CURRENT CONCEPTS IN UVEAL MELANOMA

Current Concepts in Uveal Melanoma

Uveal melanoma is the most common primary intraocular malignancy in adults, arising from melanocytes within the uveal tract, which includes the iris, ciliary body, and choroid. Although it is a rare cancer compared with cutaneous melanoma, uveal melanoma carries a high risk of metastasis and remains a major cause of vision loss and cancer-related mortality. Over the past decade, significant advances in molecular biology, imaging, prognostic classification, and targeted therapy have reshaped current concepts in the diagnosis and management of this disease.

Epidemiology and Risk Factors

Uveal melanoma predominantly affects middle-aged and older adults, with the highest incidence reported in individuals of European ancestry. Risk factors include light skin pigmentation, light-colored eyes, and certain genetic predispositions. Unlike cutaneous melanoma, ultraviolet radiation has a less clearly defined role, though it may contribute to iris melanoma. Most cases arise sporadically, but rare familial associations have been linked to germline mutations, particularly in BAP1 tumor predisposition syndrome.

Molecular and Genetic Insights

One of the most transformative developments in uveal melanoma has been the understanding of its molecular landscape. Mutations in GNAQ and GNA11 are present in the majority of tumors and are considered early oncogenic events. These mutations activate downstream signaling pathways such as the MAPK and YAP pathways, driving tumor growth.

Prognosis is strongly influenced by chromosomal abnormalities and gene expression profiles. Loss of chromosome 3 (monosomy 3), gain of chromosome 8q, and mutations in BAP1 are associated with high metastatic risk, whereas mutations in SF3B1 and EIF1AX are linked to more favorable outcomes. Gene expression profiling has become an essential tool for stratifying patients into low- and high-risk categories, guiding surveillance strategies.

Diagnosis and Imaging

The diagnosis of uveal melanoma is primarily clinical, supported by advanced imaging techniques. Indirect ophthalmoscopy, ultrasonography, optical coherence tomography (OCT), and fundus autofluorescence are routinely used to characterize tumor size, location, and activity. Advances in imaging allow for early detection of small melanocytic lesions and improved differentiation between benign nevi and malignant tumors.

Fine-needle aspiration biopsy is increasingly employed not only to confirm diagnosis in selected cases but also to obtain tissue for molecular prognostic testing, enabling personalized patient management.

Local Treatment Strategies

The primary goal of local treatment is tumor control while preserving vision and the eye whenever possible. Plaque brachytherapy remains the standard of care for medium-sized tumors, offering excellent local control rates. Proton beam therapy and stereotactic radiotherapy are valuable alternatives, particularly for tumors near critical ocular structures.

Surgical options, including local resection and enucleation, are reserved for selected cases, such as very large tumors or those with severe complications. Advances in radiotherapy planning and delivery have significantly reduced treatment-related morbidity while maintaining oncologic effectiveness.

Metastatic Disease and Systemic Therapy

Despite effective local control, up to 50% of patients develop metastatic disease, most commonly to the liver. Historically, systemic treatment options have been limited, with poor survival outcomes. However, current concepts emphasize early detection of metastasis and risk-adapted surveillance based on molecular profiling.

Follow-Up and Prognosis

Long-term follow-up is essential in uveal melanoma due to the persistent risk of late metastasis. Prognosis depends on a combination of clinical, histopathological, and molecular factors. Personalized surveillance protocols based on genetic risk stratification represent a major step forward in patient care.

Conclusion

Current concepts in uveal melanoma reflect a shift toward precision medicine, integrating molecular genetics, advanced imaging, and tailored therapeutic strategies. While challenges remain, particularly in the treatment of metastatic disease, ongoing research continues to refine prognostic models and explore innovative therapies, with the ultimate goal of improving survival and quality of life for patients with uveal melanoma.