Uveal Melanoma: an Updated Review

Abstract

This article reviews the epidemiology, pathophysiology, and treatment of uveal melanoma. Emphasis is placed on differential diagnosis and the genetics associated with tumor development and metastasis. The role of the BRCA1-associated protein 1 (BAP1) gene, a suggested uveal melanoma tumor suppressor gene, EIF1AX, a gene that encodes a protein that binds mRNA, among other genes, as well as the associated loss of chromosome 3 are discussed. While the treatment of primary uveal melanoma is generally successful, up to approximately 50% of patients ultimately develop metastatic disease; there is currently no FDA approved systemic therapy for metastatic uveal melanoma. The promising role of a variety of treatments is discussed, with emphasis on the immune checkpoint inhibitors.

Epidemiology

Melanomas develop from melanocytes that malignantly transform as a result of environmental or genetically induced changes in their DNA. While such transformation occurs most commonly in the skin, uveal melanoma represents 3-5% of all melanomas occurring in the United States and is the most frequent form of primary intraocular tumor in adults [1,2]; worldwide, the primary intraocular tumor is retinoblastoma with an incidence of 1:15,000 to 1:20,000 live births [3]. Approximately 85-90% of uveal melanomas develop from melanocytes in the choroid, 5-8% in the ciliary body, and 3-5% in the iris [1,4]. Unlike the pathogenesis of uveal melanoma, the malignant conversion of conjunctival melanocytes more closely approximates the development of cutaneous melanoma and is strongly associated with increased sun exposure [4].

In contrast to the rising incidence of cutaneous melanoma, the incidence of uveal melanoma has remained relatively stable at approximately 5 per million since the 1970s [1]. The distribution of uveal melanoma varies depending on sex, race, and geographic location [2]. Males were reported to have a significantly higher age-adjusted incidence of 5.9 per million compared to females, who had an average age-adjusted incidence of 4.5 per million [2,5,6]. Similarly, analysis of data from the European Cancer Registry-based study on survival and care of cancer patients (EUROCARE) in Europe, including 6,673 patients with uveal melanoma diagnosed from 1983 to 1994, revealed standardized incidence rates of 1.3–8.6 cases per million per year [7].

The US data were collected by the Surveillance and Epidemiology and End Result (SEER) program of the NIH which collects and provides reliable US population-based incidence data for a variety of cancers, including uveal melanoma [8]. In the US, there is a higher incidence of uveal melanoma in non-Hispanic whites (~6 per million) compared to Hispanics, Asians and blacks (~1.7, 0.4 and 0.3 per million, respectively) [2]. In contrast, cutaneous melanoma rates are 16 fold higher in whites than blacks [5]. Relative to uveal melanomas, conjunctival and mucosal melanoma rates are only about 2-3 fold higher in whites than blacks [9]. Overall, the rate of uveal melanoma in the US is lower in southern states, though the rate of iris and ciliary body melanomas are higher in southern and coastal states [5]. Uveal melanoma incidence appears to peak around the seventh or eighth decade. While, as mentioned, the incidence of uveal melanoma has remained relatively stable over the last decades [1,10], conjunctival melanomas were reported to have increased in incidence, especially among older white men, and while the incidence tended to rise in individuals 40-59 years of age, this increase was not statistically significant [11].