Department of Biomedical Sciences and Disease, New England College of Optometry, Boston, United States
Corresponding author details:
Department of Biomedical Sciences and Disease
New England College of Optometry, Boston
Copyright: © 2019 Koevary S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 international License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.
Uveal Melanoma; BAP1; EIF1AX; Immunotherapy; Differential diagnosis
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 . 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 .
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 . The distribution of uveal melanoma varies depending on sex, race, and geographic location . 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 .
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 . 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) . In contrast,
cutaneous melanoma rates are 16 fold higher in whites than blacks . Relative to uveal
melanomas, conjunctival and mucosal melanoma rates are only about 2-3 fold higher in
whites than blacks . 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 . 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 .
Well established risk factors for the development of uveal melanoma include but are not limited to increasing age, lightly pigmented eyes, fair skin, inability to tan, ocular/ oculodermal melanocytosis, dysplastic nevus syndrome, and arc welding [1,2,4,12]. The median age of diagnosis is 62 years, with many diagnoses occurring between the ages of 70- 79 [1,2]. The lifetime risk of developing a uveal melanoma from oculodermal melanocytosis is 1 in 400  while malignant transformation of choroidal nevi, which can be prevalent in Caucasians, is low . That said, giant choroidal nevi (≥10 mm in diameter) were estimated to transform into melanoma tumors in 18% of patients over 10 years . Common and atypical cutaneous nevi, cutaneous freckles, as well as iris nevi were all reported to be associated with a higher risk of developing uveal melanoma .
As mentioned, the rate of uveal melanoma is many times higher in whites than non-whites. While it is an obvious factor to consider as a cause of cutaneous melanoma, the role of ultraviolet (UV) exposure as a risk factor in uveal melanoma is controversial. In an Australian study, sun exposure was found to be an independent risk factor for choroidal and ciliary body melanoma, but surprisingly, evidence for an association between sun exposure and iris or conjunctival melanoma was not found, though the sample size of the study was small (≤25) . Logically, as the pupils constrict during illuminated conditions, it would be expected that the iris would be most vulnerable to the tumorogenic effects of UV radiation; however, uveal melanoma occurs more frequently in the ciliary body and choroid . de Lange et. al., studied the mutational status of 123 tumors and found that the role of UV light exposure varied with the location of the uveal melanoma . Accordingly, anterior or ciliochoroidal melanomas preferentially developed in non-illuminated areas in lightly-colored eyes and posterior choroidal melanomas developed in illuminated regions. As 80% of uveal melanomas appear to be associated with mutations in the Gαq-proteins GNAQ and GNA11 (see below) , de Lange et. al.’s study analyzed the substitution mutations specific to these proteins. Interestingly, anterior tumors displayed GNAQ Q209L adenine to thymine mutations (p=0.002) while posterior tumors exhibited GNAQ/GNA11 Q209P adenine to cytosine mutations (p=0.028). Li and colleagues  reported that melanomas tended to develop in the macular area, with fewer occurring closer to the ciliary body. This distribution pattern correlated positively with the dose distribution of solar light on the retinal sphere, supporting a role for solar exposure in the induction of uveal melanoma. In another study using geographic tumor mapping, data suggested that UV exposure was unlikely to be responsible for inducing the development of choroidal melanoma in a study of 92 uveal melanomas . These conflicting results must await reconciliation by future studies. Whether a protective effect of UV-generated vitamin D might mask its genotoxic effects has been speculated . Finally, in a small study of 12 uveal melanomas, a UV radiation DNA damage signature was not identified .
Occupational cooking has also been suggested as a risk factor
for uveal melanoma in a meta-analysis (OR: 1.81, 95% CI 1.33-2.46,
p<0.001) . Use of a mobile phone and occupational pesticide
exposure were not proven risk factors for tumor development
Melanocytes differentiate from pluripotent neural crest stem cells . These cells provide pigment to the skin, iris, ciliary body, choroid, and mucosal membranes of the body. An unregulated proliferation of melanocytes in any of these locations results in melanoma. As mentioned above, current evidence suggests that most uveal melanomas occur de novo and are infrequently the result of a transformed suspicious nevus . For example, even though iris nevi are relatively common, their rate of transformation into a melanoma is only about 5% at 10 years . Earlier diagnosis likely plays an important contributing role in the relatively good prognosis of patients with an iris melanoma, which is often managed with close monitoring, although large or fast-growing tumors may require immediate treatment. Iris melanomas are inherently more indolent and less likely to metastasize than ciliary body or choroidal melanomas.
Fatalities from all forms of melanoma are the result of metastasis . Uveal melanoma is an aggressive form of cancer leading to metastasis in about 50% of cases, preferentially to the liver. While tumor location, thickness, diameter, and histopathology independently influence the development of metastatic disease [29- 31], as a single modality, its genetic and molecular makeup may be a more reliable marker [32,33]. Adding size to genetic analysis was shown to provide additive power for estimating metastatic potential .
While the MAPK pathway is activated and up-regulated in all forms of melanoma, the responsible somatic mutations differ between cutaneous and uveal lesions. Cutaneous melanoma (and most forms of conjunctival melanoma) is most commonly characterized by mutations in BRAF (40-50%), NRAS(15-20%) and more rarely KIT and NFI [2,17]. As mentioned, uveal melanomas are often associated with a mutation in Gαq-proteins GNAQ and GNA11 (80% of cases) ; mutations in genes GNAQ and GNA11 are mutually exclusive. It is thought that these mutations increase proliferation by upregulating the MAPK pathway, but do not necessarily induce malignancy. Studies have also implicated CYSLTR2, which encodes a Leu129Gln substitution and drives phorbol ester-independent growth, as a uveal melanoma oncogene that occurs in a mutually exclusive manner with GNAQ and GNA11 [35,36]. These mutations act as an initiating event and signal a change in chromosomal composition. In addition to being characteristic of primary uveal tumors, GNAQ mutations are also seen in epidermal lesions such as blue nevi (Mongolian spot), conjunctival lesions (Nevi of Ota), and peri-orbital lesions ; about 1 in 400 patients with a blue nevus ultimately develops uveal melanoma. Since GNAQ or GNA11 gene mutations are also found in nevi, their presence cannot be used to predict the development of metastases [38,39] or patient outcome .
The mechanism by which uveal melanoma cells metastasize remains poorly understood. The presumption is that micrometastases spread throughout the body at the time of diagnosis . While cutaneous melanomas metastasize through the lymphatic system, uveal melanoma spreads by way of the blood . Models for estimating metastatic potential include the Liverpool Uveal Melanoma Prognosticator Online (LUMPCO), which estimates allcause and melanoma-specific mortality well , and Prediction of Risk of Metastasis in Uveal Melanoma (PRiMeUM), which predicts an individual’s personal risk of metastasis based on their individual and tumor characteristics with accuracy over 80% .
Inactivation of the BRCA1-associated protein 1 (BAP1) gene, a suggested uveal melanoma tumor suppressor gene, was reported in about 80% of metastatic uveal melanomas; this gene encodes a deubiquitinating enzyme . Diagnoses made at a younger age are more likely to be associated with the presence of a BAP1 mutation . BAP1 mutations in uveal melanoma cells seem to independently predict metastatic death and are associated with larger tumor size and ciliary body involvement . However, BAP1 mutations are not more frequently represented among metastatic lesions . BAP1 mutations correlate with reduced expression of BAP1 protein and several studies have reported a link between BAP1 immuno-staining and genetic analysis as well as the identification of a subgroup of atypical poor-prognosis disomy 3 (D3 - see below) patients [47,48]. Interestingly, germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a condition that also predisposes patients to renal cell carcinoma, malignant mesothelioma, and cutaneous melanoma [49,50]. However, while 36 of 59 metastasizing tumors in one study carried a BAP1 mutation, only 7% carried germline mutations compared to 54% with somatic mutations .
Clinicians have relied on the confirmed absence of chromosome 3, or monosomy 3 (M3), within a tumor sample to predict a patient’s relapse free time and overall survival . Gene expression profiling (GEP), which utilizes an RNA sample from the tumor, led clinicians to assign tumors to one of four subclasses - Class 1A, 1B, 2A and 2B [52,53] using an assay licensed to Castle Biosciences, Inc. which provides it for clinical use under the trade name DecisionDx-UM. Class 1 and Class 2 signatures predict low or high metastatic risk within the first five years after diagnosis, respectively [30,52]. For genetic analysis, if an eye has been enucleated, the tissue sample is collected from the removed eye; if not, a tissue sample is collected through fine needle aspiration biopsy (FNAB). Recent data suggest there is no increased metastatic risk after intraocular tumor biopsy .
Class 1A tumors express minimal aneuploidy and tissues reveal normal differentiated melanocytes [42,54]. Class 1B tumors exhibit chromosome 6p gain, which is also seen in retinoblastoma tumors . Generally, Class 1 tumors are composed of spindle shapedcells, have a low vascular/inflammatory profile, and exhibit disomy 3 (D3), 6p gain and a mutation in EIF1AX; this latter gene encodes a protein that interacts with mRNA, being a component of the 43S pre-initiation complex, and plays a role in the initiation of translation . Mutations in EIF1AX were shown to protect against metastasis , even after adjusting for the effect of other known risk factors . Interestingly, Ewens et. al., found that the combination of M3 with the EIF1AX-WT (risk) allele was significantly associated with metastasis (OR 29.7) and remained significant after adjustment for other tumor variables (OR 31.4) .
Class 2A tumors express M3 and Class 2B tumors express M3
and exhibit an 8p loss. Class 2 tumors are typically composed of
epithelioid or mixed cell types and incorporate tumor-associated
macrophages. They also display an increased vascular density and
a mutation in BAP1 [54,59]. The metastatic propensity of Class 2
tumors is believed to develop as a two-step process beginning with a
loss of chromosome 3, followed by a deletion of the tumor suppressor
gene LZTS1 on chromosome 8p . On the other hand, the presence
of a gain of 6p and loss of 6q is usually associated with better patient
survival even when chromosome 3 and 8 abnormalities are also
present [42,53,60]. While Class 2 tumors have been associated with
older age and a thicker mean ultrasound measurement prior to
treatment, the identification of a characterizing clinical marker has
yet to be discovered . PRAME, a gene that expresses a surface
protein targeted by cytotoxic T cells was reported to be associated
with a shorter time to metastasis and increased risk of melanomaassociated mortality, and to be independently predictive when added
to Class 1 or Class 2 distinction ; this protein is not expressed in
normal tissues, except the testis [Table 1].
|Uveal location||Iris||Ciliary Body
|*GEP class||Class 1||Class 2|
Spindle cell type
Epitheliod/mixed cell type
|Gene mutation||Chromosome 6p gain EIF1AX|
T4 (risk increases
thickness: ≤ 5.2 mm
T1, T2 base diameter:
≤ 12 mm Absence
extraocular extension||T3,T4 tumor
thickness: ≥ 8.9 T3,
T4 base diameter:
≥15 mm Presence
*Gene Expression Profiling (GEP)
Table 1: Metastatic Risk Profile
Analysis of 120 uveal melanoma tumors for numerical changes in chromosomes 1, 3, 6, and 8 with cytogenetic analysis, fluorescent in situ hybridization, and/or comparative genomic hybridization demonstrated that concurrent loss of the short arm of chromosome 1 and all of chromosome 3 is an independent predictor of decreased disease-free survival . Use of multiplex ligation-dependent probe amplification (MLPA) to detect abnormalities in chromosomes 1p, 3, 6q, 8p, and 8q showed that 10 year disease-specific mortality was 0% in 133 tumors with no chromosome 3 loss, 55% in tumors with chromosome 3 loss but no chromosome 8q gain, and 71% in 168 tumors showing combined chromosome 3 loss and 8q gain. In tumors with both of these abnormalities, epithelioid melanoma cytomorphology, closed microvascular loops, and high mitotic rate correlated with poor survival as did lack of chromosome 6p gain. These data support the use of MLPA for routine clinical prognostication, especially if the genetic data are considered together with clinical and histologic risk factors .
Despite prognostic correlations with the expression of a small
panel of marker genes, with M3, and with BAP1 aberrancy, the
molecular pathways involved in the development of metastatic
disease have not been elucidated, as the authors of the elaborate
Rare Tumor Project of The Cancer Genome Atlas (TCGA) study
pointed out . This group performed a global and integrated
molecular characterization of 80 primary uveal melanomas in an
attempt to uncover the distinctions in the biological processes that
underlie tumors that vary in aggressiveness. Their study identified
four molecularly distinct, clinically relevant subtypes: two associated
with poor-prognosis M3 and two with better-prognosis D3. BAP1
loss was shown to follow M3 occurrence and correlated with a global
DNA methylation state that is distinct from D3-uveal melanoma.
Poor-prognosis M3-uveal melanoma subsets were shown to have
distinct genomic, signaling, and immune profiles, and EIF1AX and
SRSF2/SF3B1 mutant D3-uveal melanoma had different genomic/
DNA methylation profiles. Mutations in EIF1AX were previously
reported in non-metastasizing tumors  and a hotspot mutation
in SF3B1, the splicing factor 3 subunit 1-gene was detected in late
metastasizing tumors [66,67]. SF3B1 mutations are associated with
a small group of cancers and in uveal melanoma, they are almost
always mutually exclusive of BAP1 mutations . Developing a
clinically relevant classification system was suggested to require
prospective evaluation of copy number and/or gene expression
data in tumors with similar clinical-pathological features to identify
patients with higher- versus lower-risk M3-uveal melanoma, and to
validate the differential metastasis intervals observed in the TCGA.
Targeted next-generation sequencing should facilitate the prediction
of patients’ metastatic risk and potentially assess eligibility for new
While choroidal melanomas can leak fluid beneath the retina,
causing the retina to detach and result in symptoms of flashing lights
and floating specks, most uveal melanoma patients are asymptomatic
and have their tumors discovered during a routine eye examination.
Differential diagnosis must rule out large uveal nevi, which are most
similar in appearance to small uveal melanoma tumors , and
tumors that have metastasized to the uvea, especially from breast and
lung cancers, which can be the first indication of an occult primary
tumor . Diagnosis is based on the results of a funduscopic
examination followed by ultrasound; optical coherence tomography
(OCT) may be useful in some cases to differentiate the lesion from a
choroidal metastasis. Studies reported that PET-CT is not sensitive in
the diagnosis of malignant uveal melanoma [72,73]. Common lesions
which simulate a uveal melanoma are described below, which in
addition to suspicious choroidal nevi include central and peripheral
exudative hemorrhagic chorioretinopathy, congenital hypertrophy
of the retinal pigment epithelium (CHRPE), choroidal hemangiomas
 and choroidal osteomas (Figure 1).