Uveal Melanoma: Evidence for Efficacy of Therapy

Armin R. Afshar, MD, MBA; Bertil E. Damato, MD, PhD


Int Ophthalmol Clin. 2015;55(1):23-43. 

In This Article


Estimation of survival probability is essential because it allows care to be individualized, empowers patients to adjust their affairs accordingly, and facilitates the planning of clinical trials.

Conventionally, survival prognostication has been based on anatomic factors, such as basal tumor diameter, ciliary body involvement, and extraocular spread.[68] These predictors form the basis of the Tumor Node Metastasis (TNM) Staging System of the American Joint Committee on Cancer (AJCC), which has recently been updated.[69]

It has long been known that histologic features such as epithelioid melanoma cytomorphology, closed laminin loops, and mitotic count are associated with increased mortality, but these have not been used extensively for prognostication in routine clinical practice.[70]

In the 1990s, it was discovered that metastatic disease from uveal melanoma occurs exclusively in patients whose tumor shows chromosome 3 loss.[71,72] Since 1999, the second author (B.E.D.) has offered genetic tumor typing to patients as a routine clinical service. This was done with fluorescence in situ hybridization in the early years and then with multiplex ligation-dependent probe amplification, which is more sensitive, using microsatellite analysis when tissue samples were small.[73–76] Others have relied on other methods, such array comparative genomic hybridization and gene-expression profiling. There has been some debate as to which method is best, but without adequate head-to-head comparisons. Presently, at the University of California, San Francisco, we are investigating next-generation sequencing, which analyzes >300 loci with minute specimens readily obtained by fine-needle aspiration biopsy. In essence, all methods only indicate whether or not the tumor has metastatic potential.

It is useful to determine not only whether or not the tumor is lethal but also when metastatic disease is likely to develop, should the tumor be of monosomy-3/class 2 type. In elderly patients, such information indicates whether the patient is likely to live long enough for metastatic disease to develop or whether death is more likely to result from unrelated causes. The TNM staging system and histologic grading of malignancy provide only very approximate prognostications, which are relevant to groups of patients and not individuals. Damato et al[77,78] have shown that accurate estimates of survival probability require multivariate analysis of clinical, histologic, and genetic predictors, also taking age and sex into account.

Prognostication has mostly been undertaken using Kaplan-Meier analysis; however, this type of analysis does not take account of competing causes of death and tends to exaggerate metastatic mortality, especially in elderly patients. The second author (B.E.D.) and colleagues have developed and validated an online tool that overcomes all these obstacles by comparing the all-cause mortality of patients having choroidal melanoma with that of the age-matched and sex-matched population.[77,79] This provides prognostication that is accurate enough to be applicable to individual patients, at least in Liverpool, where it was developed (Fig. 8). At present, we are evaluating this tool at UCSF to determine whether it is equally reliable in the United States.

Figure 8.

The Liverpool Uveal Melanoma Prognosticator Online, showing all-cause mortality for a 60-year-old female with a 16mm ciliochoroidal melanoma and no extraocular spread. A, Survival curves based solely on clinical features (ie, tumor dimensions, ciliary body involvement, and extraocular spread), with line P corresponding to patient survival and G indicating survival of general British population matched for age and sex. B, Pictogram showing same results. C, Survival curve for same patient if laboratory studies show no epithelioid cells, no closed loops, low mitotic count (ie, <2/40 high-power fields), and no monosomy-3; and (D) survival curve for same patient if laboratory studies show epithelioid cells, closed loops, mitotic rate exceeding 7/40 high-power fields, and monosomy-3. The 8-year metastatic mortality can be deduced by subtracting the patient mortality from the mortality of the matched general population and is estimated to be: 40% if only clinical features are known; 6% if the tumor is found to be of low grade, disomy-3 type; and 70% if the tumor is of high-grade malignancy with monosomy-3. From Damato et al.78

It would be ideal if the same tumor specimens and data from patients with long follow-up could be analyzed by diverse research groups using rival laboratory and statistical methods.