Photocarcinogenesis.

Epidemiological investigations on nonmelanoma skin cancer, malignant melanoma and solar UV-exposure. Historically, the association between solar UV-exposure and non-melanoma skin cancer was first reported by Unna and Dubreuilh at the end of the 19th century.1,2 These physicians recognized actinic keratoses (AK) and squamous cell carcinomas (SCC) in chronically sun-exposed skin areas of sailors and vineyard workers. At present, it is scientifically accepted that solar UV-exposure represents the most important environmental risk factor for the development of non-melanoma skin cancer.3–8 In general, skin cancer includes three major types: SCC,9,10 basal cell carcinoma (BCC),10 and primary cutaneous malignant melanoma (MM).11 It has to be noted that AK are now considered to represent cutaneous SCC in situ.10 While BCC do not and SCC rarely metastasize (with the exception of risk groups that include immunosuppressed patients, e.g., in solid organ transplant recipients), MM is often characterized by aggressive metastatic growth and fatal outcome.

Epidemiological and laboratory data have convincingly shown that sunburns are implicated in the pathogenesis of SCC,12 BCC4,13 and MM.5,14 Today, it is accepted that chronic sun exposure is the most important cause for the formation of SCC,15 but may be less important for the development of BCC.4,16,17 AK are more frequent in men, in sun-sensitive individuals chronically exposed to solar UV, and in individuals who have a history of sunburn.18 Concerning MM, numerous epidemiologic investigations analysing solar UV-exposure parameters have consistently reported an association between the development of MM and short-term intense UV-exposure, particularly burning in childhood. 14,19 It has been convincingly demonstrated by many investigators, that the incidence of MM increases with decreasing latitude towards the equator.20,21 However, in contrast to short-term intense exposure, more chronic less intense exposure has not been found to be a risk factor for the development of MM and in fact has been found in several studies to be protective.5,22–24 Grass and Bopp previously have analyzed MM mortality rates in different occupational groups.24 They concluded that indoor working males (including graduates and employees with commercial or technical education) have an increased risk affirming the association between melanoma risk and intermittent solar UV-exposure. In contrast, outdoor workers with chronic solar UV-exposure appeared slightly protected.24 It may be speculated whether these associations may be an explanation for the finding of an increased risk to develop MM after sunscreen use, that was reported previously.25 The hypothesis of an association between sunbed use and cutaneous MM was previously analyzed in a large European case-control study investigating an adult population aged between 18 and 49 years.26 In that study in Belgium, France, The Netherlands, Sweden and the UK, solar UV and sunbed exposure was recorded and analyzed between 1999 and 2001 in 597 newly diagnosed MM cases and 622 controls. 53% of cases and 57% of controls ever used sunbeds. There was a South-to-North gradient with high prevalence of sunbed exposure in northern Europe and lower prevalence in the South (prevalence of use in France 20% compared to 83% in Sweden). The authors concluded that dose and lag-time between first exposure to sunbeds and time of study were not associated with MM risk, neither were sunbathing and sunburns.26

Photocarcinogenesis of non-melanoma skin cancer. The solar UV-spectrum can be divided into several bands that vary in their physical and biological properties, namely UV-C (wavelength below 280 nm), UV-B (280–315 nm) and UV-A (315–400 nm).9 It has to be noted that the predominant part of the short-wave, high-energy and destructive UV-spectrum cannot reach the surface of the earth. This is due to the fact that the ozone layer of the earth’s outer atmosphere absorbs the shorter wavelength up to appr. 310 nm (UV-C and part of UV-B radiation).9 The different layers of human skin absorb UV-radiation in a wavelength-dependent manner. Because UV-B radiation is almost completely absorbed by the epidermis, only 20% of UV-B radiation reach the epidermal basal cell layer or the dermal stratum papillare.9 In contrast, UV-A radiation penetrates deeper into the dermis and deposits 30–50% of its energy in the dermal stratum papillare. These absorption characteristics explain at least in part why UV-B effects (including skin cancer development) have to be expected predominantly in the epidermis and UV-A effects (including skin ageing, solar elastosis) in the dermis.9 It is well known that DNA represents a major epidermal chromophore with an absorption maximum at 260 nm. Both UV-A and UV-B radiation are able to induce structural DNA-damage. UV-B radiation induces molecular rearrangements of the DNA resulting in the characteristic formation of specific photoproducts (most importantly cyclobutane pyrimidine dimers and 6-4 photoproducts), which are known to be mutagenic. The genotoxic potential of UV-A radiation has been clearly shown to be predominantly due to indirect mechanisms that include oxidative damage. Gene mutations that have been shown to be of importance for the pathogenesis of skin cancer include mutations in the p53 gene (AK, SCC), and mutations in the patched (PTCH)/sonic hedgehog pathway (BCC). The UV-induced development of skin carcinomas has been investigated previously using multiple animal and laboratory models. Mutation-associated inactivation of p53 tumor suppressor gene plays a critical role both for stages of initiation and progression of SCC.27 Analysis of data on gene mutations in human premalignant AK lesions, as well as data from UV-induced carcinogenesis experiments in mice have suggested that the first step involves acquisition of UV-induced mutations in the p53 gene by epidermal keratinocytes.27 This defect diminishes sunburn cell formation and enhances cell survival allowing retention of initiated, precancerous keratinocytes.27 Moreover, chronic exposures to solar UV results in the accumulation of p53 mutations in skin, which confer a selective growth advantage to initiated keratinocytes and allow their clonal expansion, leading to formation of AK.27 The expanded cell death-defective clones represent a larger target for additional UV-induced p53 mutations or mutations in other genes, thus enabling progression to carcinomas. Concerning the pathogenesis of BCC, the importance of PTCH, SMOH and TP53 mutations has been demonstrated.28 Suppression of the skin’s immune system has been shown to represent another mechanism by which solar UV-radiation induces and promotes skin cancer growth, even at suberythemogenic doses.29 Immunosuppressive properties have been demonstrated for both UV-B and UV-A.29 Moreover, it has been speculated that UV-B-induced production of vitamin D may be involved in UV-B induced immunosuppression.30

Our present understanding of the synthesis and metabolism of vitamin D-compounds in the skin is demonstrated in . Interestingly, a contribution of the cutaneous vitamin D system to the pathogenesis and prognosis of skin malignancies including MM has been reported.31 We have characterized the expression of key components of the vitamin D endocrine system [vitamin D receptor (VDR), vitamin D-25OHase (CYP27A1), 25(OH) D-1αOHase (CYP27B1), 1,25(OH) 2 D-24OHase (CYP24A1)] in cutaneous SCC, BCC and MM.32–36 Our findings provide supportive evidence for the concept that endogeneous synthesis and metabolism of vitamin D metabolites as well as VDR expression may regulate growth characteristics of BCC, cutaneous SCC and MM.32–36 An association of Fok 1 restriction fragment length polymorphisms of the VDR with occurrence and outcome of MM, as predicted by tumor (Breslow) thickness, has been reported.37 The same laboratory demonstrated that a polymorphism in the promotor region of VDR (A-1012G, adenine-guanine substitution −1,012 bp relative to the exon 1a transcription start site) is related in MM patients to thicker Breslow thickness groups and to the development of metastasis.38 The authors concluded that polymorphisms of the VDR gene, which can be expected to result in impaired function of biologically active vitamin D metabolites, are associated with susceptibility and prognosis in MM. The importance of VDR polymorphisms for melanoma risk has been systematically reviewed recently in a meta-analysis.39 These authors concluded that current evidence is in favor of an association between 1 VDR gene polymorphism (BsmI) and the risk of developing melanoma, and that this finding indirectly supports the hypothesis that sun exposure may have an antimelanoma effect through activation of the vitamin D system.39

Applying array CGH, amplification of the 1,25(OH) 2 D-metabolizing enzyme CYP24A1 [1,25(OH) 2 D-24OHase] was recently detected as a likely target oncogene of the amplification unit 20q13.2 in breast cancer cell lines and tumors.40 It has been speculated that overexpression of CYP24A1 due to gene amplification may abrogate 1,25(OH) 2 D-mediated growth control. Additionally, amplification of the CYP27B1 [25(OH)D-1αOHase] gene has been reported in human malignant glioma.41 The significance of these findings remains to be investigated. We have analyzed metastases of MM and found no evidence of amplification of CYP27B1 or CYP24A1 genes using Southern analysis.34 However, we detected various splicing variants of the CYP27B1 gene in cutaneous malignancies.41 The clinical significance of this finding remains to be elucidated. Additionally, we have demonstrated that serum 25(OH)D levels are not reduced in MM patients.42

Skin cancer prevention campaigns and recommendations for protection against solar and artificial UV-radiation. It is a major aim of skin cancer prevention campaigns to improve the knowledge of the general population regarding the role of environmental risk factors for the development of skin cancer. While the incidence of skin cancer has dramatically increased during the last decades, it is now accepted that the reasons for this development are multifactoral.7 It has been speculated that besides the age pyramid and other factors, cultural changes that result in increased UV-exposure, may be of particular importance.7 It has been assumed that socio-economical and cultural changes in the behavior of large groups of society may have resulted in an increase of UV-exposure in those individuals. These changes may include more recreational activities and holidays spent in the sun as well as frequent exposure to artificial UV in sunbeds. The wellness-movement with tan representing the current ideal of beauty may have supported this development as well. However, one has to keep in mind that the reported increase in skin cancer incidence may be due to other factors independent from solar UV-radiation. As an example, it has been recently published that the large increase in reported melanoma incidence is likely to be due to a diagnostic drift which classifies benign lesions as stage 1 melanoma.43 In that study, this conclusion could be confirmed by direct histological comparison of contemporary and past histological samples. The distribution of the lesions reported did not correspond to the sites of lesions caused by solar exposure. The authors concluded that these findings should lead to a reconsideration of the treatment of ‘early’ lesions, a search for better diagnostic methods to distinguish them from truly malignant melanomas, re-evaluation of the role of ultraviolet radiation and recommendations for protection from it, as well as the need for a new direction in the search for the cause of melanoma.43

To counteract against the increasing incidence of skin cancer, public health campaigns were developed and introduced, with the aim to improve the knowledge of the general population regarding the role of UV-radiation for the development of skin cancer. However, it has to be noted that positive effects of UV light were not adequately considered in most of these campaigns that in general proposed a strict “no sun policy.”44,45 The first of the campaigns were introduced and established in Australia in the early 1980s, containing neat messages and slogans which were easy to remember, including the “Slip (on a shirt), Slop (on some sunscreen), Slap (on a hat)” initiative. Afterwards several international consensus meetings profited from Australian experiences and renewed similar aims in the primary prevention of skin cancer.46 The World Health Organisation (WHO) started a Global UV Project called INTERSUN (WHO, INTERSUN, The global UV project: a guide and compendium, Geneva 2003) which aimed to encourage countries to take action to reduce UV-induced health risks, additional goals were the development and use of an internationally recognized UV Index (UVI) to fasciltate sun protection messages related to daily UV-intensity and special programmes for schools to teach children and teachers about sun protection.46 Certain intervention programmes were focused especially on children at school. In 2001 the European Society of Skin Cancer Prevention (EUROSKIN) organized an international conference “Children under the sun” in Ovieto, Italy to strengthen the importance of this issue.46 During the last decades, country-specific preventive strategies were developed by several institutions and organisations throughout the world, e.g., Skin Cancer Foundation (SCF) in the US (www.skincancer.org); German Cancer Aid and Association of Dermatological Prevention (ADP) in Germany (www.unserehaut.de).46 At the EUROSKIN conference “Children under the sun”, the ADP announced the “Periods-of-life-Programme” (POLP).46 To achieve an age-accordant education, certain target-groups were defined in an age-dependent manner. Besides dermatologists, general practicioners, gynecologists, midwifes, pediatrics, kindergarten teachers, school teachers and parents were also integrated in this program.46 When POLP started in Germany in 2002, it was first mainly focused on the target group of babies and their parents. Thereafter, kindergarten children (2003) and pupils entering elementary school (2004) were included in close relation to the former “Sun protection programmes in school” of the WHO.46 Depending on individual target-groups, different methods were applied to teach the subject matters adequately (e.g., “sun-songs,” TV-spots) and to identify individuals or groups with specific need for information. Another pursued strategy of identifying risk groups is to classify people according to their individual solar and/or artificial UV-behavior. In this way, certain risk profiles have been established by characterization of typical behavior patterns.

Until today, strict recommendations for protection against artificial and solar UV-radiation still represent a fundamental part of public health campaigns and prevention programmes aimed at reducing UV-radiation-induced skin damage and skin cancer.44,45 These recommendations include the use of sunscreens, protective clothing and avoidance of artificial and solar UV-exposure. Appropriate clothing is extremely effective in absorbing all UV-B radiation thereby preventing any UV-B photons from reaching the skin.47,48 Most sunscreen products combine chemical UV-absorbing sunscreens and physical anorganic sunscreens, which reflect UV, to provide broad spectrum protection. At present, most sunscreen products protect against both UV-B and UV-A radiation.