy.
• Intra-arterial chemotherapy delivers drug into the ophthalmic artery with limited systemic toxicity; intravitreal chemotherapy treats vitreous seeds.
• Enucleation is indicated for group E and for anterior chamber infiltration, neovascular glaucoma, optic nerve invasion or tumour involving more than half the vitreous.
• External beam radiotherapy is avoided where possible because it raises second-cancer risk. Orbital exenteration is for extensive orbital disease.
• Survival exceeds 95% in specialised centres, but outcomes are worse in developing countries because of delayed presentation.

Uveal melanoma arises from melanocytes of the uveal tract: iris, ciliary body and choroid. It accounts for about 5% of all melanomas and is the commonest non-cutaneous site of melanoma. Roughly 90% involve the choroid, about 6% the ciliary body and 4% the iris. Incidence is about 5 per million in the United States and is highest in people with light skin and light iris colour. Welding is a reported occupational risk, while UV exposure is not significantly linked, unlike cutaneous melanoma.

Metastatic uveal melanoma responds poorly to therapies that work in cutaneous melanoma. The tumour has a low mutational burden (about 0.5 per megabase) and few neoantigens. Tebentafusp, a chimeric protein that binds gp100 and the T-cell receptor, is restricted to patients with HLA-A*0201.

Choroidal melanomas typically appear as dome-shaped or mushroom-like subretinal masses; the mushroom shape results from rupture through Bruch's membrane. Colour varies from dark brown to amelanotic. Patients may have visual loss, floaters, metamorphopsia or exudative retinal detachment; ciliary body tumours can stay silent until they displace the lens or cause secondary glaucoma. Diagnosis is mainly clinical, and clinical accuracy exceeds 99% with multimodal imaging, yet up to 23% are misdiagnosed initially.

Five-year risk of transformation of a choroidal naevus rises stepwise from about 1% with no factors to 34–55% or more with three to five factors.

• Enucleation was once the standard. The Collaborative Ocular Melanoma Study (COMS) showed no survival advantage of enucleation over radiotherapy for the studied tumours, so globe-preserving radiotherapy is used whenever feasible.
• Plaque brachytherapy, proton beam radiotherapy and stereotactic radiotherapy are the main eye-conserving options.
• Radiation can cause dry eye, cataract, radiation retinopathy and maculopathy, rubeosis iridis, neovascular glaucoma and optic neuropathy.
• Large tumours may need enucleation, or endoresection after radiotherapy to lower the risk of retinal detachment and neovascular glaucoma.