Epidemiological and clinical characteristics of malignant melanoma in area of West Herzegovina from 1997 to 2010

Incidence rate of cutaneous malignant melanoma (MM), one of the most aggressive skin tumours, is increasing nowadays. Etiology of MM has not been fully understood. Various etiological factors are of relevance for the occurrence of the disease. The solar radiation as well as long term exposure to ultraviolet radiation has the greatest impact on development of this skin tumour. Melanoma risk factors have different associations with melanoma on body sites. This study investigates the epidemiological and clinical characteristics of MM such as age, gender, distribution of MM on the body and type of melanoma in the area of West Herzegovina, on the sample of 205 patients. It presents the occurrence of MM in the period from 1997. to 2010. Both, females and males have increased the risk of melanoma on the trunk (45.9%). Different body sites receive various amounts of sun exposure, yet melanomas occur on all parts of the body. This may represent different pathways in the etiology of melanoma based on body location. The most frequent type of MM was superficial spreading melanoma (SSM) 47.8%. According to our investigation incidence rate was 18.6% (per 1000 patients).     

Unravelling UVA-induced mutagenesis

Ultraviolet A (UVA) radiation represents more than 90% of the solar UV radiation reaching Earth's surface. Exposure to solar UV radiation is a major risk in the occurrence of non-melanoma skin cancer. Whole genome sequencing data of melanoma tumors recently obtained makes it possible also to definitively associate malignant melanoma with sunlight exposure. Even though UVB has long been established as the major cause of skin cancer, the relative contribution of UVA is still unclear. In this review, we first report on the formation of DNA damage induced by UVA radiation, and on recent advances on the associated mechanism. We then discuss the controversial data on the UVA-induced mutational events obtained for various types of eukaryotic cells, including human skin cells. This may help unravel the role of UVA in the various steps of photocarcinogenesis. The connection to photocarcinogenesis is more extensively discussed by other authors in this issue.     

Animal models of melanoma: an HGF/SF transgenic mouse model may facilitate experimental access to UV initiating events

Cutaneous malignant melanoma, the most lethal of the skin cancers, known for its intractability to current therapies, continues to increase in incidence, providing a significant public health challenge. There is a consensus that skin cancer is initiated by sunlight exposure. For non-melanoma skin cancer there is substantial evidence that chronic exposure to the ultraviolet B radiation (UVB) (280-320 nm) portion of the sunlight spectrum is responsible. Experimentally, UVB is mutagenic and chronic UVB exposure can cause non-melanoma skin cancer in laboratory animals. Non-melanoma tumors in animals and in humans show characteristic UVB signature lesions in the tumor suppressor p53 and/or in the patched (PTCH) gene. An action spectrum or wavelength dependence for squamous cell carcinoma in the mouse shows a major peak of efficacy in the UVB. For malignant melanoma, however, the situation is unclear and the critical direct target(s) of sunlight in initiating melanoma and even the wavelengths responsible are as yet unidentified. This lack of information is in major part a result of a paucity of animal models for melanoma which recapitulate the role of sunlight in initiating this disease. The epidemiology of melanoma differs significantly from non-melanoma skin cancer. Intense sporadic sunlight exposure in childhood, probably exacerbated by additional adult exposure, is associated with elevated melanoma risk. Melanoma is also a disease of gene-environment interactions with underlying genetic factors playing a significant role. These major differences indicate that extrapolation from information for non-melanoma skin cancer to melanoma is unlikely to be useful. We summarize in this review the experimental information available on the role of UV radiation in melanoma and give an overview of animal melanoma models. A new model derived by neonatal UV irradiation of hepatocyte growth factor/scatter factor (HGF/SF) transgenic mice is described which recapitulates the etiology, the histopathology and molecular pathogenesis of human disease. It is anticipated that the HGF/SF transgenic model will provide a means to access the mechanism(s) by which sunlight initiates this lethal disease and provide an appropriate vehicle for derivation of appropriate therapeutic and preventive strategies.     

Ultraviolet radiation-induced apoptosis in keratinocytes: on the role of cytosolic factors

Epidemiological and experimental evidences have established solar ultraviolet (UV) radiation as the leading cause of skin cancers. Specifically, the frequency of non-melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is directly related to the total exposure to solar UV light. As part of a general effort to elucidate the components of cellular signal transduction pathways, the mechanisms of cellular responses to UV radiation have received considerable attention over the last few years. These efforts were driven mainly by the conviction that understanding how normal cells respond to extracellular stimuli such as exposure to UV radiation will undoubtedly help in deciphering what goes wrong in a variety of clinical disorders including skin cancers and will assist in the development of novel therapeutic strategies. Studies over the last decade have established that UV radiation induces a bewildering array of signal transduction pathways, some of which could lead to apoptotic cell death. UV-induced cell death by apoptosis is considered to be a natural protective mechanism that removes damaged keratinocytes and circumvents the risk of malignant transformation. In this review, we summarize some of the most important findings regarding the response and role of mitogen-activated protein kinases in UVA and UVB radiation-induced signaling to apoptosis in keratinocytes. We will also briefly discuss what is known about the role of the BCL-2 family of proteins, the emerging role of lysosomal proteases and other important cytosolic signaling proteins in UV-induced apoptosis.     

New option in photoprotection

All the people are exposed to solar ultraviolet radiation. Exposure to sun with living in an oxygen-rich atmosphere causes unwanted photodemage. Sunburned skin is a leading risk factor for melanoma and non-melanoma cancers. UV exposure causes immunosuppression via multiple mechanisms in the skin. In this review the main topic is to mention new or alternative ways of photoprotection. Sunscreens are commonly used as protection against sun damage. They reduce the penetration of damaging solar UV wavelengths in skin by reflecting or absorbing them. Sunscreens are very valuable, but they have limitations. They have to be used properly to gain the full effect (application a little while before UV exposure, at frequent time points and in adequate amounts). Also, they have the problem of photoinactivation, which is the degeneration of the UV-filter due to exposure to UV rays resulting in the loss of absorbing capacity. Products with immune protection factor contain DNA-repair enzymes and antioxidants that may reduce mutations and enable the immune system to combat photodamage. The use of antioxidants and polyphenols may exert an anti-aging effect by preventing and even reversing sun damage. Adequate photoprotection is essential to control photocarcinogenesis and photoaging.     

A unique gender difference in early onset melanoma implies that in addition to ultraviolet light exposure other causative factors are important

Using US SEER17 Registry data, age‐specific melanoma incidence rates were calculated and comparisons were made between males and females. Relative Risk (RR) for males and females in each age group was computed and compared with that from Nordic Cancer Registry data set and to that for non‐melanoma skin cancer (NMSC). For age groups 44 and younger, females showed higher incidence rates, with a peak difference at age 20–24 (RR = 2.01, 95% CI = 1.21–3.33). Males exhibited higher incidence rates after age 44. The same bimodal gender difference was confirmed by the Nordic Cancer Registry data set, but it was not observed for NMSC, which is known to be strongly associated with cumulative exposure to solar UV radiation. We conclude that exposure to solar ultraviolet (UV) radiation is the major causative factor for melanoma at older age (>44 yr), but that other factors may play a role in early onset melanomas, particularly in females.     

Tanning devices--fast track to skin cancer?

The use of UVB and/or UVA emitting devices for cosmetic tanning is widespread in Western populations including young people and is especially prevalent in females. Several epidemiological studies, although not all, have shown a significant relationship between the use of tanning devices and malignant melanoma after, in some cases, adjustment for confounding factors such as solar ultraviolet radiation (UVR) exposure. A relationship between solar exposure, especially intermittent exposure, and malignant melanoma is well established so it is not surprising that a similar connection has been reported for the use of tanning devices. Several epidemiological studies show that childhood exposure to sunlight is a risk factor for malignant melanoma and this may also be the case for the use of tanning devices, especially if sunburns are obtained. Some studies have evaluated the relationship between the use of tanning devices and non-melanoma skin cancer and at least one has suggested an association. The use of tanning devices by a substantial minority of young people is a worrying trend in terms of a likely increased incidence of malignant melanoma, and possibly non-melanoma cancers in the future. Although two recent reviews by epidemiologists conclude that a clear link between tanning devices and malignant melanoma is yet to be proven, there is a strong case for effective legislation to prohibit the use of tanning devices by people under 18 yr of age.     

Parameters of protection against ultraviolet radiation‐induced skin cell damage

Epidemiological and experimental evidence has supported the notion that solar ultraviolet (UV) radiation is the leading cause of skin cell damage and skin cancer. Non‐melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is suggested to be directly related to the total exposure to solar UV light. Over the past few years, the mechanisms of cellular responses to UV radiation have received unprecedented attention. Understanding how skin cells respond to UV radiation will undoubtedly help decipher what goes wrong in a variety of clinical skin disorders including skin cancer and will facilitate the development of novel therapeutic strategies. In the past decade, studies have established that UV radiation induces multifarious signal transduction pathways, some of which lead to apoptotic cell death, while others protect against this process. In this review, we summarize some of the most recent progresses regarding the involvement of multiple signal pathways in UV radiation‐induced apoptosis in skin cells, especially in keratinocytes. These pathways include pro‐apoptosis components such as MAPK, AMPK, and p53 as well as pro‐survival components, namely, AKT and mTORC complexes. J. Cell. Physiol. 220: 277–284, 2009. © 2009 Wiley‐Liss, Inc.     

Stepping up melanocytes to the challenge of UV exposure

Exposure to solar ultraviolet radiation (UV) is the main etiological factor for skin cancer, including melanoma. Cutaneous pigmentation, particularly eumelanin, afforded by melanocytes is the main photoprotective mechanism, as it prevents UV-induced DNA damage in the epidermis. Therefore, maintaining genomic stability of melanocytes is crucial for prevention of melanoma, as well as keratinocyte-derived basal and squamous cell carcinoma. A critical independent factor for preventing melanoma is DNA repair capacity. The response of melanocytes to UV is mediated mainly by a network of paracrine factors that not only activate melanogenesis, but also DNA repair, anti-oxidant, and survival pathways that are pivotal for maintenance of genomic stability and prevention of malignant transformation or apoptosis. However, little is known about the stress response of melanocytes to UV and the regulation of DNA repair pathways in melanocytes. Unraveling these mechanisms might lead to strategies to prevent melanoma, as well as non-melanoma skin cancer.     

Reviews on sun exposure and artificial light and melanoma

Melanoma is the most common form of cancer among young adults aged 25-29 years and the second most common cancer in those aged 15-29 years. We reviewed all the evidence regarding risk factors for melanoma, looking in particular at childhood exposure to ultraviolet radiation (UV). UV radiation is clearly the predominant environmental and thus potentially modifiable risk factor for melanoma. All activities related to tan-seeking behaviour and history of sunburns were shown to be significantly associated to melanoma. Host factors, such as pigmentary characteristics, and genetic predisposition plays also an important role. UV exposure is not only due to the sun but also to indoor tanning devices that have been shown to lead to an elevated risk of melanoma. The strongest evidence for a link between artificial UV and melanoma is found among individuals who had their first exposure to indoor tanning before the age of 30: they have a 75% increase risk of developing melanoma than individuals who had no exposure to indoor tanning. Prevention is very important, especially for children and young adults, as childhood and adolescence are critical periods in the development of later melanoma. Indoor tanning is a widespread practice in most developed countries, particularly in Northern Europe and the USA. In the recent decades more and more people, especially teenagers and women, are exposed to substantially high radiant exposures of UV through artificial sources and these trends raised a considerable concern. In fact the International Agency for Research on Cancer concluded that the association between skin cancer and exposure to solar radiation and the use of UV-emitting tanning devices are causal. Interesting analyses carried out in Iceland showed that when interventions to discourage sunbed use were introduced the incidence of melanoma among women decreased. All this evidence encouraged many countries to introduce regulations on sunbed use to avoid exposure before the age of 18.     

Childhood exposure to ultraviolet radiation and harmful skin effects: epidemiological evidence

We review the general amount and patterns of exposure to solar ultraviolet (UV) radiation that children and teenagers experience and the spectrum of UV-related skin damage that can occur as a result. Data about the amount of solar UV received by children and teenagers are relatively few but suggest that around 40–50% of total UV to age 60 occurs before age 20. Among white children, those with the palest complexions suffer the most damage. Comparisons of prevalence and incidence of outcomes in children and teenagers sharing common ancestry, but living at different latitudes, show that prevalence rates of photoaging and melanocytic naevi are higher in Australian compared with British children, and similarly for melanoma. Genetic risk for the majority of the melanomas in teens is a function of genes controlling naevus propensity and pigmentation in the skin. High numbers of naevi and freckles, red hair, blue eyes, inability to tan, as well as a family history are the primary determinants of melanoma among adolescents. Beyond the signs of skin damage seen in children are the latent effects observed later in adulthood. Childhood is believed to be a susceptible window for long-term harmful effects of UV, as evidenced by clear differences in skin cancer risk between child and adult migrants from high to low latitudes. Effective UV radiation protection from childhood is necessary to control both immediate and long-term harmful effects on children’s skin.     

Synthesis and evaluation of 1,3,5-triazine derivatives as sunscreens useful to prevent skin cancer

The incidence of skin cancers such as non-melanoma skin cancer and malignant melanoma has increased in the last few years mainly because of chronic exposure to ultraviolet (UV) radiation. Sunscreens protect the skin against harmful UV radiations; however, some limitations of these products justify the discovery of new UV filters. Novel 1,3,5-triazine derivatives (12a-h) obtained by the optimization of prototype resveratrol were synthesized and characterized. All compounds exhibited sun protection factor (SPF) and UVA protection factor (UVAPF) in the range of 3–17 and 3–13, respectively. These values were superior to resveratrol and the UV filter ethylhexyl triazone (EHT) currently available on the market. In addition, all compounds demonstrated in vitro antioxidant activity and thermal stability with the decomposition at temperatures above 236 °C. In conclusion, the novel 1,3,5-triazine derivatives have emerged as new UV filters with antioxidant effect useful to prevent skin cancer.     

UV and pigmentation: molecular mechanisms and social controversies

Ultraviolet radiation (UVR) is an essential risk factor for the development of premalignant skin lesions as well as of melanoma and non-melanoma skin cancer. UVR exerts many effects on the skin, including tanning, carcinogenesis, immunomodulation, and production of vitamin D. Vitamin D (vit D) is important in the maintenance of healthy bones as well as other purported beneficial effects, amongst which is the potential for reducing risk of malignancy--though oral supplementation is fully capable of maintaining systemic levels. The known medical harm from UV exposure relates primarily to cancer of the skin--the most common organ in man to be affected by cancer. In this review, we summarize the knowledge about the ultraviolet (UV) response in regards to inflammation, immunosuppression, carcinogenesis and the tanning response. We also discuss vit D and UV, as well as public health implications of tanning behavior and commercial interests related to the promotion of UV exposure. As the most ubiquitous human carcinogen, UVR exposure represents both a challenge and enormous opportunity in the realm of skin cancer prevention.     

Green tea prevents non-melanoma skin cancer by enhancing DNA repair

Excessive exposure of the skin to solar ultraviolet (UV) radiation is one of the major factors for the development of skin cancers, including non-melanoma. For the last several centuries the consumption of dietary phytochemicals has been linked to numerous health benefits including the photoprotection of the skin. Green tea has been consumed as a popular beverage world-wide and skin photoprotection by green tea polyphenols (GTPs) has been widely investigated. In this article, we have discussed the recent investigations and mechanistic studies which define the potential efficacy of GTPs on the prevention of non-melanoma skin cancer. UV-induced DNA damage, particularly the formation of cyclobutane pyrimidine dimers, has been implicated in immunosuppression and initiation of skin cancer. Topical application or oral administration of green tea through drinking water of mice prevents UVB-induced skin tumor development, and this prevention is mediated, at least in part, through rapid repair of DNA. The DNA repair by GTPs is mediated through the induction of interleukin (IL)-12 which has been shown to have DNA repair ability. The new mechanistic investigations support and explain the anti-photocarcinogenic activity, in particular anti-non-melanoma skin cancer, of green tea and explain the benefits of green tea for human health.     

Who, what, where and when-influences on cutaneous vitamin D synthesis

The synthesis of vitamin D in skin is a two-stage process that begins with the production of previtamin D after irradiation of 7-dehydrocholesterol by ultraviolet (UV) radiation. A number of personal and environmental factors control the probability of a suitable UV photon reaching a molecule of 7-dehydrocholesterol in the skin. These are astronomical factors that govern the solar zenith angle (SZA), and the local state of the atmosphere, determining the available solar UV radiation; skin pigmentation and age, determining competing absorbers of UV radiation and available 7-dehydrocholesterol; individual behaviour in the local surroundings, determining exposure of unprotected skin to available UV radiation. The only one of these influences that can be determined unequivocally for any situation is the SZA. The other influences must be considered either as individual case studies, or be represented by "typical" and "idealised" situations for the weather, skin and behaviour. At large SZAs there is insufficient solar UV radiation to initiate significant vitamin D synthesis. At smaller SZAs assessment of solar exposure necessary for vitamin D synthesis can only be indicative and application of any such assessment necessarily requires awareness of both self- and the local environment.     

Climate change and human skin cancer.

As part of an inventory of potential interactions between effects of ozone depletion and climate change, a possible effect of ambient temperature on sun-induced skin cancers was suggested. Mouse experiments had shown that increased room temperature enhanced ultraviolet (UV) radiation-induced carcinogenesis; the effective UV dose was increased by 3-7% per degrees C. The present investigation was aimed at studying a possible temperature effect on human skin cancer. Existing data on the incidence of human skin cancer were analyzed, as available from two special surveys of non-melanoma skin cancer in the United States. The incidence of non-melanoma skin cancer in the ten regions surveyed not only correlated significantly with the ambient UV dose but also with the average daily maximum temperature in summer. For squamous cell carcinoma the incidence was higher by 5.5% (SE 1.6%) per degrees C and for basal cell carcinoma by 2.9% (SE 1.4%) per degrees C. These values correspond to an increase of the effective UV dose by about 2% per degrees C. Although the precise nature of this correlation with temperature requires further studies, it can be concluded that the temperature rises coming with climate change can indeed amplify the induction of non-melanoma skin cancers by UV radiation in human populations.     

Solar lentigines are strongly related to sun exposure in contrast to ephelides

Solar lentigines and ephelides are different types of pigmented skin lesions predominantly present on sun-exposed skin. Both lesions are risk indicators for melanoma and non-melanoma skin cancer. Solar lentigines are considered as a sign of photodamage although well-conducted epidemiological studies are lacking on this subject. Ephelides are associated with fair skin type and red hair. The aim of the present study was to investigate the relation of sun-exposure estimates with solar lentigines and ephelides. In the Leiden Skin cancer Study 577 patients with malignant melanoma and/or non-melanoma skin cancer and 385 individuals without a history of skin cancer were studied. The presence of solar lentigines and ephelides in the face and on the back was assessed. Data on skin type, hair color, sun-exposure variables and cutaneous signs of photodamage were collected, by questionnaire and physical examination. Data were analyzed by chi-square or Student t-tests and with multivariable regression. Exposure odds ratios with 95% confidence intervals (95% CI) were calculated to estimate the relative risk for the presence of solar lentigines and ephelides dependent on signs of photodamage. The association with age was strongly positive for solar lentigines whereas it was strongly negative for ephelides (P-values for trend <0.0001). After adjustment for age, sex and skin type, solar lentigines on the back were positively associated with cumulative (P = 0.01) and intermittent (P = 0.0002) sun exposure. After adjustment, solar lentigines on the back were also associated with a history of sunburns before the age of 20 yr (P = 0.0003) and the number of sunburns in childhood (P = 0.002). Solar lentigines in the face were significantly associated with cutaneous signs of photodamage, i.e. elastosis (odds ratio 2.4, 95% CI 1.7-3.3) and actinic keratosis (odds ratio 1.8, 95% CI 1.3-2.4) whereas ephelides were not. Ephelides in the face and on the back showed an inverse association with chronic sun exposure but after adjustment theses associations disappeared. Sunburns before the age of 20 appeared to be positively associated with ephelides on the back (P = 0.04). In contrast to lentigines, ephelides were much more associated with constitutional host factors such as fair skin and/or red hair (both P < 0.0001). This study indicates that both chronic and acute sun exposure are important in the pathogenesis of solar lentigines.     

The mechanisms of UV radiation in the development of malignant melanoma

The sunlight was one of the first agents recognized to be carcinogenic for humans. There is convincing evidence from epidemiologic studies that exposure to solar radiation is the major cause of cutaneous melanoma in light-pigmented populations and plays a role in the increasing incidence of this malignancy. The molecular mechanisms by which UV radiation exerts its varied effects are not completely understood, however, it is considered that UVA and UVB are equally critical players in melanoma formation. Whereas UVA can indirectly damage DNA through the formation of reactive oxygen radicals, UVB can directly damage DNA causing the apoptosis of keratinocytes by forming the sunburn cells. Besides action through mutations in critical regulatory genes, UV radiation may promote cancer through indirect mechanisms, e.g. immunosuppression and dysregulation of growth factors. The carcinogenic process probably involves multiple sequential steps, some, but not all of which involve alterations in DNA structure.     

Occupational Exposure to Ultraviolet Radiation and Risk of Non-Melanoma Skin Cancer in a Multinational European Study

Background

Studies suggest that ambient sunlight plays an important role in the pathogenesis of non-melanoma skin cancers (NMSC). However, there is ongoing controversy regarding the relevance of occupational exposure to natural and artificial ultraviolet radiation (UV) radiation.

Objectives

We investigated potential associations between natural and artificial UV radiation exposure at work with NMSC in a case-control study conducted in Hungary, Romania, and Slovakia.

Methods

Occupational exposures were classified by expert assessment for 527 controls and 618 NMSC cases (515 basal cell carcinoma, BCC). Covariate information was collected via interview and multiple logistic regression models were used to assess associations between UV exposure and NMSC.

Results

Lifetime prevalence of occupational exposure in the participants was 13% for natural UV radiation and 7% for artificial UV radiation. Significant negative associations between occupational exposure to natural UV radiation and NMSC were detected for all who had ever been exposed (odds ratio (OR) 0.47, 95% confidence interval (CI) 0.27–0.80); similar results were detected using a semi-quantitative metric of cumulative exposure. The effects were modified by skin complexion, with significantly decreased risks of BCC among participants with light skin complexion. No associations were observed in relation to occupational artificial UV radiation exposure.

Conclusions

The protective effect of occupational exposure to natural UV radiation was unexpected, but limited to light-skinned people, suggesting adequate sun-protection behaviors. Further investigations focusing on variations in the individual genetic susceptibility and potential interactions with environmental and other relevant factors are planned.     

Papillomaviruses: death-defying acts in skin cancer

Ultraviolet (UV) radiation is an environmental agent that has a major impact on humans, and cumulative exposure poses a serious risk in terms of developing skin cancer. Acute doses of UV induce apoptotic cell death in the skin via signalling pathways that are, in part, dependent on the p53 tumour suppressor protein. However, p53-independent mechanisms have also been described. Recent findings show that a high proportion of non-melanoma skin cancers contain human papillomavirus. The viral E6 protein effectively blocks the epidermal apoptotic response to UV and might play a key role in promoting tumour development in cooperation with the mutagenic effects of UV.