Ocular Melanoma: Can We Predict Metastatic Disease?

Even with aggressive systemic treatments, metastatic liver disease remains the most common cause of tumor-related mortality in choroidal malignant melanoma (CMM) with a median survival rate of 2 to 7 months and a 1-year survival rate of less than 10%. However, recent estimates of tumor doubling time have suggested that micrometastases are often present at the time of ocular tumor diagnosis (Br J Ophthalmol. 2004;88:962-967), and this suggests that clinicians may be able to identify patients who are at higher risk for CMM through molecular signatures unique to their specific ocular tumor or those tumors with a known tendency to metastasize. The purpose of this article is to further explore this new diagnostic method, which will presumably enable physicians to design protocols to treat patients empirically and systemically in order to alter their risk profile for metastatic melanoma.

The Lessons and Limitations of COMS

Despite increased clinical experience with single and multi-modality, globe-sparing local therapy for CMM such as adjuvant diode laser thermotherapy, the prospects for surviving uveal melanoma have remained essentially unchanged (Ophthalmology. 2003;110:962-965). This is because data gleaned from the Collaborative Ocular Melanoma Study (COMS) has shown that ophthalmologists and ocular oncologists are unable to alter the fundamental biology of posterior uveal tract melanomas or their propensity for micrometastatic disease using existing treatment options.

Two randomized trials (Medium Tumor and Large Tumor trials) conducted in 43 North American centers with strict inclusion criteria and a primary endpoint of all-cause mortality enrolled 46% and 77% of eligible patients respectively. The Medium Tumor trial randomized patients to receive iodine-125 plaque brachytherapy versus enucleation, while the large tumor trial compared survival outcomes after enucleation with and without pre-surgical external beam radiotherapy.

No survival benefit was afforded to patients with medium-sized tumors (>3.0 mm to 8 mm in height and =16 mm in diameter) who received plaque brachytherapy over enucleation alone. In fact, these patients had equivalent, 5-year, cumulative mortality rates in both study arms (18% and 19% respectively). Deaths in 57% of patients were attributed to metastatic melanoma and second cancers. While plaque brachytherapy was successful in mediating local tumor control in 90% of eyes, secondary enucleation was required as salvage therapy in eyes with continued tumor activity. Meanwhile, visual function after plaque therapy was limited from radiation induced vasculopathy and neuropathy and correlated to tumor features including proximity to the fovea and tumor size. The Medium Tumor study also excluded predominantly ciliary body and peripapillary tumors which touched the optic nerve, so no randomized clinical trial data exists for tumors in those locations with historically poor visual and systemic prognoses.

In patients with large melanomas (> 8 mm thick and/or >16 mm in diameter) pre-enucleation radiotherapy also afforded no significant survival benefit over enucleation alone (55% versus 60% respectively) (Am J Ophthalmol. 2004;138:936-951). The Large Tumor study confirmed that eyes with larger tumor burdens tended to have worse systemic prognoses, because these tumors were more likely to have aggressive histopathologic features and a longer detection lag, affording more time for the melanoma cells to access the systemic circulation. These results have served to largely exclude the use of pre-enucleation radiotherapy from current practice.

Molecular Diagnostics

Currently, metastatic ocular melanoma is treated by protocols used for metastatic cutaneous melanoma, a related but biologically distinct disease. Nevertheless, it is believed that patients who are identified as “high risk” at the time of ocular tumor diagnosis may benefit from entry into aggressive, prevention-based systemic chemotherapeutic or biotherapeutic trials to specifically target micrometastatic disease. This is why researchers have focused on in vivo, predictive testing of ocular melanomas in order to determine which tumors display aggressive, pro-metastatic features. Using molecular diagnostic tests such as fluorescence in-situ hybridization and genomic microarray technology, this type of research provides prognostic information to the patient and allows clinicians to follow “high risk” patients very closely with systemic screening at regular intervals to identify the earliest signs of metastatic disease.

The deeper insights that have become available regarding the cytogenetics of uveal melanoma include the following: it is now known that 30% to 60% of uveal melanomas have aneuploidic deletions of chromosome pairs, most commonly resulting in the loss of 1 copy of chromosome 3. Such tumors are associated with more aggressive histopathology, ciliary body involvement, and metastatic death (Invest Ophthalmol Vis Sci. 2003;44:1008-1011). Investigators at Washington University have also identified 2 distinct classes of uveal melanomas that correspond to metastatic spread and patient survival (Cancer Res. 2004;64:7205-7209), enabling researchers to identify candidate genes and gene products which may activate cellular signals that promote the development of aggressive histologic patterns and increased metastatic potential in these 2 classes of patients. By further characterizing this subset of cancer patients, researchers hope to gain vital insights into melanoma biology, which may guide new systemic therapies for patients with metastatic ocular melanoma.

Just as a better understanding of tumor behavior led to advances in the diagnosis and treatment of retinoblastoma (Rb), molecular diagnostics may help ocular oncologists and ophthalmologists to achieve similar results in the fight against ocular melanoma. Although many questions remain, clinical insights are guiding the ophthalmic community toward improved strategies for early detection, risk stratification, and local treatment options. As suggested by Harbour (Invest Ophthalmol Vis Sci. 2006;47:1736-1745) , future in vivo, diagnostic biopsy and cytogenetic testing of small, suspicious choroidal lesions may allow for early diagnosis and early treatment of potentially aggressive uveal melanomas. Coordinated, collaborative research is, therefore, necessary to ensure that advances in the care and therapy of patients suffering from ocular melanoma continue.

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Author Disclosure

The author states that he has no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.