Effects of aging and chronic sun exposure on melanocytes in human skin.

Both aging and sun exposure have well-documented effects on the human melanocyte system. Paired biopsies of habitually exposed and nonexposed skin from adjacent anatomic sites were obtained from 8 donors aged 28 to 80 yr in order to study the combined effect of chronic actinic irradiation and chronologic aging. Density of dopa-positive melanocytes was roughly twofold higher in the exposed than in the nonexposed skin at all ages, suggesting an irreversible effect of sun exposure. Melanocyte density declined approximately 6 to 8% of the surviving population per decade in both sites. Dopa-positivity of individual melanocytes was consistently greater in the chronically exposed skin than in the nonexposed skin of the same subject and did not vary with age. These data strengthen and expand earlier observations of age-related melanocyte changes, and explain the apparent paradox of a generalized increase in pigmentation and simultaneous decrease in melanocyte density which frequently accompany advancing age. In addition, the present study suggests that the principal effect of chronic sun exposure on the human pigmentary system is not premature "aging" as currently recognized histologically, but rather activation and/or proliferation of the exposed melanocytes.     

Melanocytic lesions and melanocyte populations in human epidermis

Basal melanocytes were counted and atypia assessed on an arbitrary scale in punch biopsies from the sun-exposed extensor aspect of the forearm of normal skin and from the covered skin of the buttock of patients with pigmented naevi and control subjects. The difference in melanocyte counts and in the presence of atypia between sun-exposed and covered skin was statistically highly significant. The only other difference was between melanocyte counts in covered skin from those with multiple atypical naevi and all other groups; the counts in the former were greater than those in the latter. No further difference was attributable to sun exposure, skin type or diagnostic group. Some degree of melanocyte atypia was seen in approximately half of the biopsies of sun-exposed skin, but atypia was seen in only six of 84 biopsies of covered skin. In each case atypia was present in the corresponding forearm biopsy and all six subjects had pigmented lesions (four with melanoma and two with multiple atypical naevi). It seems possible that while increased melanocyte counts in covered skin could correlate with the presence of atypical naevi, atypia of covered epidermal melanocytes could possibly relate to melanoma risk.     

Sensitivity of mouse Skh:HR-2 to ultraviolet radiation: melanocyte inactivation

The hairless mouse, Skh:HR-2, was exposed to doses of ultraviolet (UV) radiation known to induce skin pigmentation. Three parameters associated with perturbations in skin pigmentation were monitored following UV exposure. These include spectroscopy (skin darkness), histology (melanocyte density), and biochemistry (melanin). Within 90 min of UV exposure, the skin became lighter. This was associated with a reduction of quantifiable melanin and the inactivation of epidermal melanocytes.     

Development of a new mouse model (xeroderma pigmentosum a-deficient, stem cell factor-transgenic) of ultraviolet B-induced melanoma

It is well established that exposure to sunlight or ultraviolet radiation (UVR) is the major environmental risk factor for the development of skin neoplasms. To date, however, there have been few appropriate mouse models available for studying the role of UVR in melanoma carcinogenesis, mainly because of the murine lack of the epidermal melanocyte, which is a major source of origin of human melanoma. In this study, we established xeroderma pigmentosum group A gene-deficient, stem cell factor-transgenic mice, which are defective in the repair of damaged DNA and do have epidermal melanocytes. The mice were exposed to UVR three times a week for 10 wk. More than 30% of the irradiated mice developed tumors of melanocyte origin that metastasized to the lymph nodes. Histologically, proliferated cells exhibited lentigo maligna melanoma or nodular melanoma. Immunohistochemistry confirmed that the tumor cells were characteristic of melanoma. Non-irradiated mice did not develop skin tumors spontaneously. The newly generated model mouse might be useful for studying the photobiological aspects of human melanoma, because the mice developed melanoma from epidermal melanocytes only after UVR exposures.     

Multiple melanoma and atypical melanocytic naevi—evidence of an activated and expanded melanocytic system

Twelve patients with malignant melanoma and/or multiple atypical naevi are described. Of these, three were familial and four were sporadic cases of a syndrome characterized by multiple irregular melanocytic naevi and multiple primary cutaneous malignant melanomata. The other five were cases of multiple atypical naevi without malignant melanoma. Three new features emerge from this study: (1) in these patients malignant melanoma may develop on clinically normal skin; (2) melanocyte counts in normal skin adjacent to the lesion show an expanded population of epidermal melanocytes; (3) most of these patients (9/12) give a history of significant sun exposure. The unsatisfactory terminology previously used in describing this syndrome is discussed, and the term expanded and activated melanocyte syndrome is offered as an alternative.     

Local and systemic effects on the epidermal melanocyte population in UV-irradiated mouse skin.

Local and systemic effects of repeated UVB irradiation on the epidermal melanocytes have been studied in the C57Bl mice. A daily dose of 0.1 joule/cm2 for 10 days induced a 4-fold increase in the epidermal melanocyte population of the irradiated right ear. During the first weeks after the irradiation period, there was a gradual increase in the number of melanocytes also in the shielded left ear, up to about 3 times the age control values. Thereafter, the population density slowly decreased in both ears, but it remained well above original values as late as 20 weeks after the irradiation. Thus, a short UVB irradiation period induces a long-lasting increase in the number of epidermal melanocytes in irradiated skin areas, as well as in covered skin regions. It is suggested that the population increase in the shielded ear is initiated by one or more systemic factors originating from the UVB irradiated skin. Such factors may be involved in the regulation of a balanced melanocyte population over the entrie body surface.     

The Genes and Genetics of Malignant Melanoma

Background: Population-based studies have identified several clinical variables associated with an increased risk of developing cutaneous melanoma that include phenotype, amount of and response to sun exposure, and family history. However, these observations are of limited relevance to clinical practice as the risk associated with each factor is individually modest and the characteristics of these variables lack precision when applied to a particular individual. Objective: To review the literature regarding recent advances made in the understanding of the genes and genetics of clinical variables associated with an increased risk of melanoma. Conclusion: Variants of the MC1R (melanocortin-1 receptor) have been identified as major determinants of high-risk phenotypes, such as red hair and pale skin, and the ability to tan in response to UV exposure. Several studies also suggest that such variants may increase melanoma risk independent of their contribution to phenotype. A strong genetic basis for both nevus density and size has been demonstrated and the link between nevi and the development of MM has become better defined. Finally, germline defects in several genes involved in cell cycle regulation, namely, p16 and CDK4, have been demonstrated in many familial melanoma kindreds. This progress has introduced the prospect of genetic testing as a means of identifying a limited number of high-risk individuals who can be targeted with regular screening and education regarding UV exposure and skin self-examination. Ultimately, through rational genetic therapy targeted to correcting the underlying molecular defect, altering the natural history of melanoma development may be possible.     

Sunscreen abuse for intentional sun exposure

Skin cancer is caused by exposure to ultraviolet radiation (UV) and the sun is the main source of this radiation. Sunscreens were initially formulated to prevent sunburns; laboratory studies later revealed that in rodents they could reduce UV-induced skin cancer which resembles human squamous cell carcinoma. Three randomized trials in older adults showed the ability of sunscreens to moderately reduce the occurrence of solar keratoses and of squamous cell carcinoma. However, no effect was observed for basal cell carcinoma. There is no animal model for human melanoma and observational studies often found sunscreen use associated with a higher risk of nevus, melanoma and basal cell carcinoma. These higher risks were found when sun exposure appeared to be intentional, that is, with the desire to acquire a tan, a healthy look or simply to spend as long as possible in the sun with as much skin exposed as possible. Three randomized trials showed that sunscreen use by sun sensitive subjects engaging in intentional sun exposure could increase the duration of exposure without decreasing sunburn occurrence. This increased duration could be the reason why melanoma risk is increased when sunscreen is used. Hence, sunscreen abuse may extend sun exposure duration thus allowing sun exposure behaviours that would not be possible otherwise. Advertising for sunscreens and labeling of sunscreen bottles should inform consumers of the carcinogenic hazards associated with sunscreen abuse. It would be good to use a personal UV dosimeter which would give an alert when one's individual sunburn threshold in the absence of sunscreen use is nearing. The combination of sunscreen and a UV dosimeter may be an option for reducing the melanoma risk among sun worshippers.     

Outdoor sports and skin cancer

Ultraviolet radiation is estimated to be one of the most important risk factors for nonmelanoma and melanoma skin cancers. Athletes practicing outdoor sports receive considerable UV doses because of training and competition schedules with high sun exposure, and in alpine sports, by altitude-related increase of UV radiation and reflection from snow- and ice-covered surfaces. Extreme UV exposure in outdoor sports such as skiing, mountaineering, cycling, or triathlon has been documented in a series of dosimetric studies. Sweating because of physical exercise may contribute to UV-related skin damage as it increases the individual photosensitivity of the skin, facilitating the risk of sunburns. Large epidemiological studies showed that recreational activities such as sun exposure on the beach or during water sports were associated with an increased risk of basal cell carcinoma, whereas skiing has been shown to be at increased risk for squamous cell carcinoma. Risk factors of cutaneous melanoma such as the number of melanocytic nevi and solar lentigines have been found to be more frequent in subjects practicing endurance outdoor sports. An increased risk for cutaneous melanoma may be assumed for these athletes. In addition to the important sun exposure, exercise-induced immunosuppression may increase the risk for nonmelanoma skin cancer and cutaneous melanoma in athletes. Frequently, athletes seem to know little about the risk of sun exposure. Protective means such as avoiding training and competition with considerable sun exposure, choosing adequate clothing, and applying water-resistant sunscreen still need to be propagated in the community of outdoor sportsmen.     

Mitochondrial common deletion mutation and extrinsic skin ageing in German and Japanese women

The mitochondrial common deletion (CD) mutation is induced by oxidative stress. One main source of oxidative stress is the error-prone process of the respiratory chain located in the mitochondria. Another important source is the exposure to environmental factors, which further induces oxidative stress in the cells. For human skin, the primary damaging environmental factor is ultraviolet (UV) radiation, which is able to induce CD mutations and the characteristic extrinsic skin ageing signs. Traditionally, levels of UV exposure differ between German and Japanese populations, as tanned skin represents beauty and health in Western cultures, whereas photo-protected skin is considered ideal in Asia. We hypothesize that (i) this cultural-related UV exposure pattern might be reflected by CD concentrations in environmentally exposed skin and (ii) CD concentrations in environmentally exposed areas might be associated with the manifestation of extrinsic skin ageing. In this study, we determined the concentration of CD in skin from the neck (environmentally exposed area) and the buttock (environmentally protected area) of 22 German and 46 Japanese women between 30 and 70 years of age. We evaluated skin ageing signs by a validated clinical score, and exposure to environmental factors, such as UV exposure and smoking, was assessed using a questionnaire-based interview. Higher levels of CD were detected in neck skin than in buttock skin in both German and Japanese women. CD also increased with age in the neck skin. German women had higher CD concentrations in the neck skin than Japanese women. The CD concentrations in the buttock skin samples were similar in both populations. These findings suggest higher environmental UV exposure resulted in higher levels of CD in the skin of German women compared with Japanese women. However, only in Japanese women were the signs of extrinsic skin ageing associated with higher CD concentrations in the neck skin, in agreement with the hypothesis (ii). In German women, we did not find this latter association, which might be due to reaching a maximum level of CD, beyond which cells undergo negative selection and are lost to the population samples. In conclusion, under some conditions, there seems to be an association between the CD mutation concentration and extrinsic skin ageing, but this may be modified by cellular and tissue processes which affect the sampling rate for CD mutation concentrations and prevent a statistical association with extrinsic skin ageing.     

Mitotic activity of epidermal melanocytes in UV-irradiated mouse skin

The role of mitosis in the increase in the epidermal melanocyte population following repeated ultraviolet (UV) irradiation has been studied in C57B1 mice. Cumulative labeling with 3H-methyl-thymidine (3HTdr) was used in combination with autoradiography. A 4-6 fold increase in the melanocyte population was associated with an isotope labeling of 65-80% of the melanocytes. This indicates that cell division during the irradiation period can account for the total increase in the number of melanocytes. Labeled melanocytes were also found in the epidermis from unirradiated skin. Thus, the epidermal melanocytes seem to constitute a dynamic cell population under continuous renewal.     

Does mountaineering increase the incidence of cutaneous melanoma? A hypothesis based on cancer registry data

Exposure to ultraviolet radiation is considered a major risk factor for the development of cutaneous melanoma. In white populations in Australia or the USA, the melanoma incidence increases with the vicinity of residence to the equator. In Europe decreasing incidence rates towards southern countries may be due to the darker pigmentation of the Mediterranean population. The comparison of age-standardized incidence rates (world standard population) in Europe shows that Swiss cancer registries and the Austrian Tyrol registry have much higher incidence rates for cutaneous melanoma than other Central European cancer registries. The excess of Swiss/Austrian incidence rates is even more pronounced when head localization is analysed separately. Due to the altitude-related increase in UV radiation two possible explanations for the Swiss/Austrian excess rates may be considered: firstly, as a result of the altitude of residence, higher UV exposure is generally present in these countries; secondly, mountaineering activities may additionally increase UV exposure.     

Lack of correlation between UV-induced enhancement of melanoma development and local suppression of contact hypersensitivity

Injection of melanoma cells into the UV-irradiated ear skin of syngeneic mice results in an increased incidence of melanomas compared with that in nonirradiated ear skin. This effect of UV is localized to the site of irradiation and appears to be immunologically mediated. In these studies we test the hypothesis that the effect of UV irradiation on melanoma development is related to its ability to alter epidermal Langerhans cells and impair the induction of contact hypersensitivity. A regimen of UV irradiation that altered epidermal immune cells and interfered with the generation of contact hypersensitivity was tested for its ability to increase the incidence of melanoma. Conversely, the ear skin of C3H mice treated with a regimen of UV radiation that enhanced melanoma development was examined for the number of appearance of ATPase+ and Thy-1+ dendritic epidermal cells and tested for the ability to initiate a contact hypersensitivity response. No correlation between these effects of UV irradiation could be detected. Furthermore, implantation of melanoma cells into UV-irradiated ear skin resulted in the generation of systemic immunity against subsequent tumor challenge. Therefore, we conclude that the ability of UV irradiation to modify melanoma development is unrelated to its effects on the afferent arm of the contact hypersensitivity response and that enhanced melanoma development is not due to an impairment in the induction of tumor immunity.     

Ultraviolet exposures in different playground settings: a cohort study of measurements performed in a school population

Background: Solar erythemally effective ultraviolet (UVE) measured on the face, neck, arms, hands and legs of a cohort of school children was investigated with respect to student movement about a school environment located in Southern Queensland.
Methods: A total of 147 erythemally effective solar UV exposures were measured using polysulphone film dosimeters. Measurements were performed on exposed skin surfaces during school hours between 08:30 and 15:05 hours for the period 5 February to 4 June 2008.
Results: Median seasonal UVE exposures varied between 0.4 and 2.7 standard erythema doses (SED) for school students observing the normal school routine between winter and summer, respectively. These exposures increased significantly for school activities scheduled primarily outdoors, reaching a maximum of 50 SED recorded to a vertex site measured during a school swimming carnival.
Conclusion: The excessive erythemal UV exposures measured in this research have the potential to significantly contribute to the later development of melanoma and non melanoma skin cancers caused by acute and chronic cumulative exposure to solar UV in Queensland school environments. The research provides data on personal UV exposures measured in a school population engaged in daily school activities.     

Running behind a tourist: leisure-related skin cancer prophylaxis

The most important risk factor in the development of skin cancer is exposure to ultraviolet (UV) radiation. Cumulative lifetime UV radiation exposure has been shown to be most important in the pathogenesis of squamous cell carcinoma, whereas intermittent high-dose UV radiation exposure in childhood and adolescence may be more important in the aetiology of basal cell carcinoma and cutaneous malignant melanoma. Using established methodology and best available estimates on UV-related mortality and morbidity, it has been estimated that annually around 1·5?million disability-adjusted life years are lost through excessive exposure to UV radiation. Skin cancer is a significant health problem and its burden is such that it causes the health system more to treat than any other forms of cancer. Prevention is the key action in managing skin cancer at a population level. Investment in prevention programmes such as SunSmart encourages protective behaviours that will reduce the human and financial costs of skin cancer.     

What are melanocytes really doing all day long…?

Abstract: Everyone knows and seems to agree that melanocytes are there to generate melanin – an intriguing, but underestimated multipurpose molecule that is capable of doing far more than providing pigment and UV protection to skin ( 1 ). What about the cell that generates melanin, then? Is this dendritic, neural crest‐derived cell still serving useful (or even important) functions when no‐one looks at the pigmentation of our skin and its appendages and when there is essentially no UV exposure? In other words, what do epidermal and hair follicle melanocytes do in their spare time – at night, under your bedcover? How much of the full portfolio of physiological melanocyte functions in mammalian skin has really been elucidated already? Does the presence or absence of melanoctyes matter for normal epidermal and/or hair follicle functions (beyond pigmentation and UV protection), and for skin immune responses? Do melanocytes even deserve as much credit for UV protection as conventional wisdom attributes to them? In which interactions do these promiscuous cells engage with their immediate epithelial environment and who is controlling whom? What lessons might be distilled from looking at lower vertebrate melanophores and at extracutaneous melanocytes in the endeavour to reveal the ‘secret identity’ of melanocytes? The current Controversies feature explores these far too infrequently posed, biologically and clinically important questions. Complementing a companion viewpoint essay on malignant melanocytes ( 2 ), this critical re‐examination of melanocyte biology provides a cornucopia of old, but under‐appreciated concepts and novel ideas on the slowly emerging complexity of physiological melanocyte functions, and delineates important, thought‐provoking questions that remain to be definitively answered by future research.     

Outdoor activities in childhood: a protective factor for cutaneous melanoma? Results of a case–control study in 271 matched pairs

BACKGROUND: A matched case-control study was performed in Munich, Germany, in 1996-97 to evaluate the risk of cutaneous melanoma due to ultraviolet (UV) exposure behaviour in Southern Bavaria, Germany. OBJECTIVES: Patients with cutaneous melanoma and controls were investigated by two physicians using a standardized questionnaire to identify risk factors for the development of melanoma, such as professional and leisure sun exposure behaviour. In each person, a total body examination was performed to detect benign skin alterations, phenotypic characteristics and precursor lesions for skin cancer. PATIENTS/METHODS: A total of 271 melanoma patients and 271 controls were individually matched for residence, age and gender. A multiple conditional logistic regression analysis was performed. RESULTS: Of 56 factors, those risk factors with a strong effect on the development of melanoma were: the existence of melanoma in first degree relatives, solar lentigo, actinic keratosis, actinic cheilitis, skin phototype, immediate skin reaction to UV light at the start of the outdoor season, sunburn in childhood and sun exposure during holidays in sunny areas 20 years before melanoma was diagnosed; outdoor activities in childhood were found to be protective. CONCLUSIONS: Sunburn in childhood and increased sun exposure during annual holidays in sunny areas should be avoided. In contrast, outdoor activities in childhood, including soccer and gardening, should be encouraged because they are associated with a lower risk of melanoma formation.     

Café-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind?

Solitary café-au-lait spots are quite common in the general population but multiple café-au-lait macules (CALM) are often indicative of an underlying genetic disorder. The frequency of having more than five CALM is rare in normal individuals and is therefore considered as a cut-off for the diagnosis of neurofibromatosis type 1 (NF1). The etiopathogenesis of these macules is still very obscure. In this study we compared epidermal melanocyte and dermal mast cell numbers between four groups: control normal and control CALM skin, and NF1 normal and NF1 CALM skin and elaborated a possible role for stem cell factor (SCF) in CALM formation. The groups were analyzed by immunohistochemistry for numerical analysis of the melanocyte and mast cell population and by ELISA, western blot analysis and real-time quantitative PCR for further determination of the role of SCF. We found a significant increase in melanocyte density in NF1 CALM skin compared with the isolated CALM in control individuals. However, both groups displayed a similar increase in mast cell density. In addition, we found increased levels of soluble SCF in NF1 CALM and in NF1 normal fibroblast supernatant. We conclude that SCF is an important cytokine in NF1 skin, but that additional (growth) factors and/or genetic mechanisms are needed to induce NF1-specific CALM hyperpigmentation.