This study found that the density of melanocytic nevi is greater in chronically sun-exposed areas of the body than those that are intermittently exposed, and that there is a significant association between total sunburns and total nevi on the body. We also found a site-specific relationship between sunburns on the back and nevus prevalence on the back. This study suggests there may be two pathways to nevus accumulation: chronic sun exposure and intermittent exposure related to sunburns.
In general, host factors that were positively associated with nevus prevalence included male sex, light skin, light brown hair, blue/green eyes, freckling, and the propensity to burn slightly and tan lightly compared with other reactions to sun exposure. In contrast, red hair had a statistically significant negative association. These associations have previously been reported (23
). Degree of tanning, as measured by colorimeter, was positively associated with nevus prevalence in the current study, although this contradicts most findings (9
). In contrast to self-reported level of tanning, which is used in most studies and most likely reflects the subjects’ perceptions of their overall darkness of tan, colorimeter-based measurement of tanning is a difference score between tanned and untanned areas of skin. Persons with lighter base skin color may have higher difference scores than those with darker base skin color, although their tanned skin may be lighter.
The distribution of nevi over the body implicates a strong role for chronic sun exposure in promoting nevus development. Nevi were concentrated on areas of the body classified as chronically exposed to the sun, specifically the face and neck and lateral arms, which supports the idea that chronic sun exposure plays a role in nevogenesis. Most previous research supports the finding that nevus density is higher in chronically sun-exposed areas (arms or face and neck) than in intermittently exposed areas (back, chest, or legs), although there is some variation in this finding, especially when analysis is restricted to nevi >2 mm (14
). Almost all of the nevi in our population were <2 mm (93%). Studies with sufficient detail to describe variation in nevus density along the lateral arms have reported nevus density to decrease from the upper arms to the hands (16
). Because this is the opposite pattern than would be expected to result from sun exposure, the existence of some sort of physiologic gradient related to the apparent resistance of the backs of the hands to form nevi in response to UV exposure was proposed. In contrast to these studies, our study found that, among boys, nevus density was higher on the middle (forearm) portion of the arms compared with the upper arms and hands (). This does not necessarily contradict the existence of a physiologic component, but supports a role for sun exposure because it is consistent with our finding that boys commonly wear shirts with short sleeves.
Sex differences in chronic exposure may explain differences in nevus distribution. For boys, nevi were concentrated on the face and neck, compared with the upper lateral arms and thighs in girls. This pattern is commonly reported, although the lateral upper arm difference is not always detected (16
). It has been proposed that sex differences may result from socialization of each gender in the amount of time spent in outdoor recreation and clothing habits (14
). Higher nevus density on chronically exposed areas in boys has been attributed to the tendency of boys to spend more time outside, but in our study, boys and girls spent similar amounts of time outside. Because analysis was based on the last day spent mostly with a parent, this would not reflect any differences related to behaviors during other occasions. The fact that girls in this population are more likely to wear clothing that exposes the upper arms and thighs may explain why they have greater nevus density on these areas. Importantly, these results show that sex differences in nevus density are detectable as early as 7 to 8 years of age.
Intermittent acute exposure resulting in sunburns also plays a role in nevus development. Similar to reports in previous studies (19
), this study found a positive association of total sunburns with total nevus prevalence on the body. This effect was independent of the effect of major phenotypic factors, including the propensity to burn versus tan, and was significant for one or more sunburns. The magnitude of the association was highest for four sunburns, and leveled off for five or more sunburns, a pattern that has been reported for melanoma (3
Before this study, extremely little has been published on the site-specific effect of sunburns on nevus development. We found the association between site-specific sunburns and nevi to vary according to body site. In contrast to other body areas, sunburns on the back were significantly associated with back nevi: the association was significant for three or more sunburns, and receiving two sunburns was of borderline significance (P
< 0.10). The lack of association on other areas of the body is corroborated by the single other published study of site-specific sunburns and nevi, which reported a marginally significant effect of sunburns on the trunk but not the head and neck, shoulders, arms, or legs (30
). Because chronic sun exposure provokes UV-protective adaptations in melanocyte cells, it may moderate the effect of sunburn-inducing UV doses (31
). This observation can explain how the infrequently exposed (and consequently maladapted) trunk region is vulnerable to nevogenesis associated with sunburns, whereas the chronically sun-exposed face and neck are not. An alternative explanation is that there is a threshold of nevus density, so that chronically exposed areas, such as the face and neck, reach peak nevus density via chronic exposure, and additional acute exposures resulting in sunburn do not lead to a significant increase in nevi (26
). Yet a third possible explanation is that the trunk has an inherent capacity for melanocyte instability, but no specific physiologic explanation for this has yet been proposed (32
The association of total sunburns with nevi over the whole body apparently contradicts the fact that site-specific associations were detected only on the back. It is possible that our analysis was unable to detect associations on the limbs due to insufficient statistical power related to low frequency of sunburns on the legs and, to a lesser extent, the arms. This would not explain the lack of significant association for the face where sunburns were comparatively frequent. Alternately, a sunburn anywhere on the body may be a marker for acute exposure elsewhere, or the effect of sunburns may extend beyond the exposed area. Specifically, melanocyte populations have been shown to increase outside of the area of sun exposure, which supports the formation of some type of circulating factor in response to UV exposure (33
The patterns observed in this study between sun exposure and childhood nevi generally support the relationships found between sun exposure and melanoma. Overall, the density of childhood nevi in our population was about half that reported in Australia for children of this age, and this corresponds to differences in adult melanoma rates (13
). The higher concentration of childhood nevi on the face and neck in our population matches the distribution of melanoma reported in Australia and melanoma occurring after the age of 50 years in Canada (11
). These studies also reflect the low incidence of melanoma on the back of the hands and the tendency of girls to have a higher incidence of melanoma on the limbs than do boys, similar to our results for childhood nevi. However, melanomas in the Canadian population for younger ages were most frequent on the back, and the incidence of melanoma on the lateral arms is not notably high in either the Australian or Canadian study populations. The Canadian study also reported that melanoma incidence was higher on intermittently exposed areas of the body for younger ages, shifting to maximally exposed areas after the of age 50 years. Some of these discrepancies may reflect regional differences because the melanoma distributions correlate to nevus distribution within each population (14
The relationship between total sunburns and total childhood nevi in our study agrees with a large body of case-control studies that report sunburns in childhood as a risk factor for melanoma (4
). One case-control study on the association of site-specific sunburn with melanoma showed that site-specific sunburns were a marginally significant risk factor for melanoma on that site, but the magnitude of the association was similar across body sites (37
). It is possible that misclassification of sunburn sites due to the difficulty of recall could have diluted differences between body sites. Prospective data about total sunburns and melanoma on different areas of the body from the Nurses’ Health Study found that there was no association for the face and neck, whereas there were associations for other parts of the body including the trunk, arms, and legs (38
). This result corresponds to our finding that site-specific sunburns were related to nevi on the back but not on the face and neck.
One limitation of our study is that chronic and intermittent exposures are interrelated in the sense that sunburn frequency likely correlates with chronic exposure. Site-specific analysis dissociates these effects to some extent by isolating areas that do not receive chronic sun exposure. For the face and neck, however, the sunburn association estimates presented here are not independent of chronic exposure. A second limitation is the lack of sunburn data from the first 4 to 5 years of life; these sunburns are likely to be related to nevus distribution. Thus, the analysis did not include the effect of sunburn during this early period. Some misclassification of body sites by exposure class is expected due to individual variation. For example, forearms may be chronically exposed in some individuals and intermittently exposed in others. As a result, our estimate of the difference between chronic and intermittently sun-exposed areas of the body is likely conservative.
Overall, this study offers evidence that nevi may be accumulated in response to both chronic and intermittent exposure, as inferred from body site and sunburn, respectively. Our study is the first longitudinal nevus study of nevus distribution in U.S. children and one of the first to provide data about site-specific sunburns. Our findings are consistent with the theory of two different pathways to melanoma, proposed to explain the anatomic distribution of melanoma subtypes and associated risk factors (5
). Melanomas on the intermittently exposed trunk have been associated with earlier average age of incidence (which is taken to indicate high individual susceptibility; refs. 11
) and are more likely to be associated with a nevus or to occur in nevus-prone individuals (40
). In contrast, melanomas of the face and neck tend to occur later in life (>50 years) and to be associated with solar keratoses, which are indicators of chronic sun exposure (42
). Specific mechanisms have not yet been proposed, but melanomas on different parts of the body also seem to have different molecular features (e.g., TP53 on the face and neck and BRAF on intermittently exposed areas), which supports the notion of different pathways to melanoma (5
). These observations support the idea that melanoma results either from individual susceptibility (propensity to develop nevi) activated by intermittent exposure or from long-term chronic exposure. Similarly, our results show that nevogenesis may occur in response to both chronic and intermittent exposure to sunlight.