The results of our pooled analyses have confirmed a 2–3 fold higher risk of melanoma at all body sites associated with a high number of self-reported sunburns, but we found no statistically significant evidence that the magnitude of the risks varied by site of melanoma. While not statistically different from other sites, the associations appeared to be strongest for melanoma of the lower limbs. Somewhat higher risks were also noted in younger women, and in women without red hair. We found no evidence that the sunburn-melanoma association was modified by nevus count or differed by histologic sub-type.
The weak associations between sunburns and melanoma among women with red hair are noteworthy, and several explanations are possible. Women with red hair who are sun-sensitive may systematically avoid multiple sunburns, and this may explain the weaker association between sunburns and melanoma this group of women compared to women without red hair. A similar phenomenon has been previously reported whereby men and women self-select for outdoor work based upon their sun-sensitivity and phenotype.43
We cannot exclude chance as an explanation however, since there were relatively few women with red hair contributing to these analyses.
Our results generally agree with the published literature including the recent meta-analysis of 24 studies that also found no significant heterogeneity in the association between sunburns and melanomas of different body sites.26
Only three studies included in the current pooled analyses 32, 35, 37
were included in the meta-analyses. Similarly, the pooled analyses by Chang et al.25
did not report significant differences in the association between sunburns (both in childhood and adulthood) and melanoma of different body sites, although they did not test the significance of the differences. While that previous analysis included data from nine of the studies reported here, it included data from men as well as women, and was designed to address different research questions.
Only two studies included in our pooled analyses collected information on solar keratoses. There were insufficient data to examine the relationship between solar keratoses and melanoma at body sites other than the head and neck, where a strong association was noted. Reported results on the association between solar keratoses and risk of melanoma are scant, 2, 10, 25
and yet this is arguably the most reliable marker of high cumulative sun exposure. Rigorous investigation into the association between solar keratoses and melanoma should be pursued, along with other markers of high accumulated sun exposure such as photoageing.44
Do these findings “falsify” the divergent pathway hypothesis for melanoma? Not necessarily. Sunburns may be an insufficiently specific measure of acute sun exposure alone to test this hypothesis, or it may be that sunburn is a component of both paths to melanoma. Our observation that sunburn was associated with melanomas at all body sites, and that the magnitude of association did not differ between melanomas of the trunk and head, would support the latter. Recent genome-wide association studies have identified a number of common genetic variants associated with pigmentation and nevus development that relate to melanoma risk in Caucasian populations at all latitudes.45
It is not yet known whether these variants are associated with different site distributions of melanoma or whether they modify the risks associated with nevi or levels of personal sun exposure. Our study did not entail the analysis of genetic data, but these possibilities deserve further exploration.
Strengths of our study include the large number of cases and controls made possible by pooling data from 11 individual case–control studies. The analyses relied on individual data combined into a single dataset following a rigorous data cleaning and harmonization protocol, as distinct from meta-analyses, with an enhanced ability to control for confounding in individual studies.29
Pooling these data increased our statistical power to examine sunburn exposure in relation to melanoma, and allowed sub-group analyses to examine the effects by age, histologic subtype, nevus density and body-site distribution. Additionally, the individual study data were collected before there was a widespread awareness of the causes of melanoma, and thus recall bias is likely to be considerably less of a concern than in studies conducted more recently.
Several limitations of these analyses must be acknowledged. First, there was substantial heterogeneity in defining and collecting information on sunburns among the studies. Individual studies collected data on sunburn with different degrees of detail on severity, ranging from ever severe sunburn (often in countries with high sunburn prevalence in general) to exact number of peeling and blistering episodes (in countries with low sunburn prevalence). There was variable interpretation and/or reporting of such study terms as ‘painful’ and ‘severe’ among studies. In addition, most of the primary study data used in these analyses were obtained during the 1980s. Sunlamps used during that period differed markedly from those in use today, which must be considered when interpreting these results. A second limitation was limited power in our analyses of solar keratoses and our stratified analyses by hair colour and histological subtype (LMMs). Third, reliance on recalled sunburns may have resulted in misclassification since the reproducibility of such data is modest.19
However, such misclassification is likely to be non-differential by anatomical site of melanoma. Finally, our pooled analyses were restricted to women because the original collaborative pooling project was established to examine factors associated with female sex steroids. It is well established that the anatomical site distribution of melanoma differs for men and women 46
and thus it would be prudent to examine the relationship between UV biomarkers and site-specific melanoma in relation to the divergent pathway hypothesis in men.
In summary, we found sunburn to be positively associated with melanoma at all body sites, but found no statistical support for site-specific differences in sunburn-melanoma associations. There are insufficient data to draw conclusions regarding site-specific differences in risk with solar keratoses, which merits further research. Case-control studies, the mainstay for melanoma research during the past three decades, are limited by their reliance on recall of past sun exposure. A prospective study that collected salient phenotypic data at baseline and gathered sun exposure information at periodic intervals over time might assist in delineating the sequence of exposures that result in melanoma at different anatomic sites, although such a study would present formidable logistical challenges.