Recent evidence indicates that certain recurring, nonrandom cytogenetic abnormalities (alone or in combination) and the gene expression profiles these abnormalities produce are much more reliable prognostic factors for metastasis and metastatic death in patients with histomorphologically malignant melanocytic choroidal tumors (ie, choroidal melanomas) than conventional clinical and histopathologic prognostic factors. In most series of posterior uveal melanomas evaluated by current cytogenetic methods to date (most of which have been medium-sized and large tumors according to the Collaborative Ocular Melanoma Study size classification), approximately 30% to 60% of the tumors have exhibited cytogenetic abnormalities and gene expression profiles indicative of high likelihood of metastasis following initial treatment. Studies of metastasis and metastatic death among uveal melanoma patients whose tumors have been evaluated cytogenetically have shown rates of metastasis that approach 100% within 10 years among those whose tumor exhibited monosomy 3 or a class 2 gene expression profile, but very low rates of metastasis among uveal melanoma patients whose tumor did not show these cytogenetic abnormalities. The extremely high rate of metastasis among patients having a choroidal melanoma associated with monosomy 3 or a class 2 gene expression profile suggests that metastasis is an almost completely penetrant outcome of these cytogenetic abnormalities. Several studies have also shown that the proportion of tumors with such abnormalities is greater among larger tumors than among smaller ones. Because choroidal melanomas that have developed cytogenetic abnormalities which render them more malignant are likely to grow faster on average than melanomas that have not (because of escape from normal cell cycle regulation), the proportion of all choroidal melanomas that exhibits monosomy 3 and/or class 2 gene expression profile will be progressively higher as one goes from small to medium to large to extra-large tumors.
From published information from multiple laboratories, it appears that 30% to 40% of medium-sized melanomas, 50% to 60% of large choroidal melanomas, and over 70% of extra-large choroidal melanomas will exhibit monosomy 3 (including those with functional monosomy 3) and/or a class 2 gene expression profile predictive of high probability of future metastasis. Although relatively few small choroidal melanomas have been evaluated to date by cytogenetic methods, one can extrapolate from the published data above that about 10% to 20% of small choroidal melanomas will also exhibit such cytogenetic abnormalities. These figures correspond quite closely with the asymptotic cured fractions that have been reported among patients with primary choroidal melanoma treated by enucleation for small, medium, large, and extra-large choroidal melanomas, respectively.44
Taken together, these observations suggest that choroidal melanomas which have developed cytogenetic abnormalities making them capable of metastasizing (ie, have attained metastatic capability) have probably already metastasized by the time they are detectable clinically. In contrast, tumors that have not developed such cytogenetic abnormalities will not have metastasized and can therefore be cured; unfortunately, most of these patients would probably have survived without metastasis even if treatment for the primary tumor had not been provided.
The clinical implication of the preceding inference is that (1) treatment (including enucleation) is likely to be ineffective as a preventative of metastasis in patients having a melanoma already capable of metastasizing cytogenetically, and (2) treatment is likely to be effective in preventing metastasis only for patients whose choroidal melanoma has not developed such cytogenetic abnormalities but will do so in the future as the tumor continues to grow. At present, we have no information on the frequency of such cytogenetic transformation. However, the fact that we observe a relatively stable cured fraction after a certain tumor size suggests that such occurrence may be infrequent.
In conclusion, the better prognosis of patients with smaller choroidal melanomas is likely to be attributable to a lower probability of cytogenetic abnormalities indicative of metastatic capability among smaller tumors and not effectiveness of treatment at preventing metastasis.