Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

and oculodermal melanocytosis [44]. In a recent population-based case-control study in Australia, there was increased risk of choroidal and ciliary body melanoma associated with non-brown eye color, four or more cutaneous nevi on the back, inability to tan, and squinting while outside in the sun as a child [45]. Previous history of nonocular malignancy also has been examined as a risk factor, with equivocal results [46–49].

B.Hormones and Reproductive Factors

The role of hormones and reproductive factors has been investigated, with equivocal results. Reports of increased incidence in women of childbearing age [13,50] or disease occurrence associated with pregnancy [40,51,52] suggest an effect of hormones, but results from case-control studies examining specific hormonal factors have been inconsistent [53,54]. A recent evaluation of enucleated eyes did not support the presence of type I estrogen receptors in human uveal melanoma [55], which concurred with a previous analysis using similar modern estrogen receptor testing methods [56].

C.Genetic Susceptibility

Physiological changes or genetic modifications may be associated with the occurrence of uveal melanoma, although there have not been consistent findings among studies. There are equivocal findings regarding the role of genetics in the development of uveal melanoma. Several studies have documented family clustering of uveal melanoma [57,58], bilateral occurrence of uveal melanoma [59,60], or associations with cutaneous melanoma [43,60], suggesting a genetic or heritable component. The occurrence of uveal melanoma within members of a family and across generations suggests inheritance may play a role [61–63]. Recently, the clinical cases of three siblings afflicted with uveal melanoma were reported; all three patients were diagnosed before the age of 40 years and developed aggressive disease [64].

The role of genes has been implicated in the pathogenesis of both cutaneous melanoma and breast cancer and also has been investigated in uveal melanoma. In a study of 49 samples, there was no association between uveal melanoma and c-Ha-ras proto-oncogene point mutations nor genetic alterations in the c-Ki-ras-2 gene at codons 12, 13, and 61 [65]. Similarly, allelic variations for the melancortin-1 receptor (MC1R) gene do not appear to play a role in the development of uveal melanoma [66]. There are inconclusive findings regarding the role of CDKN2 (p16) gene as a tumor suppressor gene in uveal melanoma [67,68]. Specific genetic mutations, such as chromosomal deletions [69] or mutations in the p53 tumor-suppressor gene [70] have also been reported. In addition, germline brca2 mutations may occur in a small proportion of uveal melanoma cases [71].

Although no common germline mutations have been identified in families with members having both ocular and cutaneous melanoma, animal models have suggested a common hereditary factor [72]. The identification of genetic loci that contribute to the family aggregation of ocular and cutaneous melanoma or other cancer requires further investigation. However, the majority of reported uveal melanoma cases are not associated with factors typical of diseases with strong genetic etiology; thus, even if there is a genetic component, it is likely that

environmental or other factors are more important in triggering development of disease.

D.Environmental or Occupational Exposures

A key to the prevention of uveal melanoma is the identification of environmental or occupational exposures that place individuals at higher risk of developing the disease. Sunlight exposure and UV radiation have been implicated in the pathogenesis of cutaneous melanoma [73]. They also may play a role in the etiology of uveal melanoma but the association of environmental UV exposure and uveal melanoma is less clear than for cutaneous melanoma [17,74,75]. Studies evaluating tumor location in relation to presumed distribution of ultraviolet radiation exposure to the uvea have been contradictory [76,77], and the vulnerability of the uvea to UV radiation is not clear [78,79].

Occupational exposures to UV light or chemicals may also be involved in the etiology of uveal melanoma. Previous studies have suggested an association between uveal melanoma and use of sunlamps [36], intense sun exposure [80], and tendency to sunburn [36,39,81] . Occupational exposure to UV light among welders [82,83] or exposure to asbestos and chemicals in the workplace has been associated with increased risk of uveal melanoma [82,84–86]. However, differences in study designs and occupational coding schemes as well as selection biases influence both study findings and interpretation [87].

Exposure to radiofrequency radiation (in the form of radio sets and mobile phones) was recently shown to be associated with uveal melanoma in a case-control study from Germany [88]. Potential confounding variables that were not investigated in this study, such as occupational or recreational exposure to ultraviolet radiation, may account for the observed associations [89]. Conversely, an analysis of the incidence rate of uveal melanoma showed no correlation with the increase in mobile phone usage over time in Denmark [90]; further research is needed before recommendations can be made [91]. If radiofrequency radiation is in fact causative, future studies may demonstrate increasing incidence of uveal melanoma as these technologies become increasingly ubiquitous.

V.DETECTION OF UVEAL MELANOMA

Knowledge of the potential risk factors or predisposing elements for uveal melanoma would aid in early screening and detection of uveal melanoma. In Finland, 87% of patients had symptoms, mainly blurred vision and a visual field defect, before seeking an appointment with the health care system [31]. In the United Kingdom, most ocular melanomas are detected by optometrists [92]. An analysis of 223 patients presenting to optometrists between 1997 and 2000 revealed that as many as 45% of all detected tumors occurred in asymptomatic patients and would have been missed without appropriate screening. Also, tumors in patients with symptoms were less likely to be detected when there was reduced visual acuity, the anterior tumor margin was located anterior to the ora serrata, or the posterior margin was located in the pre-equatorial choroid [92]. The diagnosis of uveal melanoma by retinal specialists and other ophthalmologists has reached a high degree of accuracy

due to improved indirect ophthalmoscopy, fluorescein angiography, and echography [3].

VI. FUTURE RESEARCH DIRECTIONS

In spite of the large amount of epidemiologic research that has been conducted to date, our understanding of the magnitude, distribution, and risk factors for uveal melanoma is incomplete. The future of research in the epidemiology of uveal melanoma will depend to a great extent on advances in molecular biology and genetics to facilitate more precise case definition and to form a more solid ground for evaluation of the interaction between host characteristics, genetic factors, and environment and in the pathogenesis of disease. Histopathology and tissue repositories such as that developed from the Collaborative Ocular Melanoma Study [93] provide a rich source for future exploration of genetic characteristics and susceptibility. Future epidemiologic investigations will also be important to better define subgroups of individuals at increased risk of disease so that screening and programs of primary and secondary prevention can be appropriately focused. Finally, research is needed to elucidate the potential biological mechanisms through which implicated exposures may cause melanoma.

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