Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma

Background: Some melanomas form on sun-exposed body sites, whereas others do not. We previously proposed that melanomas at different body sites arise through different pathways that have different associations with melanocytic nevi and solar keratoses. We tested this hypothesis in a case-case comparative study of melanoma patients in Queensland, Australia. Methods: We randomly selected patients from among three prespecified groups reported to the population-based Queensland Cancer Registry: those with superficial spreading or nodular melanomas of the trunk (n = 154, the reference group), those with such melanomas of the head and neck (n = 77, the main comparison group), and those with lentigo maligna melanoma (LMM) (n = 75, the chronic sun-exposed group). Each participant completed a questionnaire, and a research nurse counted melanocytic nevi and solar keratoses. We calculated exposure odds ratios (ORs) and 95% confidence intervals (CIs) to quantify the association between factors of interest and each melanoma group. Results: Patients with head and neck melanomas, compared with patients with melanomas of the trunk, were statistically significantly less likely to have more than 60 nevi (OR = 0.34, 95% CI = 0.15 to 0.79) but were statistically significantly more likely to have more than 20 solar keratoses (OR = 3.61, 95% CI = 1.42 to 9.17) and also tended to have a past history of excised solar skin lesions (OR = 1.87, 95% CI = 0.89 to 3.92). Patients with LMM were also less likely than patients with truncal melanomas to have more than 60 nevi (OR = 0.32, 95% CI = 0.14 to 0.75) and tended toward more solar keratoses (OR = 2.14, 95% CI = 0.88 to 5.16). Conclusions: Prevalences of nevi and solar keratoses differ markedly between patients with head and neck melanomas or LMM and patients with melanomas of the trunk. Cutaneous melanomas may arise through two pathways, one associated with melanocyte proliferation and the other with chronic exposure to sunlight.

Induction of metallothionein in human skin by routine exposure to sunlight: Evidence for a systemic response and enhanced induction at certain body sites

Expression of metallothionein, an antioxidant induced by a variety of stimuli including ultraviolet light, was quantitated by immunohistochemistry in the skin of males aged over 50 who had known short- and long-term exposures to sunlight. Skin punch biopsies were taken from two sites in each subject: the hand in all subjects and a range of other sites matched to patients with a previously excised primary melanoma. Metallothionein expression (strongest in the basal layers of the epidermis and primarily nuclear) was associated with both short- and long-term exposure to sunlight. A plateau of staining intensity was reached after 3 h sun exposure, within the previous 3 d before biopsy. Expression was also elevated in the nonexposed skin sites of subjects who had recent sun exposure, indicating a systemic response to exposure of remote sites. Using the skin of the hand to normalize responses to chronic exposure between individuals, the systemically modulated response to sunlight was significantly greater on the unexposed back than on other sites. The possibility of ultraviolet-induced cytokines selectively modifying the response of skin on a site-specific basis was investigated. The circulating leukocytes, but not lymphocytes, of two individuals exposed to 1 minimal erythema dose whole-body solar-simulated ultraviolet showed increased interleukin-6 mRNA 4 h after exposure. Interleukin-6 was not directly induced in these cell populations 4 h after ultraviolet A or ultraviolet B irradiation ex vivo . Leukocytes may therefore contribute to and amplify the systemic effects of ultraviolet-induced interleukin-6 and metallothionein expression.

Interactive effects of MC1R and OCA2 on melanoma risk phenotypes

The relationships between MC1R gene variants and red hair, skin reflectance, degree of freckling and nevus count were investigated in 2331 adolescent twins, their sibs and parents in 645 twin families. Penetrance of each MC1R variant allele was consistent with an allelic model where effects were multiplicative for red hair but additive for skin reflectance. Of nine MC1R variant alleles assayed, four common alleles were strongly associated with red hair and fair skin (Asp84Glu, Arg151Cys, Arg160Trp and Asp294His), with a further three alleles having low penetrance (Val60Leu, Val92Met and Arg163Gln). These variants were separately combined for the purposes of this analysis and designated as strong 'R' (OR=63.3; 95% CI 31.9-139.6) and weak 'r ' (OR=5.1; 95% CI 2.5-11.3) red hair alleles. Red-haired individuals are predominantly seen in the R/R and R/r groups with 67.1 and 10.8%, respectively. To assess the interaction of the brown eye color gene OCA2 on the phenotypic effects of variant MC1R alleles we included eye color as a covariate, and also genotyped two OCA2 SNPs (Arg305Trp and Arg419Gln), which were confirmed as modifying eye color. MC1R genotype effects on constitutive skin color, freckling and mole count were modified by eye color, but not genotype for these two OCA2 SNPs. This is probably due to the association of these OCA2 SNPs with brown/green not blue eye color. Amongst individuals with a R/R genotype (but not R/r), those who also had brown eyes had a mole count twice that of those with blue eyes. This suggests that other OCA2 polymorphisms influence mole count and remain to be described.

Acceptability and feasibility of a community-based screening programme for melanoma in Australia

The evaluation of a community-based screening programme for melanoma (SkinWatch) in 18 regional communities (total adult population >30 years 63 035) in Queensland, Australia is described. The aim of the SkinWatch programme was to promote whole-body skin screening for melanoma by primary care physicians. The programme included community education, education and support for local medical practitioners and open-access skin screening clinics. Programme delivery was achieved through assistance of local volunteers. All programme activities and resources were recorded for process evaluation. A baseline telephone survey (n = 3110) and a telephone survey four months after programme launch (n = 680) assessed community awareness of the SkinWatch programme and, 37 face-to-face interviews with community members, doctors and community leaders were conducted to assess satisfaction with the programme. A sample of 1043 of 16 383 residents who attended the skin screening clinics provided as part of the programme were interviewed to assess reasons for attending, and positive and negative aspects of SkinWatch programme. Community awareness of the SkinWatch programme increased by over 30% (p < 0.001) within four months of the start of the programme. Interview participants described the SkinWatch programme as a useful service for the communities and 90% stated they would revisit the clinics. A total of 43% of all attendees were over 50 years old, and nearly 50% were men. These findings demonstrate the acceptability and feasibility of a community-based screening programme for melanoma in rural areas. Volunteers were instrumental in increasing community ownership of and involvement in the SkinWatch programme.

Primary prevention of skin cancer: A review of sun protection in Australia and internationally

The incidence of skin cancer is increasing worldwide. Protecting the skin from the sun by wearing protective clothing, using a sunscreen with appropriate sun protection factor, wearing a hat, and avoiding the sun are recommended as primary preventive activities by cancer agencies. In this paper the recent data relating to skin cancer primary preventive behaviour in Australia and other countries is reviewed. Comparison of the studies in a table format summarizing the methods, objectives, participants, findings and implications may be obtained from the corresponding author. The sun protection knowledge, attitudes and behaviour patterns observed in Australia are similar in other countries, although Australian studies generally, report higher knowledge levels about skin cancer and higher levels of sun protection. The findings suggest that sunscreen is the most frequent method of sun protection used across all age groups, despite recommendations that it should be at? adjunct to other forms of protection. While young children's sun protective behaviour is largely influenced by their parents' behaviours, they are still tinder protected, and sun protective measures such as seeking shade, avoiding the sun and protective clothing need to be emphasized. Adolescents have the lowest skin protection rates of all age groups. Within the adult age range, women and people with sensitive skin were most likely to be using skin protection. However, women were also more likely than men to sunbath deliberately and to use sun-tanning booths. The relationship between skin protection knowledge and attitudes, attitudes towards tanning and skin protection behaviour needs further investigation. Further studies need to include detailed assessments of sunscreen use and application patterns, and future health promotion activities need to focus on sun protection by wearing clothing and seeking shade to avoid increases in the sunburn rates observed to date.

Comparability of skin screening histories obtained by telephone interviews and mailed questionnaires: A randomized crossover study

The comparability of information collected through telephone interviews and information collected through mailed questionnaires has not been well studied. As part of the first phase of a randomized controlled trial of population screening for melanoma in Queensland, Australia, the authors compared histories of skin examination reported in telephone interviews and self-administered mailed questionnaires. A total of 1,270 subjects each completed a telephone interview and a mailed questionnaire 1 month apart in 1999; 564 subjects received the interview first, and 706 received the mailed questionnaire first. Agreement between the two methods was 91.2% and 88.6% for whole-body skin examination by a physician in the last 12 months and the last 3 years, respectively, and 81.9% for whole-body skin self-examination in the last 12 months. Agreement was lower for any skin self-examination. Agreement between the two methods was similar regardless of whether the interview or the questionnaire was administered first. Missing data were less frequent for interviews (0.5%) than for mailed questionnaires (3.8%). Costs were estimated at A$9.55 (US$6.21) per completed interview and A$3.01 (US$1.96) per questionnaire. The similarity of results obtained using telephone interviews and mailed questionnaires, coupled with the substantially higher cost of telephone interviews, suggests that self-administered mailed questionnaires are an appropriate method of assessing this health behavior.

Validity of self-reported skin screening histories

Screening by whole-body clinical skin examination may improve early diagnosis of melanoma and reduce mortality, but objective scientific evidence of this is lacking. As part of a randomized controlled trial of population screening for melanoma in Queensland, Australia, the authors assessed the validity of self-reported history of whole-body skin examination and factors associated with accuracy of recall among 2,704 participants in 2001. Approximately half of the participants were known to have undergone whole-body skin examination within the past 3 years at skin screening clinics conducted as part of the randomized trial. All positive and negative self-reports were compared with screening clinic records. Where possible, reports of skin examinations conducted outside the clinics were compared with private medical records. The validity of self-reports of whole-body skin examination in the past 3 years was high: Concordance between self-reports and medical records was 93.7%, sensitivity was 92.0%, and specificity was 96.3%. Concordance was lower (74.3%) for self-reports of examinations conducted in the past 12 months, and there was evidence of telescoping in recall for this more recent time frame. In multivariate analysis, women and younger participants more accurately recalled their history of skin examinations. Participants with a history of melanoma did not differ from other participants in their accuracy of recall.

Prevalence of whole-body skin self-examination in a population at high risk for skin cancer (Australia)

Objective: Whole-body skin self-examination (SSE) with presentation of suspicious lesions to a physician may improve early detection of melanoma. The aim of this study was to establish the prevalence and determinants of SSE in a high-risk population in preparation for a community-based randomised controlled trial of screening for melanoma. Methods: A telephone survey reached 3110 residents older than 30 years (overall response rate of 66.9%) randomly selected from 18 regional communities in Queensland, Australia. Results: Overall, 804 (25.9%) participants reported whole-body SSE within the past 12 months and 1055 (33.9%) within the past three years. Whole-body SSE was associated in multivariate logistic regression analysis with younger age (< 50 years); higher education; having received either a whole-body skin examination, recommendation or instruction on SSE by a primary care physician; giving skin checks a high priority; concern about skin cancer and a personal history of skin cancer. Conclusion: Overall, the prevalence of SSE in the present study is among the highest yet observed in Australia, with about one-third of the adult population reporting whole-body SSE in the past three years. People over 50 years, who are at relatively higher risk for skin cancer, currently perform SSE less frequently than younger people.

Community perceptions of adequate levels and reasons for skin protection

In this study the authors addressed whether or not community members use relevant risk factors to determine an appropriate level of skin protection behavior in the prevention of skin cancer. The authors conducted a postal survey with a community sample of 3,600 Queensland residents that they randomly selected from the Commonwealth electoral roll. The predictors of perceptions of doing enough skin protection included intrapersonal, social, and attitudinal influences. People protected themselves from the sun primarily out of a desire for future good health and on other occasions did not protect themselves from the sun because they were not out there long enough to get burnt. The predictors of perceptions of doing enough skin protection indicated that participants were aware of relevant risk factors. The main reasons that people protect themselves from the sun suggest that they are acting on many health promotion messages. However, skin cancer prevention programs need to move beyond increasing awareness and knowledge of the disease to providing a supportive environment and enhancing individual skills. Health promotion campaigns could reinforce appropriate risk assessment and shape an individual's decision about how much sun protection is needed.

Activation of the cAMP pathway by variant human MC1R alleles expressed in HEK and in melanoma cells

alpha-Melanocyte-stimulating hormone (alpha-MSH) activates the melanocortin-1 receptor (MC1R) on melanocytes to promote a switch from red/yellow pheomelanin synthesis to darker eumelanins via positive coupling to adenylate cyclase. The human MC1R locus is highly polymorphic with the specific variants associated with red hair and fair skin (RHC phenotype) postulated to be loss-of-function receptors. We have examined the ability of MC1R variants to activate the cAMP pathway in stably transfected REK293 cells. The RHC associated variants, Arg151Cys, Arg160Trp and Asp294His, demonstrated agonist-mediated increases in cAMP and phosphorylation of cAMP-responsive element-binding protein (CREB). Whereas the Asp294His variant showed severely impaired functional responses, the Arg151Cys and Arg160Trp variants retained considerable signaling capacity. Melanoma cells homozygous for either the Arg151Cys variant or consensus sequence both elicited CREB phosphorylation in response to alpha-MSH in the presence of IBMX. The common RHC alleles, Arg151Cys, Arg160Trp and Asp294His, are neither complete loss-of-function receptors nor are they functionally equivalent. (c) 2005 Elsevier Inc. All rights reserved.

Community perceptions of suspicious pigmented skin lesions: are they accurate when compared to general practitioners?

Community responses (n = 925, response rate = 71%) of a series of eight photographs of pigmented skin lesions were compared against those of general practitioners (n = 114, response rate = 77%), considered to be the most relevant gold standard. The eight photographs included three melanomas, two potentially malignant lesions and three benign pigmented lesions. Over the pool of lesions examined, the average probability that community members thought a lesion was likely to be skin cancer (0.68 [99% CI = 0.66-0.69]) was higher (p < 0.0001) than that of the comparison general practitioners 0.58 [99% CI = 0.55-0.62]. This reflects a general (but not consistent) inflated propensity to over-diagnose among community members. The average probability that respondents indicated they would seek medical advice for a lesion was 0.71 [99% CI = 0.70-0.73]. As expected, this was strongly associated with their perceptions of the skin lesion. These results suggest that the community can play a valuable role in assessing the need for medical evaluation of pigmented skin lesions. (c) 2004 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.

A genome scan for epidermal skin pattern in adolescent twins reveals suggestive linkage on 12p13.31

Deterioration in stratum corneum reticular patterning (skin pattern or skin wrinkling) has been associated with increased rates of solar keratoses and skin cancer. A previous analysis of data from the twin sample used in this investigation has shown that 86% of the variation in skin pattern is genetic at age 12 and 62% in an adult sample (mean age 47.5). Variation due to genetic influences is likely to be influenced by more than one locus. Here, we present results of a genome-wide linkage scan of skin pattern in adolescent twins and siblings from 428 nuclear twin families. Sib-pair linkage analysis was performed on skin pattern data collected from twins at age 12 (378 informative families) and 14 (316 families). Suggestive linkage was found at marker D12S397 (12p13.31, logarithm of the odds (lod) 1.94), when the effect of the trait locus was modelled to influence the skin pattern equally at both ages 12 and 14. In the same analysis, a peak was seen at 4q23 with a lod score of 1.55. A possible candidate for the peak at 12p13.31 is the protease inhibitor, alpha-2-macroglobulin.

Increase in skin cancer screening during a community-based randomized intervention trial

Survival from cutaneous melanoma is mainly dependent on the thickness of the lesion at diagnosis. Skin screening may increase detection of thin lesions and hence improve survival. Within a community-based randomized controlled trial of a population screening program for melanoma in Queensland, Australia, 9 communities were randomly assigned to the 3-year intervention and 9 communities to the control group. Skin screening prevalence was monitored by cross-sectional surveys at baseline, 1, 2 and 3 years into the intervention and 2 years later. At baseline, prevalence of whole-body clinical skin examination was similar in intervention and control communities. In intervention communities, the prevalence of whole-body skin examinations increased to 29.2%, an absolute difference of 18% from baseline, with a peak of 34.8% 2 years after baseline, and began to decline again at the end of the intervention period. The largest increases were seen in men and women ≥50 years. Uptake of screening did not differ according to melanoma risk factors; however, the decline in screening was less in participants who reported a number of melanoma risk factors. The prevalence of skin self-examination remained stable during the intervention program. No changes were observed in the control communities. These results indicate that the intervention program significantly increased the prevalence of whole-body clinical skin examinations in intervention communities. Once the intervention program ceased, and particularly after skin clinics ceased, levels of skin screening began to decline. The provision of specialized skin screening clinics may be needed to achieve sufficient screening rates should population based screening for skin cancer be considered. © 2005 Wiley-Liss, Inc.

Presentation and detection of invasive melanoma in a high-risk population

Background: Early detection of melanoma has been encouraged in Queensland for many years, yet little is known about the patterns of detection and the way in which they relate to tumor thickness. Objective: Our purpose was to describe current patterns of melanoma detection in Queensland. Methods: This was a population-based study, comprising 3772 Queensland residents diagnosed with a histologically confirmed melanoma between 2000 and 2003. Results: Almost half (44.0%) of the melanomas were detected by the patients themselves, with physicians detecting one fourth (25.3%) and partners one fifth (18.6%). Melanomas detected by doctors were more likely to be thin (\0.75 mm) than those detected by the patient or other layperson. Melanomas detected during a deliberate skin examination were thinner than those detected incidentally. Limitations: Although a participation rate of 78% was achieved, as in any survey, nonresponse bias cannot be completely excluded, and the ability of the results to be generalized to other geographical areas is unknown. Conclusion: There are clear differences in the depth distribution of melanoma in terms of method of detection and who detects the lesions that are consistent with, but do not automatically lead to, the conclusion that promoting active methods of detection may be beneficial. ( J Am Acad Dermatol 2006;54:783-92.)