uveal melanoma ( um ) is the second most common primary malignancy of the eye worldwide after childhood retinoblastoma and is the principal fatal intraocular disease in adults . the reported incidence ranges from 4 to 11 cases per million / year [ 24 ] , varying by country and ethnicity , with a significantly higher incidence in caucasians than in african and asian populations . um arises in melanocytes located within the three different regions of the uveal tract : the iris , ciliary body , and choroid . um can be diagnosed at any age but it is more common in middle to later life , with a median age of onset of 5560 years [ 1 , 3 ] . although it is a relatively rare neoplasm , um is associated with particularly high mortality , primarily due to a high level of metastatic liver disease which develops in almost half of patients within 15 years of diagnosis [ 5 , 6 ] . once liver metastasis is detected , prognosis is poor , with a reported median survival duration ranging from 2.2 to 12.5 months [ 79 ] . a poor clinical outcome , coupled with limited treatment options ( there are no specific therapeutic modalities currently available for metastatic um ) [ 1012 ] , underscores the need to define precisely the underlying risk / predisposing factors that lead to uveal melanocyte transformation and subsequent metastasis , with the focus as much on prevention as on early diagnosis . a correlation between um incidence and latitude in european populations suggests that lack of ocular pigmentation could be a risk factor for um [ 4 , 13 , 14 ] , and light iris color has also been linked to poor prognosis in patients with um . within populations with light irises , however , elevated levels of choroidal pigmentation have been linked to an increased incidence of um . other recognized risk factors include caucasian ethnicity , preexisting choroidal nevi [ 17 , 18 ] , and genetic factors such as specific chromosomal abnormalities and gnaq/11 mutations [ 19 , 20 ] . furthermore , some familial factors have been associated with an increased risk of um and the prevalence is higher in men than women . a link between ultraviolet exposure and um , as observed with cutaneous melanoma , has been suggested , but the evidence for this is inconclusive [ 21 , 22 ] . it has been known for many years that ultraviolet exposure , coupled with specific skin pigment gene polymorphisms , is a prominent factor in the development of cutaneous melanoma [ 23 , 24 ] . this strong link has in turn driven efforts to establish whether there is a similar link in patients with um ; however , epidemiological and genetic studies have generally failed to show such a connection . sunlight exposure does not show a strong association with um [ 21 , 22 ] , although arc welding ( a source of ultraviolet / blue light ) does [ 21 , 22 , 25 ] . genetic studies also suggest that ultraviolet radiation does not significantly contribute to um . for example , the oncogenic v600e braf mutation , expressed in the majority of patients with cutaneous melanoma , is thought to be the result of solar ultraviolet exposure [ 2628 ] and is absent from melanomas occurring in body locations that are naturally protected from ultraviolet radiation . this link provides a useful molecular tool that allows direct insight into the contribution of solar ultraviolet radiation to um incidence [ 29 , 30 ] . genetic analysis of v600e braf expression in patients with um has uncovered a relationship between the frequency of this mutation and the ocular location of the melanoma . v600e mutations have been detected in patients with anterior um , such as those of the iris , consistent with ultraviolet exposure ; however , most um cases arise in the posterior uveal tract and v600e mutation rates here are negligible [ 19 , 32 ] . these data imply that while ultraviolet radiation may well play a role in some cases of anterior um , it does not significantly contribute to the oncogenic changes driving the majority of um arising in the posterior uveal tract . the combined epidemiological / genetic case against a significant role for ultraviolet radiation in the etiology of this disease is consistent with the established properties of the adult crystalline lens and cornea , which collectively filter out all wavelengths below 400  nm [ 29 , 30 , 33 , 34 ] . perhaps the key to understanding the link between um and activities that generate high amounts of electromagnetic radiation ( e.g. , arc welding ) does not lie in what is filtered out but in what can pass through the lens and cornea . for instance , arc welding produces significant amounts of intense short - wave light [ 25 , 35 ] . unlike ultraviolet radiation , short - wave ( perceived as blue ) light ( 400500  nm ) can reach the posterior uveal tract while retaining sufficient energy to be deleterious to biological structures . in fact , although visible light reaching the retina is a prerequisite for sight , phototoxic damage caused by its higher energy blue component is not an uncommon feature of the mammalian eye . a significant number of articles have documented blue - light - mediated damage to cells derived from the retinal pigment epithelium , retinal ganglion cell layer , and other epithelia , especially blue light in the 425475  nm range [ 3641 ] . this cellular damage is thought to be primarily photochemical and arises from chromophores , such as melanin , retinoids , and lipofuscin . this damage usually results in cell dysfunction or death , the main causes of cellular aging and age - related macular degeneration ( amd ) , but may also contribute to tumorigenesis . in this paper , we review the available evidence for a causal link between blue light and um . systematic literature searches conducted through ovid ( embase and pubmed ) showed that the earliest reports of an association between exposure to blue light and the development of um have come from in vitro and animal work . several studies have shown that blue light has a mitotic effect on human um cell lines [ 42 , 43 ] . cultured human um cells exposed to blue light ( peak 475  nm ) significantly increased their mitotic division rate relative to blue - light - shielded controls , an effect that was blocked using a blue - light - filtering lens . although the exact mechanism underlying the relationship between blue light and increased proliferation of uveal melanoma cells is unknown , it has been shown that shorter wavelengths of light can induce retinal pigment epithelial cell death by mitochondrial - derived ros production . thus , although specific studies are required , investigating ros production following blue light exposure in uveal melanoma cells would be a good starting point for elucidating the aforementioned relationship . this interesting observation was followed up by a study that sought to mimic the effect of blue light on um cells within the context of the mammalian eye . human um cells xenografted into the eye of an albino rabbit model of ocular melanoma and subsequently exposed to blue light showed enhanced proliferation upon removal and reculture , compared with control samples protected from blue light . the significance of this finding is that the um cells were exposed to blue light while residing within the choroid , effectively demonstrating that blue light affects uveal cells and can enhance their mitotic ability , a crucial step in linking blue light to malignant changes within uveal melanocytes in vivo . a final confirmation of the link between blue light and um in vivo comes from a study in long evans rats , a strain with pigmented eyes in which there have been no reported cases of intraocular melanoma . this study described the development of an ocular tumor in one animal following blue light exposure ( 434475  nm ) coupled with the administration of an antiapoptotic agent . the tumor involved the iris , ciliary body , choroid , and sclera , and contained large amounts of melanin . paradoxically , however , 450  nm blue light appears to be phototoxic to mouse cutaneous melanoma cells [ 45 , 46 ] . initial work reported that 450  nm light from a light - emitting diode was cytostatic to b16 cells ,   as well as inhibiting the ability of these cells to metastasize to the lung when injected intravenously into mice . further work has extended these early observations to show that 450  nm light is both cytostatic and cytocidal to b16 cells . it has also been suggested that blue light therapy may be of clinical benefit in cases of hemorrhagic metastatic melanoma , based on data from a single patient receiving aggressive chemotherapy for a melanoma on the anterior forearm . it should be noted that these phototoxic data are all based on cutaneous melanoma and for the most part the behavior of a single mouse cell line . further evidence underpinning a link between blue light and um comes from neonatal blue light therapy studies . blue light therapy is an essential tool in treating neonatal jaundice because dermal / subcutaneous bilirubin absorbs light maximally at 425475  nm , leading to its conversion to a less toxic soluble form . a reported long - term side effect of this therapy is the increased risk of dysplastic nevus development in both the skin and eye ( clinically , atypical nevi , or dysplastic nevi , are generally accepted to increase an individual 's risk of melanoma ) . an initial report described a higher prevalence of atypical but not common melanocytic nevi in the skin of school children who had previously received neonatal blue light therapy . although broad - spectral emission bulbs are frequently used in this therapy ( 370600  nm , maximal emission 450  nm ) , ultraviolet a contamination remains negligible at approximately 0.3% of output . a follow - up study of monozygotic and heterozygotic twins , in which one of each pair had received and one had not received neonatal blue light therapy , not only reproduced these findings , but also found an increase in benign ocular pigmented lesions of the iris in the cohort who had received blue light therapy . the latter finding is surprising because eye protection is worn in neonatal blue light therapy ; however , accidental removal of eye coverings may occur and the neonatal eye allows greater transmission of lower frequency blue light relative to the adult eye . blue light has been shown to induce nuclear dna lesions , suggesting a possible mechanism for tumorigenesis . specific nuclear dna lesions resulting from blue light have been recorded in the presence of lipofuscin , a photoinduced intracellular generator of ros . furthermore , although no study has shown dna mutations in uveal melanocytes in the presence of blue light , the carcinogenic potential of radiation in the 365436  nm ultraviolet a / blue light crossover region has been demonstrated . in animal models of melanoma , ultraviolet a / blue light is not directly absorbed by dna but rather exerts its effect through a photochemical interaction with melanin . given the filtering power of the crystalline lens and cornea , there is a significant window of mutagenic opportunity for blue light of 400436  nm , and probably higher , because 365436  nm represented the peak of activity . interestingly , it has been shown that ultraviolet b and ultraviolet a differentially induce cutaneous melanoma through direct dna damage and indirect melanin - derived ros - mediated damage , respectively . the wavelengths of ultraviolet a and blue light are adjacent and their biological effects probably overlap , as their shared ability to generate ros demonstrates . although the relationship between melanocyte melanin ( eumelanin , pheomelanin , and their precursors ) , ros generation , and dna damage is complex , a plausible scenario involving blue - light - triggered ros - induced melanocyte mutation can be hypothesized as a precipitating factor leading to um . blue light may also play a role in neovascularization , a key event in the successful development of any solid tumor , and by extension um . a central player in this process is vascular endothelial growth factor ( vegf ) , a signaling protein that stimulates both vasculogenesis and angiogenesis . hypoxia is known to induce vegf production by um cells [ 54 , 55 ] , and high levels of vegf have been reported in both the aqueous and vitreous humors of patients with um [ 56 , 57 ] . furthermore , vegf is an associated biomarker of um metastasis [ 58 , 59 ] . in cultured retinal pigment epithelial cells , vegf production in response to white light exposure can be inhibited by directly blocking the blue light component [ 6062 ] . while it remains to be seen if this phenomenon can be replicated in either primary ocular melanocytes or um cells , particularly with respect to its relationship with hypoxia , these data lend further mechanistic credibility to the link between blue light and a critical stage in the development of um . if blue light is a known risk factor for amd and , at the very least , a suspect in um development , can this knowledge be translated into some form of meaningful preventive measure ? one area of immediate relevance is the current debate surrounding intraocular lens ( iol ) implants used after cataract surgery [ 6365 ] . the replacement of the crystalline lens by an iol is a central component of this procedure . early iol models filtered out ultraviolet radiation , but more recently developed iols filter out a wider spectral range , including at least the more energetic parts of blue light because , ideally , the spectral emission characteristics of an iol should mimic those of the lens that was removed . as the crystalline lens ages , it yellows and filters out significantly more blue light above 400  nm . this process appears to be caused by the progressive accumulation of yellow chromophore deposits , primarily 3-hydroxykynurenine glucoside derivatives , estimated to reduce the blue light transmission capacity of the crystalline lens by around 0.70.8%/year . consequently , the 400500  nm transmission capacity of 8090% associated with the lens of a healthy child or young adult [ 68 , 69 ] is cumulatively reduced in later life , dropping to around 50% by the fifth decade and to as little as 25% or less at 70 years and over [ 6872 ] . there is also evidence to suggest that retinal tissue becomes more sensitive to phototoxicity , possibly owing to increased lipofuscin concentration and impaired antioxidant activity [ 29 , 65 ] , concomitant with altered lens function . therefore , there is a clinical rationale for considering the use of blue - filtering iols , and this is further supported by the evidence presented in this paper ( figure 1 ) . in summary , cumulative epidemiological and experimental evidence indicates that blue light is a credible risk factor for the development of um . additional studies are required to clarify the risk associated with blue light and the protective potential of blue - filtering iols following cataract surgery . as life expectancy continues to increase , individuals are expected to live longer after cataract surgery . shielding individuals from the known harmful effects of blue light , a role normally performed by the aging crystalline lens , through the use of blue - filtering iols is of clinical benefit as a preventive measure against um .
uveal melanoma is the most common malignancy of the adult eye . 
 although it is a relatively infrequent tumor , clinical prognosis is often poor owing to a high incidence of aggressive metastatic disease , for which there are limited treatment options . 
 little is known about the etiology of this condition , although several risk factors have been identified . 
 unlike cutaneous melanoma , however , ultraviolet radiation does not figure prominently among these risk factors . in this review , 
 we focus on an associated form of visible electromagnetic radiation , high - energy short - wave ( blue ) light , a causative agent in various forms of age - related retina damage , as a previously overlooked risk factor in uveal melanoma development and progression . 
 finally , we discuss the impact of these data on contemporary ocular therapy , particularly the debate surrounding the filtering capabilities of intraocular lenses used to replace dysfunctional crystalline lenses during cataract surgery .