Choroidal Melanoma: Natural History and Management Options

Darren J. Bell, MD; Matthew W. Wilson, MD, FACS

Disclosures

Cancer Control. 2004;11(5) 

In This Article

Natural History and Metastasis

Much effort has been directed at determining which choroidal lesions are dangerous and therefore need to be treated. Because the treatment is severe and life altering, it would be beneficial to know which lesions are nevi and which lesions are melanomas. The upper limit of normal for benign choroidal nevi is approximately 5 mm in diameter and 1 mm in thickness, and the mortality risk from such a lesion is essentially zero.[5] Choroidal melanomas are routinely classified as small (<10 mm in diameter and <3 mm in height), medium (10 to 15 mm in diameter and 3 to 5 mm in height), or large (>15 mm in diameter and >5 mm in height).[6,7] Multiple studies, including the Collaborative Ocular Melanoma Study (COMS), have specified tumor size as the strongest indicator of metastasis and therefore survival.[8,9] Ten-year survival rates for uveal melanomas have been published as 81.2% for small melanomas, 60.0% for medium melanomas, and 34.8% for large uveal melanomas.[10] The COMS additionally identified older patient age as a baseline covariate that affected the prognosis for survival.[8]

Ocular melanomas metastasize hematogenously primarily to the liver but also to lung, bone, kidney, and brain.[9,11] Zakka et al[11] reported only 75% of ocular melanomas had metastasized at the time of death compared with 96% of nonocular melanomas. Although ocular melanomas are not as aggressive as cutaneous melanomas, they carry a substantial risk of metastasis. In a long-term study of patients treated for uveal melanoma by enucleation in Finland between 1962 and 1981, 61% of patients eventually died as a result of the disease.[12] Mortality related to uveal melanoma was 31% by 5 years, 45% by 15 years, 49% by 25 years, and 52% by 35 years. Among patients who died of uveal melanoma, 62%, 90%, 98%, and 100% died within 5, 15, 25, and 35 years, respectively. Once metastasis occurs, survival is less than 7 months.[13] Therefore, it is important to identify cancerous lesions and begin treatment before metastasis occurs.

Accuracy in diagnosing choroidal melanomas has improved in recent years as a result of more experience, a better understanding of risk factors, and improved diagnostic equipment such as ultrasound. Thirty years ago, published studies from the Armed Forces Institute of Pathology indicated that approximately 20% of eyes enucleated for melanoma in fact had benign lesions.[14] Follow-up reports described a decline in misdiagnosis rate from 12.5% to 1.4% from 1970 to 1980,[15] which was attributed to improved accuracy in diagnoses made outside of major academic centers. Most recently, the COMS, involving more than 50 centers in the United States and Canada, reported a misdiagnosis rate of 0.48%, the lowest rate ever reported.[16]

In a retrospective review of 1,329 small melanocytic choroidal tumors, Shields et al[17] found that documented growth of a lesion carried a 3.2 relative risk of metastasis. They also reported that 18% of identified lesions in the study demonstrated growth in a median time of 25 months, and 3% metastasized in a median time of 51 months. This conclusion is supported by Diener-West et al,[18] who performed a meta-analysis and found that detection of a small tumor has a more favorable prognosis than detection of a medium or large tumor, as evidenced by estimated 5-year mortality rates following enucleation of 16%, 32%, and 53% for small, medium, and large tumors, respectively. This indicates that observation of a choroidal lesion is risky, given the fact that growth may decrease survival. However, estimates indicate that it takes 7 years for a small melanoma to grow into a large melanoma and an additional 4 years before metastasis occurs.[6,10] At this rate of growth, there is ample time to initiate treatment. An alternate model published by Eskelin et al[19] estimated that micrometastases could develop as early as 5 years prior to the treatment of the primary tumor, which presumably occurs when suspicious characteristics first appear. At this estimated time of micrometastasis, the primary tumor size would be theoretically only 7 mm3, or approximately 3 mm in diameter and 1.5 mm in height at the time of metastasis.[20] Therefore, much effort has been devoted to better predict which lesions are likely to grow so that treatment may be initiated prior to metastasis.

Shields et al[17] found increased tumor thickness (>1 mm), location touching the optic disc, visual symptoms, presence of orange pigment, and subretinal fluid as factors predictive of future growth (Figure 1). The risk of tumor growth is 4% if none of these factors are present and more than 50% if three factors are present.[21] McLean[22] argued that observing tumors less than 1 mm in height in order to document growth increased the metastasis rate by only 1% (11% for tumors less than 1 mm in thickness vs 12% for tumors thicker than 1 mm). He concluded that there is little benefit to early treatment prior to clinically documenting growth.

Small pigmented choroidal tumors with orange pigment and subretinal fluid characteristic of choroidal malignant melanomas.

In 1979, Zimmerman and colleagues[6,23] proposed that enucleation of a globe with choroidal melanoma may actually decrease survival, noting the rise in the mortality rate in the years following enucleation from a baseline of 1% per year to a peak of 8% per year during the second year following enucleation. The rate subsequently returned to its baseline level of 1% per year over the next 3 to 5 years. The authors suggested two possible explanations: overwhelming tumor dissemination during surgery and a lowering of the host's immunologic defense. Their report served as the impetus for development of the no-touch surgical technique,[24,25,26] but conclusive evidence linking tumor dissemination and subsequent development of metastasis to a transient rise in intraocular pressure was not forthcoming. Furthermore, data from the COMS published in 1998 demonstrated that no survival advantage was gained by pre-enucleation radiation in more than 1,000 patients with large choroidal melanomas. This result suggests that metastasis occurs prior to enucleation.[8]

Other investigators proposed that uveal melanomas metastasize during a time of growth that coincides with the time they become clinically visible. This would be in keeping with the work of Eskelin et al[19,20] and supports the second hypothesis of Zimmerman and McLean,[23] ie, that removal of the eye alters the immune system and thus allows existing micrometastases to grow unchallenged.

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