Prognostic Factors
Several clinical and pathological prognostic factors have been identified that are associated with higher risk of metastasis of uveal melanomas. These include large tumor size, ciliary body involvement, presence of orange pigment overlying the tumor, and older patient age. Likewise several histological and cytological factors are associated with higher risk of metastasis including presence and extent of cells with epithelioid morphology, presence of looping extracellular matrix patterns, increased infiltration of immune cells, as well as staining with several immunohistochemical markers.
The most important genetic alteration associated with poor prognosis in uveal melanoma is inactivation of BAP1, which most often occurs through mutation of one allele and subsequent loss of an entire copy of Chromosome 3 (Monosomy 3) to unmask the mutant copy. Because of this function in inactivation of BAP1, monosomy 3 correlates strongly with metastatic spread Where BAP1 mutation status is not available, gains on chromosomes 6 and 8 can be used to refine the predictive value of the Monosomy 3 screen, with gain of 6p indicating a better prognosis and gain of 8q indicating a worse prognosis in disomy 3 tumors. In rare instances, monosomy 3 tumors may duplicate the BAP1-mutant copy of the chromosome to return to a disomic state referred to as isodisomy. Thus, isodisomy 3 is prognostically equivalent to monosomy 3, and both can be detected by tests for chromosome 3 loss of heterozygosity. Monosomy 3, along with other chromosomal gains, losses, amplifications, and LOH, can be detected in fresh or paraffin embedded samples by virtual karyotyping.
The most accurate prognostic factor is molecular classification by gene expression profiling of uveal melanomas. This analysis has been used to identify two subclasses of uveal melanomas: class 1 tumors that have a very low risk of metastasis and class 2 tumors that have a very high risk of metastasis. Gene expression profiling outperforms all of the above-mentioned factors at predicting metastatic spread of the primary tumor, including monosomy 3.
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