The Effects of Sun Exposure and Pigmentation Phenotype on Prognosis in Metastatic Melanoma

Aims: To evaluate whether a difference in the prevalence of risk factors for malignant melanoma in a random sample of the population and among pilots and cabin attendants could explain...

Malignant melanoma risk factors have been studied in different geographical area populations. However, no study has focused on risk factors which are more frequently associated to the over 60's age group. A case-control study was performed that included 160 patients age > or = 60 years diagnosed of cutaneous melanoma and 318 controls matched for age and sex. Both groups were assessed, by personal interview and physical examination, for different phenotype characteristics (hair and eye color, phototype), the presence of other cutaneous lesions (solar lentigines, actinic keratoses and nevi), degree and type of solar exposure and personal and family past history of cutaneous or non-cutaneous cancer. Differences were evaluated by contingency tables and univariate and multivariate logistic regression. Of 17 factors, those risk factors with a strong effect on the development of melanoma in the elderly were: fair eyes, severe sunburns, years of occupational sun exposure, smoking, > 50 melanocytic nevi and personal history of NMSC and other non-cutaneous neoplasias. Tobacco smoking is an independent risk factor for cutaneous melanoma in the elderly. Intense (both acute and chronic) sun exposure and constitutional features, such as tumor susceptibility (NMSC, non-cutaneous neoplasias, and multiple nevi) are also associated with melanoma risk. All these factors should help to better design educational campaigns in older people.

To the authors' knowledge, limited data are available from Mediterranean populations concerning risk factors for malignant melanoma. A few Italian case-control studies have produced conflicting results regarding the association between malignant melanoma and pigmentary traits, sunburns, and melanocytic nevi. A case-control study was conducted within the framework of the Italian Group for Epidemiologic Research in Dermatology (GISED). Twenty-seven centers in the north and south of Italy participated. A total of 542 cases and 538 controls were entered onto the study. A standardized questionnaire was administered to cases and controls. Cases and controls also were examined by trained dermatologists who were required to count the number of melanocytic nevi (those measuring > or = 2 mm and > 6 mm in greatest dimension, separately) and to make judgments regarding pigmentary traits. In the multivariate analysis, eye and skin color, propensity to sunburn, history of sunburns before age 15 years, and solar lentigines all were associated with malignant melanoma. In addition, the risk of melanoma increased with the number of melanocytic nevi > or = 2 mm. Nevi > 6 mm in greatest dimension had effects on risk that appeared to be independent from the effects of smaller nevi (2-6 mm). The results of the current study largely are similar to those obtained in northern European countries, the U.S., and Australia and provide further evidence of the importance of selected pigmentary traits, sun exposure, and the number of melanocytic nevi in the risk of cutaneous malignant melanoma.

In prospective observational cohort studies, increasing sun exposure habits have been associated with reduced risk of cardiovascular mortality. Our aim was to assess possible observational mechanisms for this phenomenon. A written questionnaire was answered by 23,593 women in the year 2000 regarding risk factors for melanoma, including factors of possible interest for hypertension, such as detailed sun exposure habits, hypertension, marital status, education, smoking, alcohol consumption, BMI, exercise, and chronic high stress. Hypertension was measured by the proxy “use of hypertension medication” 2005–2007, and high stress by “need of anti-depressive medication”. Sun exposure habits was assessed by the number of `yes’ to the following questions; Do you sunbath during summer?, During winter vacation?, Do you travel south to sunbath?, Or do you use sun bed? Women answering ‘yes’ on one or two questions had moderate and those answering ‘yes’ on three or four as having greatest sun exposure. The main outcome was the risk of hypertension by sun exposure habits adjusted for confounding. As compared to those women with the greatest sun exposure, women with low and moderate sun exposure were at 41% and 15% higher odds of hypertension (OR 1.41, 95% CI 1.3‒1.6, p < 0.001 and OR 1.15, 95% CI 1.1‒1.2, p < 0.001), respectively. There was a strong age-related increased risk of hypertension. Other risk factors for hypertension were lack of exercise (OR 1.36), a non-fair phenotype (OR 1.08), chronic high stress level (OR 1.8), and lack of university education (OR 1.3). We conclude that in our observational design sun exposure was associated with a dose-dependent reduced risk of hypertension, which might partly explain the fewer deaths of cardiovascular disease with increasing sun exposure.

There is evidence that the mortality rate associated with malignant melanoma can be decreased by early identification of the risk factors for melanoma and precursor lesions and by reducing sun exposure in young patients at higher risk. Many of the risk factors for malignant melanoma are seen in the pediatric age group. To determine pediatricians' awareness of risk factors for melanoma and their ability to recognize the precursors of melanoma, we studied three departments of pediatrics--at an urban and a suburban medical center and a medical college. Ninety-six members of the audience, which included full-time faculty, practicing pediatricians, and pediatrics residents, responded to questionnaires before and after a presentation on the risk factors for melanoma. Based on the results of the questionnaires, this group of pediatricians believed that they were not sufficiently knowledgeable about the risk factors for melanoma and did not routinely examine their patients for these risk factors or counsel them on proper sunlight protection. These findings indicate a need for making pediatricians aware of the risk factors for melanoma and of the critical role they play in decreasing the incidence and mortality rate associated with this disease.

Meta-analysis of risk factors for cutaneous melanoma: II. Sun exposure

Sunlight exposure and fair skin are major determinants of human vitamin D production, but they are also risk factors for cutaneous malignant melanoma (MM). There is epidemiological evidence that all-cause mortality is related to low vitamin D levels. We assessed the avoidance of sun exposure as a risk factor for all-cause mortality for 29 518 Swedish women in a prospective 20-year follow-up of the Melanoma in Southern Sweden (MISS) cohort. Women were recruited from 1990 to 1992 and were aged 25 to 64 years at the start of the study. We obtained detailed information at baseline on their sun exposure habits and potential confounders. Multivariable flexible parametric survival analysis was applied to the data. There were 2545 deaths amongst the 29 518 women who responded to the initial questionnaire. We found that all-cause mortality was inversely related to sun exposure habits. The mortality rate amongst avoiders of sun exposure was approximately twofold higher compared with the highest sun exposure group, resulting in excess mortality with a population attributable risk of 3%. The results of this study provide observational evidence that avoiding sun exposure is a risk factor for all-cause mortality. Following sun exposure advice that is very restrictive in countries with low solar intensity might in fact be harmful to women's health.

Musings on Melanoma

Skin types 1 and 2, increased numbers of moles, and excessive intermittent sun exposure are known risk factors for cutaneous melanoma, but the inter-relationship between UV radiation exposure, moles and melanoma remains unclear. There is a noteworthy site variation in melanoma, it being more common on the lower leg in women and on the back in men. In order to determine whether this site variation could provide further clues to the pathogenesis of melanoma, we examined site variation in photosensitivity and its relationship to other known melanoma risk factors (number of moles, skin type and skin colour) in 25 healthy volunteers. A marked site variation in photosensitivity was found. The pale skin of the volar aspect of the forearm was markedly less photosensitive than the darker skin of the back. Females were more photoresistant than males on the lower legs even though this is the more common site for melanoma in women. There was some correlation between the number of moles and photosensitivity at the two sites.

Reducing mortality in individuals at high risk for advanced melanoma through education and screening

Background/Aim: The aim of this study was to quantify ultraviolet radiation (UVR) exposure of fully employed indoor workers during a Working Period and a Holiday Period in the summer months. A further aim was to investigate the correlation between individual personal UVR dosimeter reading and self‐reported data in a diary about sun exposure habits and to investigate whether skin type, age and gender influence sun exposure.Methods: The solar UVR, in standard erythema doses (SED) measured by UV sensitive spore‐film filter type personal dosimeters (VioSpor®), and sun exposure diaries were compared. The study included 44 healthy Danish adult indoor workers during a Working Period of a mean of 13 days and a Holiday Period of a mean of 17 days from June to September.Results: The individual total UVR exposure correlated significantly (P&lt;0.001) in both the Holiday and Working Periods with individual total hours spent outdoors from 07:00 to 19:00 and with skin area exposure hours. There was no significant correlation between sun exposure dose and gender, age or skin type I‐IV, or between the individual solar exposure dose in the Working and the Holiday Period. However, subjects with UVR exposures in the upper quartile spent their Holiday Period in Southern Europe, and/or had been more than the mean time outdoors at the beach/sea and/or between 12:00 and 15:00. Subjects with UVR exposure in the lower quartiles spent their holidays in Denmark or Northern Europe and did not stay at the beach at all. They received an average solar UVR dose which was 22% of ambient in Denmark in the same period while subjects having their holidays in Southern Europe received as much as 90% of the ambient dose in Denmark.Conclusions: Despite information campaigns to avoid the midday sun, on average 35% of the recorded hours outdoors were spent between 12:00 and 15:00 in the Holiday Period. Total hours outdoors give the best estimate of the total sun exposure dose. Registration in a diary of total hours outdoors and whether the Holiday Period was in Northern or Southern Europe can be used to predict the solar exposure dose in a Holiday Period of a few weeks.

Hardly a week goes by when the attention of the scientific press and the general public is not focused on a new report about the health effects of sunshine. Most studies of the effects of strong or prolonged ultraviolet radiation (UVR) exposure on the skin have emphasized the importance of sun avoidance and protection against sun exposure to reduce skin cancer risk. In recent years, though, these reports have competed for attention with studies about the health benefits and protective effects of vitamin D, and the potentially serious health risks caused by vitamin D insufficiency and deficiency. Because most vitamin D is produced in the skin by sun exposure, and specifically by DNA-damaging and carcinogenic UVB wavelengths, the development of tension within the medical community over the costs and benefits of sun exposure was inevitable. Important data bearing on this dilemma come from the study of Lindqvist and colleagues in this issue. The authors report the results of a longitudinal cohort study designed to assess how all-cause mortality risk may be influenced by avoidance of active sun exposure. The population studied by Lindqvist et al. consisted of women had been recruited for a prospective 20-year follow-up of the Melanoma in Southern Sweden (MISS) cohort. Equal numbers of women aged 25–64 years with no history of cancer were invited into the study in 1990; 29,518 (74%) formally entered the study. The survey questions about sun exposure explored the frequency of activities that involved exposure of large surface areas of the body under strong sunlight or simulated sunlight; these activities included summertime sunbathing, vacation sunbathing and the use of tanning beds. Along with standard anthropometrics, hereditary disposition to malignant melanoma (MM) was assessed, smoking habits at the inception of the study were recorded, and level of exercise was categorized. Cases of MM and fatalities due to MM were dichotomized by Breslow thickness. At the inception of the study in 1990, the investigators almost certainly did not anticipate that avoidance of sun exposure would be associated with an increase in all-cause mortality, but that is exactly what they discovered. Data available at that time indicated a strong causal relationship between sun exposure and MM, but no relationship between avoidance of sun exposure and increased mortality. In fact, in 1990, avoiding sun exposure was considered one of the healthiest things one could do because data on increased prevalence of skin cancers – especially amongst light-skinned people of European ancestry living in or even vacationing in sunny places – presented a dramatic picture of the risks of unprotected sun exposure. At that time, relatively few details were known about the relationship between sun exposure and the cutaneous production of vitamin D or other bioactive compounds, and there was no intimation that avoidance of sun exposure might pose a significant health risk. The primary finding of Lindqvist et al. was that the mortality rate amongst sun avoiders in their cohort was approximately twice that of the most active sun exposers, yielding an excess mortality with a population attributable risk of 3%. This is a small effect, but very significant due to sample size and power. The authors are guarded in their discussion of the reasons why sun avoidance is associated with increased mortality. In previous studies, they speculated that this was due to insufficient vitamin D levels amongst sun avoiders, but cautioned that their results could not indicate a causal relationship. They are even more restrained here. They go to great lengths to point out that vitamin D is just one of several bioactive compounds produced by strong UVR solar ultraviolet exposure that may have an effect on morbidity and mortality. The ‘dose-dependent’ inverse relationship between sun exposure and all-cause mortality seen in their models is intriguing and supports the argument that some unidentified factor correlated with sun exposure is protective. Vitamin D is a strong candidate because of its myriad immune system boosting functions 1, but it probably cannot account entirely for the effects observed in the study. Cutaneous vitamin D production is strictly the product of UVB exposure, and southern Sweden boasts a highly seasonal UVB regime and a long UVB-free winter. Studies show at the autumnal equinox (September 22), Boston, Massachusetts, at 42.5°N still receives ample UVB to catalyse vitamin D formation in the skin, but Malmö, Sweden, at 55.5°N does not (Fig. 1) 2. One of the most interesting implications of the Lindqvist et al. data is that the most active sun exposers with the lowest mortality rates in the study were almost certainly experiencing high UVA loads because of their winter sun and tanning bed exposures. Thus, the mortality-reducing effects observed amongst the most active exposers probably were due to many factors including a suite of bioactive compounds produced by both UVB and UVA exposure: vitamin D and nitrous oxide, respectively. The skin is now recognized as harbouring a reservoir of nitric oxide (NO) metabolites, which are activated by UVA and which appear to exert a benign effect of cardiovascular homeostasis 3. Sun avoiders thus lose out on both photosynthesized vitamin D and photoactivated NO. Detailed data on the nature and duration of sun and tanning bed exposures of the MISS cohort would have helped significantly to illuminate the origin of the protective effects experienced by the active sun exposers in the Lindqvist et al. study. The ratio of UVB to UVA in sunlight varies according to latitude, season, time of day, levels of air pollution and other factors which were not possible to consider in the study 4. Although UVA is present in sunlight throughout the year, UVB becomes more seasonal and attenuated with increasing latitude, resulting in significantly reduced potential for cutaneous biosynthesis of vitamin D 5. Successful adaptations to high-latitude environments such as southern Sweden have been both biological and cultural, involving increasing amounts of vitamin D-rich foods in the diet to supplement seasonally photosynthesized vitamin D 6. Throughout history and in most places, however, human vitamin D is derived primarily from sun exposure and not from food 7. The biggest questions to emerge from the Lindqvist et al. study surround the nature and activity of the compounds produced by sun exposure and what happens in sun avoiders when these compounds are absent or present only at low levels. If this is primarily a vitamin D effect, then remedial measures such as additional food fortification or recommendations for vitamin supplementation can be implemented relatively easily, with no risk of additional skin cancers. Vitamin D deficiency is associated with increased susceptibility to infectious diseases such as tuberculosis and complex chronic diseases such as type 2 diabetes 8, 9, and it is widely accepted that that the high prevalence of vitamin D deficiency requires some kind of intervention. What is a modern human supposed to do? If sun exposure is to be recommended, it should be of the wavelengths and energies to which a person's skin is adapted. Our ancestors spent most of their time outdoors, but did not sunbathe or subject themselves to intense prolonged solar irradiation on foreign holidays. With skin as the major interface with our physical environment, we faced changing solar conditions, outside, day by day. Only in the last few thousand years have large numbers of us spent significant amounts of time indoors, and only in the last century have large numbers of people engaged in the kinds of episodic sun exposure on weekends and foreign vacations – often leading to sunburns – that we consider normal today. In today's highly urbanized world, most people pursue indoor lifestyles whilst wearing concealing clothing. And, because of migration, many of us live under vastly different solar conditions than those of our ancestors. Understanding these changes will allow us to compensate for modernity through bespoke prescriptions for sun exposure and diet that are appropriate to our ancestry, location and lifestyle. The results of the Lindqvist et al. study indicate that we need to think about these things sooner rather than later. The author is a member of the Scientific Advisory Board of L'Oréal.

The aim of this study was to quantify ultraviolet radiation (UVR) exposure of fully employed indoor workers during a Working Period and a Holiday Period in the summer months. A further aim was to investigate the correlation between individual personal UVR dosimeter reading and self-reported data in a diary about sun exposure habits and to investigate whether skin type, age and gender influence sun exposure. The solar UVR, in standard erythema doses (SED) measured by UV sensitive spore-film filter type personal dosimeters (VioSpor), and sun exposure diaries were compared. The study included 44 healthy Danish adult indoor workers during a Working Period of a mean of 13 days and a Holiday Period of a mean of 17 days from June to September. The individual total UVR exposure correlated significantly (P<0.001) in both the Holiday and Working Periods with individual total hours spent outdoors from 07:00 to 19:00 and with skin area exposure hours. There was no significant correlation between sun exposure dose and gender, age or skin type I-IV, or between the individual solar exposure dose in the Working and the Holiday Period. However, subjects with UVR exposures in the upper quartile spent their Holiday Period in Southern Europe, and/or had been more than the mean time outdoors at the beach/sea and/or between 12:00 and 15:00. Subjects with UVR exposure in the lower quartiles spent their holidays in Denmark or Northern Europe and did not stay at the beach at all. They received an average solar UVR dose which was 22% of ambient in Denmark in the same period while subjects having their holidays in Southern Europe received as much as 90% of the ambient dose in Denmark. Despite information campaigns to avoid the midday sun, on average 35% of the recorded hours outdoors were spent between 12:00 and 15:00 in the Holiday Period. Total hours outdoors give the best estimate of the total sun exposure dose. Registration in a diary of total hours outdoors and whether the Holiday Period was in Northern or Southern Europe can be used to predict the solar exposure dose in a Holiday Period of a few weeks.

Revised UK guidelines for the management of cutaneous melanoma 2010

BackgroundSun exposure in combination with skin pigmentation is the main determinant for vitamin D status. Human skin color seems to be adapted and optimized for regional sun ultraviolet (UV) intensity. However, we do not know if fair, UV-sensitive skin is a survival advantage in regions with low UV radiation.MethodsA population-based nested case–control study of 29,518 Caucasian women, ages 25 to 64 years from Southern Sweden who responded to a questionnaire regarding risk-factors for malignant melanoma in 1990 and followed for 25 years. For each fair woman, defined as having red hair or freckles (n = 11,993), a control was randomly selected from all non-fair women from within the cohort of similar age, smoking habits, education, marital status, income, and comorbidity, i.e., 11,993 pairs. The main outcome was the difference in all-cause mortality between fair and non-fair women in a low UV milieu, defined as living in Sweden and having low-to-moderate sun exposure habits. Secondary outcomes were mortality by sun exposure, and among those non-overweight.ResultsIn a low UV milieu, fair women were at a significantly lower all-cause mortality risk as compared to non-fair women (log rank test p = 0.04) with an 8% lower all-cause mortality rate (hazard ratio [HR] = 0.92, 95% CI 0.84‒1.0), including a 59% greater risk of dying from skin cancer among fair women (HR 1.59, 95% CI 1.26‒2.0). Thus, it seem that the beneficial health effect from low skin coloration outweigh the risk of skin cancer at high latitudes.ConclusionIn a region with low UV milieu, evolution seems to improve all-cause survival by selecting a fair skin phenotype, i.e., comprising fair women with a survival advantage.