This review and meta-analysis is the first to pool data on the number of sunburns in relation to cutaneous melanoma. Other analyses have considered sunburn to be a dichotomous exposure of either ever/never or lowest versus highest category of sunburns. Our pooled analyses of dose-response data on number of sunburns provide evidence for causality (81
). Even with misclassification known to exist in ordered categories, an estimation of numbers of sunburns will give a better characterization of the true relationship between CM and sunburns. We found CM to be related to increasing numbers of sunburns during all life-periods. Traditional comparisons across time periods appear at first glance to suggest the lowest risk for lifetime sunburns. However, ORs per time period are comparing an increase of 5 sunburns across different lengths of times, thus it is not surprising that adolescence has one of the highest ORs because it covers the shortest time period, whereas lifetime has a lower OR for an increase of 5 sunburns over a very long time. When these pooled ORs are transformed to the same scale of 5 sunburns per decade, then the highest risks appear to be across adulthood and lifetime. While experts often focus on childhood sunburns as the primary risk factor for CM, our pooled analyses found increased risk of CM for sunburns experienced in adolescent, adult and lifetime number of sunburns as well as childhood. However, analyses per decade suggest a stronger association if individuals continue to experience sunburns at the same rate per decade into adulthood, and thus over a lifetime. Ultimately, these pooled data show that sunburns, regardless of timing, affect the risk of CM.
The conservative random-effects pooled dose-response ORs per life-period show high ORs for childhood (OR=1.8) and adolescent (OR=1.7) sunburns, but adult (OR=1.5) and lifetime (OR=1.3) sunburns also confer an increased risk of CM. When the 4 life-period models are all re-scaled to 5 sunburns per decade, higher ORs are seen for adult (OR=3.3) and lifetime (OR=3.2) sunburns compared to childhood (OR=2.0) and adolescence (OR=1.4). Since the models per life-period and per decade are identical models but on different scales, the OR for sunburns in adolescence decreases when rescaled from 5 sunburns per 7 years to 5 sunburns per 10 years. Although ORs for 5 sunburns per decade allow for comparison of risk across life-periods, it is unclear if the difference in number of sunburns between two individuals is likely to remain constant (5 sunburns) over each decade or between life-periods since sun behavior changes with age and responsibilities.
The magnitude of the pooled OR for lifetime number of sunburns varies depending on the scale (per lifetime or per decade). If sunburns during different life-periods were independent, then we would expect a comparable number of sunburns over a lifetime to be the sum of the individual life-periods. Estimates per decade are one way to address this. However, sunburns are not independent in that they are related to skin type and UV exposure. Individuals with fair skin type may learn from experience and in turn avoid UV exposure as suggested by Holly et al. (36
). Therefore, after receiving multiple sunburns during childhood or adolescence individuals may receive less as adults imparting a low lifetime number of sunburns. Overall, each life-period shows a relationship between number of sunburns and risk of CM. While sunburns may be caused by acute UV exposure, which may interact with sun sensitivity, sunburns appear to represent real damage to the skin that may eventually cause CMs. Thus, sunburns are likely the mechanism through which sun sensitivity and sun exposure are related to CM.
Our dose-response analyses are robust as shown by the minimal differences seen in sensitivity analyses. However, several studies had ORs that were outliers in comparison to other studies. For lifetime number of sunburns, a German study (42
) reported protective ORs likely due to a non-population control group that consisted of patients from the dermato-oncologic clinic with other skin diseases. This control group gives justification to removing Garbe et al. (42
) from the pooled analyses. When Garbe et al. (42
) was removed from the pooled analyses the heterogeneity between studies went away and the OR of 5 sunburns per decade increased from 2.7 to 2.9 (95% CI of 2.4–3.4; heterogeneity p=0.40, and 5% heterogeneity between studies). The three studies (19
) that lumped lifetime sunburns into 0, 1, and 2+ sunburns had similar ORs for the linear dose-response analyses as other studies, as did the Brazilian study (41
) that reported more than 30 lifetime sunburns. Among the 9 studies reporting adolescent sunburns, the study by Shors et al. (40
) had a higher OR for fewer sunburns (3+); when it was removed from the pooled analyses the heterogeneity between studies went away (OR=1.2, 95% CI 1.2–1.3; heterogeneity p=0.36, and 9% heterogeneity between studies). This population-based study was conducted using the Seattle SEER program and random-digit dialing to recruit population based controls (40
). Lacking obvious reasons this population may differ from other studies, the heterogeneity may have occurred due to lumping all sunburns > 2 together without reporting the mean or maximum number of sunburns in these subjects. Of all life-periods, the studies reporting on number of childhood sunburns were the most heterogeneous. The heterogeneity was only eliminated when three studies with high ORs (Argentina, Lazio Italy, Denmark) (23
) and one study with a protective association (Hawaii males) (37
) were eliminated (OR=1.4, 95% CI 1.3–1.5; heterogeneity p=0.37, and 8% heterogeneity between studies). While the Argentinean study (23
) had the largest ORs it also had large variability due to a small sample size, whereas the studies in Denmark (29
) and Italy (50
) had small variances weighting these two studies more in the pooled analyses.
Only two studies reported risk for number of sunburns adjusted for other life-periods. One study (21
) adjusted childhood and adult exposure for each other, whereas a second study (48
) adjusted childhood, adolescent, and adult sunburns for one another. Pooling these two studies gave an OR for adult sunburns that decreased from 1.60 to 1.54 with adjustment for other life-period sunburns, whereas, the pooled OR for childhood only decreased from 1.56 to 1.49. These two studies would suggest that different life-periods do not confound other life-periods regarding sunburn and CM risk. However, more studies are needed to look at this relationship.
A few studies also reported data regarding recent sunburns. The five ORs for “any” sunburn in last 5–10 years (17
) were heterogeneous, whereas, the three studies (17
) reporting the number of recent sunburns appear to be homogeneous with a fixed-effects OR=2.1 (95% CI 1.6–2.8) for 5 sunburns per decade; this higher pooled OR for sunburns reported just prior to CM diagnosis may suggest recall bias. Recall bias would exist if cases reported more recent sunburns than they actually experienced, attempting to account for behavior that may have caused their CM. Alternatively, this higher OR for recent sunburns could indicate that progression to CM is accelerated by sunburns just prior to development. However, it is difficult to draw firm conclusions since few studies reported such data and there is a large potential for recall bias.
Pooled “ever” sunburned data had the strongest association for childhood sunburns and significant associations for all life-periods. While the ORs for vaguely defined sunburns were high, they tended to display the most heterogeneity, suggesting recall bias where cases may be more likely to over-report “undefined” sunburns than controls. Additionally, the poor categorization of sunburns into “ever sunburned” is difficult to interpret (regardless of definitions) given that such categorization lumps someone sunburned “once” with someone who has experienced repeated sunburns, thus causing severe heterogeneity among the “exposed” group. Future studies should focus on sunburns that are blistering or painful for 2 or more days.
Potential for Bias or Misclassification
Measurement of sunburns as “ever” or “never” sunburned as a child, adolescent, adult, or during one’s lifetime may appear to be simpler; however, such categorization loses valuable information and should not be over interpreted. The heterogeneity seen for “ever” sunburned during a specific life-period may reflect overly simplified dose data of different magnitudes of number of sunburns in different populations. Combining all number of sunburns into “ever” assumes the risk for CM of 1 sunburn is equivalent to 20 sunburns.
While in general retrospective studies may have reporting bias (non-differential) or recall bias (differential), sunburns are thought to be more easily recalled than other types of sun exposure since sunburns are frequently associated with memorable discomfort. Studies that reported reliability of “ever sunburned” used repeated measures more than 3 months apart, leaving questions as to whether differences were due to changes in sunburns or low reliability. “Ever sunburned” lumps those sunburned once with those who experienced many sunburns, causing severe heterogeneity among those “ever sunburned”. Dichotomous analyses are only stronger if “never” sunburned is measured completely accurately, but still would not quantify how many sunburns are important. Reliability studies (test-retest) examining sunburns (less than 3 months apart), showed consistency in reporting number of sunburns with Kappas ranging from 0.5 to 0.8 with the highest consistency among those defining sunburns as “blistering or pain lasting 2 or more days” (Kappas of 0.7 to 0.8) (82
). This suggests that individuals can recall number of sunburns, particularly when sunburns are defined as severe with blisters or pain lasting 2+ days. But clear scientific evidence on how to best define sunburns is lacking. Among dose-response analyses, only 28% of studies did not clearly specify how they defined “sunburns” compared to 39% of those reporting “ever sunburned”. Since there is a difference in CM risk for sunburn susceptibility across skin-types, the heterogeneity in “ever” reporting childhood sunburns may reflect differences in sun sensitivity across those with a childhood sunburn.
Adjustment for Sun Sensitivity
The effect of UVR on CM risk may be strongly modified by sun sensitivity. Sun sensitivity characteristics are widely accepted as risk factors for CM, including eye, hair and skin color, tendency to sunburn and inability to tan (20
). Lighter complexion as measured by both Fitzpatrick skin-type (21
) and self-reported skin color (fair, medium, or dark) (87
) appear to be the most consistent risk factors for CM. In theory, the same amount of UV exposure imparts a greater risk among individuals with fair complexions who sunburn easily than among those with darker complexions who tan. Therefore, sun sensitivity may modify or confound the association seen between CM and sunburns. However, only 14 of the 26 studies in dose-analyses adjusted for sun sensitivity. It is possible that studies examined measures of sun sensitivity as possible confounders but did not find that they confounded the data; however, this was not stated. Two studies adjusted for sunburns by Fitzpatrick skin-type (45
), one adjusted for both Fitzpatrick and skin color (33
), and two additional studies adjusted for skin color (44
). Skin color should predict the skin’s acute (tendency to burn) and chronic reactions (ability to tan) to sun exposure. Three studies in the pooled dose-response analyses adjusted for acute or chronic reaction to the sun (35
). While the risk of CM within light-skinned populations is also influenced by other pigmentary characteristics (adjusted for in the remaining seven (4
) of 14 studies), such as hair color, eye color, and freckling, such factors often segregate with skin-type. Sunburn histories are clearly related to these measures of sun sensitivity. Adjustment for sun-sensitivity factors tells us the risk of CM for sunburns beyond host susceptibility. In Bayesian sub-analyses all studies were included with a covariate to identify which studies adjusted for sun sensitivity showing slightly lower ORs that remained significant. For fixed-effects, we restricted the models to only those studies that adjusted for sun sensitivity thus only lifetime had more than two studies to pool with a slightly higher OR. Overall, the reported articles on sunburns have not provided enough information to appropriately quantify the effect of adjustment for sun sensitivity. However, if sunburns initiate the development of CM, then the risk may be better described as crude risk stratified by sun sensitivity. Stratification would help in understanding if sunburns in darker skinned individuals are important.
The number of nevi as a potential confounder is more complex. Nevi are both genetically determined and influenced by sun exposure. Studies consistently show an increased number of nevi are related to an increased risk of CM. If nevi are precursors or markers of CM risk, it may be inappropriate to adjust for nevi when examining CM risk with sun exposure. Thus, for a study (21
) reporting multiple models, we selected the model unadjusted for nevi (21
). However, when nevi adjustment was examined as a covariate in the Bayesian model, minimal differences were seen in the magnitude of the OR for number of sunburns.
There have been previous meta-analyses on the association between sunburn history and CM that included 10–32 articles (90
). We excluded one article included in the prior reviews because they only presented data on the highest severity of sunburn, but pooled additional articles published more recently or not previously included in other meta-analyses. In addition, our analyses differ in critical methodology. First, we pooled data separately for “ever” sunburned and for dose-response data. Prior meta-analyses pooled dissimilar categories: “ever” sunburned, the highest category reported from dose-response analyses, and severity of sunburns using simple methods for dichotomous exposures. The upper categories ranged from 2+ to 7+ sunburns. Pooling ever sunburned with 7+ sunburns and the highest severity of sunburns is likely to create misclassification and heterogeneity among such diverse measures. We used a method that considers the number of sunburns as a linear dose-response factor. Overall, the most important difference in this meta-analysis in comparison to previous publications is our linear dose-response analyses using fixed-effects and random-effects (Bayesian) models.
Meta-analyses cannot overcome limitations of the original studies related to their data collection including misclassification, selection bias or recall bias. Publication bias is also an issue if significant studies are more likely to be published, however, we did not see much evidence of this since 40 of the 86 dichotomous ORs pooled for had CIs that included 1.0.
This meta-analysis pooled ORs from 51 studies on CM and “ever” experiencing a sunburn. Our analyses further examined linear dose-response data among 26 studies, which had not previously been reported. These results suggest increasing number of sunburns increase the risk of CM regardless of when they are received. The large ORs seen per decade for adult and lifetime exposure suggest that it is the number of sunburns that increases melanoma risk not when they are received. More consistency may be seen in reported ORs for sunburns if clear definitions of sunburns are used to survey subjects. Future studies should focus on number of sunburns with blisters or pain lasting 2 or more days. A better understanding of the independence of sunburns and sun sensitivity would be gained if studies stratified their results for sun exposure by sun sensitivity factors such as skin type, skin color, or tendency to burn. Prevention efforts should focus on reducing all sunburns, regardless of what age they are acquired.