uveal melanoma

uveal melanoma
Name	Uveal melanoma
Synonyms	Choroidal melanoma, ciliary body melanoma, iris melanoma
Caption	A fundus photograph showing a choroidal melanoma.
Field	Ophthalmology, Oncology
Symptoms	Blurred vision, photopsia, visual field loss
Complications	Metastasis, retinal detachment, glaucoma
Onset	Typically adulthood
Duration	Chronic
Types	Based on location: choroidal, ciliary body, iris
Causes	Unknown; associated with specific genetic mutations
Risks	Light eye color, fair skin, dysplastic nevus syndrome, ocular melanocytosis
Diagnosis	Ophthalmoscopy, ultrasonography, optical coherence tomography, biopsy
Differential	Choroidal nevus, choroidal hemangioma, metastatic tumor
Prevention	Sunglasses with UV protection
Treatment	Plaque radiotherapy, proton therapy, enucleation, local resection
Prognosis	Depends on size, cell type, and genetic profile; high risk of liver metastasis
Frequency	~5-7 per million per year in the US

uveal melanoma is the most common primary intraocular malignancy in adults, arising from melanocytes within the uveal tract of the eye. This tract includes the iris, ciliary body, and choroid, with the majority of tumors originating in the posterior choroid. Although rare compared to cutaneous melanoma, it is a serious disease with a distinct biological behavior and a pronounced tendency for hematogenous spread, particularly to the liver. Management requires a multidisciplinary approach involving ophthalmologists, radiation oncologists, and medical oncologists.

Signs and symptoms

Symptoms often depend on the tumor's location and size, with many peripheral choroidal tumors remaining asymptomatic until advanced. Common presentations include painless blurred vision, photopsia (light flashes), and progressive visual field loss resembling a curtain. A visible iris mass or change in eye color may be noted with anterior tumors. Larger tumors can lead to complications such as exudative retinal detachment, vitreous hemorrhage, or secondary neovascular glaucoma, causing pain and redness. Tumors may also be discovered incidentally during routine dilated fundus examination for other reasons.

Causes and risk factors

The exact etiology is unknown, unlike cutaneous melanoma which is strongly linked to ultraviolet radiation exposure. Established host risk factors include light iris color, fair skin, and an inability to tan, suggesting a role for genetic pigmentation pathways. Specific congenital conditions like ocular melanocytosis (nevus of Ota) and dysplastic nevus syndrome significantly increase risk. There is no clear association with sunlight exposure, though some studies suggest a link with occupational welding. Unlike other melanomas, it is not associated with the BRAF mutations common in skin cancers.

Pathophysiology

Uveal melanoma originates from neural crest-derived melanocytes residing in the uveal stroma. The tumor exhibits a wide spectrum of cytologic features, classified by the Callender system into spindle cell, epithelioid, and mixed cell types, with epithelioid morphology correlating with worse prognosis. Crucially, over 80% of tumors harbor mutually exclusive initiating mutations in the GNAQ or GNA11 genes, which activate the MAPK/ERK pathway. Subsequent molecular alterations, particularly loss of chromosome 3 (monosomy 3) and mutations in BAP1 on chromosome 3p21, are strongly linked to metastatic progression and define high-risk disease.

Diagnosis

Diagnosis is primarily clinical, based on ophthalmoscopic appearance. A classic choroidal melanoma appears as a pigmented, dome-shaped or mushroom-shaped subretinal mass. Key diagnostic adjuncts include B-scan ultrasonography, which shows characteristic internal reflectivity and acoustic hollowness, and optical coherence tomography to assess associated retinal changes. Fundus autofluorescence and indocyanine green angiography can help differentiate it from simulating lesions like choroidal nevus or hemangioma. For atypical cases, fine-needle aspiration biopsy or trans-scleral biopsy can provide histologic and genomic confirmation, often assessing for monosomy 3 and BAP1 status.

Treatment

Treatment aims to preserve the eye and vision while controlling the tumor, dictated by size, location, and the patient's overall health. For small to medium tumors, brachytherapy using iodine-125 or ruthenium-106 plaque radiotherapy is the most common globe-conserving approach. Charged-particle therapy such as proton beam therapy is also highly effective. Larger tumors or those causing severe complications may require enucleation. Local surgical options include transscleral or transretinal endoresection. Emerging therapies for systemic control include immunotherapy agents like tebentafusp and liver-directed therapies such as chemoembolization for metastatic disease.

Prognosis

Prognosis is primarily determined by the tumor's genetic profile and American Joint Committee on Cancer (AJCC) staging based on size. The most significant predictor of metastasis is the presence of monosomy 3 and BAP1 mutation, which can lead to a metastatic rate exceeding 50% within 10 years. The liver is the dominant site of metastasis in over 90% of cases. Despite successful local control, metastatic uveal melanoma remains challenging to treat, with a median survival after detection of metastasis of approximately 12-18 months. Ongoing trials with novel immunotherapies and targeted therapies aim to improve outcomes for high-risk patients.

Category:Melanoma Category:Eye cancers Category:Ophthalmology