Clinical Epidemiology Unit, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Via Monti di creta 104, Rome 00167, Italy. E-mail: c.deppermann{at}idi.it
Rosso and colleagues conducted a helpful reliability study using dual response.1 This method should produce less biased risk estimates, with confidence intervals that correctly reflect the true uncertainty in the data. This study not only serves to encourage more extensive use of the data obtained from internal validation study designs but also emphasizes the need for developing more accurate methods to assess sun exposure.
Non-melanocytic skin cancer is the most common cancer occurring in humans and was first identified and associated with sun exposure by Dubreuilh in 1896.2 The support for this stems first from the observation that skin cancer at all sites, among Caucasians, increases with proximity to the equator. The incidence of three major types of skin cancer (basal cell carcinoma, squamous cell carcinoma and melanoma) have increased steadily over the past decades, and it has been suggested that this is the result of changes in lifestyle that have led to increased exposure to sun.3 Since ozone is the major barrier protecting the earth from ultraviolet (UV) radiation, further increases in UV radiation exposure and skin cancer incidence are expected as a result of stratospheric ozone depletion.4
Ultraviolet radiation has been shown to suppress cell-mediated immunity at both local and systemic levels.5,6 However, response to UV radiation and subsequent immunosuppression appear to be skin type dependent.7,8 Ultraviolet radiation has also been associated with mutations in the DNA of tumour suppressor genes.9,10
Data from epidemiological studies suggest that cumulative sun exposure is strongly associated with squamous cell carcinomas,1113 while for basal cell carcinoma1416 and melanoma1719 both the type and timing of exposure (e.g. frequency of sunburns and sun exposure occurring during childhood) seem more important than total cumulative dose in accounting for risk.
The findings of Rosso and colleagues show that for some sun exposure variables, such as the number of sunburns in a lifetime and sun exposure occurring during childhood, reproducibility is rather low. Because non-differential misclassification leads to attenuation of odds ratios (OR), the observable risks could be even higher if a more accurate instrument had been used.
There is strong evidence for increased risk of melanoma related to intermittent sun exposure,1721 whereas the relationship with chronic sun exposure and with total sun exposure are much more variable, with OR ranging from 0.30 to 2.4817,2024 and from 0.38 to 5.40, respectively.17,2225 The instability of risk estimates for sunlight exposure and melanoma could be partially explained by measurement errors in sun exposure. Errors in the measurement of exposure can also distort relative risk estimates in any direction, in particular when a differential bias is observed. This is illustrated by the International Twin Study on melanoma in which the belief that sunlight was a cause of melanoma was related to an observed higher OR for sunbathing as a child.26
There is a clear need to develop more reproducible and valid methods to assess sun exposure in epidemiological studies. Digital imaging followed by computer analysis of facial images27 and the amount of elastotic material adjacent to the tumour by image analysis28 have been suggested as methods to quantify skin damage due to sun exposure. This type of measurement could be also used as an additional correction factor for adjusting risk estimates for measurement errors in sun exposure, assuming that errors in the two measurements being compared are independent.
The lack of stability of risk estimates for sunlight and melanoma could be also explained by the existence of two independent pathways in the pathogenesis of melanoma. The findings of two studies suggest this hypothesis.
Whitman and colleagues showed that p53-immunopositive melanoma was associated with inability to tan and history of non-melanoma skin cancer while factors such as naevus density were strongly associated with p53-immunonegative melanoma.29 Carli and co-workers showed that frequent sunburn was strongly associated with naevus-associated melanoma with a dose-response relationship but not as much as for melanoma de novo.30 It is interesting to note that solar keratoses are known to be associated with increased risk of squamous cell and basal cell carcinomas,29,31,32 but their association with melanoma is less clear.3335 Solar keratoses are more prevalent in individuals with fair skin, increase with age, are associated with chronic sun exposure and negatively associated with numbers of common naevi.36 These data suggest that of the two independent pathways in the pathogenesis of melanoma, one might depend more on cumulative sunlight exposure and is probably associated with p53 expression (melanoma de novo) and the other depends less on cumulative sun exposure and is associated with high naevus density (naevus associated melanoma). A multi-centre case-control study of melanoma risk factors, which integrates gene-environmental interactions and better instruments to assess sun exposure, is needed to test this hypothesis.
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