Epidemiologic aspects of uveal melanoma

SURVEY OF OPHTHALMOLOGY

MAJOR

VOLUME 32 * NUMBER 4 *JANUARY-FEBRUARY

1988

REVIEW

Epidemiologic Aspects of Uveal Melanoma KATHLEEN M. EGAN, M.P.H.,’ JOHANNA M. SEDDON, M.D.,‘,* ROBERT J. GLYNN, Sc.D., PH.D., l EVANGELOS S. GRAGOUDAS, AND DANIEL M. ALBERT, M.D.S

M.D.,*

‘Epidemiology Unit, -‘Retina Service, and “Howe Laboratory of Ophthalmology. Massachusetts &Ye and Ear Injrmay, Department of Ophthalmolq~, Harvard Medical School, Boston, Massachusett.s

Abstract. Although

the underlying cause or causes of uveal melanoma have yet to be elucidated, important insights may be gained by examining the epidemiologic features of the disease. Uveal melanoma is an uncommon cancer with an incidence of only six cases per million population per year. It is most often diagnosed in the sixth decade and is somewhat more common in males. Apart from sporadic reports of family clusters, uveal melanoma is not considered an inherited disease. Whether some environmental exposure triggers the development of uveal melanoma remains an open question. Sunlight has been proposed as an environmental risk factor because sunlight is known to cause melanoma of the skin and both diseases are rare in nonwhite races. Unlike cutaneous melanoma, however, rates have not been increasing over time and do not vary

by latitude. This paper evaluates the available evidence for sunlight and other potential risk factors for uveal melanoma, highlighting areas requiring further research. (Surv Ophthalmol 32:239-251, 1988)

Key words. ultraviolet

epidemiology melanoma radiation uveal melanoma l

l

risk factors

l

tumor

l

l

half of patients will die from the disease within 10 to 15 years of enucleation”*“+ and late metastases occurring many years after treatment are not uncommon. Despite diagnostic advances and the introduction of new treatment modalities over the last several decades, the rate of metastatic disease from these tumors has not been substantially reduced. Recent advances in the treatment of metastatic disease have shown some encouraging results.“’ For the present, however, prevention may be the only effective means to reduce the mortality and morbidity associated with uveal melanoma. Toward this end, the identification of risk factors for the development of uveal melanoma is a major goal of current re-

Uveal melanoma is an uncommon malignant tumor with a high incidence of metastasis. It is the most common primary intraocular malignancy and is the only primary intraocular disease in adults that can be fatal. Melanomas of the uveal tract are the most common noncutaneous melanomas but have an incidence one-eighth that of cutaneous melanoma in the United States.‘“” Melanomas ofthe iris are rare, comprising less than 10% of uveal tract melanomas. B.~“,“~ These tumors may be distinguished from melanomas of the choroid and ciliary body by their smaller size and relatively benign histopathology.W Iris melanomas seldom metastasize and have been effectively treated by local excision.‘“’ Tumors of the choroid and ciliary body, on the other hand, pose a serious threat to life. Approximately

*Kurland,

239

I. -

personal communication.

240

Surv Ophthalmol

32(4) January-February

TABLE Incidence Rates of heal

EGAN

1988

Melanoma

1 Reported for

Various Populations

Rate (Incidence

Shammas (1977) Kurland ( 1987) Egan (1987) Ganley (1973) Raivio (1977) Birdsell ( 1980) Jensen ( 1963) Abrahamsson ( 1983) Mork (1961) *Primary

anatomic

x

106)

Population

Interval

With iris

Iowa (USA) (whites only) Rochester and Olmstead County, Minnesota (USA) New England (USA) Washington County, MD (USA) Finland Alberta, Canada Denmark Swedish west coast Norway

1969-1971 1935-1974

5.6 6.7

4.9 6.0

1984-1985 1956-1965 1953-1973 1967-1976 1943-1952 1956-1975 1953-1960

5.0 6.0 7.4 *8.0

6.5 6.6 -

Author

site unavailable

ET AL

Without

iris

5.5 7.1 7.2 -

in this series.

treated by enucleation in the early years following Longer follow-up of irradiated patreatment.‘3~‘32 tients will determine whether metastasis continues at similar rates in later post-treatment years. The most comprehensive, longterm studies of I. Incidence survival following enucleation derive from Denmark and Finland. Raivio”4 compiled a roster of all paBased on the Third National Cancer Survey of tients diagnosed with uveal melanoma between 1969 to 1971, the annual age-adjusted incidence estimate for ocular melanoma in the United States is 1923 and 1966 in Finland. Of 359 identified cases, six cases per one million population.‘2g Similar estisurvival status at 10 years was known for all but five mates for uveal melanomas of the choroid and cilipatients. Follow-up was 15 or more years in 314 ary body,W-.W* or choroid, ciliary body and iris’3520 cases (89%) and at least 20 years in 214 cases have been reported for individual states or regions (60%). The 5, 10 and 15-year survival rates based within the United States. Other surveys ofprimarily on melanoma-related deaths were 65%, 52% and white populations have found incidence rates simi46%, respectively. Of the 42 patients who survived lar to those of the United States’.23.70.g7~“4(Table 1). at least 20 years, nine later developed metastasis. The incidence rate among African blacks is unJensen evaluated survival at least 25 years after enuknown, but is thought to be extremely low.7g~g3~g5~‘53 cleation in Danish patients with uveal melanoma. In the United States, the rate of the disease in blacks The majority of patients included in the original is less than one-eighth that found in whites.lzg Alseries had died (82%), 150 of these 292 patients though small fluctuations for several populations (51%) due to metastasis. Actuarial survival rates at have been observed,58j’4* the incidence and mortality 5, 10 and 15 years were similar to those reported by rates of uveal melanoma have been shown to be Raivio.7’ fairly stable over the last several decades.73s’47 This is in sharp contrast to the markedly increasing inciIII. Demographic Risk Factors dence of cutaneous melanoma occurring over the A. AGE AND SEX same interva1.65,‘54 search in this field. Studies with this objective have recently been undertaken and important insights into the epidemiology of uveal melanoma are now emerging.

II. Mortality Metastatic spread of uveal melanoma is associated with an extremely poor prognosis. The median survival following diagnosis of hepatic metastasis is only 211 months. “5,130Although the highest rate of metastasis occurs within the first five years after enucleation, recurrences up to 42 years following treatment have been reported.‘37 Patients treated by radiation therapies introduced over the last 10 to 20 years have a rate of metastasis comparable to those

Uveal melanoma is rarely diagnosed in children 1',17,42,70,75,'01,'09.128,158 1 n most series, the median age at diagnosis is about 55 years.70.“4 In Jensen’s series, rates ofdisease dropped after age 69, but only in males.70 Raivio found that in females rates of disease began to level off beginning in the mid-60s, but in males continued to increase.‘14 Data from Norway show rates dropping in both sexes after age 70.g7 This is in contrast to the majority of adult cancers in which there is an exponential increase in incidence with age. In addition, uveal melanoma

EPIDEMIOLOGIC

ASPECTS

OF UVEAL

MELANOMA

tends to be diagnosed nearly a decade earlier.‘55 There is some evidence that uveal melanoma is more common in males. A slight predominance of males is found in many large surveys of patients with uveal melanoma.5”~i”~134 Yanoff and Zimmerman reported a 614 ratio of males to females in a group of 100 eyes referred to the Armed Forces Institute of Pathology, a pattern that persisted even after excluding military personnel.“jj Other studies presenting gender-specific rates of ocular melanoma:36.tr) ~‘3,!l7.l’“).lt9 have found somewhat higher rates in males. Higher rates in males have also been found in studies that used all eye cancers among persons aged 15 years or older as a surrogate for ocular melanomas.is.‘“~“R (It has been shown that in white populations, over 90% of these eye cancers are ocular melanomasj8 and the great majority involve the meal tract.lzg). These higher rates among men may suggest either an independent gender effect or that specific exposures related to disease may be somewhat more common among males. B. RACE U\eal melanoma is rare among non-white races. Data from the Third National Cancer Survey indicate that whites have more than 8 times the risk of developing the disease than blacks in the United States.‘“” In a series of over 4000 cases of ocular melanoma on file at the Armed Forces Institute of Pathology, only 24 patients were black.‘Og Surveys of eye disease in African populations reveal the same low risk in black Africans.‘“,““,‘“.“” In a South African study. one case of uveal melanoma occurred in a black patient over a 25-year period, compared to approximately 150 cases among white patients who represented only 25% of the population studied.g5 (Detection bias may account for some of this difference if blacks were less likely to be diagnosed.) The risk ofuveal melanoma is also low in races of intermediate pigmentation.7”~H’~“9 In the United States, the disease is rare among Americans of Chinese extraction”g and there has never been a reported case of uveal melanoma in a native American.*’ C. SOCIOECONOMIC

STATUS

Socioeconomic status has been linked to higher rates of certain cancers including cutaneous melanoma.” The role of socioeconomic status has not been directly studied in uveal melanoma, however. In two studies, the distribution of cases of uveal melanoma by occupation was found to be similar to that of the general population from which the cases were drawn.“‘.“’ In a study of eye cancer among persons 15 years and older, cases were more likely to hold non-manual occupations relative to the population of England and 1Yales.l’”

IV. Host Risk Factors A. GENETICS Silcock was the lirst to question whether there might be a hereditary basis for uveal melanoma when in 1892 he described a daughter/mother pair, both with apparent intraocular melanoma.‘4’ Since that time, there have been at least 13 clusters occurring among blood relatives reported in the world literature ?X.,~1.34.51.~~.88.1o).i 12.1I’.1 12.lill.lh~l.lhl In several, involvement of more than two generations was documented histopathologicallyg’,‘“’ or was suspected”‘,“” based on medical history. In the largest of these family groups, reported by Silcock,“’ later Parsons,“” and then Davenport,‘l seven family members in four generations had eyes enucleated, live with histologically proven choroidal or ciliary body melanomas. The reason for enucleation in the other two members was known only to be due to some cause other than trauma. Although family history of uveal melanoma is rare. a few cases may have a heritable component. Cutaneous melanoma is now recognized as an inherited disease in as many as 10% of cases.?” Recent evidence suggests that family members of persons with cutaneous melanoma who possess large numbers of dysplastic nevi have several hundred times the risk of developing cutaneous melanoma compared to the general population.‘” This inheritable form of melanoma is referred to as the familial atypical multiple mole melanoma (FAMMM) syndrome by Lynch and colleagues,” although alternative names have been proposed by authors who feel that a percentage of cases are sporadic rather than familial.“” Reports of cutaneous melanoma and uveal melanoma occurring as double primary malignancies 2.1t.l’l.lrr4.10i.123.157 some in the presence of dysplastic nevi,?,“‘,‘04 and melanomas of both sites occurring among

family

~~~~~~~t.i4.~h.‘~l.l~l4.llli.lii

have

led

to

speculation that cutaneous and uveal melanoma may have a common inheritable variant. Recently, Jensen has described a case of a seven-month-old boy with a choroidal melanoma and FAMMM (called “dysplastic nevus syndrome” here), both conditions extremely rare in children.” This newly described syndrome has provided investigators with a means by which to study the putative relationship between uveal melanoma and the inherited variant of cutaneous melanoma. In one such study, persons with FAMMM were more likely to possess conjunctival, iris and choroidal nevi,lT4 In other studies, persons with cutaneous melanoma have been found to be more likely to of iris possess iris nevi” or have a larger number nevi’“” than controls. These studies reported similar though not statistically significant patterns for chor-

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Surv Ophthalmol

32(4) January-February

EGAN ET AL

1988

oidal nevi. In an earlier study, Reese reported that nevi of the facial skin and iris tended to occur on the same side of the face.“’ Since the majority of uveal melanomas are thought by some to arise from preexisting nevi,‘65 the above findings could be indirect evidence for a genetic link between melanomas of the two sites. However, Taylor and associates were not able to demonstrate a higher than expected rate of dysplastic nevi among a group of persons with ocular melanoma.15* Likewise, there have been no reports of a higher frequency of ocular melanoma among persons with dysplastic nevi or cutaneous melanoma. Greene and colleagues found no cases of intraocular melanoma or suspicious choroidal nevi in a group of 26 patients with hereditary cutaneous melanoma, dysplastic nevus syndrome, or both.“4 In a subsequent study, these authors examined cancer registry data and found only one case of intraocular melanoma among 13,841 cases with cutaneous melanoma. Since the number of cases that would have been expected if there were no association between the two diseases (0.76) was similar to the observed value of one case, Greene et al concluded that simultaneous occurrences of the two diseases were coincidental.5j A study comparing the frequency of skin melanomas in cases with uveal melanoma to that of controls would be the most practical approach to studying whether there is an association between the two malignancies. Future work may establish that a small percentage of uveal melanomas are inheritable as part of the FAMMM syndrome, but heredity is clearly not a major determinant of uveal melanoma. In a series of 1200 patients with uveal melanoma treated by proton beam irradiation, there are only two verified cases of the disease among first degree relatives (Gragoudas E: unpublished data). Jensen was not able to document any family history of the disease among 305 cases in his survey.” Even in cases among blood relatives, there remains the possibility that some shared environmental exposure caused the disease. For example, cases of melanomas of the uveal tract and skin occurring in husbands and wivesg6.‘22~‘36and among other nonblood relatives sharing the same household’B have been reported. While heredity does not appear to play a major role in uveal melanoma, there is new evidence to suggest a possible genetic component in the occurrence of a few cases. Mukai and Dryja recently demonstrated the loss of alleles on chromosome #2 in 2 of 15 patients with uveal melanoma.qg This finding led the authors to speculate that recessive mutant alleles, expressed only with loss of the homologous allele, may be responsible for the development of some ocular melanomas.

B. OCULAR

NEVI

Although nevi on the skin have been shown in several studies to increase the risk of cutaneous melanoma,38@ there appears to be a low risk associated with nevi of the uveal tract for choroidal and ciliary body melanomas. Ganley and Comstock estimated that 3% of the population over age 30 have choroidal nevi posterior to the equator.46 Since nevi may also occur anterior to the equator,‘jO the prevalence of choroidal nevi may be as much as twice that reported. Based on their figures, these authors predict that only 1 in 5000 persons possessing such nevi will develop a melanoma each year (assuming all melanomas arise from preexisting nevi).46 Although the absolute risk of uveal melanoma in individuals with choroidal nevi is low, this risk may still be much greater than the risk in individuals without choroidal nevi. Examination of rates ofnevi in melanoma cases and controls is required to document the relative risk associated with choroidal nevi. Iris nevi have been reported to be more common in eyes with choroidal or ciliary body melanomas.“6 Wilder compared eyes enucleated for choroidal melanoma to eyes enucleated due to trauma and found that more of the eyes with a melanoma had iris nevi (66.5% versus 49.7%).16’ Michelson and Shields examined the eyes of 50 subjects with choroidal and ciliary body melanomas and 50 agematched control subjects with cataracts for the presence of iris nevi.ql While somewhat more of the eyes with melanoma had iris nevi (31 versus 26), the difference was not statistically significant. A potential bias in all three of these studies, however, was that the examiner was not masked with respect to the diagnosis and nevi may have been more likely to be identified in the eyes with tumors.

C. MELANOCYTOSIS Other melanocytic conditions which have been linked to uveal melanoma are ocular (melanosis oculi) and oculodermal (Nevus of Ota) melanocytosis. These are typically congenital unilateral conditions in which there is hyperpigmentation of the episclera and uveal tract in ocular melanocytosis and of the periorbital skin in oculodermal melanocytosis. Both conditions are more common among females and the highest prevalence has been reported to exist among orientals4’ As discussed, uveal melanoma may be somewhat more common in males and the disease is extremely rare in non-white races. However, several factors tend to support the view of Yanoff 66 and others that ocular and oculodermal melanocytosis are etiologically linked to uveal melanoma. First, uveal melanoma has been reported to occur in 5%4” to 25%“” of persons with

EPIDEMIOLOGIC

ASPECTS

OF UVEAL

MELANOMA

ocular melanocytosis. Second, there are a few reports of patients with melanocytosis presenting with multiple choroidal melanomas in the same eye ““.“7.“‘h when by far the most common finding in patients with uveal melanoma is a single lesion in one eye. Third, only 5% of cases of Nevus of Ota occur bilaterally and yet there are at least three reports ofpersons with bilateral Nevus of Ota developing uveal melanoma.“‘~““~!” Fourth, although blacks are normally at extremely low risk for uveal melanoma, there have been reports of black patients with Sevus of Ota developing the disease.“” Fifth, nearly all reported cases of uveal melanoma in persons with either form of melanocytosis have developed in the affected eye. Blodi, reporting a case of uveal melanoma occurring in the unaffected eye of a person with ocular melanocytosis, argued that the incidence of uveal melanoma in melanocytosis has most likely been overstated.” This may reflect a greater tendency for this typically benign condition to come to medical attention if a more serious disease like uveal melanoma develops. Gonder and associates attempted to determine whether the prevalence of both forms of melanocytosis was higher among persons with uveal melanoma compared to the general population. In a clinic population of 5251 whites, two patients (.038%) were found to ha\re ocular melanocytosis. The authors compared these results to the prevalence estimate of melanocytosis for a group of 1250 whites enuclcated for uveal melanoma (1.23%) and found a greater than 30-fold increase among uveal melanoma patients. tll Unfortunately, the authors did not state the age distribution of the clinic population. Since as many as 40% of cases of ocular or oculoderma1 melanocytosis develop later in life,‘” a substantial proportion of younger persons among the clinic population could result in an underestimation of the prevalence in that population relative to persons with uveal melanoma. A better approach would be to compare the frequency, of either melanocytic condition in patients with uveal melanoma to that found in a group of age-matched controls. D. HORMONES Hormonal influences are suspected in cutaneous melanoma based on reports of an increased risk among women in the child-bearing years8’,R” and the apparently aggravating influence of pregnancy on progno~i~,l”~_l?l,l’~~Pregnancy may also pose an added risk in uveal melanoma although reports of presentation”.“,““, t” and tumor growth13’ during pregnancy are rare. Increases during the child-bearing years in mortality due to tumors of the eyes” and in the incidence of ocular melanomas”g have been re-

1243 ported. The hormonal mechanisms responsible for these observations remain speculative. Steroid hormone dependence is well established for several cancers including prostatic carcinoma and some breast melanomas have been found cancers. “I Cutaneous to have cytoplasmic estrogenic receptors” which may indicate a similar steroid dependency for some cutaneous melanomas. The same may hold for uveal melanomas although one study showed an absence of estrogen receptors in choroidal melanomas and adjacent choroidal tissue.“’ An alternative possibility is that melanocyte-stimulating hormone (MSH) may be involved. MSH activity in the serum has been shown to be increased during pregnancy.‘” One author has suggested that the increased risk of malignant melanoma of the skin associated with higher alcohol consumption found in data from the Third National Cancer Survey ma); be mediated via MSH since alcohol stimulates the pituitary in its production of that hormone.“” hlSH may also play a permissive role in the action ofultra\riolet light on melanocvtes.“” E. IMMUNOCOMPETENCE Char has reviewed the literature on the role of immunology in the pathogenesis of ocular tumors.“” Most research on uveal melanomas in this area has focused on the influence of the host’s immune response to tumor growth and the metastatic spread of tumor cells and will not be reviewed here. Impaired host immunity, perhaps induced by an environmental exposure, could lead to the onset of uveal melanoma. In animal studies, ultraviolet (I-V) exposure has been found to induce primary skin carcinomas but only in mice that developed suppressor lymphocytes. ‘I In humans, ultraviolet radiation may act as a ‘permissive carcinogen’ by suppressing host immunologic surveillance. In studies of psoriasis patients undergoing therapy with near ultraviolet light and 8-methoxyporalen, inhibition of delayed hypersensitivity was dcmonstrable in over half of these patients who were skintested compared to 2 of 12 controls.’ “I Whether immunosuppression via UVR exposure plays a role in uveal melanoma is unknown but offers a mechanism by which an exposure such as sunlight could trigger the formation oftumors in relatively unexposed sites such as the eye. F. EYE COLOR *Jensen, in 1963, was the first to compare iris color among persons with uveal melanoma to that of a comparison group. ‘” He found that the 111 surviving patients (eye color had not been recorded on the original series), who had been diagnosed between 1943 and 1952, were nearly three times more likely

244

Surv Ophthalmol

32(4) January-February

to have light colored-irides compared to a group of clinic patients over age 25 (P < .OOl). Two recent studies have also found that individuals with light irides are at increased risk of developing uveal melanoma,45~‘56 a finding which implicates sunlight as an environmental risk factor for this disease. In the first of these studies,45 persons with blue or grey eyes were found to have three times the risk of disease (unadjusted for other host factors) compared to persons with brown eyes. Among individuals with the same eye color, there was a trend toward a higher risk with lighter hair color. The number of cases interviewed was small (N = 65) and the adjusted odds ratios (OR)* (5.2 for blonde or red hair and 2.1 for blue or grey eyes) were not significantly different from unity in this study. In a larger study of over 400 cases which combined iris with other uveal melanomas, the risk among blueeyed persons was 1.7 times that of persons with confidence interval [CI]: brown eyes (95% 1.3-2.5). Hair and skin color were not found to be independent risk factors after adjusting for eye color. ‘56 The protective influence of pigment may be particularly important in the iris, since the iris is the only part of the uveal tract positioned in front of the lens, an effective ultraviolet filter. Support for this observation comes from a study that found a higher prevalence of blue and grey eyes among cases with iris melanoma compared to ciliary body and choroida1 melanoma controls. ‘26 Kliman and associates also found that light irides were more common in persons with iris melanocytic lesions but suggested that such lesions may simply be more noticeable in light eyes and hence more likely to be brought to medical attention.80 However, the well-documented tendency for iris melanomas to occur in the inferior sector of the eye,6*~70~“4~‘25 where exposure to sunlight is presumably greatest, supports the view that the origin of these tumors is environmentally-related. In one study which considered only choroidal or ciliary body melanomas, the distribution of eye color in cases was similar to that of cataract controls.g4 Future studies should stratify by anatomic site when considering the influence of eye color on the risk of uveal melanomas.

V. Environmental A. SUNLIGHT

Risk Factors

EXPOSURE

Sunlight exposure has been examined as a potential environmental risk factor for a number of ocular diseases, including age-related macular degener*Odds ratio is the odds of the disease in exposed unexposed individuals; the odds ratio approximates rare diseases.

EGAN ET AL

1988

compared with relative risk for

ation,25,67 senile cataract30,6’ and, most recently, melanoma of the uveal tract. The latter disease has been linked to sunlight exposure since sunlight is a probable cause of cutaneous melanoma and the diseases share a common cellular origin, the melanocyte. Several lines of investigation offer evidence both in favor of and against a role for sunlight in uveal melanoma.

1. Cutaneous Melanoma There is strong evidence to suggest that sunlight exposure causes cutaneous melanoma in susceptible persons. Melanoma of the skin is only rarely found in non-white races. Among white populations, higher rates of the disease are found at lower geographic latitudes.‘2g Melanoma of the uveal tract is also rare in non-white populations. Unlike cutaneous melanoma, however, the rates of uveal melanomas have remained fairly uniform over the last several decades,73,‘47 and no latitudinal gradient has been demonstrated in uveal melanoma.35~45.‘2g.‘48 Studies have shown that the largest increases over time in cutaneous melanoma have occurred in the trunk area in males and lower legs in females.“j*‘j5. ‘45*‘54The marked increase of cutaneous melanomas of these sites has been attributed to changing styles of dress and behaviors, like sunbathing, beginning in the early decades of this cenmelanomas of the face have retury. 64 In contrast, mained fairly stable,65,‘45 perhaps because the face has been subjected to less variation in exposure than other sites. Thus, the fact that temporal trends are not seen in uveal melanoma may indicate that sunlight does not cause this tumor, directly or indirectly, or that it has reached a maximum incidence and leveled off, as has occurred with melanomas of the face. It is also possible that small increases in uveal melanoma have been overlooked due to the rareness of the disease and/or limited registry data on which incidence studies have been based. Cutaneous melanoma has been reported to occur with increased frequency among persons with xeroderma pigmentosum. ‘lo This is an autosomal recessive disease characterized by abnormal sensitivity to sunlight, premature skin-aging and multiple neoplasia. Individuals with xeroderma pigmentosum are most sensitive to short ultraviolet wavelengths, i.e., 290-320 nm. Wavelengths in this range cause the formation of pyrimidine dimers in the DNA. The most common defect in xeroderma pigmentosum is a lack of the excision repair processes which normally recognize and remove these dimers. Thus, in patients with xeroderma pigmentosum ultraviolet radiation causes more chromosome damage than in normal cells resulting in chromosome mutations and cell death.“O

EPIDEMIOLOGIC

ASPECTS

OF UVEAL

MELANOMA

If sunlight induces uveal melanoma it would be reasonable to expect an excess of cases among persons with xeroderma pigmentosum. Persons with xeroderma pigmentosum do exhibit an increased risk ofdeveloping a variety of sunlight-induced neoplasms, but the only reported case of an ocular melanoma occurring in a person with xeroderma pigmrntosum was that of a conjunctival melanoma.@’ 2. Geography In addition to stable rates of disease, uveal melanoma also differs from cutaneous melanoma in that there is no marked latitudinal gradient seen in uveal me1anoma.35.45*‘2g,‘4* Hakulinen reported that the countries included in his survey with the highest incidence of ocular cancer were those at the greatest distances from the equator. While this may have been the result of more complete reporting in the North, findings were similar when analysis was restricted to European countries. Rates were higher among Scandinavian countries than in the United Kingdom.jR Raivio found greater than expected numbers in the south of Finland, which he felt was due to underreporting in the north.“+ Scotto concluded that there was no latitudinal gradient for uveal melanoma in the United States, but noted that the highest incidence occurred in the southernmost region studied.‘“” In a study in veterans hospitals, higher rates of uveal melanoma were reported in southern hospitals,” but this may have reflected a tendency for elderly veterans to retire in the South. In a Canadian study, altitude, not latitude, was positively correlated with the incidence of uveal melanoma.z” In both Norway and Denmark, higher rates ofuveal melanoma were found in more urbanized areas.“‘,“’ There are several possible explanations to account for the lack of a latitudinal gradient in uveal melanoma, assuming that sunlight is an etiologic factor in the disease. First, higher rates of uveal melanoma might not be seen in southern latitudes since the greater intensity of overhead sunlight in the South may be offset by the greater reflectivity of UVR from snow cover in the North.“” This phenomenon has been used to explain the high prevalence of so-called “Labrador Keratopathy,” a condition caused by solar radiation, in a region 50” to 60” north of the equator. rti4 Second, the quality of correlational studies depends both on uniform case ascertainment and risk for disease throughout the population(s) studied. Geographic patterns could be obscured by variations in the completeness of case finding, a problem in several of the studies described above, or regional differences in the racial or ethnic mix of the population. An alternative ap-

245 proach is to directly compare the residential histories of persons with uveal melanoma to that of nondiseased controls. In one study of this type, being born in the South was associated with a three-fold increase in risk. Number of years lived in the South was not related to the risk of disease after adjusting for place of birth. Ii6 This is in accordance with studies of cutaneous melanoma which have found that the risk of cutaneous melanoma among migrants to sunnier latitudes is also not related to length of residence after adjustment for age at migration.“’ 3. Biological

Mechanism

A more serious problem with the possible link between sunlight exposure and uveal melanoma lies in establishing whether ultraviolet radiation actually reaches the uveal tract through the effective filters of the cornea and lens. In both animal models and studies of enucleated eyes,lh’ it has been shown that virtually no UV-A or UV-B is transmitted through both the lens and cornea in adults. The juvenile lens, on the other hand, may transmit small amounts of ultraviolet radiation.“’ Tucker et al proposed that this exposure of the posterior eye to ultraviolet radiation during childhood explains their finding that being born in the southern United States was associated with an increased risk of disease. Others have argued, however. that tissues directly overlying uveal tract structures. including the retina, would provide the necessary protection should significant amounts of UVR penetrate the lens.“” The net effect, then, would be the total blockage of UVR from direct contact with the choroid and ciliary body at all ages. Sunlight may instead work indirectly by triggering the production of socalled “solar circulating factor”“’ or by inducing a systemic alteration in immunologic function.‘4” However, if a systemic effect is operative. increases in all body sites would be expected. Instead, melanomas of the skin are rising in most recently exposed sites~“,lti,l~’ while melanomas of the head and the eye have remained fairly stable.“‘.“~‘“~” 4. Case-Control

Studies

Two studies published to date have compared sunlight exposure histories of cases with uveal melanoma to that of controls.‘i,‘“6 In the study of Tucker et al,“” analysis was based on 497 patients with melanomas of the uveal tract (iris, choroid, ciliary body) that had been evaluated during the 5-year period prior to the study. Controls were patients with retinal detachment that had been diagnosed during the same interval. These authors found that patients with uveal melanoma were 1.7 times (95% CI: 1.2-2.5) more likely to have blue than brown irides and 1.4 times (95% CI: 1.04-2.0) more likely

246

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32(4) January-February

1988

to have 25 or more freckles. Cases were 2.7 times (95% CI: 1.3-5.9) more likely to have been born in the South (defined as south of 40” N latitude) although the number of years lived in the South was not independently associated with disease. Of the various sun exposure habits assessed, only gardening (OR 1.6; 95% CI: 1.Ol-2.4) and not using some form of eye protection while outside (OR 1,6; 95% CI: 1.2-2.2) were significantly more common seemed to be more among cases. Eye protection important in iris melanoma since the risk was higher and increased with less frequent eye protection use in this subgroup of patients. Spending leisure time outdoors, sunbathing and engaging in outdoor hobbies, were not found to significantly increase the risk of uveal melanoma. In a smaller study, Gallagher et a145 compared new cases of ocular melanoma occurring in several provinces of Canada over a three-year period to age and sex-matched controls drawn from lists of medical insurance plan subscribers. Various measures of sun sensitivity and accumulated exposure were assessed but none were found to be significant.45 The negative findings of Gallagher and associates may have several explanations if it is assumed that sunlight does trigger the development of uveal melanoma. First, there were seven times as many patients interviewed in the larger of the two studies. The Canadian study might not have had suficient power to detect weak associations of the magnitude found by the Tucker group. Second, the Canadian population may be more homogeneous with respect to sunlight exposure making differences between cases and controls more difficult to detect. Third, the two studies differed somewhat in the type of sunlight exposures investigated. Tucker assessed the impact of exposures occurring early in life, whereas Gallagher focused on current and cumulative sunlight exposures. The case for sunlight exposure as a risk factor for uveal melanoma should not be considered closed based on the findings of Tucker and associates, however. An important potential limitation in this study was the use of eye patient controls who may have altered their sunlight exposures and related behaviors as a consequence of their disease. The resulting bias could create an artificially low exposure rate among the controls and thereby inflate the apparent rate of exposure among cases. A second potential source of bias was the comparison of cases drawn from a wide geographic area to controls who were selected on the basis of acute diagnoses and were therefore more likely to be drawn from the surrounding community. An elevated risk associated with southern birth place would result ifsouthern cases were more likely than northern cases to be

EGAN ET AL referred to the treatment center from which cases were recruited. However, the authors stated that results were similar when analysis was restricted to cases and controls drawn from the surrounding metropolitan area. An additional problem was the inclusion of cases who had been diagnosed several years before the study and may therefore have differed in their recall of events prior to diagnosis. Data obtained from interviews of next of kin (17% of cases, 14% of controls) were of questionable value and it would have been informative if the authors had also reported results without these responses. B. OTHER

RADIATION

SOURCES

The carcinogenic effect of ionizing irradiation is well known.66 However, Jensen reported that diagnostic and therapeutic radiation exposures were actually lower among patients with uveal melanoma compared to the general population of Denmark.” A second radiation source of potential importance is fluorescent lighting since fluorescent bulbs may emit in the ultraviolet range.74 In a study exploring the relationship between melanoma and oral contraceptive use, Beral and colleagues noted that cases with cutaneous melanoma were twice as likely to report being exposed to fluorescent lightin subseing. *’ These findings were not duplicated quent studies that directly studied the issue, however.38 There are no published studies that have considered the role of fluorescent lighting in uveal melanoma. A third radiation exposure worth consideration is that derived from sun lamps and tanning booths. There is reason to suspect that this latter exposure may be particularly harmful since the proportion of wavelengths absorbed by DNA emitted by tanning lamps may be higher than that emitted by the sun.‘O” In Tucker’s study, cases were somewhat more likely to have used a tanning larnp,15’j although this was not a statistically significant finding. Given the current popularity of tanning salons, it will be important to confirm these findings in further studies. C. OCCUPATIONAL EXPOSURES

AND CHEMICAL

A number of rare cancers are caused by chemical or radiation exposures occurring in the workplace9 and an occupational exposure has also been sought in the etiology of uveal melanoma. Jensen found approximately the same occupational distribution among patients with uveal melanoma as was found in the general population of Denmark.70 Swerdlow reported that cases in England and Wales were more likely to be nonmanual workers than manual, and a higher risk was found among electrical work14*Gallagher did not find an elevaters in particular.

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247

MELANOMA

ed risk among electrical workers or any other specific occupation in Western Canada but noted an excess of cases among government workers, a man,(-’The only specific occupaagerial job classification. tional exposure which has been linked to uveal melanoma is welding. Four of the cases and none of the controls reported having worked as a welder in one of the case-control studies discussed above.15” Another report described a cluster of cases which occurred among employees of the DuPont Belle, West Virginia plant.” Four cases were diagnosed between 1972 and 1978 and a fifth case had been diagnosed in 1952. Upon investigation, no production area or job title was common to all cases. The small number of cases, large number of chemicals to which each was potentially exposed, and incomplete occupational histories made the identilication of a specific causative agent unlikely in this investigation. however. Ocular melanomas and other ocular tumors have been produced in laboratory animals after administration ofmethylcholanthrene,‘“” N-2_fluorenylacetamide and ethionine,‘” radium’“’ and nickel subsulfide.’ Exposure to polychlorinated biphenyls (PCBs) has been linked to the development of cutaneous melanoma.‘” A study which examined the distribution of uveal melanoma diagnoses in the state of Ohio found no correlation between the incidence of disease and areas of the state with heavy PCB concentrations.” In a small Pennsylvania community,, three choroidal melanomas were diagnosed over a 2.5 year period. Although no common exposure was identified among cases, laboratory mice given community water developed abnormalities in anterior lens capsules which were not seen in control mice.“’ D. VIRUSES Albert has summarized the available evidence for a viral etiology of uveal melanoma.3 First, in vitro neoplastic transformation of uveal and other intraocular tissues has been induced by oncogenic DNA viruses.; In subsequent studies, injection of these transformed cells into laboratory animals resulted in the formation of injection site spindle cell, epithelioid and mixed cell tumors similar in appearance to uveal melanomas.’ Ocular melanomas have been induced in cats following inoculation with a naturally occurring RNA-type virus (feline sarcoma virus).“” Second, the enzyme reverse transcriptase has been demonstrated in uveal melanomas.‘20 In these studies, the identification of this enzyme was interpreted as a marker for the presence of oncogenie RNA viruses. Third, virus particles have been identified in human uveal melanoma tissues.3 In the latter studies, a togavirus was identified in 3 of the 5

human tumors in which virus was demonstrated. These findings should be interpreted with caution since virus particles are often constituents of normal tissues and few cancers have been positively linked to a viral etiology. E. TRAUMA Trauma may be a provoking cause of a few cutaneous mclanomas+7,7x and the subject has recently been reviewed.“’ There are a few reports of uveal melanoma developing at the site of a previous in
jur);.(i.l”’

VI. Summary Uveal melanoma has been studied intensively over the last several decades, but relatively little attention has been focused on the underlying cause of the disease. Unlike cutaneous melanoma, no ohvious geographic patterns or temporal changes have implicated an environmental basis for uveal melanoma. The only consistent finding among descriptive studies is the extreme rarity of uveal melanoma among blacks. Geographic or other patterns are less likely to be observed in rare diseases and without a nondiseased comparison group, the detection of common exposures linked to disease occurrence is unlikely. ,4 practical approach to studying etiologic factors in uncommon or rare cancers is the case-control study in which the exposure histories of a sufficient number of persons with the disease are compared to that of a referent group. A higher (or lower) frequency of an exposure or a trait among cases compared to nondiseased controls may implicate that factor as an etiologic agent in the former case or as a protective mechanism in the latter. The challenge is to obtain reliable information on exposures possibly occurring years before disease onset. Ultraviolet radiation has been proposed as a likely environmental cause of uveal melanoma and the results of two casecontrol studies that explored this association have recently been published with conflicting results. Although these studies have contributed to our knowledge concerning risk factors for unreal melanoma, they are not definitive. Future case-control studies, if well designed and executed, should help establish whether sunlight induces uveal melanoma, as there is little remaining doubt it induces cutaneous melanoma. These stud-

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ies should not rely solely on residential histories. Individual behaviors and patterns of exposure may be more important determinants of risk than place of residence. Objective measures of sunlight exposure based on degree of dermal elastosis or ultraviolet sensing devices which quantitate sunlight exposure could be more accurate than self-reported exposures. Such objective methods become increasingly important once an exposure has been linked to a cancer. In subsequent studies exploring that association, cases may differ from controls in their recall of the exposure of interest. Future studies should establish whether reports of uveal melanoma occurring among relatives are chance occurrences or represent a subgroup of patients who inherit the disease. Shared environmental exposures or increased susceptibility to environmental risk factors must also be evaluated. In addition, studies should determine whether ocular melanocytosis and oculodermal melanocytosis predispose to uveal melanoma. Such investigation could help establish whether uveal melanoma is one manifestation of a generalized melanocytic dysfunction, as has been suggested by a few authors. Among women, potential hormonal mechanisms have yet to be quantified. Finally, further studies should examine the small but consistently higher rates of disease among males. Exposures occurring in the workplace, such as exposures to welding arcs, should be further investigated.

8. Albert DM, Sear1 SS, Forget B, et al: Uveal findings in patients with cutaneous melanoma. Am J Ophthalmol9.5:474-479, 1983 9. Althouse R, Huff J, Tomatis L, et al: An evaluation of chemicals and industrial processes associated with cancer in humans based on human and animal data: IARC Monographs Volumes 1 to 20. Cancer Res 40:1-12, 1980 10. Antes IG, Pomerantz SH: Serum concentration of B-melanocyte stimulating hormone in human pregnancy. Am J Obstet Gynecol 119: 1062-1068, 1974 11. Apt L: Uveal melanomas in children and adolescents. Int Ophthalmol Clin 2:403-410, 1962 12. Ashton N, Wybar K: Primary tumors of the iris. Ophthalmologica 151:97-l 13, 1966 13. Augsburger JJ, Game1 JW, Sardi VF, et al: Enucleation vs cobalt plaque radiotherapy for malignant melanomas of the choroid and ciliary body. Arch Ophthalmol I&:655-661, 1986 14. Augsburger J, Shields J, Frank P, et al: Diffuse primary malignant melanoma ofthe choroid arising in a patient with primary cutaneous melanoma. Arch Ophthalmol 98:1261-1264, 1980 15. Bahn AK, Rosenwaike I, Herrmann N, et al: Melanoma after exposure to PCB’s. (letter to the editor). NEngl JMed295:450, 1976 16. Balch CM, Soong SJ, Shaw HM, et al: An analysis ofprognostic factors in 4000 patients with cutaneous melanoma, in Balch CM, Milton GW (ed): Cutaneous melanoma. Clinical Management and Treatment. Results Worldwide, Philadelphia, JB Lippincott, 1985. pp 321-352 LE: Uveal melanoma in 17. Barr CC, McLean IW, Zimmerman children and adolescents. Arch Ophthalmol99:2133-2136, 1981 in relatives. (Letter to the Editor). 18. Bauman L: Melanoma JAMA 218:1300-1301, 1971 19. Bellet RE, Shields JA, So8 DB, et al: Primary choroidal and cutaneous melanomas occurring in a patient with the B-K mole syndrome phenotype. Am J Ophthalmol89:567-570, 1980 tumor after ethionine and N-2-fluo20 Benson WR: Intraocular renylactamide. Arch Path01 73:404-406, 1962 melanoma and 21 Beral V, Shaw H, Evans S, et al: Malignant exnosure to fluorescent lighting at work. Lancet 2:29&293, Y

22

Acknowledgment 23

We would like to thank the following individuals for their invaluable help in the preparation of this manuscript: Ms. Pauline Calliste; Ms. Jane Curran; Ms. Joyce Greer; and Kathleen Shamban MS

References M: Malignant melanoma of the choroid and 1. Abrahamsson ciliary body 195&1975 in Halland and Gothenburg: Incidence, histopathology and prognosis. Acta Ophthalmol61:6OC610, 1983 DH, Rodriguez-Sains R, Rubman R: B-K mole *2. Abramson syndrome: cutaneous and ocular malignant melanoma. Arch Ophthalmol g&1397-1399, 1980 3. Albert DM: The association of viruses with “veal melanoma. Tram Am Ophthalmol Sot 77:367-421, 1979 4. Albert DM, Chang MA, Lamping K, et al: The dysplastic nevus syndrome: A pedigree with primary malignant melanomas of the choroid and skin. Ophthalmology 92: 1728-l 734, 1985 5. Albert DM, Gonder JR, Papale J, et al: Induction of ocular neoplasms in Fischer rats by intraocular injection of nickel subsulfide. Invest Ophthalmol Vis Sci 22:76%782, 1982 6. Albert DM, Pulialito CA, Fulton AB, et al: Increased incidence of choroidal malignant melanoma occurring in a single population of chemical workers. Am J Ophthalmol89:323-337, 1980 7. Albert DM, Rabson AS, Dalton AJ: In vitro neoplastic transformation of “veal and retinal tissue by oncogenic DNA viruses. Invest Ophthalmol 7:357-365, 1968

24 25

26. 27. 28.

29. 30.

31.

32. 33.

34. 35.

*Same case reported

in reference

123.

I

19'82 Bettman JW, Jr: Eye disease among American Indians of the Southwest. I. Overall analysis. Arch Ophthalmol 88:263-268, 1972 Birdsell JM, Gunther BK, Boyd TA, et al: Ocular melanoma: a population-based study. Can J Ophthalmol 15.9-12, 1980 Blodi FC: Ocular melanocytosis and melanoma. Am J Ophthalmol80:38%395, 1975 Blumenkranz MS, Russell SR, Robey MG, et al: Risk factors in age-related maculopathy complicated by choroidal neovascularization. Ophthalmology 93:552-558, 1986 Boettner EA, Walter JR: Transmission of the ocular media. Invest Ophthalmol Vis Sri 1:77&783, 1962 Borner R, Goder G: Melanoblastom der uvea und Schwangerschaft. Klin Monatsbl Augenheilkd 149:684-693, 1966 Bowen SF, Brady H, Jones VL: Malignant melanoma of eye occurring in two successive generations. Arch Ophthalmol 71: 805806, 1964 Briggs JC: The role of trauma in the aetiology of malignant melanoma: a review article. Br J Plas Surg 37~514-516, 1984 Brilliant LB, Grasset NC, Pokhrel RP, et al: Associations among cataract prevalence, sunlight hours, and altitude in the Himalayas. Am J Epidemiol 118:250-264, 1983 Carrasco CH, Wallace S, Charnsangavej C, et al: Treatment of hepatic metastases in ocular melanoma: Embolization of the hepatic artery with polyvinyl sponge and cisplatin. JAMA 255:3152-3154, 1986 Char DH: Immunology of Uueitis and Ocular Tumors. New York, Grune & Stratton, 1978 Crawford JB, Char DH: Histopathology of “veal melanomas treated with charged particle radiation. Ophthalmology 94: 63%643, 1987 Davenport RC: A family history of choroidal sarcoma. BrJ Ophthalmol 11:443-445, 1927 Davidorf FH, Knupp JA: Epidemiology of ocular melanoma: Incidence and geographic relationship in Ohio (1967-1977). Ohio State Med J 7.5:561-564, 1979

EPIDEMIOLOGIC

ASPECTS

OF UVEAL

MELANOMA

ES. et al: Uveal melanoma in 36. I
65. 66. 67.

68.

69.

70.

71.

pre-invasive and invasive malignant mrlanoma in western i2ustralia. Int J Cancer 253317-323, 1980 Houghton A, Flannery J, Viola MV: llalignant melanoma in Connecticut and Denmark. Int J Cancer -?i:9>104. 1980 Hutchison GB: Late neoplastic changes following m&Cal irradiation. Cancer 37:1102-l 107. 1976 Hyman LG. Lilienfeld AM, Frrris FL III, ct al: Senile macular degenrration: A case-control study. .4m ,/ &idemiol 118:213‘27, 1983 Jakobiec FA. Silbert G: Are most iris ‘melanomas’ rrally nexi? .\ clinicopathologic study of 189 leTions. .4rth Ophthalmol W:2117-2132, 1981 Jensen 0.~: Xrrodcrma pigmentosum observed in a Grecnlander: Report of a case complicatrd by malignant melanoma of thr conjunctiva. dcta Ophthalmol 40:9&103. 1962 ,Jensen 0.4: Mali:gnant melanomas of the urea in Denmark 1943-1952: A chmcal, histopathological and prognostic study. .-lrta 0,bhthalmol (Sup/~/) 75: 17-78. 1963 ,Jrnsen 0.4: Malignant melanomas ofthc human uvra: 25-yrar 1943~1952. .4& Ophthahol follow-up of casts in Denmark, f%io:161-182.

1982

,Jenscn 0.~. Irlovin VI, Mu1lrr.J: hlalignant melanoma of the choroid in an infant with the dysplastic narvus svndromr. drto Ophthalmol (Tj;91-100, 1987 73. ,Jensrn <)A. Prause .Jl_‘: Xfalignant mtlanomas of thr human uvea in Denmark. Incidence and a 25-)-ear I‘ollow-up of casts diagnosrd betwren 1943 and 1952. in Lommatzsch PK. Blodi FC (f,dl: Intraocular Tumors. Brrlin. SprinTcr-\Tcrlaq. 1983. pp 85-92 74. ,Jrwess BLV: Ultraviolet contents oflampa in common use. .Sut Photooptical Instrumentation En<< X,7:55-61. 1981 75, ,Jonea ST: Choroidal malignant melanoma in a child. Hr ,/ Ophthalmol .51;48%-491. 1967 76. Kancko A: Incidence of malignant melanoma of the rye in ,Japan, 1972-1976. Kinsho Sanka 3313:941-947. l!li9 77. Kellrr AZ: Histology, survivorship and rrlated lactors in thr epidemiology of rye cancers. ,-lm ,J Epidfmzo[ 97:386-393. 1973 78. Kirsch N: Malignant melanoma drvclopiny in a tattoo. .4rch Dermatol W:59&598, 1969 79. Klauss \‘. Ghana HS: Ocular tumors in Aliiic,a. .Snr .Oi .Wen 17:1743-1750. 1983 80. Kliman GH. A,ugsburger,J,J. ShirldsJ.4: .-\ssorlation between iris color and nx mrlanocvtic Itsions. .-lm J 0,bhthnlmol 101). ,547- 548. 1983 81. Kuo PK. Puliafito C.4. \Vang KIWI, Ct al: Irvral melanoma in China. fnt Ojhthalmol Clin llL’:57i I. 1982 82. Ler JA. hlerrill J-11: Sunlight and thr rrioloq of malignant melanoma: A synthesis. d4ed J Au.rtL’t84SH51. 1970 83. Lrr~JA. Storer BE: Excess ofmalignant melanoma in women in the British Isles. Lancet ?:1337~1339. 1980 8-1. Ler ,JA. Storer BE: 5lalignant melanoma f~m&/malr death ratios. (letter to the editor) Lancet l:l419. 1981 85. I.ee,JA. Strickland D: Malignant melanoma: Social Status and outdoor work. Br J Cancer 41:757-763. 1980 86, Lerman S: Letter to the editor. .VEql,].lfed.7/4.7 12-713, 1986 87. Louria DB. Coumbis R,J. Lavenhar X1.4. (‘1 al: An apparent small cluster of choroidal mrlanomn vases. .4m ,I Ophthalmol 944: 172-180. 1982 88. Lynch H. Anderson D. Krush .\: Heredity and intraocular maliqnant melanoma: Study of two families and rcvirw of forty-tier cases. Cancer 21: 119~125. 1968 89. Lynch HT. Fusaro RM. Danes BS, rt al: A rrvirw ofhereditary malignant melanoma including- biomarkers in bmilial atypical multiple mole melanoma $yndromc. f.‘nnr-ur (;envf C:vtoeenet 8:325-358. 1983 90. Lynch HT. Fusaro R.V, Prster,J. et al: Naming thr melanomaprone syndrome. (letter to the rditor). Lancet L’:817, 1981 91. I.ynch H. Krush A: Heredity and malignant melanoma: implications Ibr rarly cancer detrction. Chnnd .lud -4 r
250

Surv Ophthalmol

32(4) January-February

1988

nant melanoma of the uvea. AmJOphthalmol83:694-696, 1977 95. Miller B, Abraham C, Cole GC, et al: Ocular malignant melanoma in South African blacks. Br J Ophthalmol 65:72&722, 1981 96. Mintzis MJ, Berger AP, Greenwald E, et al: Malignant melanoma in spouses. Cancer 422:804-807, 1978 97. Mark T: Malignant neoplasms of the eye in Norway: Incidence, treatment and prognosis. Acta Ophthalmologica 39:824831, 1961 98. Morpurgo G, Porro MN, Passi S, et al: The role of UV light in the control of melanogenesis. J Theor Biol 83:247-254, 1980 99. Mukai S, Dryja T: Loss of alleles at polymorphic loci on chromosome 2 in uveal melanoma. Cancer Genet Cytogenet 22:45-53, 1986 100. Nachtwey DB, Randel RD: A photobiological evaluation of tanning booths. Science 211:405-407, 1981 101. Newman LP, Walter JR: Malignant melanoma of the choroid in a nine-year-old girl. J Pediatr Ophthalmol 10:44-46, 1973 102. Nik NA, Glew WB, Zimmerman LE: Malignant melanoma of the choroid in the Nexus ofOta ofa black patient. Arch Ophthalmol 100:1641-1643, 1982 103. Nordlund J, Kirkwood J, Forget B, et al: Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 4.55:1855-1861, 1985 104. Oosterhuis JA, Went LN, Lynch HT: Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas. Br J Ophthalmol66;23~233, 1982 105. Pack GT, Scharnagel IM. The prognosis for malignant melanoma in the pregnant woman. Cancer 4:324-334, 1951 106. Parsons J: The Pathology of the Eye, Vol.2: Histopathology. Pt II. New York, GP Putnam’s Sons, 1905, pp 49&497 107. Paton D, Thomas L: Simultaneous occurrence ofprimary malignant melanomas of the eye and skin. Arch Ophthalmol 62: 64.!+652, 1959 108. Patz A, Wulff LB, Rogers SW: Experimental production of ocular tumors. Am J Ophthalmol 488:98-l 17, 1959 109. Paul EV, Parnell BL, Fraker M: Prognosis of malignant melanoma of the choroid and ciliary body. Int Ophthalmol Clin 2:387-402, 1962 110. Pawsey SA, Magnus IA, Ramsay CA, et al: Clinical, genetics and DNA repair studies on a consecutive series ofpatients with xeroderema pigmentosum. Q J Med 48: 17%2 10, 1979 111. Pertschuk LP, Tobin EH, Brigati DJ, et al: Morphologic assay of steroid hormone receptors in human neoplasia. Path01 Ann 15:143-180, 1980 112. Pfingst A, Graves S: Melanosarcoma of the choroid occurring in brothers. Arch Ophthalmol 50:431-439, 1921 113. Pomerantz GA, Bunt AH, Kalina RE: Multifocal choroidal melanoma in ocular melanocytosis. Arch Ophthalmol 99:857863, 1981 114. Raivio I: Uveal melanoma in Finland: An epidemiological, clinical, histological and prognostic study. Acta Ophthalmol (Suppl) 133:3-64, 1977 115. Rajpal S, Moore R, Karakousis CP: Survival in metastatic ocular melanoma. Cancer 52:334-336, 1983 116. Reese AB: Pigment freckles of the iris (benign melanomas): their significance in relation to malignant melanoma of the uvea. Am J Ophthalmol27:217-226, 1944 117. Reese AB: Association of uveal nevi with skin nevi. Arch Ophthalmol48:271-275, 1952 118. Reese AB: Tumors of the Eye. New York, Hoeber, ed 2, 1963, pp 332-335 119. Reese AB: Tumors of &heEye. Hagerstown, MD, Harper and Row, ed 3, 1976, pp 177-178 120. Reid TW, Albert DM: RNA-dependent DNA polymerase activity in human tumors. Biochem Biophys Res Comm 46:383-390, 1972 121. Reintgen D, McCarty K, Vollmer R, et al: Malignant melanoma and pregnancy. Cancer 55: 1340-l 344, 1985 122. Robertson MG: Malignant melanoma in husband and wife (Letter to the editor). JAMA 217:1553, 1971 123. Rodriguez-Sains RS, Abramson DH, Rubman RH: B-K mole syndrome: Cutaneous and ocular malignant melanoma. Invest Ophthalmol Vis Sci (Suppl) 18: 108, 1980

EGAN

ET AL

124. Rodriguez-Sains R: Ocular findings in patients with dysplastic nevus syndrome. Ophthalmology 93:661-665, 1986 125. Rones B, Zimmerman L: The prognosis of primary tumors of the iris treated by iridectomy. Arch Ophthalmol 60:193-205, 1958 126. Rootman J, Gallagher R: Color as a risk factor in iris melanoma. Am J Ophthalmol 98:558-561, 1984 127. Sabates FN, Yamashita T: Congenital melanosis oculi complicated by two independent malignant melanomas of the choroid. Arch Ophthalmol 77:801-803, 1967 128. Scheffer CH, Binkhorst PG, Hamburg A: Malignant melanoma of the choroid in a P-year-old infant. Ophthalmologica 169:401-410, 1974 129. Scotto J, Fraumeni JF Jr, Lee JAH: Melanomas of the eye and other noncutaneous sites: Epidemiologic aspects. J Nat Cancer Inst 56.489491, 1976 130. Seddon JM, Albert DM, Lavin PT, et al: A prognostic factor study of disease-free interval and survival following enucleation for uveal melanoma. Arch OphthalmolZO1:1894-1899, 1983 131. Seddon JM, MacLaughlin DT. Albert DM, et al: Uveal melanomas presenting during pregnancy and the investigation of oestrogen receptors in melanomas. BrJOphthalmol66:695-704, 1982 132. Seddon JM, Gragoudas ES, Albert DM, et al: Comparison of survival rates for patients with uveal melanoma after treatment with proton beam irradiation or enucleation. Am J Ophthalmol 99:282-290, 1985 133. Shadduck JA, Albert DM, Niederkorn JY: Feline uveal melanomas induced with feline sarcoma virus: potential model of the human counterpart. J Nut Cancer Inst 67~619-625, 1981 134. Shammas HF, Blodi FC: Prognostic factors in choroidal and ciliary body melanomas. Arch Ophthalmol 95:63-69, 1977 135. Shammas HF, Watzke RC: Bilateral choroidal melanomas: Case report and incidence. Arch Ophthalmol95:617-623, 1977 136. Shields J, Augsburger JJ, Arbizo V, et al: Malignant melanoma of the choroid in a husband and wife. Br J Ophthalmol 68:623-625, 1984 137. Shields JA, AugsburgerJJ, Donoso LA, et al: Hepatic metastasis and orbital recurrence of uveal melanoma after 42 years. Am J Ophthalmol IOO:66&668, 1985 138. Shiu MH, Schottenfeld D, Maclean B, et al: Adverse effect of pregnancy on melanoma: A reappraisal. Cancer 37:181-187, 1976 139. Shuangshoti S, Panyathanya R: Retinoblastoma and uveal melanoma: A study of 206 cases. J Med Asst Thai 56.331-336, 1973 140. Siegel R, Ainshe WH: Malignant ocular melanoma during pregnancy. JAMA 185:542-543, 1963 141. Silcock A: Hereditary sarcoma of the eyeball in three generations. Br Med J I: 1079, 1892 142. Simons KB, Hale LAM, Morrison HM, et al: Choroidal malignant melanoma in siblings. Am J Ophthalmol!%:675-680, 1983 143. Sliney D: Physical factors in cataractogenesis: Ambient ultraviolet radiation and temperature. Invest Ophthalmol Vis Sci 27:781-790, 1986 144. Stern RS: Dermatology. JAMA 252:2194-2198, 1984 145. Stevens RG: Malignant melanoma: dependence ofsite-specific risk on age. Am J Epidemiol II9:89&895, 1984 146. Strauss G, Greaves M, Price M, et al: Inhibition of delayed hypersensitivity reaction in skin (DNCB test) by 8-methoxypsoralen photochemotherapy: Possible basis for pseudo-promoting action in skin carcinogenesis? Lancet 2:556-559, 1980 147. Strickland D, Lee JAH: Melanomas of eye: Stability of rates. Am J Epidemiol 113:70&702, 1981 148. Swerdlow AJ: Epidemiology ofeye cancer in adults in England and Wales, 1962-1977. Am J Epidemiol II8:294-300, 1983 149. Swerdlow AJ: Epidemiology of melanoma of the eye in the Oxford Region, 1952-78. Br J Cancer 47:311-313, 1983 150. Tasman W: Familial intraocular melanoma. Tram Am Acad Ophthalmol Otola~ngol 74:955-958, 1970 151. Taylor GN, Dougherty TF, Mays CW, et al: Radium-induced eye melanoma in dogs. Radiat Res 52:361-373, 1972 152. Taylor MR, Guerry D, Bondi EE, et al: Lack of association between intraocular melanoma and cutaneous dysplastic nevi. Am J Ophthalmol 98:478-482, 1984

EPIDEMIOLOGIC

ASPECTS

OF UVEAL

MELANOMA

AC:: Tumors of the eye and adnexa in Africans of 153. Trmpleton Uganda. Cancer 20:1689-1698, 1967 154. Teppo L, Pakkancn M. Hakulinen T: Sunlight as a risk factor of malignant melanoma of the skin. Cancer ~Zt2018-2@21, 1978 155 Thomas DB: Cancer, in LastJM (ed): Public Health and Prewntile .Ifedicine. Norwalk CT. Appleton Century Crofts, 1986. cd 12, pp 1135 156 Tncker .ZlA. ShirldsJA. Hartge P. et al: Sunlight exposure as risk factor for intraocular malignant melanoma. 11’EqlJ ‘Wed :i13:789-792. 1985 157 ‘l‘ul-kington R\V: Familial factor in malignant melanoma. J;1.W.+l IYL’:i7-82, 1965 Prrpuberal and puberal melanomas in ophthal158 1’erdaaucr.J: moloqy. .im ,J Ophfhalmol 60: 1002-1011. 1965 159 \.ic ary D: Malignant melanoma at the site of a penetrating ocular trauma. Arch Ophthalmol 20~:1130, 1986 CJ: Melanosarcoma van het oog bi,j verschilI60 LVaardenburg lrndc lcdvn crner zelfdr familic. Ned& T Geneesk &I:17 18-47 19. 1!NO 161 LValkrr JP. \Veitrr ,J.J%Albert DM. et al: Uveal malignant melanoma in thrrr grncratirms ofthe samr family. AmJOphthaimoi Mt:723-726. 1979 162 Cz’lldcr HC: Relationship of pigment cell clusters in the iris to malienant melanoma of thy uveal tract. Bull SF Acad Sci 4.137-142, 1948 163 12’illlams RR: Breast and thyroid cancer and malignant mclanoma pr~nnotrd hy alcohol-induced pituitary secretion of proIactin. ‘F.S.H.. and M.S.H. Lancet 1:99&999, 1976 164 !\‘ltwnhcrg S: Solar radiation and the ey: A review of knowlcdq:r rrlcvant to cyz cart. Am J Optom P/ysiol Opt 63t676689, l’W6 165 1.:tnoff 11. Zimmerman LE: Histogenesis of malignant nwlanomas of the uvca. II. Relationship of weal nevi to malignant nx~lanomas. Cancer X:493-507. 1967 166 I’.molT hl. Zimmerman LE: Histogem-sis of malignant mclanomas of the uvca. III. Thr relationship of congenital ocular m~~lanocvtusis and neurofibromatosis to uveal melanomas. .-l?& Ophthalmul 77:331-336, 1967 16i %i
Outline I. Incidence II. Mortality III. Demographic risk factors A. .4ge and sex B. Race C:. Socioeconomic status I\‘. Host risk factors 11. Genetics B. Ocular nevi (1. blelanocytosisa I). Hormones E. Immunocompetence F. Eye color \.. Environmental risk factors .I. Sunlight exposure 1. Cutaneous melanoma 2. Geograph! 3. Biological mechanism &. case-control studies B. Other radiation sources CZ. Occupational and chemical D. Viruses E. ‘Trauma \‘I.

exposures

Summar\

Supported in part by grant EYO5076 from thr National Eye Institute, Bethesda. MD (Dr. Seddon). Reprint requests should be addressed to Kathleen M. Egan. M.P.H., Epidemiology Unit. Massachusetts Ey and Ear Infirmary. 243 (:harlrs Street. Boston. 11.4 0211-l.