Melanoma and Ultraviolet Radiation J.
MARK ELWOOD, MD
xternal ultraviolet radiation (UVR) is the major causative factor for human cutaneous melanoma. In this article the evidence supporting this statement and some of the implications are dis-
E
cussed.
Background The evidence is based on analytical epidemiologic studies (case-control and cohort studies). Although there were some early less satisfactory studies, the main ones were set up in the late 1970s after basic clinical and epidemiologic evidence suggested that melanoma was related to sun exposure, but not in a simple linear dose-response relationship. The clinical evidence included the obvious feature that melanocytes are in the skin, and their normal function is to respond to UVR by producing and distributing pigments. The descriptive epidemiology showed that in many areas such as North America and Australia, melanoma incidence and mortality rates were higher closer to the equator. That trend did not apply in Europe as a whole but was still seen within individual countries in Europe, and the overall European pattern with higher rates in the Scandinavian than in the Mediterranean countries seemed likely to be the result of complexion differences. In this, the distribution of melanoma was similar to that of other skin cancers. In contrast, melanoma incidence and mortality rates were increasing rapidly with time and were much higher in the higher socioeconomic groups, in contrast to the distribution of other skin cancers.1*2 Outdoor workers are represented mainly in the lower socioeconomic groups,
From the Hugh Adam Cancer Epidemiology Unit, Otago University Medical School, Dunedin, New Zealand. Addresscorrespondence to]. MarkElwood, HughAdamCancerEpidemiology Unit, Department of Preventive and Social Medicine, Otago University Medical School, P.O. Box 913, Dunedin, New Zealand.
0
2992 by Elsevier
Science
Publishing
Co., Inc.
l
0738-081x/92/$5.00
and comparisons of indoor and outdoor jobs from routine incidence and mortality data showed in several countries that melanoma was more common in indoor workers, even within the same socioeconomic group.’ Moreover, the body site distribution of melanoma was clearly different from that of squamous and basal cell carcinomas. These latter tumors occur almost exclusively on exposed skin areas and are clearly more common in individuals with a great deal of outdoor exposure. Squamous cell carcinoma is readily produced in animals by UVR.3*4 Thus it appeared that nonmelanoma skin cancer has a simple relationship to UVR. Further analysis of the body site distribution of melanoma (Fig 1) showed that the common superficial spreading (SSM) and nodular (NM) forms, although not clearly concentrated on the most exposed areas, showed a distribution pattern and differences between the sexes consistent with an effect of moderate degree of exposure .5 Clinically, lentigo maligna melanoma (LMM) appeared quite different from SSM and NM, occurring in older patients, predominantly in men, and being virtually limited to heavily exposed areas such as the face.’ These epidemiologic and clinical findings led to proposal of the “intermittent exposure” hypothesis-that the risk of SSM and NM was increased primarily by intermittent exposure to UVR of skin that was not heavily tanned or thickened, with the suggestion that longerterm chronic exposure would have a neutral or even protective effect6,’ In contrast, the model suggested for nonmelanoma skin cancer, and also for LMM, was simpler, relating risk to total cumulative dose of UVR on that body site (Table 1).
Case - Control Studies A number of case-control studies were designed to assess the association with sun exposure and to distinguish the intermittent from the cumulative dose model.8 For
41
42
Clinics in Dermatology
ELWOOD
MELANOMA
2992;10:41-50
.. :i’ .-.* \ . ! T\,
5 ITES
l
l.
l
3
l
..
MELANOMA
SITES
. ..
.‘-=J..=
.
d1 l
l
I
a .I . .. .. .-: .* .
.
.
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MALE
FEMALE
MA LE
FEMALE
Figure 1. Body site distribution of a continuous series of 282 new cases of cutaneous melanoma of the superficial spreading or nodular type, seen in the A. Maxwell Evans Clinic in Vancouver from 1976 to 1979. Reprinted, with permission, from Elwood and Gallagher.5
these studies methods for the recall of sun exposure over lifetime had to be developed. Some biologic indicators of chronic sun damage were used (prior or current history of nonmelanoma skin cancer or solar keratoses, and photographic and impression techniques to look at skin thickening and wrinkles), but no such markers were available that would relate specifically to past intermittent exposure. Questionnaire techniques were developed that have had reasonable reproducibility, although formal evaluation is still lacking, and of course there were no ultimate “true” data with which responses could be compared. The major studies followed the principles of good design by including all newly incident melanoma cases in a defined population as eligible, obtaining clinical and interview data on a large proportion of cases and controls, using centralized pathologic review, using comparison subjects chosen as a representative sample of the healthy population from which the melanoma cases were drawn, and using extensive interview techniques. Interviews would last between 1 and 2.5 hours typically, were done by trained interviewers in the subjects’ homes, and were standardized and pretested to minimize response bias. Such bias cannot be excluded, but these studies preceded most of the interest of the profession and the lay public in the dangers of sun exposure and the issue of deliberate response bias is likely to be less than it will be in current or future studies.
The analysis of these studies is also complex. Usually those who tolerate the sun well are likely to spend more time in it, so an analysis looking at sun exposure without adequate adjustment for sun sensitivity factors, pigrnentation, tendency to burn, and so on will underestimate the true relationship; however, statistical adjustment for factors such as the number of benign nevi, which have been shown to be at least in part a consequence of sun exposure,9 is not appropriate and will also diminish a true association as nevi lie in the causal pathway between sun exposure and melanoma. Appropriate and complex analyses are thus important. A further complexity, particularly in comparing studies, is that the same recorded exposure, an hour of sunlight in the summer for example, represents a different UV intensity depending on the latitude and geographic conditions of the exposure, and represents a different dose to the melanocyte depending on clothing, skin characteristics, and thickening. Therefore it would not necessarily be expected that different studies, even using compatible methods, would give similar quantitative results on the relationship between melanoma and recorded sun exposure.
Northern Hemisphere
Studies
Of the now large and rapidly growing number of such studies the four major studies first reported fall naturally
Clinics in Dermatology
ELWOOD MELANOMA AND UV RADIATION
1992;10:42-50 Table 1. Comparison of Nonmelanoma Skin Cancer (NMSC) and Superficial Spreading and Nodular Types of Melanoma with Respect to Major Features NMSC
Feature
classification, within
Yes Yes Yes
Yes Yes Yes
Strong concentration on exposed sites Male excess Increased in outdoor workers Rapid increase in risk by age*
Yes Yes Yes
No No No
Yes
No
More common in higher socioeconomic
No
Yes
groups Rates increasing rapidlyt
?No
Yes
Easily produced experimentally by IJVS Risk proportional to cumulated dose of UV
Yes Yes
No No
l Although both types of tumor increase with age, the increase in NMSC is a simpler and steeper trend; the increase in melanoma by age is complicated by birth cohort effects. t Several recent studies do report increases in NMSC incidence. $ Until recently there was no useful animal model ofmelanoma produced by UVR alone, although it acted as a promoter after chemical initiators.
into two groups. The Western
Canada and the eastern Denmark studies relate to northern populations, at about 50 and 56”N, respectively, and the results are very consistent.‘O*” In both studies, different types of sun exposure were assessed by looking at involvement in different types of activities. Activities associated with increased exposure which is likely to be intermittent are accompanied by an increased risk of SSM and NM in both studies (Table 2). The increases are reasonably moderate and underestimate the true situation because of random misTable 2. Melanoma
Risks Associated
Activities
Place
Type
Relative Risk
Results in Major Northern Hemisphere Studies Swimsuit-type activities Sunny vacations Sunbathing Boating Swimming Skiing (snow) Sunny vacations
Canada Canada Denmark Denmark Denmark Denmark Denmark Results
Boating Fishing Swimming Sunbathing, ages 15 - 24 Recreation > 60% of total outdoor time, ages IO-24 Beach time > 5000 h Beach time > 500 h, ages lo-19
in
and are seen results
apply and for
In contrast, both these northern hemisphere studies show protective effects of high levels of occupational exposure in men (there are few women with such high occupational exposures) (Table 3). The findings therefore support the intermittent exposure hypothesis and argue against a simple cumulative dose model. The more detailed results from the Canadian study have quantified sun exposure, using a unit representing exposure of the whole body surface area for 1 hour in the summer, and show significantly increased risks with the maximum recorded levels of vacation and recreational exposure (Fig 2). For occupational exposure, there is no increased risk at the maximum levels, and as noted earlier, a significantly reduced risk was seen for males with high occupational exposure. Moderate levels of occupational exposure, however, show a significantly increased risk similar to that seen with recreational and vacation activities. This level of occupational dose represents a type of short-term or intermittent exposure; it is achieved by a seasonal job held for a few years or a short period of regular outdoor work. Such exposure often occurs in early adulthood in relationship to higher education or military service. This suggests that a relatively short period of high exposure can increase risk, which is supported by a few other studies. One study that does not suffer from the problem of recall bias is the cohort study of college students in the United States in which outdoor exposure recorded at college age was associated with a fourfold increase in mela-
with Recreational
Activity
significant and these
after statistical adjustment for host characteristics other exposures to sunlight.
Melanoma
Mainly in white populations Increased with light pigmentation Increased at lower latitudes
but are statistically
age and sex subgroups,
43
Excl. Excl. Excl. Excl. Excl. Excl. Excl.
LMM’ LMM LMM LMM LMM LMM LMM
1.7t 1.5t 1.6t 1.4t l.l$ 1.4t 1.7t
Major Australian Studies
Western Australia Western Australia Western Australia Western Australia Western Australia Western Australia Queensland Queensland
SSM SSM SSM SSM All SSM Excl. LMM Excl. LMM
Data are from papers referenced in the text. * LMM, lentigo maligna malanoma; SSM, superfifial spreading melanoma. t Statistically significanf association; ns, not significant. $ Trend test ooer all categories significant; ever/never comparison, not significant.
2.4t 2.7t 1.1 ns 1.3 ns 1.3 ns 1.6 ns 1.9 ns 1.0 ns
44
Clinics in Dermatology
ELWOOD
1992;10:41-50 Table 3. Melanoma Risk in Men with Heavy Occupational Study Canada
Sun Exposure
Type
Exposure
Excl. LMM*
> 32 h/wk Farmers Construction workers Woodworkers Outdoor work Farmers, construction workers, foresters, and fishermen Top quartile of occupational exposure Outdoor work
Denmark
Excl. LMM
Western Australia Queensland
SSM Excl. LMM
Relative Risk 0.5
t
0.3 0.4
:
0.7 0.3 0.6
: ns
0.5 no assoc.
t
Data are from papers referenced in the text. * LMM, lentigo maligna melanoma; SSM, superficial spreading melanoma. t Statistically significant association; ns, not significant
noma in later life.12 Other case-control studies have shown associations with short periods spent in more sunny locations; one specific study compared melanoma in U.S. servicemen who had served in the Pacific as compared with the European theater during World War II; a higher rate was found in the former.13
Southern Hemisphere Studies Two other major studies have come from Queensland and Western Australia.14*15 The results are in part different from those of the northern hemisphere studies, and these differences are likely to relate to the much higher sun exposure levels in these areas, at latitudes of 32”s in Perth and from 25 to 17”s in Queensland, allied to a culture that involves considerable intense sun exposure. The Western Australia study showed strong positive associations with measures of likely sun exposure, such as sunshine hours in the place of residence and biologic markers such as skin wrinkling.15 A substantial proportion of residents of Western Australia have moved there from much less sunny environments, such as the United Kingdom. The migrant studies are very useful, indicating
that the risk of melanoma is much lower in subjects who arrive in Australia after the age of 15 years, whereas the risk in those who arrive at around age 5 is similar to the risk for native-born Australians (Fig 3).15 This suggests that exposure between ages 5 and 15 is particularly important. Such measures provide indications of a positive risk with total sun exposure, and the main association seen in the Queensland study was a strong positive association with total sun exposure from all sources.14 Other results, however, are consistent with a more complex etiology. Results in Western Australia for specific activities show stronger risks associated with activities that would involve moderate exposure, boating and fishing, compared with the more intense sun exposures of swimming and sunbathing16 (Table 2). Measures constructed to indicate likely high-exposure activities, such as the proportion of all outdoor exposure spent on recreational activities in Western Australia16 and the amount of time spent on the beach while a teenager in Queensland,14*17 do not show strong associations (Table 2). In Western Australia
Figure 3. Risk of superficial spreading melanoma (SSM) for Western Australia residents by age at arrival in Australia, controlled for ethnicity. Data from Holman and Armstrong.‘5
Figure 2. Summary of the results of the Western Canada Melanoma Study, showing the relative risk of melanoma in relationship to occupational, vacation, and recreational sun
2.0
exposures. ---, recreation; **a, vacation; -, occupation; II, significantly greater than 1.0. Data from Elwood et al.‘O
1.8
1.6Y
1.4-
.2
1.2-
.-%J l.O;ij a 0.8-
0.8
K
-- recreahon ---vocation - occupahon
t-
0
I
0
I
I
10 20
I
50
slgnlflcanUygrealer than I
100 200
10
I
I
500
mid-range exposure, whale body equivalent hours
0.6-
Clinics in Dermatology
ELWOOD MELANOMA AND UV RADIATION
1992;20:41-50 Table 4. Measured Sun Exposures in Northern Europeans Annual Number of MEDs*
Annual Irradiation (I/cm’ at 300 nm)
270 90
6.6 2.2
100
2.5
Outdoor worker Indoor worker (including weekend exposure) 2-wk Mediterranean holiday with sunbathing
Reprinted, with permission, from Diffey.‘B
* MED. minimal eythemnl dosage.
also, the maximum levels of occupational exposure in men were associated with a decrease in melanoma risk,16 although a similar result was not seen in Queensland” (Table 3). In general, UVR intensity is about two to three times higher in these southerly areas as in the northern areas at which the former studies were done. The distinction between intermittent and occupational exposure is likely to be much less clear. Individual dosimetry measurements using UVR-sensitive badges has shown that in northern Europe, an individual who regularly works indoors can readily double his or her total annual UVR dose by taking a 2-week holiday in the Mediterranean area and spending considerable time outdoors’* (Table 4). Such a clear distinction is less likely in the Australian culture. The Australian results also show some evidence of site specificity; for example, women who wore a two-piece bathing suit or bathed nude had an extremely high risk of superficial spreading melanoma of the trunk, compared with those who usually wore a one-piece trunk-covering bathing suit.16
Dose-Risk Relationships A large number of other studies are now available, but the results in general are consistent with those just exemplified. The general conclusion is that melanoma (SSM and NM) is clearly related to UVR exposure, with a complex dose-response relationship. In the northern hemisphere studies the intermittent exposure hypothesis is supported, and the major increase in melanoma risk is related to intermittent exposure, which can be defined as unusually intense exposure of skin that has not been extensively tanned or thickened to provide a protective shield. In outdoor exposure, contrast, regular long-continued achieved by occupation, produces a lower melanoma risk, presumably because the tanning and skin thickening involved provide protection that overcomes any initial damage done by early exposures. In the Australian studies some of the data on activities and occupation support that model, but the distinction
45
between intermittent and chronic exposure is less clear. Recreational activities may well produce levels of sun exposure that would be reached by regular outdoor occupation only at a higher northerly latitude. The Western Australia group has therefore proposed a complex dose response relationship (Fig 4) where risk rises initially with moderate levels of likely intermittent exposure, then falls at the levels of sun exposure typical of regular occupation, but can then rise again if even higher levels of sun exposure are achieved, as could apply to Australian residents who spend a great deal of time in beach-type activities.6 According to an alternative model, suggested by some of the Canadian data, regular and intermittent exposures have intrinsically different actions, and therefore the risk is predicted well by any addition of these two exposures, but has to be looked at as a function of each exposure independently. Thus in the Western Canada data, subjects with high levels of occupational exposure still show a substantial increased risk in association with added intermittent exposure, although in dose terms this is only a small increment.
Other Types of Melanoma The preceding results are based on analyses either of SSM and NM specifically or of all cutaneous melanomas, usually excluding acral lentiginous melanoma (ALM). As noted earlier, the general features of LMM are more suggestive of an association with chronic sun exposure, and this is suggested although not clearly demonstrated by comparative analyses. l9 Most of the available studies Figure 4. Speculative representation of exposure-response relationships between sun exposure and malignant melanoma. Reprinted, with permission, from Armstrong8
FREOVENCY
OF EXPOSURE
TO SVNLIOHT
46
ELWOOD
Clinics in Dermatology
2992;10:41-50 contain relatively few cases of LMM, and there is a major problem in that the classification of a tumor as LMM may be influenced by the body site or the finding of evidence of chronic solar damage in surrounding skin, making the independent assessment of its etiology impossible. ALM is too uncommon in light-skinned populations to have been studied specifically. It constitutes a large proportion of melanomas in Japan, and the incidence of melanoma in Japan is reported to have risen rapidly; however, no major etiologic studies either of ALM or of melanoma in populations of other than European origin have yet been doneezO Several studies of ocular melanoma are available, and this is much more common in subjects with blue rather than darker eyes. Some studies suggest a higher risk in those with likely higher levels of sun exposure, for example, those who live in southerly rather than northerly parts of the United States.21
Relationship to Host Factors All these studies show strong associations of the common types of melanoma with host factor characteristics, which are dealt with in the article by Sober et al in this issue. These host features are divided into two groups. There are those genetically controlled features that influence an individual’s susceptibility to the sun. These include racial background; skin pigmentation, which, in turn, is related to hair and eye pigmentation; and tendency to burn or to produce a suntan, which is clinically characterized as skin type. The available studies are generally consistent with respect to these features, and higher susceptibility to the acute effects of sun exposure in producing erythema and sunburn is strongly associated with a higher risk of melanoma. This is supported by studies that have shown lower minimal erythemal dosages and slower recovery from erythemal damage in melanoma subjects than in controls.22,23 The studies reviewed are all consistent with the concept that this inherent susceptibility and the effects of recorded sun exposure are generally independent, on the usual multiplicative scale. Thus for any of the aforementioned exposure situations, the risks will be higher in those who have ethnic and pigmentary characteristics associated with greater susceptibility. The other set of host factors, which are very strong and useful clinically as risk indicators, includes the number of acquired nevi. Several studies now suggest that the number of nevi is at least in part a response to sun exposure. In particular, recent studies of nevus prevalence in young children in different areas of Australia have shown that higher prevalences in the more northerly areas are apparent between ages 5 and 10. 24 Acquired nevi may be a risk marker of melanoma by acting as an early biologic indi-
cator of sun exposure, and there is some evidence that they may indicate an intermittent type of exposure, in that some studies have shown the maximum prevalence of nevi in individuals with moderate levels of exposure, the prevalence being reduced in those with high exposures.9 Another characteristic shown to be strongly associated with melanoma in the aforementioned studies, and also useful as a clinical indicator of risk, is the frequency of previous sunburn. Its etiologic role is, however, uncertain. In two of the major studies, the Western Canada and Western Australian studies, the association with a history of sunburn largely disappeared when adjusted for susceptibility to sunburn, suggesting that the association represents the increased risk of those with high susceptibility rather than a direct effect of the presence of sunbum.16,25 In the Queensland and Danish studies, and in some others, however, the association persisted after such contro1.11,26,27Attempts have been made to relate sunburn on particular body sites to melanoma on those same sites, but it is difficult to achieve such specificity in the recorded information and the results have as yet not been conclusive.” The question of the time of maximum susceptibility is best answered by the migrant data that have been referred to, which strongly indicate that adolescence and early adult life are particularly important. This is supported by some of the studies on sun exposure and sunburn, which indicate that sunburn in early life is a stronger indicator of later melanoma than subsequent sunburn. The migrant data therefore suggest an early life effect on subsequent melanoma risk, with a long latent period. It is likely, however, that there are also short-term effects. This is supported by the considerable evidence that UVR acts as a promoter and an immunosuppressant, which would suggest late shorter-term effects.2 It is directly supported by evidence from Australia which shows higher levels of mitotic activity in nevi excised in the summer months.28 There is also support from studies of seasonal variation in the diagnosis of melanoma, and from studies showing short-term increases after particularly sunny years, but these types of studies are very difficult to interpret, first because of recognition bias and second because of multiple testing. The remaining major risk factors are the presence of dysplastic nevi and a family history of melanoma, which together confer an extremely high risk. These studies are discussed in the article by Bergman and Fusaro in this issue. The evidence of a clearly genetically-linked dysplastic nevus -melanoma syndrome shows that the tendency to dysplastic nevi is constitutionally inherited, but there is also evidence that the number of dysplastic nevi is increased by ultraviolet exposure.
Clinics in Dermatology 1992;20:42-50 It is possible that the majority of melanomas develop in a sequence from a normal melanocyte to a nevus cell as part of an acquired nevus, then transform to a dysplastic nevus cell and then to a melanoma.‘J9 Each of these stages is likely to represent a specific genetic event within the cell. Subjects who inherit the dysplastic nevusmelanoma susceptibility trait will have already have one or more of these changes and may already have dysplastic nevus cells. The mechanisms by which UVR may influence the development of melanoma remain to be clarified. One important observation is that in different geographic areas with very different total incidence rates of melanoma, the distribution of melanoma by body site does not vary greatly, and this led to the suggestion in 1970 that UVR might act by a systemic mechanism, through a “solar circulating factor.” Recent experimental evidence has shown that UVR results in melanocyte proliferation in shielded as well as exposed areas of skin in human volunteers, giving support to this concept.30,31
Ozone Depletion There is evidence that stratospheric ozone depletion has led to increases in ground-level UVR in both the southern and northern hemispheres, and that these effects are likely to increase. The effects of ozone depletion on melanoma incidence and mortality have been estimated primarily by looking at geographic variation, usually within North America, in relation to the difference in UVR levels between different geographic locations. The estimates vary with whether linear, exponential, or power models of the relationship between risk and exposure are used, whether incidence or mortality data are used, and whether differences in annual UVR levels or in peak UVR levels are used. Typical estimates are that a 1% depletion of ozone is predicted to result in an increase of 1 to 2% in the incidence and 0.8 to 1.5% in the mortality from melanoma.32*33 Although such effects are important, the increases predicted from the most reasonable estimates of ozone depletion in the next few decades are therefore still small compared with the increases of from 4 to 7% per year in melanoma mortality and incidence rates that have been observed in many countries over recent decades, before an effect of ozone depletion would have occurred.
Artificial Sources of Ultraviolet Radiation All the epidemiologic and clinical evidence, although expressed in the preceding as UVR, in fact refers to solar exposure, and the studies cannot separate effects of different components of this exposure. Although UVR can be used as a tumor promoter after exposure to a chemical
ELWOOD
47
MELANOMA AND LJV RADIATION
carcinogen in animal experimentation, models in which UVR induces melanoma when used alone have only very recently been developed,34,35 and no substantive studies on the effects of different components or dose rates on melanoma have been published. Thus it is largely speculation whether different components of UVR, as can be delivered by artificial UVR sources, have any effects different from those of natural sunlight. Sunlamps and sunbeds are designed to produce a suntan, and do this by using very large dosages of ultraviolet A (UVA). A suntan could be produced by a much lower dose of ultraviolet B (UVB), but this would run the greater risk of producing erythema and sunburn; however, as we do not know the precise action spectrum for the production of melanoma in humans, there are no grounds to claim that a UVA source will have any lower carcinogenic effect than a dose of UVB radiation sufficient to produce the same tanning effect. Several studies have reported on the use of sunbeds and sunlamps in relationship to melanoma (Table 5) and empirically show increased risks. In these studies, however, detailed assessments of sun exposure were not used. If users of sunbeds have greater solar exposure than others, which seems quite likely, these results may be due to the solar exposure; however, these results do provide evidence against the concept that the use of sunbeds and suntans should lower melanoma risk by producing a suntan before natural sun exposure or by maintaining a suntan throughout the year; if that were so, we would expect a null or even a protective effect in these analyses. It is true that in many experimental situations, including the two most recent models,34*35 the carcinogenic effects of UVB radiation are reduced by the use of UVA or even visible light, which can stimulate DNA photorepair mechanisms; however, these same photorepair mechanisms may not act in humans, and the experimental evidence shows that for this effect to work, UVA or visible light has to be given after the UVB exposure. With that logic, pretanning with artificial sources would not be protective, although UVA exposure after exposure to natural sunlight might be helpful. Another potential source of UVR that is quite common is fluorescent lighting. Fluorescent tubes emit some UVR at relatively low wavelengths, and it has been shown that at a particular narrow UVB wavelength band around 305 nm, the dose of UVR that would be received from an unshielded fluorescent tube during a regular working day could exceed that achieved by a reasonable amount of outdoor exposure. That would provide a biologic rationale for an association with fluorescent light exposure if there were also evidence that that particular wavelength was important in melanoma production; such evidence does not exist. Moreover, most fluorescent lights are
48
Clinics in Dermatology
ELWOOD
2992;10:42-50 Table 5. Studies of Melanoma
Risk Associated
with Artificial UV Exposures
First Author, Reference
Year
Place
Swerdlow et aP
1988
Scotland
Both
2.9 (1.3, 6.4) 9.1 (2.0, 40.6)
Ma&e
1989
Scotland
1990
Ontario
Men Women Men Women Men Women
2.6 1.5 1.9 1.5 2.1 3.0
et al*r
Walter et aP
Sex
Relative Risk (95% Limits)
(0.9, (0.8, (1.2, (1.0, (0.9, (1.1,
7.3) 2.9) 3.0) 2.1) 5.3) 9.6)
Measurement
of Exposure*
a Ever used UV lamps or sunbeds Used more than 5 y before diagnosis b Sunbed used for 3 months or longer c Ever used LJV lamps or sunbeds c Use of UV longer
sourcesfor 1 year or
* (a) Crude results; adjustment for nevi, hair, and eye color; exposure to sun made little difference. (b) Crude results; adjustment for total nevi, atypical nevi, freckling, sunburn, tropical residence, skintype reduced risk to 1.3 (men) and 1.2 (women). (c) crude results.
shielded by diffusers of plastic or glass material, and these in general are effective blockers of UVB. The original studies suggesting an association with fluorescent light show that the excess tumors were distributed over the body, not particularly in the sites likely to be exposed, and further studies have not in general supported the relationship.36 There are many occupational sources of UVR, and these have been little investigated. Studies in England have suggested increased risks with certain sources including plan copiers, which use an ultraviolet source to produce blueprints. 37 Among the most intense occupational exposures are those in medical areas with respect to phototherapy, and such exposures can be monitored in a method analogous to x-ray exposure; appropriate safety limits have been set. In this regard patients who receive phototherapy are obviously of special interest, and studies are available that show excesses of nonmelanoma skin cancer in patients treated for psoriasis by a method using UVA and psoralens (PUVA). No increase in melanoma has been shown.38,39 From the risk models discussed earlier, it could be expected that the dosages received would be too great to produce an increase in melanoma.
Conclusions It is reasonable to conclude that the great majority of melanomas in light-skinned people are due to UVR, and that at least at moderate total levels of exposure, intermittent relatively intense exposure of unacclimated skin is the major risk factor for the more common types of melanoma (SSM and NM). On this basis, melanoma should be preventable by a reduction in sun exposure and by a specific effort to avoid such intermittent intense exposure patterns. This would best be achieved by avoidance techniques, ranging from individual actions about the wear-
ing of shirts and hats on sunny days to community actions such as the provision of shade in the form of trees or artificial shelters at public areas and beaches and, in sunny regions, the alteration of school hours to avoid outdoor exposure of children during the most intense periods of the day. All these activities are being strongly promoted in some areas, particularly in Australia.40 The reduction of UVR received by the use of UVR blockers is also likely to be effective unless it is merely compensated by an increase in solar exposure time, which may result in receipt of the same dose or receipt of a greater dose if the ultraviolet blocker is applied inconsistently or has a limited effect. Public education campaigns aimed at primary prevention are now a familiar concept in most high-risk and even moderate-risk areas. It will be difficult to assess their impact, as it may take several years or decades for the impact to be seen, and it is difficult to imagine a rigorous study design evaluating these effects in the primary prevention of melanoma. An important and unresolved question is whether the amount of reduction in sun exposure achievable by such campaigns is likely to be enough to make a major difference in melanoma incidence. More limited evaluation studies looking at the extent to which such programs produce behavioral changes or assessing their effect on likely markers of sun exposure would still be useful. For example, it has been suggested that trials of sun reduction campaigns in children could use the prevalence of benign nevi as a short-term endpoint (D. English, personal communication). In urban, largely indoor communities a major stimulus for sun exposure is the fashionable aspects of a suntan, and although there is evidence of a move away from this behavsocial change ior, it may require a considerable particularly affecting the attitudes and body image of adolescents to produce a major effect. A satisfactory tanned appearance can be achieved by cosmetics that dye
Clinics in Dermatology 2992;10:41-50
ELWOOD MELANOMA AND UV RADIATION
epithelial cells; if free from hazards, such methods could be encouraged. We can, however, inform individuals that their melanoma risk will be reduced if they reduce their sun exposure, particularly intermittent relatively intense exposure. There is no evidence to recommend the use of artificial ultraviolet tanning sources, and it is likely that the hazards associated with such exposures are similar to the hazards of an equivalent amount of natural sunlight. These warnings can be reinforced for those with a greater genetic susceptibility to the ill effects of the sun, ranging from the extreme situation of a family history of melanoma and dysplastic nevi to the general characteristics of light or red hair color and a skin type that burns easily and does not tan easily.
References 1. Lee JAH. Melanoma and exposure to sunlight. Epidemiol Rev 1982;4:110-36. 2. Elwood JM. Initiation and promotion actions of ultraviolet radiation on malignant melanoma. In: Borzsonyi M, Day NE, Lapis K, Yamasaki H, editors. Models, mechanisms and etiology of tumor promotion. 1ARC Scientific Publication No. 56. Lyon: MRC-OUP, 1984;421-525. Research Council. Causes and effects of strutospheric ozone reduction: An update. Washington, DC: Na-
3. National
tional Academy of Sciences, 1982.
49
12. Paffenbarger RS Jr, Wing AL, Hyde RT. Characteristics in youth predictive of adult-onset malignant lymphomas, melanomas, and leukemias. J Nat1 Cancer Inst 1978;60: 89-92. 13. Brown J, Kopf AW, Rigel DS, Friedman RJ. Malignant melanoma in World War II veterans. Int J Dermatol 1984;23:661-3. 14. Green AC. Sun exposure and the risk of melanoma. Australas J Dermatol 1984;25:99-102. 15. Holman CDJ, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: An analysis separating histogenetic types. J Nat1 Cancer Inst 1984;73:75-82. 16. Holman CDJ, Armstrong BK, Heenan PJ. Relationship of cutaneous malignant melanoma to individual sunlight-exposure habits. J Nat1 Cancer Inst 1986;76:403-14. 17. Green AC, Bain C, McLennan R, Siskind V. Risk factors for cutaneous melanoma in Queensland. In: Gallagher RP, editor. Epidemiology of malignant melanoma: Recent results in cancer research. Heidelberg: Springer-Verlag, 1986:76-97. 18. Diffey BL. Analysis of the risk of skin cancer from sunlight and solaria in subjects living in northern Europe. Photodermatology 1987;4:118-26. 19. Elwood JM, Gallagher RI’, Worth AJ, et al. Etiological differences between subtypes of cutaneous malignant melanoma: Western Canada Melanoma Study. J Nat1 Cancer Inst 1987;78:37-44.
Environ Car-
20. Elwood JM. Epidemiology and control of melanoma in white populations and in Japan. J Invest Dermatol 1989;92:214S-2218.
5. Elwood JM, Gallagher RI’. Site distribution of malignant melanoma. Can Med Assoc J 1983;128:1400-4.
2 1. Tucker MA, Shields JA, Hartge P, et al. Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med 1985;313:789-92.
4. Urbach F. Cutaneous photocarcinogenesis. cinogen Rev 1987;C5:211-34.
6. Elwood JM, Hislop TG. Solar radiation in the etiology of cutaneous malignant melanoma in Caucasians. Nat1 Cancer Inst Monogr 1982;62:167-71. 7. Holman CDJ, Armstrong BK, Heenan PJ. A theory of the etiology and pathogenesis of human cutaneous malignant melanoma. J Nat1 Cancer Inst 1983;71:651-6. 8. Armstrong BK. Epidemiology of malignant melanoma: Intermittent or total accumulated exposure to the sun? J Dermatol Surg Oncol 1988;14:835-49. 9. Armstrong BK, de Klerk NH, Holman CDJ. Etiology of common acquired melanocytic nevi: Constitutional variables, sun exposure, and diet. J Nat1 Cancer Inst 1986;77:329-35. 10. Elwood JM, Gallagher RP, Hill GB, Pearson JCG. Cutaneous melanoma in relation to intermittent and constant sun exposure: The Western Canada Melanoma Study. Int J Cancer 1985;35:427-43. 11. Osterlind A, Tucker MA, Stone BJ, Jensen OM. The Danish case-control study of cutaneous malignant melanoma. II. Importance of UV-light exposure. Int J Cancer 1988;42:319-24.
22. Beitner H, Ringborg U, Wennersten G, Lagerlof B. Further evidence for increased light sensitivity in patients with malignant melanoma. Br J Dermatol 1981;104:289-94. 23. Azizi E, Wax Y, Lusky A, et al. The recovery from ultraviolet radiation-induced erythema and melanoma risk factors: A case-control study. J Am Acad Dermatol 1990; 23:30-6. 24. McLennan R. Anatomic distribution of melanocytic nevi in Australian school children. Second International Symposium on Epidemiology of malignant melanoma, 199 1. Abstract. 25. Elwood JM, Gallagher RI’, Davison J, Hill GB. Sunburn, suntan and the risk of cutaneous malignant melanoma: The Western Canada Melanoma Study. Br J Cancer 1985; 51:543-9. 26. Green AC, Siskind V, Bain C, Alexander J, Sunburn and malignant melanoma. Br J Cancer 1985;51:393-7. 27. MacKie RM, Aitchison T. Severe sunburn and subsequent risk of primary cutaneous malignant melanoma in Scotland. Br J Cancer 1982;40:955-60.
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28. Holman CDJ, Heenan PJ, Caruso V, et al. Seasonal variation in the junctional component of pigmented naevi. Int J Cancer 1983;31:213-5. 29. Elder DE. Human melanocytic neoplasms and their etiologic relationship with sunlight. J Invest Dermatol 1989;92:297S_303S. 30. Lee JAH, Merrill JM. Sunlight and the aetiology of malignant melanoma: A synthesis. Med J Aust 1970;2: 846-51. 31. Stierner U, Rosdahl I, Augustsson A, Kagedal B. UVB irradiation induces melanocyte increase in both exposed and shielded human skin. J Invest Dermatol 1989;92:561-4.
36. Elwood JM. Could melanoma be caused by fluorescent light? A review of relevant epidemiology. In: Gallagher RP, editor. Epidemiology ofmalignant melanoma. Recent results in cancer research. Heidelberg: Springer-Verlag, 1986:12736. 37. Elwood JM, Williamson C, Stapleton PJ. Malignant melanoma in relation to moles, pigmentation, and exposure to fluorescent and other lighting sources. Br J Cancer 1986;53:65 - 74. 38. Stern RK, Lange R. Cardiovascular disease, cancer, and cause of death in patients with psoriasis: 10 years prospective experience in a cohort of 1,380 patients. J Invest Dermatol 1988;91:197-201.
32. Longstreth J. Cutaneous malignant melanoma andultraviolet radiation: A review. Cancer Metastasis Rev 1988;7:32133.
39. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: A large-scale epidemiological study. Lancet 1991;338:91-3.
33. Elwood JM. The epidemiology of melanoma: Its relationship to ultraviolet radiation and ozone depletion. In: Russell-Jones R, Wigley T, editors. Ozone depletion: Health and environmental consequences. London: Wiley, 1989: 169-89.
40. Marks R, McCarthy WH. Skin cancer: Increasing incidence and public awareness. Med J Aust 1990;153:505-6. 41. Swerdlow AJ, English JSC, Ma&e RM, et al. Fluorescent lights, ultraviolet lamps, and risk of cutaneous melanoma. Br Med J 1988;297:647-50.
34. Ley RD, Applegate LA, Padilla RS, Stuart TD. Ultraviolet radiation-induced malignant melanoma in Monodelphis domestica. Photochem Photobiol 1989;50:1-5.
42. MacKie RM, Freudenberger T, Aitchison TC. Personal riskfactor chart for cutaneous melanoma. Lancet 1989;2:48790.
35. Setlow RB, Woodhead AD, Grist E. Animal model for ultraviolet radiation-induced melanoma: Platyfish-swordtail hybrid. Proc Nat1 Acad Sci USA 1989;86:8922-6.
43. Walter SD, Marrett LD, From L, et al. The association of cutaneous malignant melanoma with the use of sunbeds and sunlamps. Am J Epidemiol 1990;131:232-43.
MARK ELWOOD, MD
xternal ultraviolet radiation (UVR) is the major causative factor for human cutaneous melanoma. In this article the evidence supporting this statement and some of the implications are dis-
E
cussed.
Background The evidence is based on analytical epidemiologic studies (case-control and cohort studies). Although there were some early less satisfactory studies, the main ones were set up in the late 1970s after basic clinical and epidemiologic evidence suggested that melanoma was related to sun exposure, but not in a simple linear dose-response relationship. The clinical evidence included the obvious feature that melanocytes are in the skin, and their normal function is to respond to UVR by producing and distributing pigments. The descriptive epidemiology showed that in many areas such as North America and Australia, melanoma incidence and mortality rates were higher closer to the equator. That trend did not apply in Europe as a whole but was still seen within individual countries in Europe, and the overall European pattern with higher rates in the Scandinavian than in the Mediterranean countries seemed likely to be the result of complexion differences. In this, the distribution of melanoma was similar to that of other skin cancers. In contrast, melanoma incidence and mortality rates were increasing rapidly with time and were much higher in the higher socioeconomic groups, in contrast to the distribution of other skin cancers.1*2 Outdoor workers are represented mainly in the lower socioeconomic groups,
From the Hugh Adam Cancer Epidemiology Unit, Otago University Medical School, Dunedin, New Zealand. Addresscorrespondence to]. MarkElwood, HughAdamCancerEpidemiology Unit, Department of Preventive and Social Medicine, Otago University Medical School, P.O. Box 913, Dunedin, New Zealand.
0
2992 by Elsevier
Science
Publishing
Co., Inc.
l
0738-081x/92/$5.00
and comparisons of indoor and outdoor jobs from routine incidence and mortality data showed in several countries that melanoma was more common in indoor workers, even within the same socioeconomic group.’ Moreover, the body site distribution of melanoma was clearly different from that of squamous and basal cell carcinomas. These latter tumors occur almost exclusively on exposed skin areas and are clearly more common in individuals with a great deal of outdoor exposure. Squamous cell carcinoma is readily produced in animals by UVR.3*4 Thus it appeared that nonmelanoma skin cancer has a simple relationship to UVR. Further analysis of the body site distribution of melanoma (Fig 1) showed that the common superficial spreading (SSM) and nodular (NM) forms, although not clearly concentrated on the most exposed areas, showed a distribution pattern and differences between the sexes consistent with an effect of moderate degree of exposure .5 Clinically, lentigo maligna melanoma (LMM) appeared quite different from SSM and NM, occurring in older patients, predominantly in men, and being virtually limited to heavily exposed areas such as the face.’ These epidemiologic and clinical findings led to proposal of the “intermittent exposure” hypothesis-that the risk of SSM and NM was increased primarily by intermittent exposure to UVR of skin that was not heavily tanned or thickened, with the suggestion that longerterm chronic exposure would have a neutral or even protective effect6,’ In contrast, the model suggested for nonmelanoma skin cancer, and also for LMM, was simpler, relating risk to total cumulative dose of UVR on that body site (Table 1).
Case - Control Studies A number of case-control studies were designed to assess the association with sun exposure and to distinguish the intermittent from the cumulative dose model.8 For
41
42
Clinics in Dermatology
ELWOOD
MELANOMA
2992;10:41-50
.. :i’ .-.* \ . ! T\,
5 ITES
l
l.
l
3
l
..
MELANOMA
SITES
. ..
.‘-=J..=
.
d1 l
l
I
a .I . .. .. .-: .* .
.
.
l
‘.
l.
MALE
FEMALE
MA LE
FEMALE
Figure 1. Body site distribution of a continuous series of 282 new cases of cutaneous melanoma of the superficial spreading or nodular type, seen in the A. Maxwell Evans Clinic in Vancouver from 1976 to 1979. Reprinted, with permission, from Elwood and Gallagher.5
these studies methods for the recall of sun exposure over lifetime had to be developed. Some biologic indicators of chronic sun damage were used (prior or current history of nonmelanoma skin cancer or solar keratoses, and photographic and impression techniques to look at skin thickening and wrinkles), but no such markers were available that would relate specifically to past intermittent exposure. Questionnaire techniques were developed that have had reasonable reproducibility, although formal evaluation is still lacking, and of course there were no ultimate “true” data with which responses could be compared. The major studies followed the principles of good design by including all newly incident melanoma cases in a defined population as eligible, obtaining clinical and interview data on a large proportion of cases and controls, using centralized pathologic review, using comparison subjects chosen as a representative sample of the healthy population from which the melanoma cases were drawn, and using extensive interview techniques. Interviews would last between 1 and 2.5 hours typically, were done by trained interviewers in the subjects’ homes, and were standardized and pretested to minimize response bias. Such bias cannot be excluded, but these studies preceded most of the interest of the profession and the lay public in the dangers of sun exposure and the issue of deliberate response bias is likely to be less than it will be in current or future studies.
The analysis of these studies is also complex. Usually those who tolerate the sun well are likely to spend more time in it, so an analysis looking at sun exposure without adequate adjustment for sun sensitivity factors, pigrnentation, tendency to burn, and so on will underestimate the true relationship; however, statistical adjustment for factors such as the number of benign nevi, which have been shown to be at least in part a consequence of sun exposure,9 is not appropriate and will also diminish a true association as nevi lie in the causal pathway between sun exposure and melanoma. Appropriate and complex analyses are thus important. A further complexity, particularly in comparing studies, is that the same recorded exposure, an hour of sunlight in the summer for example, represents a different UV intensity depending on the latitude and geographic conditions of the exposure, and represents a different dose to the melanocyte depending on clothing, skin characteristics, and thickening. Therefore it would not necessarily be expected that different studies, even using compatible methods, would give similar quantitative results on the relationship between melanoma and recorded sun exposure.
Northern Hemisphere
Studies
Of the now large and rapidly growing number of such studies the four major studies first reported fall naturally
Clinics in Dermatology
ELWOOD MELANOMA AND UV RADIATION
1992;10:42-50 Table 1. Comparison of Nonmelanoma Skin Cancer (NMSC) and Superficial Spreading and Nodular Types of Melanoma with Respect to Major Features NMSC
Feature
classification, within
Yes Yes Yes
Yes Yes Yes
Strong concentration on exposed sites Male excess Increased in outdoor workers Rapid increase in risk by age*
Yes Yes Yes
No No No
Yes
No
More common in higher socioeconomic
No
Yes
groups Rates increasing rapidlyt
?No
Yes
Easily produced experimentally by IJVS Risk proportional to cumulated dose of UV
Yes Yes
No No
l Although both types of tumor increase with age, the increase in NMSC is a simpler and steeper trend; the increase in melanoma by age is complicated by birth cohort effects. t Several recent studies do report increases in NMSC incidence. $ Until recently there was no useful animal model ofmelanoma produced by UVR alone, although it acted as a promoter after chemical initiators.
into two groups. The Western
Canada and the eastern Denmark studies relate to northern populations, at about 50 and 56”N, respectively, and the results are very consistent.‘O*” In both studies, different types of sun exposure were assessed by looking at involvement in different types of activities. Activities associated with increased exposure which is likely to be intermittent are accompanied by an increased risk of SSM and NM in both studies (Table 2). The increases are reasonably moderate and underestimate the true situation because of random misTable 2. Melanoma
Risks Associated
Activities
Place
Type
Relative Risk
Results in Major Northern Hemisphere Studies Swimsuit-type activities Sunny vacations Sunbathing Boating Swimming Skiing (snow) Sunny vacations
Canada Canada Denmark Denmark Denmark Denmark Denmark Results
Boating Fishing Swimming Sunbathing, ages 15 - 24 Recreation > 60% of total outdoor time, ages IO-24 Beach time > 5000 h Beach time > 500 h, ages lo-19
in
and are seen results
apply and for
In contrast, both these northern hemisphere studies show protective effects of high levels of occupational exposure in men (there are few women with such high occupational exposures) (Table 3). The findings therefore support the intermittent exposure hypothesis and argue against a simple cumulative dose model. The more detailed results from the Canadian study have quantified sun exposure, using a unit representing exposure of the whole body surface area for 1 hour in the summer, and show significantly increased risks with the maximum recorded levels of vacation and recreational exposure (Fig 2). For occupational exposure, there is no increased risk at the maximum levels, and as noted earlier, a significantly reduced risk was seen for males with high occupational exposure. Moderate levels of occupational exposure, however, show a significantly increased risk similar to that seen with recreational and vacation activities. This level of occupational dose represents a type of short-term or intermittent exposure; it is achieved by a seasonal job held for a few years or a short period of regular outdoor work. Such exposure often occurs in early adulthood in relationship to higher education or military service. This suggests that a relatively short period of high exposure can increase risk, which is supported by a few other studies. One study that does not suffer from the problem of recall bias is the cohort study of college students in the United States in which outdoor exposure recorded at college age was associated with a fourfold increase in mela-
with Recreational
Activity
significant and these
after statistical adjustment for host characteristics other exposures to sunlight.
Melanoma
Mainly in white populations Increased with light pigmentation Increased at lower latitudes
but are statistically
age and sex subgroups,
43
Excl. Excl. Excl. Excl. Excl. Excl. Excl.
LMM’ LMM LMM LMM LMM LMM LMM
1.7t 1.5t 1.6t 1.4t l.l$ 1.4t 1.7t
Major Australian Studies
Western Australia Western Australia Western Australia Western Australia Western Australia Western Australia Queensland Queensland
SSM SSM SSM SSM All SSM Excl. LMM Excl. LMM
Data are from papers referenced in the text. * LMM, lentigo maligna malanoma; SSM, superfifial spreading melanoma. t Statistically significanf association; ns, not significant. $ Trend test ooer all categories significant; ever/never comparison, not significant.
2.4t 2.7t 1.1 ns 1.3 ns 1.3 ns 1.6 ns 1.9 ns 1.0 ns
44
Clinics in Dermatology
ELWOOD
1992;10:41-50 Table 3. Melanoma Risk in Men with Heavy Occupational Study Canada
Sun Exposure
Type
Exposure
Excl. LMM*
> 32 h/wk Farmers Construction workers Woodworkers Outdoor work Farmers, construction workers, foresters, and fishermen Top quartile of occupational exposure Outdoor work
Denmark
Excl. LMM
Western Australia Queensland
SSM Excl. LMM
Relative Risk 0.5
t
0.3 0.4
:
0.7 0.3 0.6
: ns
0.5 no assoc.
t
Data are from papers referenced in the text. * LMM, lentigo maligna melanoma; SSM, superficial spreading melanoma. t Statistically significant association; ns, not significant
noma in later life.12 Other case-control studies have shown associations with short periods spent in more sunny locations; one specific study compared melanoma in U.S. servicemen who had served in the Pacific as compared with the European theater during World War II; a higher rate was found in the former.13
Southern Hemisphere Studies Two other major studies have come from Queensland and Western Australia.14*15 The results are in part different from those of the northern hemisphere studies, and these differences are likely to relate to the much higher sun exposure levels in these areas, at latitudes of 32”s in Perth and from 25 to 17”s in Queensland, allied to a culture that involves considerable intense sun exposure. The Western Australia study showed strong positive associations with measures of likely sun exposure, such as sunshine hours in the place of residence and biologic markers such as skin wrinkling.15 A substantial proportion of residents of Western Australia have moved there from much less sunny environments, such as the United Kingdom. The migrant studies are very useful, indicating
that the risk of melanoma is much lower in subjects who arrive in Australia after the age of 15 years, whereas the risk in those who arrive at around age 5 is similar to the risk for native-born Australians (Fig 3).15 This suggests that exposure between ages 5 and 15 is particularly important. Such measures provide indications of a positive risk with total sun exposure, and the main association seen in the Queensland study was a strong positive association with total sun exposure from all sources.14 Other results, however, are consistent with a more complex etiology. Results in Western Australia for specific activities show stronger risks associated with activities that would involve moderate exposure, boating and fishing, compared with the more intense sun exposures of swimming and sunbathing16 (Table 2). Measures constructed to indicate likely high-exposure activities, such as the proportion of all outdoor exposure spent on recreational activities in Western Australia16 and the amount of time spent on the beach while a teenager in Queensland,14*17 do not show strong associations (Table 2). In Western Australia
Figure 3. Risk of superficial spreading melanoma (SSM) for Western Australia residents by age at arrival in Australia, controlled for ethnicity. Data from Holman and Armstrong.‘5
Figure 2. Summary of the results of the Western Canada Melanoma Study, showing the relative risk of melanoma in relationship to occupational, vacation, and recreational sun
2.0
exposures. ---, recreation; **a, vacation; -, occupation; II, significantly greater than 1.0. Data from Elwood et al.‘O
1.8
1.6Y
1.4-
.2
1.2-
.-%J l.O;ij a 0.8-
0.8
K
-- recreahon ---vocation - occupahon
t-
0
I
0
I
I
10 20
I
50
slgnlflcanUygrealer than I
100 200
10
I
I
500
mid-range exposure, whale body equivalent hours
0.6-
Clinics in Dermatology
ELWOOD MELANOMA AND UV RADIATION
1992;20:41-50 Table 4. Measured Sun Exposures in Northern Europeans Annual Number of MEDs*
Annual Irradiation (I/cm’ at 300 nm)
270 90
6.6 2.2
100
2.5
Outdoor worker Indoor worker (including weekend exposure) 2-wk Mediterranean holiday with sunbathing
Reprinted, with permission, from Diffey.‘B
* MED. minimal eythemnl dosage.
also, the maximum levels of occupational exposure in men were associated with a decrease in melanoma risk,16 although a similar result was not seen in Queensland” (Table 3). In general, UVR intensity is about two to three times higher in these southerly areas as in the northern areas at which the former studies were done. The distinction between intermittent and occupational exposure is likely to be much less clear. Individual dosimetry measurements using UVR-sensitive badges has shown that in northern Europe, an individual who regularly works indoors can readily double his or her total annual UVR dose by taking a 2-week holiday in the Mediterranean area and spending considerable time outdoors’* (Table 4). Such a clear distinction is less likely in the Australian culture. The Australian results also show some evidence of site specificity; for example, women who wore a two-piece bathing suit or bathed nude had an extremely high risk of superficial spreading melanoma of the trunk, compared with those who usually wore a one-piece trunk-covering bathing suit.16
Dose-Risk Relationships A large number of other studies are now available, but the results in general are consistent with those just exemplified. The general conclusion is that melanoma (SSM and NM) is clearly related to UVR exposure, with a complex dose-response relationship. In the northern hemisphere studies the intermittent exposure hypothesis is supported, and the major increase in melanoma risk is related to intermittent exposure, which can be defined as unusually intense exposure of skin that has not been extensively tanned or thickened to provide a protective shield. In outdoor exposure, contrast, regular long-continued achieved by occupation, produces a lower melanoma risk, presumably because the tanning and skin thickening involved provide protection that overcomes any initial damage done by early exposures. In the Australian studies some of the data on activities and occupation support that model, but the distinction
45
between intermittent and chronic exposure is less clear. Recreational activities may well produce levels of sun exposure that would be reached by regular outdoor occupation only at a higher northerly latitude. The Western Australia group has therefore proposed a complex dose response relationship (Fig 4) where risk rises initially with moderate levels of likely intermittent exposure, then falls at the levels of sun exposure typical of regular occupation, but can then rise again if even higher levels of sun exposure are achieved, as could apply to Australian residents who spend a great deal of time in beach-type activities.6 According to an alternative model, suggested by some of the Canadian data, regular and intermittent exposures have intrinsically different actions, and therefore the risk is predicted well by any addition of these two exposures, but has to be looked at as a function of each exposure independently. Thus in the Western Canada data, subjects with high levels of occupational exposure still show a substantial increased risk in association with added intermittent exposure, although in dose terms this is only a small increment.
Other Types of Melanoma The preceding results are based on analyses either of SSM and NM specifically or of all cutaneous melanomas, usually excluding acral lentiginous melanoma (ALM). As noted earlier, the general features of LMM are more suggestive of an association with chronic sun exposure, and this is suggested although not clearly demonstrated by comparative analyses. l9 Most of the available studies Figure 4. Speculative representation of exposure-response relationships between sun exposure and malignant melanoma. Reprinted, with permission, from Armstrong8
FREOVENCY
OF EXPOSURE
TO SVNLIOHT
46
ELWOOD
Clinics in Dermatology
2992;10:41-50 contain relatively few cases of LMM, and there is a major problem in that the classification of a tumor as LMM may be influenced by the body site or the finding of evidence of chronic solar damage in surrounding skin, making the independent assessment of its etiology impossible. ALM is too uncommon in light-skinned populations to have been studied specifically. It constitutes a large proportion of melanomas in Japan, and the incidence of melanoma in Japan is reported to have risen rapidly; however, no major etiologic studies either of ALM or of melanoma in populations of other than European origin have yet been doneezO Several studies of ocular melanoma are available, and this is much more common in subjects with blue rather than darker eyes. Some studies suggest a higher risk in those with likely higher levels of sun exposure, for example, those who live in southerly rather than northerly parts of the United States.21
Relationship to Host Factors All these studies show strong associations of the common types of melanoma with host factor characteristics, which are dealt with in the article by Sober et al in this issue. These host features are divided into two groups. There are those genetically controlled features that influence an individual’s susceptibility to the sun. These include racial background; skin pigmentation, which, in turn, is related to hair and eye pigmentation; and tendency to burn or to produce a suntan, which is clinically characterized as skin type. The available studies are generally consistent with respect to these features, and higher susceptibility to the acute effects of sun exposure in producing erythema and sunburn is strongly associated with a higher risk of melanoma. This is supported by studies that have shown lower minimal erythemal dosages and slower recovery from erythemal damage in melanoma subjects than in controls.22,23 The studies reviewed are all consistent with the concept that this inherent susceptibility and the effects of recorded sun exposure are generally independent, on the usual multiplicative scale. Thus for any of the aforementioned exposure situations, the risks will be higher in those who have ethnic and pigmentary characteristics associated with greater susceptibility. The other set of host factors, which are very strong and useful clinically as risk indicators, includes the number of acquired nevi. Several studies now suggest that the number of nevi is at least in part a response to sun exposure. In particular, recent studies of nevus prevalence in young children in different areas of Australia have shown that higher prevalences in the more northerly areas are apparent between ages 5 and 10. 24 Acquired nevi may be a risk marker of melanoma by acting as an early biologic indi-
cator of sun exposure, and there is some evidence that they may indicate an intermittent type of exposure, in that some studies have shown the maximum prevalence of nevi in individuals with moderate levels of exposure, the prevalence being reduced in those with high exposures.9 Another characteristic shown to be strongly associated with melanoma in the aforementioned studies, and also useful as a clinical indicator of risk, is the frequency of previous sunburn. Its etiologic role is, however, uncertain. In two of the major studies, the Western Canada and Western Australian studies, the association with a history of sunburn largely disappeared when adjusted for susceptibility to sunburn, suggesting that the association represents the increased risk of those with high susceptibility rather than a direct effect of the presence of sunbum.16,25 In the Queensland and Danish studies, and in some others, however, the association persisted after such contro1.11,26,27Attempts have been made to relate sunburn on particular body sites to melanoma on those same sites, but it is difficult to achieve such specificity in the recorded information and the results have as yet not been conclusive.” The question of the time of maximum susceptibility is best answered by the migrant data that have been referred to, which strongly indicate that adolescence and early adult life are particularly important. This is supported by some of the studies on sun exposure and sunburn, which indicate that sunburn in early life is a stronger indicator of later melanoma than subsequent sunburn. The migrant data therefore suggest an early life effect on subsequent melanoma risk, with a long latent period. It is likely, however, that there are also short-term effects. This is supported by the considerable evidence that UVR acts as a promoter and an immunosuppressant, which would suggest late shorter-term effects.2 It is directly supported by evidence from Australia which shows higher levels of mitotic activity in nevi excised in the summer months.28 There is also support from studies of seasonal variation in the diagnosis of melanoma, and from studies showing short-term increases after particularly sunny years, but these types of studies are very difficult to interpret, first because of recognition bias and second because of multiple testing. The remaining major risk factors are the presence of dysplastic nevi and a family history of melanoma, which together confer an extremely high risk. These studies are discussed in the article by Bergman and Fusaro in this issue. The evidence of a clearly genetically-linked dysplastic nevus -melanoma syndrome shows that the tendency to dysplastic nevi is constitutionally inherited, but there is also evidence that the number of dysplastic nevi is increased by ultraviolet exposure.
Clinics in Dermatology 1992;20:42-50 It is possible that the majority of melanomas develop in a sequence from a normal melanocyte to a nevus cell as part of an acquired nevus, then transform to a dysplastic nevus cell and then to a melanoma.‘J9 Each of these stages is likely to represent a specific genetic event within the cell. Subjects who inherit the dysplastic nevusmelanoma susceptibility trait will have already have one or more of these changes and may already have dysplastic nevus cells. The mechanisms by which UVR may influence the development of melanoma remain to be clarified. One important observation is that in different geographic areas with very different total incidence rates of melanoma, the distribution of melanoma by body site does not vary greatly, and this led to the suggestion in 1970 that UVR might act by a systemic mechanism, through a “solar circulating factor.” Recent experimental evidence has shown that UVR results in melanocyte proliferation in shielded as well as exposed areas of skin in human volunteers, giving support to this concept.30,31
Ozone Depletion There is evidence that stratospheric ozone depletion has led to increases in ground-level UVR in both the southern and northern hemispheres, and that these effects are likely to increase. The effects of ozone depletion on melanoma incidence and mortality have been estimated primarily by looking at geographic variation, usually within North America, in relation to the difference in UVR levels between different geographic locations. The estimates vary with whether linear, exponential, or power models of the relationship between risk and exposure are used, whether incidence or mortality data are used, and whether differences in annual UVR levels or in peak UVR levels are used. Typical estimates are that a 1% depletion of ozone is predicted to result in an increase of 1 to 2% in the incidence and 0.8 to 1.5% in the mortality from melanoma.32*33 Although such effects are important, the increases predicted from the most reasonable estimates of ozone depletion in the next few decades are therefore still small compared with the increases of from 4 to 7% per year in melanoma mortality and incidence rates that have been observed in many countries over recent decades, before an effect of ozone depletion would have occurred.
Artificial Sources of Ultraviolet Radiation All the epidemiologic and clinical evidence, although expressed in the preceding as UVR, in fact refers to solar exposure, and the studies cannot separate effects of different components of this exposure. Although UVR can be used as a tumor promoter after exposure to a chemical
ELWOOD
47
MELANOMA AND LJV RADIATION
carcinogen in animal experimentation, models in which UVR induces melanoma when used alone have only very recently been developed,34,35 and no substantive studies on the effects of different components or dose rates on melanoma have been published. Thus it is largely speculation whether different components of UVR, as can be delivered by artificial UVR sources, have any effects different from those of natural sunlight. Sunlamps and sunbeds are designed to produce a suntan, and do this by using very large dosages of ultraviolet A (UVA). A suntan could be produced by a much lower dose of ultraviolet B (UVB), but this would run the greater risk of producing erythema and sunburn; however, as we do not know the precise action spectrum for the production of melanoma in humans, there are no grounds to claim that a UVA source will have any lower carcinogenic effect than a dose of UVB radiation sufficient to produce the same tanning effect. Several studies have reported on the use of sunbeds and sunlamps in relationship to melanoma (Table 5) and empirically show increased risks. In these studies, however, detailed assessments of sun exposure were not used. If users of sunbeds have greater solar exposure than others, which seems quite likely, these results may be due to the solar exposure; however, these results do provide evidence against the concept that the use of sunbeds and suntans should lower melanoma risk by producing a suntan before natural sun exposure or by maintaining a suntan throughout the year; if that were so, we would expect a null or even a protective effect in these analyses. It is true that in many experimental situations, including the two most recent models,34*35 the carcinogenic effects of UVB radiation are reduced by the use of UVA or even visible light, which can stimulate DNA photorepair mechanisms; however, these same photorepair mechanisms may not act in humans, and the experimental evidence shows that for this effect to work, UVA or visible light has to be given after the UVB exposure. With that logic, pretanning with artificial sources would not be protective, although UVA exposure after exposure to natural sunlight might be helpful. Another potential source of UVR that is quite common is fluorescent lighting. Fluorescent tubes emit some UVR at relatively low wavelengths, and it has been shown that at a particular narrow UVB wavelength band around 305 nm, the dose of UVR that would be received from an unshielded fluorescent tube during a regular working day could exceed that achieved by a reasonable amount of outdoor exposure. That would provide a biologic rationale for an association with fluorescent light exposure if there were also evidence that that particular wavelength was important in melanoma production; such evidence does not exist. Moreover, most fluorescent lights are
48
Clinics in Dermatology
ELWOOD
2992;10:42-50 Table 5. Studies of Melanoma
Risk Associated
with Artificial UV Exposures
First Author, Reference
Year
Place
Swerdlow et aP
1988
Scotland
Both
2.9 (1.3, 6.4) 9.1 (2.0, 40.6)
Ma&e
1989
Scotland
1990
Ontario
Men Women Men Women Men Women
2.6 1.5 1.9 1.5 2.1 3.0
et al*r
Walter et aP
Sex
Relative Risk (95% Limits)
(0.9, (0.8, (1.2, (1.0, (0.9, (1.1,
7.3) 2.9) 3.0) 2.1) 5.3) 9.6)
Measurement
of Exposure*
a Ever used UV lamps or sunbeds Used more than 5 y before diagnosis b Sunbed used for 3 months or longer c Ever used LJV lamps or sunbeds c Use of UV longer
sourcesfor 1 year or
* (a) Crude results; adjustment for nevi, hair, and eye color; exposure to sun made little difference. (b) Crude results; adjustment for total nevi, atypical nevi, freckling, sunburn, tropical residence, skintype reduced risk to 1.3 (men) and 1.2 (women). (c) crude results.
shielded by diffusers of plastic or glass material, and these in general are effective blockers of UVB. The original studies suggesting an association with fluorescent light show that the excess tumors were distributed over the body, not particularly in the sites likely to be exposed, and further studies have not in general supported the relationship.36 There are many occupational sources of UVR, and these have been little investigated. Studies in England have suggested increased risks with certain sources including plan copiers, which use an ultraviolet source to produce blueprints. 37 Among the most intense occupational exposures are those in medical areas with respect to phototherapy, and such exposures can be monitored in a method analogous to x-ray exposure; appropriate safety limits have been set. In this regard patients who receive phototherapy are obviously of special interest, and studies are available that show excesses of nonmelanoma skin cancer in patients treated for psoriasis by a method using UVA and psoralens (PUVA). No increase in melanoma has been shown.38,39 From the risk models discussed earlier, it could be expected that the dosages received would be too great to produce an increase in melanoma.
Conclusions It is reasonable to conclude that the great majority of melanomas in light-skinned people are due to UVR, and that at least at moderate total levels of exposure, intermittent relatively intense exposure of unacclimated skin is the major risk factor for the more common types of melanoma (SSM and NM). On this basis, melanoma should be preventable by a reduction in sun exposure and by a specific effort to avoid such intermittent intense exposure patterns. This would best be achieved by avoidance techniques, ranging from individual actions about the wear-
ing of shirts and hats on sunny days to community actions such as the provision of shade in the form of trees or artificial shelters at public areas and beaches and, in sunny regions, the alteration of school hours to avoid outdoor exposure of children during the most intense periods of the day. All these activities are being strongly promoted in some areas, particularly in Australia.40 The reduction of UVR received by the use of UVR blockers is also likely to be effective unless it is merely compensated by an increase in solar exposure time, which may result in receipt of the same dose or receipt of a greater dose if the ultraviolet blocker is applied inconsistently or has a limited effect. Public education campaigns aimed at primary prevention are now a familiar concept in most high-risk and even moderate-risk areas. It will be difficult to assess their impact, as it may take several years or decades for the impact to be seen, and it is difficult to imagine a rigorous study design evaluating these effects in the primary prevention of melanoma. An important and unresolved question is whether the amount of reduction in sun exposure achievable by such campaigns is likely to be enough to make a major difference in melanoma incidence. More limited evaluation studies looking at the extent to which such programs produce behavioral changes or assessing their effect on likely markers of sun exposure would still be useful. For example, it has been suggested that trials of sun reduction campaigns in children could use the prevalence of benign nevi as a short-term endpoint (D. English, personal communication). In urban, largely indoor communities a major stimulus for sun exposure is the fashionable aspects of a suntan, and although there is evidence of a move away from this behavsocial change ior, it may require a considerable particularly affecting the attitudes and body image of adolescents to produce a major effect. A satisfactory tanned appearance can be achieved by cosmetics that dye
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ELWOOD MELANOMA AND UV RADIATION
epithelial cells; if free from hazards, such methods could be encouraged. We can, however, inform individuals that their melanoma risk will be reduced if they reduce their sun exposure, particularly intermittent relatively intense exposure. There is no evidence to recommend the use of artificial ultraviolet tanning sources, and it is likely that the hazards associated with such exposures are similar to the hazards of an equivalent amount of natural sunlight. These warnings can be reinforced for those with a greater genetic susceptibility to the ill effects of the sun, ranging from the extreme situation of a family history of melanoma and dysplastic nevi to the general characteristics of light or red hair color and a skin type that burns easily and does not tan easily.
References 1. Lee JAH. Melanoma and exposure to sunlight. Epidemiol Rev 1982;4:110-36. 2. Elwood JM. Initiation and promotion actions of ultraviolet radiation on malignant melanoma. In: Borzsonyi M, Day NE, Lapis K, Yamasaki H, editors. Models, mechanisms and etiology of tumor promotion. 1ARC Scientific Publication No. 56. Lyon: MRC-OUP, 1984;421-525. Research Council. Causes and effects of strutospheric ozone reduction: An update. Washington, DC: Na-
3. National
tional Academy of Sciences, 1982.
49
12. Paffenbarger RS Jr, Wing AL, Hyde RT. Characteristics in youth predictive of adult-onset malignant lymphomas, melanomas, and leukemias. J Nat1 Cancer Inst 1978;60: 89-92. 13. Brown J, Kopf AW, Rigel DS, Friedman RJ. Malignant melanoma in World War II veterans. Int J Dermatol 1984;23:661-3. 14. Green AC. Sun exposure and the risk of melanoma. Australas J Dermatol 1984;25:99-102. 15. Holman CDJ, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: An analysis separating histogenetic types. J Nat1 Cancer Inst 1984;73:75-82. 16. Holman CDJ, Armstrong BK, Heenan PJ. Relationship of cutaneous malignant melanoma to individual sunlight-exposure habits. J Nat1 Cancer Inst 1986;76:403-14. 17. Green AC, Bain C, McLennan R, Siskind V. Risk factors for cutaneous melanoma in Queensland. In: Gallagher RP, editor. Epidemiology of malignant melanoma: Recent results in cancer research. Heidelberg: Springer-Verlag, 1986:76-97. 18. Diffey BL. Analysis of the risk of skin cancer from sunlight and solaria in subjects living in northern Europe. Photodermatology 1987;4:118-26. 19. Elwood JM, Gallagher RI’, Worth AJ, et al. Etiological differences between subtypes of cutaneous malignant melanoma: Western Canada Melanoma Study. J Nat1 Cancer Inst 1987;78:37-44.
Environ Car-
20. Elwood JM. Epidemiology and control of melanoma in white populations and in Japan. J Invest Dermatol 1989;92:214S-2218.
5. Elwood JM, Gallagher RI’. Site distribution of malignant melanoma. Can Med Assoc J 1983;128:1400-4.
2 1. Tucker MA, Shields JA, Hartge P, et al. Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med 1985;313:789-92.
4. Urbach F. Cutaneous photocarcinogenesis. cinogen Rev 1987;C5:211-34.
6. Elwood JM, Hislop TG. Solar radiation in the etiology of cutaneous malignant melanoma in Caucasians. Nat1 Cancer Inst Monogr 1982;62:167-71. 7. Holman CDJ, Armstrong BK, Heenan PJ. A theory of the etiology and pathogenesis of human cutaneous malignant melanoma. J Nat1 Cancer Inst 1983;71:651-6. 8. Armstrong BK. Epidemiology of malignant melanoma: Intermittent or total accumulated exposure to the sun? J Dermatol Surg Oncol 1988;14:835-49. 9. Armstrong BK, de Klerk NH, Holman CDJ. Etiology of common acquired melanocytic nevi: Constitutional variables, sun exposure, and diet. J Nat1 Cancer Inst 1986;77:329-35. 10. Elwood JM, Gallagher RP, Hill GB, Pearson JCG. Cutaneous melanoma in relation to intermittent and constant sun exposure: The Western Canada Melanoma Study. Int J Cancer 1985;35:427-43. 11. Osterlind A, Tucker MA, Stone BJ, Jensen OM. The Danish case-control study of cutaneous malignant melanoma. II. Importance of UV-light exposure. Int J Cancer 1988;42:319-24.
22. Beitner H, Ringborg U, Wennersten G, Lagerlof B. Further evidence for increased light sensitivity in patients with malignant melanoma. Br J Dermatol 1981;104:289-94. 23. Azizi E, Wax Y, Lusky A, et al. The recovery from ultraviolet radiation-induced erythema and melanoma risk factors: A case-control study. J Am Acad Dermatol 1990; 23:30-6. 24. McLennan R. Anatomic distribution of melanocytic nevi in Australian school children. Second International Symposium on Epidemiology of malignant melanoma, 199 1. Abstract. 25. Elwood JM, Gallagher RI’, Davison J, Hill GB. Sunburn, suntan and the risk of cutaneous malignant melanoma: The Western Canada Melanoma Study. Br J Cancer 1985; 51:543-9. 26. Green AC, Siskind V, Bain C, Alexander J, Sunburn and malignant melanoma. Br J Cancer 1985;51:393-7. 27. MacKie RM, Aitchison T. Severe sunburn and subsequent risk of primary cutaneous malignant melanoma in Scotland. Br J Cancer 1982;40:955-60.
50
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Clinics in Dermatology 1992;20:41-50
28. Holman CDJ, Heenan PJ, Caruso V, et al. Seasonal variation in the junctional component of pigmented naevi. Int J Cancer 1983;31:213-5. 29. Elder DE. Human melanocytic neoplasms and their etiologic relationship with sunlight. J Invest Dermatol 1989;92:297S_303S. 30. Lee JAH, Merrill JM. Sunlight and the aetiology of malignant melanoma: A synthesis. Med J Aust 1970;2: 846-51. 31. Stierner U, Rosdahl I, Augustsson A, Kagedal B. UVB irradiation induces melanocyte increase in both exposed and shielded human skin. J Invest Dermatol 1989;92:561-4.
36. Elwood JM. Could melanoma be caused by fluorescent light? A review of relevant epidemiology. In: Gallagher RP, editor. Epidemiology ofmalignant melanoma. Recent results in cancer research. Heidelberg: Springer-Verlag, 1986:12736. 37. Elwood JM, Williamson C, Stapleton PJ. Malignant melanoma in relation to moles, pigmentation, and exposure to fluorescent and other lighting sources. Br J Cancer 1986;53:65 - 74. 38. Stern RK, Lange R. Cardiovascular disease, cancer, and cause of death in patients with psoriasis: 10 years prospective experience in a cohort of 1,380 patients. J Invest Dermatol 1988;91:197-201.
32. Longstreth J. Cutaneous malignant melanoma andultraviolet radiation: A review. Cancer Metastasis Rev 1988;7:32133.
39. Lindelof B, Sigurgeirsson B, Tegner E, et al. PUVA and cancer: A large-scale epidemiological study. Lancet 1991;338:91-3.
33. Elwood JM. The epidemiology of melanoma: Its relationship to ultraviolet radiation and ozone depletion. In: Russell-Jones R, Wigley T, editors. Ozone depletion: Health and environmental consequences. London: Wiley, 1989: 169-89.
40. Marks R, McCarthy WH. Skin cancer: Increasing incidence and public awareness. Med J Aust 1990;153:505-6. 41. Swerdlow AJ, English JSC, Ma&e RM, et al. Fluorescent lights, ultraviolet lamps, and risk of cutaneous melanoma. Br Med J 1988;297:647-50.
34. Ley RD, Applegate LA, Padilla RS, Stuart TD. Ultraviolet radiation-induced malignant melanoma in Monodelphis domestica. Photochem Photobiol 1989;50:1-5.
42. MacKie RM, Freudenberger T, Aitchison TC. Personal riskfactor chart for cutaneous melanoma. Lancet 1989;2:48790.
35. Setlow RB, Woodhead AD, Grist E. Animal model for ultraviolet radiation-induced melanoma: Platyfish-swordtail hybrid. Proc Nat1 Acad Sci USA 1989;86:8922-6.
43. Walter SD, Marrett LD, From L, et al. The association of cutaneous malignant melanoma with the use of sunbeds and sunlamps. Am J Epidemiol 1990;131:232-43.
