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Sun exposure and the epidemiology of melanoma and melanocytic nevi

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 THE AUSTRALASIAN
COLLEGE
OF TROPICAL
MEDICINE
Online Book Section
Rural and Remote Environmental
Health I
Editors: Dr. Deon Canyon and Professor Rick Speare

AVAILABLE FROM: http://www.tropmed.org/rreh/rrehi.htm

Sun Exposure and the Epidemiology of

Melanoma and Melanocytic Nevi (Moles)
Simone Harrison (MPHTM, PhD, FACTM)
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.

Geographical Variation
Melanoma:
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).
Nevi:
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).

Studies Of Migrants
Melanomas:
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.

Nevi:
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.

Body Site Distribution

Melanomas:
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.

Nevi:
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
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).

Other Indicators of Solar Ultraviolet Exposure

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.

Conclusion
Exposure to solar ultraviolet radiation is the only known exogenous causal factor for the
development of melanocytic nevi and cutaneous melanoma. It is likely that further
atmospheric ozone depletion, unless counteracted by behavioral change, is likely to result in
significant increases in ground level ultraviolet radiation in temperate regions, and a rise in
melanoma incidence in the Caucasian populations occupying these regions (Elwood and
Gallagher 1994).

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