Risk Factors for Melanoma by Anatomical Site

An Evaluation of Aetiological Heterogeneity

R. Laskar; A. Ferreiro-Iglesias; D.T. Bishop; M.M. Iles; P.A. Kanetsky; B.K. Armstrong; M.H. Law; A.M. Goldstein; J.F. Aitken; G.G. Giles; H.A. Robbins; A.E. Cust

Disclosures

The British Journal of Dermatology. 2021;184(6):1085-1093. 

In This Article

Discussion

To shed light on the aetiological heterogeneity of melanoma, we analysed a harmonized dataset of two population-based case–control studies in Australia and the UK to characterize risk factors for cutaneous melanoma according to anatomical site. Several of our findings are consistent with the dual pathway hypothesis, which proposes that there is heterogeneity in the aetiological pathways to melanoma such that risk of melanomas on the trunk is determined by propensity to form naevi (which are both genetically determined and caused by early-life sun exposure)[6,31–33] and intermittent sun exposure, whereas melanoma on the head and neck is more likely to be caused by chronic (more continuous) sun exposure.[11,12,14,16,34] Consistent with this, we found that the number of naevi was more strongly associated with trunk melanoma than head and neck melanoma. Increased weekday sun exposure (a proxy for occupational sun exposure) was associated with head and neck melanoma, which has been reported by other studies,[7,16,17] although not consistently.[35] This positive association with head and neck melanoma was more apparent for the Leeds study than the Australian study, which may be due to the older age distribution of the Leeds study than that of the Australian study, as melanomas associated with chronic UV exposure are more common among older ages.[36] Sunbed use and sunburns, considered intermittent exposures, appeared more strongly associated with trunk melanoma, which is also consistent with the dual pathway hypothesis and other studies,[37,38] although there was no statistical evidence for heterogeneity and the risk estimates differed between studies.

Evidence for melanoma on the limbs is less clear, but one recent study suggested that lower-limb melanoma, similar to trunk melanoma, may tend to arise via a naevus-related pathway whereas upper-limb melanoma, similar to head and neck melanomas, may tend to arise via the sun-damage pathway.[23] In contrast with this suggestion, we found the strongest associations with naevi for upper-limb melanoma and trunk melanoma, although the association of naevi with melanomas on the lower limb was weaker for female participants than male participants.

In addition to number of naevi, the other risk factor with heterogeneity by anatomical site in our study was skin colour. In particular, the increased risk associated with very fair skin was weaker for melanoma on the trunk than for other sites, although this difference was smaller than for the number of naevi. A similar difference by site was also observed in a previous meta-analysis.[7] Taken together, our results do not support a clear classification of upper- and lower-limb melanoma into the two pathways indicated by melanoma on the trunk and head or neck. Rather, they suggest that both pathways may be important for development of melanoma on the limbs.

While certain findings based on phenotypic risk factors showed clear support for aetiological heterogeneity by anatomical site, we did not find clear evidence of heterogeneity in associations with PRS quantifying genetic pathways for pigmentation, naevi and telomere/other biological processes. Unlike the phenotypic naevus and skin colour variables, the naevus and pigmentation pathway PRS ORs were similar between melanoma on the head/neck and on the trunk. Despite naevi being one of the strongest risk factors for melanoma,[39] a naevus-pathway PRS has a relatively weak overall association with melanoma risk.[20] This discrepancy may be because our current naevus PRS captures only a small proportion of the total variation in naevus phenotypes.[40]

Contrary to previous studies,[4,7,17,41] we did not observe positive associations between melanoma risk and sunburn at all anatomical sites, nor with measures of recreational sun exposure. The inverse association with weekend and summer holidays and melanoma risk has been previously reported for the Leeds study and was hypothesized to be mediated by photoadaptation or higher vitamin D levels.[22] This study also observed a stronger association with melanoma for sunburns after the age of 20 years.[22] Interestingly, painful sunburns (but not sunburns causing blisters) were inversely associated with melanoma risk on all sites except the trunk in the Australian study, and this was stronger after adjustment for phenotypic characteristics. Sun sensitivity may modify or confound this association,[42] and we previously showed that the association with sunburn was modified by host factors because a positive association was observed only in people who tended to tan rather than burn and in people who had few naevi.[43] We observed null associations with total sun exposure at all sites. A meta-analysis by Chang et al. also found mostly null associations at different body sites except for an increased risk of melanoma on the limbs at low latitudes.[17]

The key strengths of our study are its size and comprehensive genetic and phenotypic risk factor measures, which allowed detailed analysis by anatomical sites of melanoma, and which was achieved by pooling two population-based case–control studies that used the same measures for data collection. The approach of pooling these data sources was supported by our previous finding that the associations between melanoma and self-reported pigmentary and naevus phenotypes were similar across countries.[6] We also examined the associations by site in each study separately, although these subgroup analyses had limited statistical power.

The younger age of participants in the Australian study (< 40 years at diagnosis) is a limitation for the study of divergent pathways of melanoma, particularly for the UV-related exposures. However, as ambient sun exposure varies greatly between Australia and Leeds, at any given age the cumulative dose of UV exposure is expected to be higher for Australia than the UK. The main focus of our analysis was on pigmentary and naevus characteristics, as fewer studies have examined associations of these risk factors by anatomical site. Other limitations of our study include the lack of detailed pathological information, as some studies have suggested that the presence of solar elastosis and naeval remnants influence aetiologically distinct subtypes.[8,44] When using self-reported risk factors people tend to underestimate their naevus counts and pigmentation;[45] although associations with melanoma have been shown to be very similar for most self-reported and clinically-assessed risk factors.[6] Measurement error, recall bias and selection bias may have also influenced the observed sun-exposure associations. Participation was higher for cases than controls. Sun exposure is a widely known risk factor for melanoma, and controls with high sun exposure may have been more interested in participating in the study, which would lead to inverse associations. Personal lifetime sun exposure is also a complex behaviour to measure,[46] and nondifferential measurement error usually biases the result towards the null.[47] We previously showed stronger associations of childhood total sun exposure and sunburn with melanoma risk when exposure level was recalled concordantly by participants and their parents.[43] We had lower numbers of controls than cases in our analysis. Most previous studies have conducted a case-only analysis; however, including controls produces risk estimates that are more easily communicated to the public and comparable with other risk factor studies. The Leeds study recruited people with thicker melanomas (≥ 0·75 mm) in the later years of the study, but stratification of our results by this factor did not materially alter the results.

In conclusion, in our analysis by anatomical site we found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. The evidence was strongest for naevus phenotype measures, but weaker for pigmentary phenotype, sun exposure and genetically measured risk factors. These findings promote a better understanding of melanoma development. They may also be helpful for guiding skin examination education and practices, for example by highlighting to patients and clinicians which areas of the body may require closer or more regular examination, according to their risk factor profile.

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