Senior Research Fellow, Skin Cancer Research Group, School of Public Health and Tropical Medicine, James Cook University, Townsville Qld 4811, Australia. Ph: (07) 47225775 Fax: (07) 47225788 Simone.Harrison@jcu.edu.au
Epidemiological studies suggest that sun exposure is a common etiologic factor for both melanocytic nevi (benign tumors of the pigment producing cells in the skin; better known as moles) and melanoma (Armstrong and English 1992).
The role of sunlight in the pathogenesis of melanoma was first proposed by McGovern (1952). Since then, more than 30 case-control studies have examined the role of sun exposure in the development of melanoma (Elwood and Gallagher 1994) resulting in substantial evidence implicating sunlight as the principal environmental cause of melanoma in white-skinned populations (IARC 1992). However, the dose response relationship appears to be quite complex (Fitzpatrick 1989).
Interest in melanocytic nevi stems from their clinical, histological and epidemiological association with malignant melanoma. Numerous case-control studies have shown that the number of melanocytic nevi is the strongest phenotypic risk factor for melanoma (Armstrong and English 1992). Similar to melanoma, melanocytic nevi appear to have a complex relationship with sun exposure, and are also associated with phenotypic markers of sun-sensitivity (Armstrong and English 1988).
The ultraviolet wavelengths of the electromagnetic spectrum appear to be the most relevant to the pathogenesis of melanoma (Diffey and Elwood 1994). UVA (315-400 nm), UVB (280-315 nm) and UVC (100-280 nm) radiation are all considered to be potentially carcinogenic to humans (IARC 1992), and their ability to induce skin damage is thought to be inversely related to wavelength (Marrett 1994). The known adverse effects of UVA and UVB include erythema, skin thickening, photoaging, photosensitivity reactions, melanocyte proliferation, DNA damage, inhibition of DNA repair, immunosuppression and carcinogenesis (Marrett 1994). However, the strength of these effects and the level of penetration into the skin varies between these two wavebands (Marrett 1994). As the UVC component of sunlight does not reach the earth’s surface, only non-solar sources such as arc welding equipment present a problem (Marrett 1994).
As the etiology of melanocytic nevi has been under investigation for a shorter period of time than melanoma, numerous questions remain to be answered (Armstrong and English 1988). However, there are many epidemiologic observations linking solar UVR to the development of acquired melanocytic nevi.
The geographic variation in melanoma incidence and mortality among predominantly Caucasian populations tends to parallel the intensity of solar ultraviolet radiation with relatively few exceptions (Elwood and Gallagher 1994). Within the relatively homogenous populations of Australia and New Zealand in the southern hemisphere, a south-north latitude gradient in melanoma incidence and mortality has been observed (Lancaster 1954, Lancaster 1956; McGovern and MacKie 1959; Holman et al 1980; Lee 1982; Jelfs et al 1994). In the northern hemisphere (Wales, England, Canada, the United States of America and the Nordic countries) a north-south gradient is evident (Elwood et al 1974; Magnus 1977; Crombie 1979; Lee 1982; MacKie et al 1987; Scotto and Fears 1987; Jensen et al 1988a; Magnus 1991). However, the association between melanoma and increasing proximity to the equator does not hold for southern Europe (Crombie 1979; Jensen et al 1988a; Jensen et al 1988b), probably because of the deeper pigmentation of people of Italian, Greek and Spanish descent (Khlat et al 1992; Elwood and Gallagher 1994).
There have also been reports of an elevated risk of melanoma in people in the Northern hemisphere if they have lived for some time at southerly latitudes (Graham et al 1985; Weinstock et al 1989; MacKie et al 1989). In a case-control study in Scotland, MacKie et al (1989) found that 19 cases, but only four controls, had spent five or more years living in a tropical or sub-tropical climate. Tropical residence of five years or longer was significantly associated with melanoma risk in males (crude RR 2.6 [95% CI: 1.3-5.4]) with a non-significant association in females (crude RR 1.8 [95% CI: 0.8-4.0]), but was not independent of constitution, nevi and history of sun exposure for either sex. Similarly, in a nested case-control study within the Nurses’ Health Study cohort, a more equatorial latitude of residence (i.e.< 35ºN) between the ages of 15 and 20 was positively associated with melanoma risk in these women (Weinstock et al 1989). After controlling for age and sun-sensitivity, each 12.6 degrees of latitude was associated with a relative risk of 2.2 [95% CI: 1.1-4.2]). Latitude of residence after 30 years of age was not an independent predictor of melanoma incidence. Thus, sun exposure before the age of 20 years is more closely related to melanoma risk than later sun exposure (Weinstock et al 1989). Coastal residence has also been associated with increased risks of melanoma in some studies (Green and Siskind 1983; Green 1984; Østerlind et al 1988).
Studies of prevalent melanocytic nevi, particularly those conducted in similar age groups, show a general tendency for nevus frequency to be highest in white populations living closest to the equator (Harrison et al 1999). However, temporal and methodological differences may cloud the results of such broad comparisons. Therefore, only population-based studies of prevalent nevi which have used identical methods in subjects of the same age with similar ancestral origins, from contrasting UVR environments should be compared for valid interpretations. At least 4 such comparative studies have been published, and all have provided some support for an association between nevi and ambient solar UVB, as indicated by latitude of residence (Green et al 1988; Kelly et al 1994; Fritschi et al 1994, Harrison et al 2000).
The earliest published comparison of nevus frequency in children with similar ancestral origins from different UVR environments is that of 181 white 8 to 9 year old children from Kidderminster (52.3ºN) in the United Kingdom (Sorahan et al 1990), and 211 white children from Brisbane (27.3ºS), Australia, most of whom were 8 to 10 years old with a range of 7 to 11 years (Green et al 1989). Large differences in mean and median nevus counts were found between the studies, with a mean of 4.3 (median 2) and 28 (median 19) nevi ³ 2 mm in diameter reported for the British and Australian samples, respectively. Likewise, British children had fewer raised nevi (mean 0.4; median 0) than their Australian counterparts (mean 11; median 8). Both studies (Green et al 1989; Sorahan et al 1990) used the same clinical criteria to define a countable nevus, examined the same body sites, and assessed phenotypic characteristics and sun exposure using a similar questionnaire. However, they differed with respect to observers (Kidderminster, two research nurses; Brisbane, three senior medical students); response rates (Kidderminster 54%; Brisbane 75%); and the sex distribution of subjects (males:females, Kidderminster 1:0.79; Brisbane 1:1.27).
In 1990, three highly trained examiners (one dermatologist, and two dermatology residents) used the same protocol to examine approximately 350 to 400 school children aged 6, 9, 12 and 15 years of age, in each of three different Australian cities (Melbourne 37.49ºS, Sydney 33.55ºS, Townsville 19.16ºS; Kelly et al 1994). The only factors which varied between the three locations were those which were beyond the control of the investigators; namely, response by age (response rates decreased with age) and city (response rates in 9 to 15 year olds decreased with increasing latitude). Nevus frequency increased with proximity to the equator, particularly in the younger age groups (Kelly et al 1994). The relationship to latitude of residence was independent of age, sex and constitution, and adjusted geometric mean nevus counts were 50% [95% CI: 1.3-1.8] and 30% [95% CI: 1.2-1.5] higher for children from Townsville and Sydney (respectively), compared with children from Melbourne. However, despite the significance of the relationship overall, and separately for children up to 12 years of age, the difference in nevus counts between 15 years olds from Townsville, Sydney and Melbourne was negligible. There are two contrasting, yet equally plausible explanations for this. The first explanation, as suggested by the authors, is that this result is due to self-selection on the basis of “moliness” in 15 year olds, particularly in Melbourne, where only about a quarter of the selected sample agreed to participate (Kelly et al 1994). The second possibility is that peak nevus density is achieved more rapidly in intense UVB environments. It might be that achieving peak densities of nevi at an earlier age increases the risk of developing melanoma later on, thereby explaining the latitude gradient seen for melanoma in Australian adults.
The comparative study of nevus frequency published by Fritschi and co-workers (1994) used identical nevus counting protocols, but different examiners at each location to compare the frequency of nevi ³ 2 mm on the right arm of 13 to 15 year olds from the contrasting environments of Brisbane, Australia (27.3ºS) and Glasgow, Scotland (55.53ºN) (Fritschi et al 1994). Unlike the earlier comparison by Green et al (1988), Fritschi and co-workers (1994) controlled for differences in constitution and sex ratios, and found that nevus counts were still significantly higher in adolescents from Brisbane than Glasgow (Glasgow versus Brisbane residence: regression coefficient - 6.66, p<0.001). Fritschi et al (1994) also found that the sex differences in nevus counts paralleled the sex differences in melanoma in these populations.
The most recent comparative study of this type assessed the development of melanocytic nevi longitudinally in 2 cohorts of children of similar ethnicity from contrasting climates (Harrison et al 2000). One hundred and fifteen Caucasian neonates from Townsville, Australia (19.16ºS) and 157 Caucasian neonates from Glasgow, Scotland (55.53ºN) were recruited at birth and regularly examined for melanocytic nevi until age 3. The proportion of Australian children with melanocytic nevi increased rapidly in the first 2 years of life from 2.3% at birth to 10.8% at 6 months, 65.2% at 12 months, 92% at 18 months and 100% at 24 months. Corresponding proportions for the Scottish cohort were similar at birth, but considerably less at 12, 24 and 36 months when 30.5%, 61.7% and 83.6% of children presented with melanocytic nevi (p<0.001, respectively). The median rate of acquisition of new nevi in Australian children was 1 [IQR 0, 2] in the first year, 5 [IQR 3, 8] in the second year and 6 [IQR 4, 10] in the third year of life compared to 0 [IQR 0, 1], 0 [IQR 0, 2] and 2 [IQR 0, 4], respectively for the Scottish children. These results provide further evidence for the association between melanocytic nevus development and sun exposure, and also suggest that the early onset of nevus development may be a risk factor for melanoma (MacKie et al 1985; Harrison et al 2000).
Epidemiological studies of migrants have played a key role in helping to identify and separate the environmental and genetic factors relevant to the etiology of melanoma (Kaldor et al 1990). Studies of migrants who have moved from temperate to sunny climates including Australia, New Zealand, Israel and California (Movshovitz and Modan 1973; Anaise et al 1978; Holman and Armstrong 1984; Cooke and Fraser 1985; McCredie et al 1990a; McCredie et al 1990b; Mack and Floderus 1991; Khlat et al 1992; Tyczynski et al 1994) have been instrumental in demonstrating the importance of sun exposure to melanoma development in later life and some have confirmed the suspicion that childhood exposure is particularly important (Holman and Armstrong 1984; Cooke and Fraser 1985; Khlat et al 1992). One exception is the study by Hinds and Kolonel (1980), which showed that age-adjusted rates were higher in Caucasians born outside Hawaii than Caucasians born in Hawaii.
The most commonly cited migrant study is that by Holman and Armstrong (1984), who demonstrated that the risk of melanoma increased with duration of residence in Australia for all types of melanoma, and also separately for Hutchinson’s melanotic freckle, superficial spreading melanoma (SSM), nodular melanoma and unclassifiable melanoma. However, after adjusting for age at arrival in the multivariate model for all melanomas, there was no residual effect for duration of residence in Australia. They showed that the risk of developing SSM approximated the native born-rate in migrants arriving before age 10 years with a reduced risk among those arriving between the ages of 10 and 14 years, and a further risk reduction to 25 percent of the native-born rate among those arriving between the ages of 15 and 19 years. There was no further reduction in risk for those arriving after 19 years of age. Likewise, the analysis of all histogenic types combined showed that arrival in Australia after 10 years of age was protective. Similarly, Cooke and Fraser (1985) found that early age of migration to New Zealand from the British Isles was associated with a mortality rate similar to that of New Zealand-born non-Maoris, and Khlat et al (1992) demonstrated that the risk of dying from melanoma was related to age at arrival and duration of residence in Australia.
Migrant studies have also shown that sun exposure in early life may be a factor in nevus development. Holman and Armstrong (1984) studied the number of palpable melanocytic nevi on the forearms of control subjects of predominantly Celtic or English ethnic origin and found a significantly higher frequency of nevi among those who arrived in Australia before 10 years of age, than those arriving at or after the age of 10. In a later analysis (Armstrong et al 1986), the same investigators found that after adjusting for age and sex, older age at arrival in Australia was not significantly related to the presence/absence of palpable nevi on the forearms, although the direction of the trend was the same as in their previous analysis (Holman and Armstrong 1984). The lack of significance in the later study may have been due to a substantial reduction in statistical power when they collapsed their nevus frequencies into a dichotomous variable. In subsequent analyses they controlled for birthplace outside Australia rather than age at arrival, and concluded that “the protective effect of birthplace outside Australia was due to the corresponding low mean annual hours of bright sunlight at places of residence between the ages of 10 and 24 years”. However, as the study was based on the number of nevi present in adulthood, the results may have been influenced by the maturation and elimination of nevi, which might occur at different rates in people with different exposure histories (Armstrong et al 1986).
Around the same time, Cooke and Fraser (1985) found that British immigrants to New Zealand had fewer nevi than the locally-born Caucasian population, even though they were just as likely to have experienced severe sunburn. The authors suggested that “the lower melanoma mortality, and the effect of age at migration, could be mediated by differences in mole frequency”.
These studies provide general support for the hypothesis that early childhood years are a critical time for the influence of ambient solar irradiation in the development nevi, and subsequent melanoma risk, particularly SSM.
There are two added advantages of studies conducted in children which may help to further elucidate the role of sun exposure in the etiology of melanocytic nevi. Firstly, the outcome measure is obtained when nevi are appearing rather than disappearing, and secondly, assessment of early sun exposure should be more accurate because it is more recent.
The body site distribution of melanoma has received considerable attention. Authors who plotted the regional distribution of melanoma on anatomical maps of the body (Pack et al 1952; Sober 1987) noted that sun protected sites such as the females breasts and lower abdomen, and the area that would be covered by “boxer shorts” in both sexes were virtually spared. Many early studies considered the proportion of melanomas occurring at particular sites and concluded that because melanoma developed most frequently on body surfaces which were only intermittently exposed to sunlight such as the trunk in males, and the legs in females, the anatomical distribution of melanoma was inconsistent with a causal role for sun exposure (Elwood and Hislop 1982; Armstrong and Holman 1987). As different body sites account for different proportions of the total surface area of the body (e.g. the trunk is 10 times larger than the face), some sites are more likely than others to have a higher incidence of melanoma based on their size alone (Pearl and Scott 1986). When Pearl and Scott (1986) included the relative surface proportions of the various parts of the body in their analysis of the anatomical distribution of melanoma using data from the USA (Hawaii separately), Sweden, Finland, England, Germany, Czechoslovakia, and Queensland, Australia, melanoma was found to be most dense on the skin of the face, ears and neck in all of these populations. The authors also noted that compared to non-melanocytic skin cancers, melanoma was more evenly distributed over the surface of the body, and suggested that its occurrence may be related to a pattern of intense recreational exposure with minimal protection from clothing (Pearl and Scott 1986). Observations of the age-specific incidence of melanoma by site in European populations show that the incidence of facial melanoma increases exponentially with age, consistent with “long-term exposure to the provoking factor”. In contrast, the site-specific incidence of melanoma of the trunk, lower limbs and upper arms is maximal in middle-age subjects, declining thereafter (Østerlind 1992), which is more compatible with an intermittent recreational pattern. These site specific dose-relationships are also influenced by the histological type of melanoma (Østerlind 1992).
In reporting the site-specific incidence of melanoma per unit surface area for melanoma in Queensland in 1987, Green and MacLennan (1994) found that the highest rates for pre-invasive melanoma (including lentigo maligna) were on the chronically exposed skin of the face in both sexes. When invasive melanoma was considered, the incidence was highest on the ears, shoulders, back, face and neck in males, and the face, shoulders, arms, back and forearms in women. All of these sites, except the back are habitually sun-exposed sites in Queensland because of the climate. The difference in the anatomical distribution of melanoma was generally consistent with different levels of sun exposure at these sites due to gender differences in clothing and hairstyles (e.g. higher rates for ears, neck, back and scalp of men; Sober et al 1987; Green and MacLennan 1994). Nevertheless, some anomalies, such as the low rates of melanoma on the dorsal surface of the hands could not be explained by a simple dose-response relationship with solar radiation. Green and MacLennan (1994) suggest that this may be due to a protective factor or differential-susceptibility according to site.
Some of the early studies of the body site distribution of melanocytic nevi noted that they occurred more frequently on sun exposed than sun protected surfaces (McGovern and MacKie 1959; Nicholls 1973). Nicholls (1973) found that the frequency of nevi on subjects from Sydney, aged 5 to 69 years, peaked on the sun exposed parts of the body first, and gender differences were consistent with the behavior of each sex in the sun. For instance, women are more likely to cover their torso than men, and correspondingly, the acquisition of nevi on the trunk occurred at a slower rate in women than in men (Nicholls 1973). Similar sex differences in nevus frequency have been reported more recently (Kelly et al 1989).
Some studies of nevi, like the studies of melanoma before them, assessed the proportion of nevi occurring at different sized body sites without taking surface area into consideration, and concluded that large sites such as the trunk and upper limbs had the most nevi (Stegmaier and Becker 1960; Cooke et al 1985; Sigg and Pelloni 1989; Colonna and Zina 1990), although some studies have noted that the number of nevi on the arms is in excess of what would be expected on the basis of area alone (Pack et al 1952). This finding was confirmed by Pearl and Scott (1986) who analysed Pack’s nevus frequencies as a function of surface area and found that nevi occurred 2.8 and 1.7 times more densely on the upper arms and forearms, respectively, than on the body as a whole. There was also considerable disparity between the proportion of nevi and melanomas occurring on the arms, with Pack et al (1952) reporting that 30.2% of all nevi, but only 10.9% of melanomas occurred at this site. This evidence provides some support for the hypothesis that the susceptibility of melanocytic nevi to malignant change in response to sunlight, may vary according to body site (Green 1992).
Some studies compared nevus counts for similar sized body sites with different opportunities for exposure to sunlight (Kopf et al 1978; Kopf et al 1986; Richard 1993; Augustsson 1991; Augustsson et al 1992). In 1978, Kopf and co-workers compared the prevalence of raised melanocytic nevi ³ 2 mm on the lateral and medial aspects of arms of 1000 subjects aged 2 to 87 years. The sample was predominantly Caucasian. Kopf and co-workers (1978) found that raised nevi were significantly more prevalent on the relatively sun exposed surface of the outer arms than on the relatively sun protected inner arms, and concluded that sunlight may promote nevus development. Later, in studies in Caucasians with the dysplastic nevus syndrome, they reported that benign nevi were also more common on the relatively sun exposed surfaces of the thorax (i.e. anterior and posterior thorax; Kopf et al 1985) and lumbosacral region (i.e. cephalad region; Kopf et al 1986) than on the relatively sun protected surfaces of the same sites (i.e. lateral thorax and caudad region, respectively).
Augustsson et al (1991) found that controls had median counts of nevi ³ 2 mm which were three times higher for the intermittently exposed surface of the back, than for the sun protected buttocks. She also noted that healthy 30 to 50 year old subjects from Sweden had more than three times as many nevi ³ 2 mm on the exposed lateral surface of the arms, as on the relatively sun protected medial aspect of the arms (Augustsson 1992). In a similar investigation in French 17 to 24 year old males, Richard et al (1993) found higher concentrations of nevi on the outer aspect of the upper limbs compared to the medial protected side, providing further evidence that exposure to solar UVR promotes the development of melanocytic nevi.
When comparing nevus densities by body site in 310 controls, Augustsson et al (1992) found that the highest concentrations of nevi ³ 2 mm occurred on the lateral aspects of the arms and the back, both of which are considered to be intermittently exposed to sunlight in Sweden. Similarly, MacKie et al (1985) reported that the highest densities of nevi ³ 3mm on Caucasian subjects of all ages from Scotland occurred on the arms of females, but gave no other site specific nevus densities for this group.
A comparison of chronically exposed surfaces (face and backs of hands), intermittently exposed surfaces (chest, back, outer arms, legs, dorsa of the feet) and rarely exposed surfaces (buttocks, inner arms, abdomen and genitals) in Swedish adults revealed that nevi were most concentrated on the intermittently exposed surfaces, followed by rarely exposed and chronically exposed sites (Augustsson et al 1992). In contrast, Richard and co-workers (1993) found that the mean density of nevi was higher in habitually exposed body sites (face, neck, backs of hands, lateral forearms) of young French men, than those that are never exposed (buttocks, inner upper arms, soles and palms). In addition, they included the size of nevi and the relative sun exposure of the body sites in their analyses and found that the density of small nevi (>2 and <5 mm) was maximal on habitually exposed body sites. Large (³ 5 mm) were most concentrated on the intermittently exposed surfaces (anterior and posterior trunk and legs, outer upper arms, medial aspect of forearms, and dorsum of the feet) and were positively associated with cumulative intense sun exposure at the beach in those who had fair skin, light hair and were unable to tan (Richard et al 1993). Differences in the results of these two studies may be explained by different cultural attitudes to, and opportunities for, exposure to sunlight in these two populations. Residents of the south of France presumably have greater opportunities for sun exposure than those living in Sweden, as evidenced by the allocation of different body sites (e.g. the outer forearms) to the always exposed and intermittently exposed categories in these two populations (Augustsson et al 1992; Richard et al 1993).
It is also worth reiterating at this point, that because these studies were conducted in adults, the frequency of nevi seen may be the net result of the appearance and disappearance of nevi in these age groups. Therefore, a better indication of the relationship between nevi and sun exposure, as indicated by their distribution over the surface of the body, may be gleaned from studies conducted in children.
At least three studies of nevi in children reported the proportion of children with at least one nevus at each of the body sites considered, and all found a higher proportion of children had nevi on the trunk than on any other site (Green et al 1989; Sigg and Pelloni 1989; Sorahan et al 1990). Comparisons of the distribution of nevus counts over the surface of the body have found higher numbers of nevi on the trunk or part thereof (e.g. the back), than any other site (Rampen et al 1986; Colonna and Zina 1990; Sorahan et al 1990). However, relatively few of the studies conducted in children have reported site-specific median or geometric mean nevus densities (Gallagher et al 1990a; English and Armstrong 1994; Harrison et al 1999), although nevus numbers are generally skewed to the right, and comparison of anatomical sites of different sizes is difficult unless relative surface proportions are considered. Nevertheless, some useful information about the body site distribution of nevi has emerged even from studies with less sophisticated analyses, by comparing the frequency of nevi occurring on sun protected and sun exposed body sites of similar size. As in the findings of Kopf et al (1978) and Augustsson et al (1992) in adults, Sorahan et al (1990) found the mean number of nevi was higher on the lateral aspects of the upper arms and forearms (0.5, 0.2, respectively) than on the relatively sun protected medial aspects of the same sites (0.1 for both) on children from England. English and Armstrong (1994) and Harrison et al (1999) found an even larger difference between these sites in Australian children. Sorahan et al (1990) also reported a higher mean frequency of nevi for the upper back and chest than for the less exposed regions of the abdomen and lower back. Furthermore, Rampen et al (1986) found that the number of nevi on the chest, back and legs was higher in fair-complexioned subjects than in Caucasians who had a darker complexion.
Canadian schoolboys had higher site-specific densities of nevi on the head and neck, and trunk than girls, whereas girls tended to have more nevi on the limbs than boys (Gallagher et al 1990a). Gallagher et al (1990a) also noted that nevi were more concentrated on intermittently exposed skin (♂ and ♀: back, shoulders and outer arms; ♂ chest and abdomen; ♀ calves), followed by maximally (♂ and ♀: face and anterior neck; ♂ posterior neck; ♀ hands) then minimally exposed sites (♂ and ♀: inner arms, thighs, feet, ♂ calves; ♀ chest, abdomen, posterior neck). However, the allocation of specific body sites to one of the three categories of exposure was quite different to that used in Swedish adults (Augustsson et al 1992), and may partly explain the differences seen with respect to the density of nevi on chronically exposed sites in these studies. There is also evidence to suggest that high levels of cumulative solar exposure increase the rate of elimination of nevi in adulthood (Harth et al 1992), and assuming all other things are equal, may explain why habitually exposed sites have fewer nevi in older subjects when compared to children.
English and Armstrong (1994) and Harrison and co-workers (1999) presented more detailed body site analyses than Gallagher et al (1990a). Both of the Australian studies found that the concentration of nevi (all sizes) was highest on the lateral surfaces of the upper limbs, and the neck and face in both sexes, whereas larger nevi were most common on the back (English and Armstong 1994; Harrison 1999).
In summary, the site distribution of melanocytic nevi implicates sun exposure, but as with cutaneous malignant melanoma (CMM), the relationship is more complex than that for non-melanoma skin cancer (Pearl and Scott 1986; Green and Swerdlow 1989; Augustsson 1991).
Sunburn is an inflammatory response following acute exposure of the skin to solar ultraviolet radiation. In its mildest form, sunburn consists of delayed erythema of the skin, appearing one to four hours after exposure and gradually fading after one to three days. However, sunburn may also cause pain, edema, and in severe cases, blistering and desquamation (peeling) of the epidermis. A tan may also be visible within a few days of an episode of sunburn in those who are able to tan (Green et al 1986; Whiteman and Green 1994; Aubin and Humbert 1997).
The relative effectiveness of different wavelengths in inducing sunburn is characterized by the erythemal action spectrum (Parrish et al 1982). The most effective wavelengths for causing erythema are found predominantly in the UVB range, and the amount of UVB necessary to cause minimal erythema in an individual varies according to skin phototype (Fitzpatrick 1986, Fitzpatrick 1988). Because the action spectra for erythema, melanogenesis and carcinogenesis of the skin are so similar, De Gruijl and Van der Leun (1994) proposed that the same event (i.e. DNA damage) could be the crucial factor in all three responses.
Sunburn is often used in case-control studies of melanoma as a marker of sun exposure because it is relatively easy for subjects to remember episodes with reasonable accuracy (Whiteman and Green 1994). All but one of the 16 case-control studies of melanoma reviewed by Whiteman and Green (1994) showed a significant association between a history of sunburn and melanoma. Compared to subjects who had never experienced sunburn, crude odds ratios for the highest category of sunburn exposure ranged from 1.3 - 8.9. Pooled estimates of the crude risk of melanoma, based only on studies that scored highly when assessed for methodological quality, indicated that those subjects who had been sunburned at least once had a two-fold risk of developing melanoma, and the risk doubled (OR 3.7) when the highest category of sunburn exposure was compared to subjects who had never been sunburnt. In a number of studies, risk estimates were no longer statistically significant after controlling for constitutional factors, particularly tendency to burn, which is highly correlated with sunburn history (Whiteman and Green 1994; Elwood and Gallagher 1994). This may imply that the actual association between melanoma and sunburn is with tendency to burn more so than with sunburn history (Longstreth 1988; Elwood and Gallagher 1994). However, some studies have shown a significant association even after controlling for skin type (MacKie and Aitchison 1982; Zanetti et al 1992) and other studies which excluded skin reaction on the basis of colinearity, found sunburn to be independent of other constitutional variables and nevus frequency in predicting the risk of melanoma (Holly et al 1987; Østerlind et al 1988; Westerdahl et al 1994).
The influence of age at time of sunburn on melanoma risk has also been considered in a number of studies, with the strongest associations usually found for sunburn experienced prior to adulthood (Elwood et al 1985; Østerlind et al 1988; Weinstock et al 1989; Elwood et al 1990; Zanetti et al 1992).
Despite differences in the definitions of sunburn and the age categories used, many epidemiological studies of melanocytic nevi have found an association with sunburn, expressed as either a dichotomous or ordinal variable. Seven of the eight studies which considered sunburn reported an association between sunburn in childhood and nevi, although nevi were most prevalent for the intermediate category of sunburn frequency in two of these studies (Table 1). Both of these studies assessed the prevalence of nevi on the arms as an adult, and neither study achieved statistical significance. However, the studies showing statistical significance were based on full body nevus counts, and many of them were in children when the involution of nevi does not pose a problem (Table 1). The two remaining studies of nevi in adults (Richard et al 1993; Garbe et al 1994) found that sunburns during the first 20 years of life were associated with significantly elevated total body nevus counts.
Sunburn as a child appears to be related to a small but significant increase in nevus development. Green et al (1989) found that 7 to 11 year old children from Brisbane who had experienced at least one severe painful sunburn had an excess of raised nevi ³ 2 mm on their bodies compared to children who had never been sunburnt. However, only crude risk estimates were presented. Canadian school children who had experienced numerous or severe sunburns in the five years prior to being examined were also found to have significantly higher nevus counts than children who had not been similarly exposed (Gallagher et al 1990b). In that study, the association between the highest sunburn score category (index of frequency and severity of sunburns) and nevus frequency was borderline significant (rate ratio 1.3; 95% CI: 1.0 - 1.7) even after adjusting for age, skin and hair color, skin reaction to first sunshine, and tanning score (Gallagher et al 1990b). Likewise, Pope et al (1992) in a study of 4 to 11 year old English children found a history of sunburn, defined as least one episode of uncomfortable reddening of the skin to be associated with significantly elevated age and sex-adjusted total body nevus counts (rate ratio 1.17; 95% CI: 1.15-1.19). Similarly, in 1-6 year old children born and raised in Townsville, a history of sunburn was associated with an almost two-fold increase in risk of being in the highest quartile of nevi within each age group (RR 1.89; 95% CI: 1.1 – 3.2; Harrison et al 1994).
People who live at northerly latitudes receive most of their solar exposure during leisure time activities, particularly during summer vacation. Consequently, holidays in a sunny climate are often used as a measure of irregular periods of relatively intense exposure to sunlight in people who normally live in areas with low ambient solar UVR. However, this approach is a less useful measure in populations living in sunny climates such as Australia’s (Elwood and Gallagher 1994). A history of vacations in a sunny climate has been shown to be related to an increased risk of melanoma in populations living in temperate climates (Adam et al 1981; Lew et al 1983; Elwood et al 1985; Østerlind et al 1988; MacKie et al 1989; Westerdahl et al 1992; Elwood and Gallagher 1994).
There is also some evidence that the prevalence (i.e. presence versus absence), and the frequency of nevi is higher in individuals who spend their holidays in the sun. MacKie et al (1985) found that Scottish subjects who had recently had a continental holiday or spent at least three months in a tropical or sub-tropical climate had non-significantly elevated numbers of nevi on their bodies compared to subjects without such exposures. Although this relationship was not statistically significant, the number of study participants exposed in this way was small.
In contrast, Rampen et al (1988) found no evidence of a relationship between nevus frequency and holidays in sunny climates in 18 to 30 year old students from the Netherlands.
Pope et al (1992) found a positive association between nevi in English children and the number of holidays spent in a hot climate. Even after adjusting for age, sex, history of sunburn, tanning ability and freckling in multivariate analysis, ratios of prevalent nevi increased linearly with the number of sunny holidays from a ratio of one for no sunny holidays, to 1.55 [95% CI: 1.43-1.57] for children who had been on six or more sunny vacations (Pope et al 1992). In contrast, Coombs et al (1992) found no significant association between holidays in a sunny environment and the frequency of nevi in teenagers from New Zealand, although the direction of the trend was compatible with the sun exposure hypothesis. This finding is consistent with the suggestion that holidays in the sun are a less useful measure of sun exposure for those living in countries with high levels of solar UVR.
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