Cancer Epidemiology 39S (2015) S75–S83

Contents lists available at ScienceDirect

Cancer Epidemiology
The International Journal of Cancer Epidemiology, Detection, and Prevention

journal homepage: www.cancerepidemiology.net

European Code against Cancer 4th Edition: Ultraviolet radiation and

cancer§
Rüdiger Greinert a, Esther de Vries b, Friederike Erdmann c, Carolina Espina c,
Anssi Auvinen d,e, Ausrele Kesminiene c, Joachim Schüz c,*
a
Center of Dermatology, Department of Molecular Cell Biology, Elbekliniken Stade/Buxtehude, Am Krankenhaus 1, D-21614 Buxtehude, Germany
b
Department of Public Health, Erasmus MC/Section of Cancer Information, Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands
c
International Agency for Research on Cancer (IARC), 150 Cours Albert Thomas, 69372 Lyon, France
d
School of Health Sciences, University of Tampere, FI-33014 Tampere, Finland
e
STUK – Radiation and Nuclear Safety Authority, Research and Environmental Surveillance, Helsinki, Finland

A R T I C L E I N F O A B S T R A C T

Article history: Ultraviolet radiation (UVR) is part of the electromagnetic spectrum emitted naturally from the sun or
Received 23 June 2014 from artificial sources such as tanning devices. Acute skin reactions induced by UVR exposure are
Received in revised form 10 October 2014 erythema (skin reddening), or sunburn, and the acquisition of a suntan triggered by UVR-induced DNA
Accepted 14 December 2014
damage. UVR exposure is the main cause of skin cancer, including cutaneous malignant melanoma,
Available online 19 June 2015
basal-cell carcinoma, and squamous-cell carcinoma. Skin cancer is the most common cancer in fair-
skinned populations, and its incidence has increased steeply over recent decades. According to estimates
Keywords:
for 2012, about 100,000 new cases of cutaneous melanoma and about 22,000 deaths from it occurred in
Ultraviolet radiation
Europe. The main mechanisms by which UVR causes cancer are well understood. Exposure during
Ultraviolet light
Skin cancer childhood appears to be particularly harmful. Exposure to UVR is a risk factor modifiable by individuals’
Melanoma behaviour. Excessive exposure from natural sources can be avoided by seeking shade when the sun is
Sunburn strongest, by wearing appropriate clothing, and by appropriately applying sunscreens if direct sunlight is
Tanning unavoidable. Exposure from artificial sources can be completely avoided by not using sunbeds. Beneficial
Adverse effects effects of sun or UVR exposure, such as for vitamin D production, can be fully achieved while still
Primary prevention avoiding too much sun exposure and the use of sunbeds. Taking all the scientific evidence together, the
Europe
recommendation of the 4th edition of the European Code Against Cancer for ultraviolet radiation is:
‘‘Avoid too much sun, especially for children. Use sun protection. Do not use sunbeds.’’
ß 2015 International Agency for Research on Cancer; Licensee ELSEVIER Ltd https://creativecom-
mons.org/licenses/by-nc-nd/3.0/igo/

1. Ultraviolet radiation (UVR): sources and physical and

biological properties
§
This is an Open Access article published under the CC BY NC ND 3.0 IGO license
which permits users to download and share the article for non-commercial 1.1. Introduction
purposes, so long as the article is reproduced in the whole without changes, and
provided the original source is properly cited. This article shall not be used or UVR is part of the electromagnetic spectrum with wavelengths
reproduced in association with the promotion of commercial products, services or
any entity. There should be no suggestion that IARC endorses any specific
100–400 nm; it is emitted by the sun and by artificial sources (e.g.
organisation, products or services. The use of the IARC logo is not permitted. This sunbeds). Historically, this wavelength band has been further
notice should be preserved along with the article’s original URL. subdivided into three wavelength regions: UVC (100–280 nm),
Abbreviations: AAD, American Academy of Dermatology; AK, actinic keratosis; ASR, UVB (280–315 nm) and UVA (315–400 nm). The UV components
age-standardised incidence rates; BCC, basal cell carcinoma; CI, confidence interval;
reaching the Earth’s surface comprise about 95% UVA and only 5%
CM, malignant melanoma; CPDs, cyclobutane-pyrimidine dimers; DT, delayed
tanning; IARC, International Agency for Research on Cancer; IPD, immediate UVB [1]. Solar UVC is absorbed by (an intact) stratospheric ozone
pigment darkening; MED, minimal erythemal dose; NMSC, non-melanoma skin layer and hardly reaches the Earth’s surface.
cancer; ROS, reactive oxygen species; SCC, squamous-cell carcinoma; SPF, sun Acute skin reactions induced by UVR exposure are erythema
protection factor; UVI, ultraviolet index; UVR, ultraviolet radiation; US FDA, Food (skin reddening) – or sunburn with increasing UVA dose – and
and Drug Administration of the United States; WHO, World Health Organization.
acquisition of a suntan triggered by UVR-induced DNA damage.
* Corresponding author at: IARC European Code Against Cancer Secretariat, 150
Cours Albert Thomas, 69372 Lyon Cedex 08, France. Tel.: +33 04 72 73 84 85. UVR exposure is the main cause of skin cancer, including cutaneous
E-mail address: secretariat-cancer-code-europe@iarc.fr (J. Schüz). malignant melanoma (CM), basal-cell carcinoma (BCC) and

http://dx.doi.org/10.1016/j.canep.2014.12.014
1877-7821/ß 2015 International Agency for Research on Cancer; Licensee ELSEVIER Ltd https://creativecommons.org/licenses/by-nc-nd/3.0/igo/
S76 R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83

exposure [5]. In fair-skinned populations there is approximately a

Box 1. European Code Against Cancer.
four-fold range in the MED of exposure to UVR depending on the
[1_TD$IF]EUROPEAN CODE AGAINST CANCER person’s skin type (Fig. 1) [6]. When the term MED is used as a unit of
‘exposure dose’, a representative value for sun-sensitive individuals
12 ways to reduce your cancer risk
1. Do not smoke. Do not use any form of tobacco of 200 J/m2 is usually chosen. Measurements of many biological
2. Make your home smoke free. Support smoke-free policies in your effects (including erythema) show that UVB is about 103–104 times
workplace more effective in inducing biological effects than UVA.
3. Take action to be a healthy body weight The UV index (UVI) is a standardised tool intended for the
4. Be physically active in everyday life. Limit the time you spend sitting
5. Have a healthy diet:
communication of the UVR intensity to the general public. It
 Eat plenty of whole grains, pulses, vegetables and fruits expresses the erythemal intensity of the sun as:
 Limit high-calorie foods (foods high in sugar or fat) and avoid sugary
UVI ¼ k  Ebiol
drinks
 Avoid processed meat; limit red meat and foods high in salt
where Ebiol represents the erythemal irradiance (in W/m2) in the
6. If you drink alcohol of any type, limit your intake. Not drinking alcohol is
better for cancer prevention wavelength band 250–400 nm. Introduction of the constant
7. Avoid too much sun, especially for children. Use sun protection. Do not k = 40 m2/W converts UVI in a dimensionless number which can
use sunbeds be used as a measure of solar UV. A UVI = 1 corresponds to an
8. In the workplace, protect yourself against cancer-causing substances by erythemal irradiance of 0.025 W/m2.
following health and safety instructions
The clear-sky UVI at solar noon is generally in the range of 0–12
9. Find out if you are exposed to radiation from naturally high radon levels
in your home; take action to reduce high radon levels at the Earth’s surface, with values over 11 considered extreme.
10. For women:
 Breastfeeding reduces the mother’s cancer risk. If you can, breastfeed 1.3. Biological properties of UVR
your baby
 Hormone replacement therapy (HRT) increases the risk of certain
cancers. Limit use of HRT 1.3.1. DNA damage
11. Ensure your children take part in vaccination programmes for: The main intracellular target for UVR is DNA. A multitude of
 Hepatitis B (for newborns) photoproducts – the ratio of which depends markedly on UV
 Human papillomavirus (HPV) (for girls) wavelength – is formed in DNA and can give rise to pre-mutagenic
12. Take part in organised cancer screening programmes for:
lesions. These photoproducts may be formed either via a direct
 Bowel cancer (men and women)
 Breast cancer (women) mechanism (photon absorption in DNA) or via an indirect
 Cervical cancer (women) mechanism (excitation of other cellular chromophores which
The European Code Against Cancer focuses on actions that individual
subsequently interact with DNA). Unlike UVB, UVA is only weakly
citizens can take to help prevent cancer. Successful cancer prevention absorbed by DNA. Induction of DNA damage by UVA occurs
requires these individual actions to be supported by governmental policies indirectly via absorption of UVA photons by endogenous photo-
and actions. sensitisers (melanins, porphyrin, flavin groups) or exogenous
photosensitisers (e.g. azathioprine, an immunosuppressive drug)
squamous-cell carcinoma (SCC). In 2009, the International Agency [7]. These photosensitisers absorb in the UVA range and release, in
for Research on Cancer (IARC) classified solar UVR, as well as UV a complex reaction scheme, reactive oxygen species (ROS), giving
radiation used in tanning devices, as carcinogenic to humans rise for example to guanine modifications, including 8-oxo-
(group 1) [1,2]. guaninine, which is an important pre-mutagenic lesion after
In the 4th edition of the European Code Against Cancer (Box 1) UVA irradiation [7]. UVA can also cause the production of reactive
avoiding too much sun and not using sunbeds are recommended in nitrogen species (e.g. nitric acid and peroxynitrite), which can
order to prevent skin cancer. This recommendation is based on cause cellular and DNA damage [8]. UVA predominantly induces
evidence from epidemiological studies, established causal mecha- oxidation of purines and of relatively few pyrimidines, as well as a
nisms, the increasing skin cancer burden in the mostly fair-skinned few (single-)strand breaks in DNA [9–11]. In vitro, UVA also
European populations, and the modifiability of the risk factor by induces double-stranded breaks in DNA of human keratinocytes
individual action, considering also the beneficial effects of sunlight and skin fibroblasts [12,13], rendering an UVA-irradiated genome
such as vitamin D production. prone to the production of chromosomal aberrations. UVA can also
induce epigenetic changes (CpG island promoter methylation,
1.2. UV index histone methylation, etc.) in human keratinocytes through chronic
exposure (200 kJ/m2 once a week for 15 weeks), and via these
The amount of solar UV irradiance measured at the Earth’s modifications it can silence for example tumour suppressor p16
surface depends on several factors. The most important ones are expression [14]. UVA can also induce the formation of cyclobutane
the time of day and season: in summer, about 20–30% of the total – pyrimidine dimers (CPDs) – the most harmful pre-mutagenic
daily amount of UVR is received between 11 am and 1 pm, and 75% lesions resulting from UVA exposure – in the genome of human
between 9 am and 3 pm (solar time, not local time) [3]. Seasonal skin cells; CPDs (not oxidative lesions) represent the most frequent
variations in terrestrial UV irradiance at the Earth’s surface, type of DNA damage induced in human skin irradiated with UVA
especially in UVB, are substantial in temperate regions, but less [15,16].
pronounced closer to the equator. Other important factors UVB is >1000 time more effective than UVA in producing CPDs
influencing UVR at the Earth’s surface are geographical latitude, (via direct photon absorption by DNA), and is therefore the main
altitude, clouds, surface reflection and air pollution. Annual UV source of CPDs in human cells [17]. Irradiation of in vitro human
doses decrease with increasing distance from the equator keratinocytes with UVB (300 J/m2) induces hundreds of thousands
(latitude) [3], and in general each 300 m increase in altitude of CPDs in the genome [18]. If these CPDs are not repaired by
increases the sun-burning effectiveness of sunlight by about 4% [4]. cellular repair systems, or if they undergo error-prone repair
In order to measure the biological effects of UVR, the concept of during replication, they give rise to C ! T or **CC ! TT transitions
‘minimal erythemal dose’ (MED) has been developed. One unit of or tandem mutations, which are considered ‘‘UV signature
MED has been defined as the lowest radiant exposure to UVR that is mutations’’ [19]. These types of mutation have frequently been
sufficient to produce erythema with sharp margins 24 h after found in tumour suppressor genes and oncogenes (e.g. p53, PTCH,
[(Fig._1)TD$IG] R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83 S77

Fig. 1. Skin type chart: a numerical classification scheme for the colour of the skin according to the response of the different types of skin to ultraviolet radiation.

p16, RAS) which play important roles in the aetiology of skin three times lower than those required for immunosuppression in
cancer. For instance, >90% of all SCCs detected in the United States women [1,26].
carry UV signature mutations in the p53 gene [20].
In addition to CPDs, UVB induces a second pyrimidine dimer, 1.3.3. Tanning of the skin
the pyrimidine-(6-4)-pyrimidone photoproduct ((6-4)PP), in a UVR-induced melanogenesis, or tanning, is widely recognised
ratio of 3:1 (CPD:(6-4)PP) [21]. as the major defence of exposed skin against further UV damage
[27]. Two types of tanning can be distinguished according to their
1.3.2. Immunosuppression UV-wavelength dependence: UVA-induced early pigmentation
UVR, in addition to inducing mutations which may lead to skin (immediate pigment darkening, IPD) and UVB-induced delayed
cancer, also causes suppression of certain aspects of the immune pigmentation (delayed tanning, DT). Tanning provides a limited
system [1,22]. In human skin all the necessary cellular require- degree of protection against subsequent UVR (though not against
ments to elicit anti-tumour immunity are present. Therefore, the the primary mutagenic effects of UV exposure). Tanning induced
development of skin cancer appears to involve failures in or by solar-simulated UVR in human skin (skin types II and III)
suppression of immune responses [23]. For this reason, any induces only moderate protection against erythema [28], and
suppression of the immune system may facilitate the development pigmentation delivers a sun protection factor of only about 2 for
of UV-induced skin cancer. Patients with organ transplants who CPD induction in persons of skin types III/IV (i.e. it doubles the
receive immunosuppressive medication are very prone to skin amount of UVR exposure necessary to produce a similar effect) and
cancer [24]. gives no protection at all for skin types I/II [29,30].
Exposure to UVB suppresses the immune system by (1) The tanning process appears to involve cross-talk between
inducing the production of immunosuppressive mediators, (2) keratinocytes and melanocytes, and results in the transfer of
damaging and triggering the premature migration of the antigen- melanin-containing melanosomes into the more superficially
presenting cells required to stimulate antigen-specific immune located keratinocytes, where the pigment forms a ‘‘cap’’ over
responses, (3) inducing the generation of suppressor cells, and (4) the sun-exposed surface of the nucleus [31].
inhibiting the activation of effector and memory T cells [1]. However, the stimulus that triggers the tanning pathway [27] is
For UVA-induced immunosuppression the production of DNA damage. Therefore, it is very unlikely that tanning can occur
reactive oxygen species and reactive nitrogen species alters the without an increase in carcinogenic risk. The proposed concept of
redox equilibrium, targeting proteins, lipids and DNA. This altered ‘‘safe tanning’’ thus warrants scientific scepticism [32], and tan
equilibrium may modulate immunocompetent cells, resulting in should be considered a sign of damaged skin, not a sign of good
aberrant behaviour and migration of antigen-presenting cells, the health.
inhibition of T-cell activation, and generation of suppressor cells
[25]. In experimental systems and in human skin, UVR can induce 1.3.4. Vitamin D production
immunosuppression locally and systemically [1]. Immunosuppres- UVB triggers cutaneous synthesis of pre-vitamin D from
sion by solar-simulated UVR in men has been observed at doses 7-dehydrocholesterol [33,34]. This is the body’s principal source
S78 R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83

of vitamin D, because usually only small amounts are obtained exposure (sum of ‘‘intermittent’’ and ‘‘chronic’’ exposure) generally
from the diet [35]. It has long been known that vitamin D showed weak, null or negative associations [1,49].
deficiency leads to severe bone disorders such as rickets and Recent large meta-analyses indeed show that most risk factors
osteomalacia. There is also strong evidence that vitamin D for CM are associated with UVR, such as the number of acquired
deficiency is associated with secondary hyperparathyroidism, nevi (which are UV-induced), number of atypical nevi, sunburn,
bone loss, fractures, muscle weakness and reduced calcium intermittent sun exposure, presence of actinic tumours and total
absorption [36,37]. sun exposure (all statistically significantly related with CM).
In addition to these well-known positive effects of vitamin D, Chronic sun exposure seemed not to be associated with overall CM
there is some debate as to whether increased levels of vitamin D risk. However, studies which focus more on the anatomical site of
(and thereby UVR) potentially have a protective effect on the the melanoma show that CM of the head and neck is strongly
development of certain types of cancer. The evidence base of such associated with actinic keratoses (caused by ‘‘chronic’’ UVR
an effect is still poor, and current evidence from randomised trials exposure), whereas CM on the trunk is strongly associated with
does not support it. acquired nevi (‘‘intermittent’’ UVR exposure) [1,50,51].
Other beneficial effects of vitamin D on many other conditions About 50–60% of all CMs carry BRAF mutations, leading to
(in addition to cancer) have been suggested: for instance, kinase activation in the MAPK pathway inducing proliferation of
cardiovascular disease, metabolic syndrome, diabetes, asthma, melanocytes and impairment of apoptotic response to metabolic
multiple sclerosis, neuropsychological functioning, pregnancy stress. BRAF mutations occur more frequently in CM on intermit-
outcomes, and overall mortality. The evidence for such effects is tent UVR-exposed human skin areas than in CM in more
weak, and alternative explanations for findings in observational chronically exposed areas of human skin [52], indicating that
studies are plausible (e.g. confounding, reverse causation, etc.); UVR exposure pattern is a determinant of mutation induction.
further randomised trials seem warranted [38–41]. Although BRAF mutations make up only about 2–3% ‘‘UV signature
The World Health Organization (WHO) and other institutions mutations’’ [53], they seem to play an important role in the
request more ‘‘balanced’’ communications when dealing with UVR aetiology of CM. This has been shown in a recent sequencing study
protection [42], but more scientific evidence backing up this of a melanoma metastasis genome, which demonstrated that
request appears to be needed, especially in the context of UV about 70% of single- and di-nucleotide substitutions in the genome
causing skin cancer. In 2008, a literature review by the IARC represent C–T, CC–TT ‘‘UV signature mutations’’ [54].
suggested a possible protective role for high vitamin D levels in Important risk factors for NMSC are closely related to the
colon cancer and adenomas of the colon [43–46]. However, a individual sensitivity of the skin to UVR, such as skin type [55,56]),
protective role for vitamin D supplementation in the development presence of actinic keratosis [57], a personal history of NMSC [58],
of colon cancer was not observed in one of the largest and immunosuppression [59–61].
interventional trials on vitamin D supplementation [47]. There is increasing evidence that certain risk factors for CM (e.g.
intermittent UVR exposure and sunburn) are also relevant for BCC
2. Cancer association with ultraviolet radiation (UVR) [62,63]; UV signature mutations have been found in the p53, PTCH
and smoothened genes [64,65], all involved in BCC development.
2.1. Carcinogenicity of UVR This has been taken as a further indication that UVR plays an
important role in the aetiology of BCC.
UVA and UVB from the sun and from UV-emitting devices (e.g. SCC appears frequently on sun-exposed areas of the human
sunbeds) are classified as known carcinogens in humans (IARC body (nose, forehead, ears) and depends to a high degree on total
Group 1) [1]. This classification is based on experimental and cumulative sun exposure [49]. Therefore, SCCs are common in
epidemiological data and their meta-analyses. It was concluded occupationally UVR-exposed populations such as farmers, street
that there is sufficient evidence in humans for the carcinogenicity workers, or seamen.p53 mutations are found in more than 90% of
of solar radiation in CM, BCC and SCC. With regards to artificial in situ SCC cases [66]. These mutations are predominantly of a ‘‘UV
sources of UVR, there is sufficient evidence for an increased risk of signature’’ type and occur non-randomly in the p53 gene in so-
CM and of ocular melanoma, and a positive association was called ‘‘mutational hot spots’’, which are located in the gene in
observed between sunbed use and SCC [1]. certain positions where nucleotide excision repair of pre-
Skin cancer is the most common type of cancer in fair-skinned mutagenic lesions (CPDs) is hindered [67]. According to a well-
populations around the world [48]. CM accounts for about 5–10% described model for SCC development, specific p53 mutations lead
of all skin cancers, whereas of non-melanoma skin cancer (NMSC) to a pre-cancerous skin lesion (actinic keratosis, AK) where one
BCC accounts for approximately 80–85% and SCC for 15–20%. CM allele of the p53 gene is already mutated. This mutation disturbs
derives from pigment- (melanin-)producing melanocytes, whereas the p53-dependent apoptosis of UVR-damaged cells (‘‘sunburn
NMSC develops from epidermal keratinocytes. cells’’) and favours clonal expansion of AK cells [68]. If AK cells are
Overwhelming evidence from epidemiological studies and further exposed to UVR, this can induce mutation of the second p53
basic science shows that the main risk factor for the three main allele, leading to a total loss of the ‘‘p53 checkpoint’’ responsible for
types of skin cancer is UVR; most other important risk factors are cell-cycle control in skin keratinocytes. This leads to uncontrolled
related to sensitivity to UVR (sensitive skin type, characterised by cell division and eventually to the development of invasive SCC
low MED) [1]. alongside additional gene mutations (e.g., RAS) [69,70]. There is
Most of the evidence for a causal relationship between solar good evidence that SCC in mouse models as well as in human skin
radiation and CM comes from descriptive epidemiological and case- originates from inter-follicular epidermal stem cells [71] which
control studies. The main measures of exposure were participant- might not be able to fully repair UVR-induced damage and
recalled sun exposure. ‘‘Intermittent’’ sun exposure – which loosely therefore accumulate persistent DNA lesions (CPD retaining basal
equates with certain sun-intensive activities such as sunbathing, cells) [72,73].
outdoor recreations, and holidays in sunny climates – has shown
moderate to strong positive associations with melanoma, particu- 2.2. Burden of skin cancer
larly if exposure occurred during childhood or adolescence (see
below). However, ‘‘chronic’’ or ‘‘more continuous’’ exposure, which The incidence of both CM and NMSC has increased steeply in
generally equates with ‘‘occupational’’ exposure, and total sun fair-skinned populations over the past 50 years [74,75]. Worldwide,
 R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83 S79

the highest incidence rates are by far those observed in Australia and registry; registration of BCC is either absent or rather sporadically
New Zealand, where fair-skinned populations are exposed to registered in population-based cancer registries.
intensive UVR [74,75]. Among European countries, Denmark, Finland, Scotland, Malta
According to estimates for 2012, more than 230,000 new cases and the Netherlands have extensive population-based registration
of CM occurred globally, of which 100,000 occurred within Europe of NMSC over long time periods. Age-standardised incidence rates
[76]. The lifetime risk of CM is highest in New Zealand and (ASRs) of primary BCC are estimated to be 77–158 cases per
Australia (3.6%) compared to 0.3–1.6% in European countries 100,000 person-years in those regions [78]. In Denmark, the BCC
[74]. In Europe, incidence rates are particularly high in the Nordic ASR increased from 27.1 to 96.6 cases per 100,000 among women
countries, Switzerland, the Netherlands, the Czech Republic and and from 34.2 to 91.2 cases among men between 1978 and 2007
Slovenia, while Mediterranean countries, as well as the Baltic and (world standard population). For the Netherlands, an increase from
Eastern European countries, tend to have lower rates [74,76] 34.4 to 157.3 among women and from 40.2 to 164.7 among men
(Fig. 2). In most parts of Europe, the incidence rates are higher was observed between 1973 and 2009 (per 100,000, European
among women than among men. Recent findings indicate a standard) [79]. The largest relative increases in BCC in both
uniformly increasing trend in European countries over the last Denmark and the Netherlands occurred in young women [79,80]. A
decades, with the strongest increases seen among older ages and recent systematic review of geographical variations and trends
with strong North-to-South and East-to-West variation (higher worldwide indicated that the BCC incidence rates have increased at
incidences in the North and East) [74,77]. However, for Norway a similar rate (about 5.5% per year on average) over the past four
and perhaps also France and Iceland indications of a levelling off in decades in mainland Europe [75].
CM incidence rates are observed, most notably in young people In comparison to BCC, the SCC incidence rates are much lower
aged 25–44 years. Nonetheless, incidence rates continue to rise [75,80,81]: for instance, 12 cases per 100,000 person-years among
irrespective of age in most European populations, and predictions women and 19.1 among men in Denmark (world standard) [80],
suggest a continuation of this trend [74,77]. 13.8 among women and 36.9 among men in Scotland [81], and 20.5
Incidence rates and time trends are difficult to estimate for among women and 35.4 among men in the Netherlands (per
NMSC, as they are often either not registered at all or incompletely 100,000, European standard) [82]. However, SCC incidence rates
covered by population-based cancer registries [75]. Of the specific are increasing rapidly, although the rate of increase varies between
NMSC types, SCC is included in relatively few cancer registries. populations [75].
Actinic keratosis is considered by some to be in situ SCC, and to our In general, the steep increase in incidence rates of all skin
knowledge is not registered by any population-based cancer cancers has been attributed to population changes in lifestyle from
sun avoidance towards sun-seeking behaviour, as well as improved
[(Fig._2)TD$IG] diagnosis and registration. A more positive attitude towards
sunbathing, more revealing fashion trends (e.g. the bikini in the
1960s), more outdoor leisure activities, and an increasing trend of
holidays spent at sunny destinations has resulted in increasing
both intermittent and cumulative sun exposure, and probably to
increasing skin cancer rates [83,84]. In the 1960s, artificial UV
sources (e.g. tanning devices such as sunbeds) were introduced and
became increasingly popular during the following decades [85,86].
According to recent estimates 55,500 deaths from melanoma
occurred worldwide in 2012, including 22,200 in Europe
[76]. Whilst NMSC represents the most frequent type of cutaneous
cancer, and contributes to the rising morbidity as well as to a
significant economic burden to health services, mortality has
remained consistently low (only <0.1% of diagnosed cases die
because of NMSC) [87,88]. CM is the most serious skin cancer
due its high potential for metastasis [89]. CM mortality rates in
Europe range between 3.6/100,000 in Norway and 0.7/100,000 in
Malta (Fig. 3) [76]. Overall, mortality rates continue to rise in
several European countries as a result of increasing incidence,
particularly in older age groups. However, in some countries – for
instance Scandinavia – mortality rates appear to be already
levelling off [90]. Survival of CM depends on the gender of the
patient (better in women irrespective of stage), histological type,
tumour thickness, body site, and – most importantly – stage at
diagnosis [86]. A steady improvement in survival among CM
patients has been reported over the last decades, with 5-year
survival exceeding 80% in Europe [91]. Improvements in survival
are most likely due to diagnosis at earlier stages of the disease for
which effective treatment is available. Recently important break-
throughs have been made in the treatment of late-stage cases,
which may be reflected in improved survival in the coming years
Fig. 2. Estimates of age-standardised incidence rates (ASR) of malignant melanoma [92].
in 2012: European variation in estimates of national age-standardised cutaneous
malignant melanoma incidence rates (per 100,000) in 2012 (a) among men, and (b) 2.3. UVR risk in children
among women, all ages.
Adapted from Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality
Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency Epidemiological findings from several migrant studies into
for Research on Cancer; 2013. Available from: http://globocan.iarc.fr. countries with a high UVI indicate childhood as a susceptible
[(Fig._3)TD$IG]
S80 R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83

(82% of all CMs), and altogether 3.5% of cancers in both sexes

combined (86% of all CMs), NMSC being excluded from this
analysis; the population-attributable fractions are likely to be
comparable for other European countries [101].
UVR is received mainly from natural but also from artificial
sources, and individual exposure to either source can be relatively
easily modified. UVR from the sunlight can be reduced, but cannot
be completely avoided. Moreover, complete avoidance of UVR
exposure should not be the aim, because of the health benefits of
UVR exposure (largely related to vitamin D, see below), and also
the health benefits related to physical outdoor activities [102]. Ef-
fective sun protection methods allow being outdoors without
excessive direct sun exposure. There is scientific evidence that too
much UVR exposure should particularly be avoided during
childhood and adolescence.
Specifically with regard to artificial UVR, a 2012 meta-analysis
including 27 epidemiological studies reported a meta-relative risk
of ever versus never use of sunbeds for CM of 1.20 (95% confidence
interval (95%CI) 1.08–1.34), increasing to 1.59 (95%CI 1.36–1.85) if
the first sunbed use was before the age of 35 years (13 studies)
[103]. A dose–response relationship was seen with a 1.8% (95%CI
0–3.8%) increase in CM risk for each additional session of sunbed
use per year. From this, an estimated 5% of all CM cases in Europe
could be attributable to sunbed use, most of them occurring in
women. In the meta-analysis, relative risk estimates of ever versus
never sunbed use for SCC was 2.23 (95%CI 1.39–3.57) and for BCC
1.09 (95%CI: 1.01–1.18) [103].
UVR from artificial sources (i.e. tanning devices) can be
completely avoided by the individual.
Fig. 3. Estimates of age-standardised mortality rates (ASR) of malignant melanoma Overall, this leads to the evidence-based recommendation:
in 2012; European variation in estimates of national age-standardised cutaneous ‘‘Avoid too much sun, especially for children. Use sun protection.
malignant melanoma mortality rates (per 100,000) in 2012 (a) among men, and (b) Do not use sunbeds.’’
among women, all ages.
Adapted from Ferlay J, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality
4. Individual action for protection
Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency
for Research on Cancer; 2013. Available from: http://globocan.iarc.fr.
The best protection against natural UVR is to avoid exposure by
staying inside when the UVI is highest or, second best, by seeking
period for UV carcinogenesis. In some studies conducted in shade. However, even in the shade one receives UVR, depending on
Australia the incidence of and mortality from NMSC was generally the source of the shade [104,105] and the amount of reflection
lower in migrants from Northern Europe than in those born in from the ground surface. A parasol used on a beach might block
Australia [93,94]. However, immigrants who arrived during the around 40–50% of the UVR [105]; the rest reaches the skin by passing
first 10 years of life had the same risk of BCC as people born in through the parasol or being reflected by the sand (up to 15%).
Australia. Migration into Australia later in life resulted in a lower Alternatively, the skin can be covered with textiles, clothing and
relative risk (of the order of 0.2) compared to that in people born in a (preferably wide-brimmed) hat; loose clothing with long sleeves
Australia. Similar results were obtained in migration studies in made of tightly woven fabrics provides good protection (UV
Israel, Australia and New Zealand, showing that persons who protection factor >15) [106,107]. Sunglasses with UV protection
migrated during childhood had the same relative risk of developing shield the eyes against the harmful effects of sunlight [107].
CM as if they were born in the country to which they moved, while Application of sunscreens is another possibility for reducing the
the relative risk decreased if they migrated later in life [95–98]. The harmful effects of UVR exposure. Sunscreens have been developed
underlying cellular and molecular biological mechanisms for an to prevent sunburn. If sunscreens are properly used, they have
increased risk of CM induction at young ages may lie in the fact that been shown to reduce the risk of developing actinic keratosis (AK)
the bulge region of hair follicles hosting melanocytic stem cells are and NMSCs [108–110]. There was concern that sunscreen use
located deeper (more UV-protected) in the skin in adults (terminal could increase the risk of CM as it motivates people to stay longer
hair) than in pre-pubertal children (vellus hair) [99,100]. in the sun, but recent studies show that proper application of
sunscreens, under controlled conditions, reduces the CM risk as
3. Scientific justification for the recommendation well [111,112]. According to the standards of the Food and Drug
Administration of the United States (US FDA) for sun protection
The carcinogenicity of UVR is well documented [1]. UVR is factor (SPF) testing, proper application requires 2 mg/cm2 of
the predominant cause of all types of skin cancer, which is sunscreen on the body surface to protect the skin [113]. However,
the commonest cancer in fair-skinned (i.e. the European) popula- application thickness in ‘‘real life’’ is estimated to be 0.5–1.0 mg/
tions. CM, when diagnosed at a late stage, is a lethal disease, while cm2, which lowers the effective SPF. Sunscreen failures can
early-stage CM and (normally) NMSC have very good prognoses. therefore stem from insufficient amounts being applied, but also
However, NMSC sometimes occurs at visible body sites (e.g. from infrequent reapplication [114,115]. The American Academy
the face), resulting in disfigurement, and carries a substantial of Dermatology (AAD) recommends regular sunscreen use to
economic burden. In the UK, UVR has been estimated to cause 3.4% prevent skin cancer. Selecting a sunscreen with broad band (UVB/
of all cancers in men (90% of all CMs), 3.5% of all cancers in women UVA) coverage is vital, and daily use of an SPF30 product is
[(Fig._4)TD$IG] R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83 S81

recommendation: ‘‘Avoid too much sun, especially for children. Use

sun protection. Do not use sunbeds.’’

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

The European Code Against Cancer project was co-funded by

the European Union [grant agreement numbers: 2011 53 05; 2010
53 04 and 2007IARC01] and the International Agency for Research
on Cancer. The authors alone are responsible for the views
expressed in this manuscript.

References

[1] IARC. A review of human carcinogens. D. Radiation. IARC Monographs on the

Evaluation of Carcinogenic Risks to Humans. IARC Monogr 2012;100:35–101
(D). Solar and UV Radiation.
[2] El Ghissassi F, Baan R, Straif K, Grosse Y, Secretan B, Bouvard V, et al. A review
of human carcinogens – Part D: Radiation. Lancet Oncol 2009;10:751–2.
Fig. 4. Action spectra for pre-vitamin D3 formation (blue), induction of squamous-
[3] Diffey BL. Solar ultraviolet radiation effects on biological systems. Phys Med
cell carcinomas (SCCs) and cyclobutane-pyrimidine dimers (CPDs) (nearly identical, Biol 1991;36:299–328.
green), and erythema induction (red) (taken from [118]). [4] Diffey BL. Human exposure to ultraviolet radiation. Semin Dermatol
1990;9:2–10.
[5] Leslie KS, Lodge E, Garioch JJ. A comparison of narrowband (TL-01) UVB-
recommended. Sunscreens must be applied uniformly, 15–30 min induced erythemal response at different body sites. Clin Exp Dermatol
before exposure. To remain effective, they must be re-applied often 2005;30:337–9.
(at least every 2 h), especially when perspiring or swimming [6] Diffey BL, Farr PM. The normal range in diagnostic phototesting. Br J Dermatol
1989;120:517–24.
[113]. The vehicle type of the sunscreen determines its durability
[7] Ridley AJ, Whiteside JR, McMillan TJ, Allinson SL. Cellular and sub-cellular
and water resistance. The FDA designates sunscreens with intact responses to UVA in relation to carcinogenesis. Int J Radiat Biol
photo-protective properties after 20 min exposure to water as 2009;85:177–95.
‘‘water-resistant’’ [113]. [8] Didier C, Emonet-Piccardi N, Beani JC, Cadet J, Richard MJ. L-Arginine
increases UVA cytotoxicity in irradiated human keratinocyte cell line: poten-
Exposure to artificial UVR should be completely avoided, unless tial role of nitric oxide. FASEB J 1999;13:1817–24.
under medical guidance. In contrast to what is often advertised by [9] Kielbassa C, Roza L, Epe B. Wavelength dependence of oxidative DNA damage
the tanning industry, the use of sunbeds to increase (or stabilise) induced by UV and visible light. Carcinogenesis 1997;18:811–6.
[10] Didier C, Pouget JP, Cadet J, Favier A, Beani JC, Richard MJ. Modulation of
vitamin D serum levels in order to ‘‘stay healthy’’ is not necessary. exogenous and endogenous levels of thioredoxin in human skin fibroblasts
The action spectrum for the induction of UV-induced DNA damage, prevents DNA damaging effect of ultraviolet A radiation. Free Radic Biol Med
skin cancer induction and cutaneous vitamin D production are 2001;30:537–46.
[11] Pouget JP, Douki T, Richard MJ, Cadet J. DNA damage induced in cells by
broadly alike (Fig. 4), with their most effective wavelengths in the gamma and UVA radiation as measured by HPLC/GC–MS and HPLC-EC and
UVB range 290–310 nm. Therefore, no such advertised vitamin D comet assay. Chem Res Toxicol 2000;13:541–9.
production is possible without increasing DNA damage and hence [12] Wischermann K, Popp S, Moshir S, Scharfetter-Kochanek K, Wlaschek M, de
Gruijl F, et al. UVA radiation causes DNA strand breaks, chromosomal
an increased skin cancer risk [116]. aberrations and tumorigenic transformation in HaCaT skin keratinocytes.
Recent findings have shown that the amount of UVR needed to Oncogene 2008;27:4269–80.
produce a sufficient level of vitamin D under ‘‘realistic’’ conditions [13] Greinert R, Volkmer B, Henning S, Breitbart EW, Greulich KO, Cardoso MC,
et al. UVA-induced DNA double-strand breaks result from the repair of
(e.g. summer sun at noontime, informal clothing such as T-shirt
clustered oxidative DNA damages. Nucleic Acids Res 2012;40:10263–73.
and short trousers) is limited to 27–38 min, depending on latitude [14] Chen IP, Henning S, Faust A, Boukamp P, Volkmer B, Greinert R. UVA-
(30–608 N). However, one should keep in mind that these times are induced epigenetic regulation of P16(INK4a) in human epidermal kerati-
already long enough to induce erythema for sensitive skin types nocytes and skin tumor derived cells. Photochem Photobiol Sci 2012;11:
180–90.
(skin type I/II). Times longer than 27–38 min are needed to [15] Mouret S, Baudouin C, Charveron M, Favier A, Cadet J, Douki T. Cyclobutane
produce sufficient vitamin D, if UV exposure does not occur around pyrimidine dimers are predominant DNA lesions in whole human skin
noontime or in other seasons of the year. To reach the levels of UVR exposed to UVA radiation. Proc Natl Acad Sci U S A 2006;103:13765–70.
[16] Mouret S, Leccia MT, Bourrain JL, Douki T, Beani JC. Individual photosensitiv-
exposure sufficient to regulate vitamin D levels one does not have ity of human skin and UVA-induced pyrimidine dimers in DNA. J Invest
to spend much time in the sun, or use sunbeds. Short periods Dermatol 2011;131:1539–46.
outdoors, perhaps repetitively, are sufficient in most circum- [17] Mouret S, Philippe C, Gracia-Chantegrel J, Banyasz A, Karpati S, Markovitsi D,
et al. UVA-induced cyclobutane pyrimidine dimers in DNA: a direct photo-
stances [117,118]. People with vitamin D deficiency should consult chemical mechanism? Org Biomol Chem 2010;8:1706–11.
their physician. [18] Greinert R, Boguhn O, Harder D, Breitbart EW, Mitchell DL, Volkmer B. The
Worldwide, several countries have legislative limits or bans dose dependence of cyclobutane dimer induction and repair in UVB-irradi-
ated human keratinocytes. Photochem Photobiol 2000;72:701–8.
on sunbed use for minors [119]. Regulatory action is also required to
[19] Matsumura Y, Ananthaswamy HN. Molecular mechanisms of photocarcino-
support the individual to take action. For outdoor workers, sun genesis. Front Biosci 2002;7:d765–83.
protection has to be provided, complemented with education on [20] Rochette PJ, Lacoste S, Therrien JP, Bastien N, Brash DE, Drouin R. Influence of
cytosine methylation on ultraviolet-induced cyclobutane pyrimidine dimer
how and when to apply it, and with instructions to comply with
formation in genomic DNA. Mutat Res 2009;665:7–13.
the safety guidelines. For the general public shady places need to be [21] Mitchell DL, Brash DE, Nairn RS. Rapid repair kinetics of pyrimidine(6-
provided where people tend to stay in the sun for longer time 4)pyrimidone photoproducts in human cells are due to excision rather than
periods, in particular in kindergartens and schools. conformational change. Nucleic Acids Res 1990;18:963–71.
[22] Fisher MS, Kripke ML. Systemic alteration induced in mice by ultraviolet light
Overall, scientific knowledge on the excess cancer risk from UVR irradiation and its relationship to ultraviolet carcinogenesis. Proc Natl Acad
and on effective protection measures leads to the evidence-based Sci U S A 1977;74:1688–92.
S82 R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83

[23] Schroder JM, Reich K, Kabashima K, Liu FT, Romani N, Metz M, et al. Who is [54] Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Green-
really in control of skin immunity under physiological circumstances – man CD, et al. A comprehensive catalogue of somatic mutations from a
lymphocytes, dendritic cells or keratinocytes? Exp Dermatol 2006;15: human cancer genome. Nature 2010;463:191–6.
913–29. [55] Gallagher RP, Hill GB, Bajdik CD, Fincham S, Coldman AJ, McLean DI, et al.
[24] Bordea C, Wojnarowska F, Millard PR, Doll H, Welsh K, Morris PJ. Skin cancers Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin
in renal-transplant recipients occur more frequently than previously recog- cancer I. Basal cell carcinoma. Arch Dermatol 1995;131:157–63.
nized in a temperate climate. Transplantation 2004;77:574–9. [56] Gallagher RP, Hill GB, Bajdik CD, Coldman AJ, Fincham S, McLean DI, et al.
[25] Norval M, McLoone P, Lesiak A, Narbutt J. The effect of chronic ultraviolet Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin
radiation on the human immune system. Photochem Photobiol 2008;84: cancer II. Squamous cell carcinoma. Arch Dermatol 1995;131:164–9.
19–28. [57] Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J
[26] Damian DL, Patterson CR, Stapelberg M, Park J, Barnetson RS, Halliday GM. UV Am Acad Dermatol 2000;42:4–7.
radiation-induced immunosuppression is greater in men and prevented by [58] Marcil I, Stern RS. Risk of developing a subsequent nonmelanoma skin cancer
topical nicotinamide. J Invest Dermatol 2008;128:447–54. in patients with a history of nonmelanoma skin cancer: a critical review of
[27] Gilchrest BA, Eller MS. DNA photodamage stimulates melanogenesis and other the literature and meta-analysis. Arch Dermatol 2000;136:1524–30.
photoprotective responses. J Investig Dermatol Symp Proc 1999;4:35–40. [59] Espana A, Redondo P, Fernandez AL, Zabala M, Herreros J, Llorens R, et al.
[28] Sheehan JM, Potten CS, Young AR. Tanning in human skin types II and III offers Skin cancer in heart transplant recipients. J Am Acad Dermatol 1995;32:
modest photoprotection against erythema. Photochem Photobiol 1998;68: 458–65.
588–92. [60] Jensen P, Hansen S, Moller B, Leivestad T, Pfeffer P, Geiran O, et al. Skin cancer
[29] Potten CS, Chadwick CA, Cohen AJ, Nikaido O, Matsunaga T, Schipper NW, in kidney and heart transplant recipients and different long-term immuno-
et al. DNA damage in UV-irradiated human skin in vivo: automated direct suppressive therapy regimens. J Am Acad Dermatol 1999;40:177–86.
measurement by image analysis (thymine dimers) compared with indirect [61] Ong CS, Keogh AM, Kossard S, Macdonald PS, Spratt PM. Skin cancer in
measurement (unscheduled DNA synthesis) and protection by 5-methox- Australian heart transplant recipients. J Am Acad Dermatol 1999;40:27–34.
ypsoralen. Int J Radiat Biol 1993;63:313–24. [62] Kricker A, Armstrong BK, English DR, Heenan PJ. Does intermittent sun
[30] Young AR, Potten CS, Chadwick CA, Murphy GM, Hawk JL, Cohen AJ. Photo- exposure cause basal cell carcinoma? A case-control study in Western
protection and 5-MOP photochemoprotection from UVR-induced DNA Australia. Int J Cancer 1995;60:489–94.
damage in humans: the role of skin type. J Invest Dermatol 1991;97: [63] Zanetti R, Rosso S, Martinez C, Nieto A, Miranda A, Mercier M, et al. Compari-
942–8. son of risk patterns in carcinoma and melanoma of the skin in men: a multi-
[31] Duval C, Regnier M, Schmidt R. Distinct melanogenic response of human centre case-case-control study. Br J Cancer 2006;94:743–51.
melanocytes in mono-culture, in co-culture with keratinocytes and in recon- [64] Kim MY, Park HJ, Baek SC, Byun DG, Houh D. Mutations of the p53 and PTCH
structed epidermis, to UV exposure. Pigment Cell Res 2001;14:348–55. gene in basal cell carcinomas: UV mutation signature and strand bias. J
[32] Tran TT, Schulman J, Fisher DE. UV and pigmentation: molecular mechanisms Dermatol Sci 2002;29:1–9.
and social controversies. Pigment Cell Melanoma Res 2008;21:509–16. [65] Ratner D, Peacocke M, Zhang H, Ping XL, Tsou HC. UV-specific p53 and PTCH
[33] Holick MF. Vitamin D status: measurement, interpretation, and clinical mutations in sporadic basal cell carcinoma of sun-exposed skin. J Am Acad
application. Ann Epidemiol 2009;19:73–8. Dermatol 2001;44:293–7.
[34] Holick MF, Chen TC, Lu Z, Sauter E, Vitamin. D and skin physiology: a D- [66] Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J Dermatol
lightful story. J Bone Miner Res 2007;22(Suppl. 2):V28–33. 2002;146(Suppl. 61):20–3.
[35] Hollis BW. Circulating 25-hydroxyvitamin D levels indicative of vitamin D [67] Tornaletti S. DNA repair in mammalian cells: transcription-coupled DNA
sufficiency: implications for establishing a new effective dietary intake repair: directing your effort where it’s most needed. Cell Mol Life Sci
recommendation for vitamin D. J Nutr 2005;135:317–22. 2009;66:1010–20.
[36] Bischoff HA, Stahelin HB, Dick W, Akos R, Knecht M, Salis C, et al. Effects of [68] Zhang W, Hanks AN, Boucher K, Florell SR, Allen SM, Alexander A, et al. UVB-
vitamin D and calcium supplementation on falls: a randomized controlled induced apoptosis drives clonal expansion during skin tumor development.
trial. J Bone Miner Res 2003;18:343–51. Carcinogenesis 2005;26:249–57.
[37] Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive associa- [69] Brash DE. Roles of the transcription factor p53 in keratinocyte carcinomas. Br
tion between 25-hydroxy vitamin D levels and bone mineral density: a J Dermatol 2006;154(Suppl. 1):8–10.
population-based study of younger and older adults. Am J Med 2004;116: [70] Brash DE, Ziegler A, Jonason AS, Simon JA, Kunala S, Leffell DJ. Sunlight and
634–9. sunburn in human skin cancer: p53, apoptosis, and tumor promotion. J
[38] IOM. Institute of medicine. Dietary reference intakes for calcium and vitamin Investig Dermatol Symp Proc 1996;1:136–42.
D. Washington (DC): The National Academies Press, 2011. [71] Watt FM, Lo Celso C, Silva-Vargas V. Epidermal stem cells: an update. Curr
[39] Autier P, Boniol M, Pizot C, Mullie P, Vitamin. D status and ill health: a Opin Genet Dev 2006;16:518–24.
systematic review. Lancet Diab Endocrinol 2014;2:76–89. [72] Mitchell DL, Volkmer B, Breitbart EW, Byrom M, Lowery MG, Greinert R.
[40] Lamberg-Allardt C, Brustad M, Meyer HE, Steingrimsdottir L. Vitamin D – a Identification of a non-dividing subpopulation of mouse and human epider-
systematic literature review for the 5th edition of the Nordic Nutrition mal cells exhibiting high levels of persistent ultraviolet photodamage. J
Recommendations. Food Nutr Res 2013;57. Invest Dermatol 2001;117:590–5.
[41] Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, [73] Nijhof JG, van Pelt C, Mulder AA, Mitchell DL, Mullenders LH, de Gruijl FR.
et al. Vitamin D supplementation for prevention of mortality in adults. Epidermal stem and progenitor cells in murine epidermis accumulate UV
Cochrane Database Syst Rev 2014;1:CD007470. damage despite NER proficiency. Carcinogenesis 2007;28:792–800.
[42] http://www.who.int/uv/sun_protection/en/. [74] Erdmann F, Lortet-Tieulent J, Schuz J, Zeeb H, Greinert R, Breitbart EW, et al.
[43] Zeeb H, Greinert R. The role of vitamin D in cancer prevention: does UV International trends in the incidence of malignant melanoma 1953–2008 – are
protection conflict with the need to raise low levels of vitamin D? Dtsch recent generations at higher or lower risk? Int J Cancer 2013;132:385–400.
Arztebl Int 2010;107:638–43. [75] Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide
[44] IARC. IARC working group reports vitamin D and cancer; 2008. incidence of nonmelanoma skin cancer. Br J Dermatol 2012;166:1069–80.
[45] Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: [76] Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al.
longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment GLOBOCAN 2012 v1.0, cancer incidence and ortality worldwide: IARC Cancer
Pharmacol Ther 2009;30:113–25. Base No. 11. Lyon, France: International Agency for Research on Cancer, 2013 .
[46] Huncharek M, Muscat J, Kupelnick B. Colorectal cancer risk and dietary intake [77] Arnold M, Holterhues C, Hollestein LM, Coebergh JW, Nijsten T, Pukkala E,
of calcium, vitamin D, and dairy products: a meta-analysis of 26,335 cases et al. Trends in incidence and predictions of cutaneous melanoma across
from 60 observational studies. Nutr Cancer 2009;61:47–69. Europe up to 2015. J Eur Acad Dermatol Venereol 2013;28(9):1170–8.
[47] Wactawski-Wende J, Kotchen JM, Anderson GL, Assaf AR, Brunner RL, O’Sul- [78] de Vries E, Micallef R, Brewster DH, Gibbs JH, Flohil SC, Saksela O, et al.
livan MJ, et al. Calcium plus vitamin D supplementation and the risk of Population-based estimates of the occurrence of multiple vs first primary basal
colorectal cancer. N Engl J Med 2006;354:684–96. cell carcinomas in 4 European regions. Arch Dermatol 2012;148:347–54.
[48] Diepgen TL, Mahler V. The epidemiology of skin cancer. Br J Dermatol [79] Flohil SC, Seubring I, van Rossum MM, Coebergh JW, de Vries E, Nijsten T.
2002;146(Suppl. 61):1–6. Trends in Basal cell carcinoma incidence rates: a 37-year Dutch observational
[49] Armstrong BK, Kricker A. The epidemiology of UV induced skin cancer. J study. J Invest Dermatol 2013;133:913–8.
Photochem Photobiol B 2001;63:8–18. [80] Birch-Johansen F, Jensen A, Mortensen L, Olesen AB, Kjaer SK. Trends in the
[50] Purdue MP, From L, Armstrong BK, Kricker A, Gallagher RP, McLaughlin JR, incidence of nonmelanoma skin cancer in Denmark 1978–2007: rapid inci-
et al. Etiologic and other factors predicting nevus-associated cutaneous dence increase among young Danish women. Int J Cancer 2010;127:2190–8.
malignant melanoma. Cancer Epidemiol Biomarkers Prev 2005;14: [81] Doherty VR, Brewster DH, Jensen S, Gorman D. Trends in skin cancer inci-
2015–22. dence by socioeconomic position in Scotland, 1978–2004. Br J Cancer
[51] Whiteman DC, Stickley M, Watt P, Hughes MC, Davis MB, Green AC. Anatomic 2010;102: 1661–4.
site, sun exposure, and risk of cutaneous melanoma. J Clin Oncol 2006;24: [82] Hollestein LM, de Vries E, Nijsten T. Trends of cutaneous squamous cell
3172–7. carcinoma in the Netherlands: increased incidence rates, but stable relative
[52] Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, et al. survival and mortality 1989–2008. Eur J Cancer 2012;48:2046–53.
Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst [83] Kojo K, Jansen CT, Nybom P, Huurto L, Laihia J, Ilus T, et al. Population
2003;95:1878–90. exposure to ultraviolet radiation in Finland 1920–1995: exposure trends and
[53] Hocker T, Tsao H. Ultraviolet radiation and melanoma: a systematic review a time-series analysis of exposure and cutaneous melanoma incidence.
and analysis of reported sequence variants. Hum Mutat 2007;28:578–88. Environ Res 2006;101:123–31.
 R. Greinert et al. / Cancer Epidemiology 39S (2015) S75–S83 S83

[84] Bentham G, Aase A. Incidence of malignant melanoma of the skin in Norway, [103] Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to
1955–1989: associations with solar ultraviolet radiation, income and holi- sunbed use: systematic review and meta-analysis. BMJ 2012;345:e4757.
days abroad. Int J Epidemiol 1996;25:1132–8. [104] Parisi AV, Kimlin MG, Wong JC, Wilson M. Solar ultraviolet exposures at
[85] Chapman S, Marks R, King M. Trends in tans and skin protection in Australian ground level in tree shade during summer in south east Queensland. Int J
fashion magazines, 1982 through 1991. Am J Public Health 1992;82:1677–80. Environ Health Res 2001;11:117–27.
[86] de Vries E, Coebergh JW. Cutaneous malignant melanoma in Europe. Eur J [105] Wong CF. Scattered ultraviolet radiation underneath a shade-cloth. Photo-
Cancer 2004;40:2355–66. dermatol Photoimmunol Photomed 1994;10:221–4.
[87] Jensen AO, Bautz A, Olesen AB, Karagas MR, Sorensen HT, Friis S. Mortality in [106] Gambichler T, Laperre J, Hoffmann K. The European standard for sun-
Danish patients with nonmelanoma skin cancer, 1978–2001. Br J Dermatol protective clothing: EN 13758. J Eur Acad Dermatol Venereol 2006;20:
2008;159:419–25. 125–30.
[88] Lewis KG, Weinstock MA. Trends in nonmelanoma skin cancer mortality rates [107] Wang SQ, Balagula Y, Osterwalder U. Photoprotection: a review of the current
in the United States, 1969 through 2000. J Invest Dermatol 2007;127:2323–7. and future technologies. Dermatol Ther 2010;23:31–47.
[89] MacKie RM. Long-term health risk to the skin of ultraviolet radiation. Prog [108] Darlington S, Williams G, Neale R, Frost C, Green A. A randomized controlled trial
Biophys Mol Biol 2006;92:92–6. to assess sunscreen application and beta carotene supplementation in the
[90] de Vries E, Schouten LJ, Visser O, Eggermont AM, Coebergh JW. Rising trends in prevention of solar keratoses. Arch Dermatol 2003;139: 451–5.
the incidence of and mortality from cutaneous melanoma in the Netherlands: a [109] Gordon LG, Scuffham PA, van der Pols JC, McBride P, Williams GM, Green AC.
Northwest to Southeast gradient? Eur J Cancer 2003;39:1439–46. Regular sunscreen use is a cost-effective approach to skin cancer prevention
[91] Sant M, Allemani C, Santaquilani M, Knijn A, Marchesi F, Capocaccia R. in subtropical settings. J Invest Dermatol 2009;129:2766–71.
EUROCARE-4. Survival of cancer patients diagnosed in 1995–1999. Results [110] Naylor MF, Boyd A, Smith DW, Cameron GS, Hubbard D, Neldner KH. High sun
and commentary. Eur J Cancer 2009;45:931–91. protection factor sunscreens in the suppression of actinic neoplasia. Arch
[92] Amaria RN, Lewis KD, Gonzalez R. Therapeutic options in cutaneous mela- Dermatol 1995;131:170–5.
noma: latest developments. Ther Adv Med Oncol 2011;3:245–51. [111] Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular
[93] Armstrong BK, McMichael AJ. Cancer in migrants. Med J Aust 1984;140:3–4. sunscreen use: randomized trial follow-up. J Clin Oncol 2011;29:257–63.
[94] Oliveria SA, Saraiya M, Geller AC, Heneghan MK, Jorgensen C. Sun exposure [112] Hirst NG, Gordon LG, Scuffham PA, Green AC. Lifetime cost-effectiveness of
and risk of melanoma. Arch Dis Child 2006;91:131–8. skin cancer prevention through promotion of daily sunscreen use. Value
[95] Cooke KR, Fraser J. Migration and death from malignant melanoma. Int J Health 2012;15:261–8.
Cancer 1985;36:175–8. [113] Sambandan DR, Ratner D. Sunscreens: an overview and update. J Am Acad
[96] Khlat M, Vail A, Parkin M, Green A. Mortality from melanoma in migrants to Dermatol 2011;64:748–58.
Australia: variation by age at arrival and duration of stay. Am J Epidemiol [114] Bimczok R, Gers-Barlag H, Mundt C, Klette E, Bielfeldt S, Rudolph T, et al.
1992;135:1103–13. Influence of applied quantity of sunscreen products on the sun protection
[97] Parkin DM, Steinitz R, Khlat M, Kaldor J, Katz L, Young J. Cancer in Jewish factor – a multicenter study organized by the DGK Task Force Sun Protection.
migrants to Israel. Int J Cancer 1990;45:614–21. Skin Pharmacol Physiol 2007;20:57–64.
[98] Steinitz R, Parkin DM, Young JL, Bieber CA, Katz L. Cancer incidence in Jewish [115] Faurschou A, Wulf HC. The relation between sun protection factor and
migrants to Israel, 1961–1981. IARC Sci Publ 1989;98:1–311. amount of suncreen applied in vivo. Br J Dermatol 2007;156:716–9.
[99] Vogt A, Hadam S, Heiderhoff M, Audring H, Lademann J, Sterry W, et al. [116] Wolpowitz D, Gilchrest BA. The vitamin D questions: how much do you need
Morphometry of human terminal and vellus hair follicles. Exp Dermatol and how should you get it? J Am Acad Dermatol 2006;54:301–17.
2007;16:946–50. [117] Webb AR, Kift R, Durkin MT, O’Brien SJ, Vail A, Berry JL, et al. The role of
[100] Volkmer B, Greinert R. UV and children’s skin. Prog Biophys Mol Biol sunlight exposure in determining the vitamin D status of the U.K. white adult
2011;107:386–8. population. Br J Dermatol 2010;163:1050–5.
[101] Parkin DM, Mesher D, Sasieni P. 13. Cancers attributable to solar (ultraviolet) [118] Webb AR, Kift R, Berry JL, Rhodes LE. The vitamin D debate: translating
radiation exposure in the UK in 2010. Br J Cancer 2011;105(Suppl. 2):S66–9. controlled experiments into reality for human sun exposure times. Photo-
[102] Leitzmann M, Powers H, Anderson AS, Scoccianti C, Berrino F, Boutron-Ruault chem Photobiol 2011;87:741–5.
M-C, et al. European Code against Cancer 4th Edition: physical activity and [119] Sinclair C, Makin JK. Implications of lessons learned from tobacco control for
cancer. Cancer Epidemiol 2015;39:S46–55. tanning bed reform. Prev Chronic Dis 2013;10:E28.