Development and external validation study of a melanoma risk prediction model incorporating clinically assessed naevi and solar lentigines.

BACKGROUND: Melanoma risk prediction models could be useful for matching preventive interventions to patients' risk. OBJECTIVES: To develop and validate a model for incident first-primary cutaneous melanoma using clinically assessed risk factors. METHODS: We used unconditional logistic regression with backward selection from the Australian Melanoma Family Study (461 cases and 329 controls) in which age, sex and city of recruitment were kept in each step, and we externally validated it using the Leeds Melanoma Case-Control Study (960 cases and 513 controls). Candidate predictors included clinically assessed whole-body naevi and solar lentigines, and self-assessed pigmentation phenotype, sun exposure, family history and history of keratinocyte cancer. We evaluated the predictive strength and discrimination of the model risk factors using odds per age- and sex-adjusted SD (OPERA) and the area under curve (AUC), and calibration using the Hosmer-Lemeshow test. RESULTS: The final model included the number of naevi ≥ 2 mm in diameter on the whole body, solar lentigines on the upper back (a six-level scale), hair colour at age 18 years and personal history of keratinocyte cancer. Naevi was the strongest risk factor; the OPERA was 3·51 [95% confidence interval (CI) 2·71-4·54] in the Australian study and 2·56 (95% CI 2·23-2·95) in the Leeds study. The AUC was 0·79 (95% CI 0·76-0·83) in the Australian study and 0·73 (95% CI 0·70-0·75) in the Leeds study. The Hosmer-Lemeshow test P-value was 0·30 in the Australian study and < 0·001 in the Leeds study. CONCLUSIONS: This model had good discrimination and could be used by clinicians to stratify patients by melanoma risk for the targeting of preventive interventions. What's already known about this topic? Melanoma risk prediction models may be useful in prevention by tailoring interventions to personalized risk levels. For reasons of feasibility, time and cost many melanoma prediction models use self-assessed risk factors. However, individuals tend to underestimate their naevus numbers. What does this study add? We present a melanoma risk prediction model, which includes clinically-assessed whole-body naevi and solar lentigines, and self-assessed risk factors including pigmentation phenotype and history of keratinocyte cancer. This model performs well on discrimination, the model's ability to distinguish between individuals with and without melanoma, and may assist clinicians to stratify patients by melanoma risk for targeted preventive interventions.

Association of sunbed use with skin cancer risk factors in Europe: an investigation within the Euromelanoma skin cancer prevention campaign.

INTRODUCTION: Sunbed use has been significantly associated with increased risk of melanoma and non-melanoma skin cancer (NMSC), but its relationship with melanoma's risk factors such as high nevus count, atypical nevi and lentigines is poorly studied. Euromelanoma is a skin cancer prevention campaign conducted all over Europe. It offers a once-a-year screening during which participants' data, including sunbed use and phenotype, are collected via questionnaires. OBJECTIVES: To investigate the association of sunbed use with nevus count, atypical nevi, lentigines and suspicion of skin cancer. METHODS: To ensure reliability of the data, we defined inclusion and exclusion criteria for countries' eligibility for the risk analysis. Multivariate logistic regression models (including age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure and any sunscreen use) were used to calculate summary odds ratios (SORs) of each clinical endpoint for ever sunbed use. RESULTS: Overall, 227 888 individuals from 30 countries completed the Euromelanoma questionnaire. After the data quality check, 16 countries were eligible for the multivariate analysis, for a total of 145 980 participants (64.8% females; median age 43 years; 62.3% highly educated; 28.5% skin type I-II; 11.0% ever sunbed use). Ever sunbed use was independently associated with nevus count >50 [SOR = 1.05 (1.01-1.10)], atypical nevi [SOR = 1.04 (1.00-1.09)], lentigines [SOR = 1.16 (1.04-1.29)] and suspicion of melanoma [SOR = 1.13 (1.00-1.27)]. Conversely, no significant association was found between ever sunbed use and suspicion of NMSC [SOR = 1.00 (0.91-1.10)]. CONCLUSIONS: Indoor tanning is significantly associated with well-recognized risk factors for melanoma (including high nevus count, presence of atypical nevi and lentigines) as well as suspicion of melanoma within the Euromelanoma screenees. In order to reduce the prevalence of melanoma risk factors, avoidance/discontinuation of sunbed use should always be encouraged, especially but not exclusively for individuals with high-risk phenotypes.

Exposure to fine particulate matter associated with senile lentigo in Chinese women: a cross-sectional study.

BACKGROUND: Skin ageing especially senile lentigo directly affects self-esteem. For decades, senile lentigo has been associated with chronic exposure to solar radiation. However, a study conducted recently in Caucasian subjects suggested that exposure to air pollution was significantly correlated with extrinsic skin ageing, in particular senile lentigines. OBJECTIVE: To investigate the association between fine particulate matter (PM2.5 ) and skin ageing, particularly senile lentigo and seborrheic keratosis. METHODS: The study enrolled 400 Chinese women aged 40-90 years including 210 from the Yanqing county in Beijing (low PM2.5 exposure group) and 190 from the Xuanwumen in Beijing (high PM2.5 exposure group). Skin ageing symptoms, particularly senile lentigines and seborrheic keratoses, were clinically assessed using scores of intrinsic and extrinsic skin ageing. An ordinal logistic regression model was used to analyse the effect of PM2.5 on skin ageing adjusted for factors underlying skin ageing. RESULTS: In the study population of Xuanwumen, we found that senile lentigo on cheeks and back of hands was 1.48 times and 2.8 times higher, respectively, compared with those from Yanqing county. However, no association was found between PM2.5 and seborrheic keratosis. We found that other variables such as smoking, second-hand smoking, contact with fossil fuels and skin types were significantly associated with skin ageing. CONCLUSION: These results indicate that PM2.5 was another extrinsic factor promoting skin ageing.

Freckles and solar lentigines have different risk factors in Caucasian women.

BACKGROUND: To date, few epidemiological data on the relationships between solar lentigines, freckles and behavioural and constitutional risk factors in Caucasian populations exist. OBJECTIVES: To investigate the potential impact of behavioural and phenotypic variables, as well as the MC1R genetic background, on the history of facial freckles and the severity of solar lentigines in Caucasian women. METHODS: The severity of solar lentigines was graded from facial digital images of 523 French middle-aged women by a dermatologist and summarized by a score afterwards. The history of facial freckles was assessed and the sun-exposure behaviour was characterized using a six-category typology. Risk factors including MC1R polymorphism were evaluated using logistic regression models. RESULTS: Two constitutive host factors were found to be independently associated with a history of facial freckles: frequent sunburns and the presence of diminished function variants of the MC1R gene. In addition to age, five factors were independently associated with solar lentigines: constitutive host factors (dark skin colour and tanning capacity), a history of freckles, sun-exposure behaviour and current intake of oral contraceptive or progestogen treatments. CONCLUSION: These results strengthen the hypothesis that solar lentigines are markers of photoaging, whereas freckles are mainly determined by genetic factors. The finding that hormonal treatment is associated with a higher risk for solar lentigines merits further investigations.

Genetic Variants in Telomerase Reverse Transcriptase Contribute to Solar Lentigines.

Solar lentigines (SLs) are a hallmark of human skin aging. They result from chronic exposure to sunlight and other environmental stressors. Recent studies also imply genetic factors, but findings are partially conflicting and lack of replication. Through a multi-trait based analysis strategy, we discovered that genetic variants in telomerase reverse transcriptase were significantly associated with non-facial SL in two East Asian (Taizhou longitudinal cohort, n = 2,964 and National Survey of Physical Traits, n = 2,954) and one Caucasian population (SALIA, n = 462), top SNP rs2853672 (P-value for Taizhou longitudinal cohort = 1.32 × 10‒28 and P-value for National Survey of Physical Traits = 3.66 × 10‒17 and P-value for SALIA = 0.0007 and Pmeta = 4.93 × 10‒44). The same variants were nominally associated with facial SL but not with other skin aging or skin pigmentation traits. The SL-enhanced allele/haplotype upregulated the transcription of the telomerase reverse transcriptase gene. Of note, well-known telomerase reverse transcriptase‒related aging markers such as leukocyte telomere length and intrinsic epigenetic age acceleration were not associated with SL. Our results indicate a previously unrecognized role of telomerase reverse transcriptase in skin aging‒related lentigines formation.

Prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking.

BACKGROUND: Melanocytic nevi have a complex evolution influenced by several endogenous and exogenous factors and are known risk factors for malignant melanoma. Interestingly, tobacco use seems to be inversely associated with melanoma risk. However, the association between tobacco use and nevi and lentigines has not yet been evaluated. METHODS: We investigated the prevalence of nevi, atypical nevi, and lentigines in relation to tobacco smoking in a cohort of 59 smokers and 60 age- and sex-matched nonsmokers, using a questionnaire and performing a total body skin examination by experts. RESULTS: No significant differences were detected between smokers and nonsmokers in the numbers of nevi, atypical nevi, and lentigines in sun-exposed areas (p = 0.966, 0.326, and 0.241, respectively) and in non-sun-exposed areas (p = 0.095, 0.351, and 0.546, respectively). CONCLUSION: Our results revealed no significant differences in the prevalence of nevi, atypical nevi, and lentigines between smokers and nonsmokers in sun-exposed and non-sun-exposed areas.

Increased melanocytic nevi in patients with inherited ichthyoses: report of a previously undescribed association.

Ichthyosis is a heterogeneous cornification disorder. Melanocytic lesions have not been previously described in association with ichthyosis. Their clinical importance lies in the fact that they may simulate melanoma clinically and dermoscopically, as seen in epidermolysis bullosa. The objective of this study was to evaluate the clinical, dermoscopic, and histopathologic features of nevi and lentigines in 16 patients with autosomal recessive congenital ichthyosis-lamellar ichthyosis and nonbullous ichthyosiform congenital erythroderma. Patients underwent general clinical examination dermoscopy. The more suspicious lesions were excised and to histopathologic examination. Most patients (n = 13) reported no personal or familial history of melanoma or atypical nevi. All of the patients had at least five atypical melanocytic lesions. Ten of the 16 patients had at least one atypical nevus or lentigo. This study suggests that increased atypical melanocytic nevi may be a feature of long-standing congenital ichthyoses. Whether this finding is disease-related or a coincidental observation is difficult to ascertain. As an unequivocal discrimination from malignant melanoma in vivo is not always possible, regular clinical follow-up of patients with ichthyosis and increased or unusual nevi is recommended.

Clinical and epidemiological aspects of subtypes of melanocytic nevi (Flat nevi, Miescher nevi, Unna nevi).

The term "melanocytic nevus" comprises a group of clinically and pathologically distinct subtypes. In this prospective clinical study we evaluated the frequency, localization, and age and gender distribution of flat nevi (FN), Miescher nevi (MN), and Unna nevi (UN) in a caucasian population. Nevi were counted in 400 patients, of which 47 had a history of melanoma. Additionally, the patients answered to a detailed UV questionnaire. Flat nevi represented the most common type of melanocytic nevi, with a peak in the 3rd decade of life. They were mostly found on the extremities and on the trunk. Miescher nevi were most common in the 6th decade and were predominantly found in the head and neck region. Unna nevi showed a maximum in the 8th decade and they were mainly situated on the trunk. The counts of all three nevus subtypes were elevated in the melanoma group. Our results confirm that FN, MN, and UN represent melanocytic nevi with distinctive morphological and clinical characteristics. The role of sunlight seems to be more prominent in the pathogenesis of FN. The precise description of FN, MN, and UN may serve as a base for a pathogenetic distinction of subtypes of melanocytic nevi in the future.

Lifetime UVR Dose and Skin Cancer Risk, Determined by Their Common Relation to Solar Lentigines.

BACKGROUND/AIM: Ultraviolet radiation (UVR) causes solar lentigines (SL) and skin cancer (SC) in humans. The association between measured lifetime UVR dose and SC has not been investigated. This study investigated this relation through their common relationship to SL. MATERIALS AND METHODS: First we investigated the association between lifetime UVR dose and SL for 16,897 days in 38 healthy participants, and secondly, the relation between SL and SC was investigated in 2,898 participants, including 149 with SC. By combining both studies, SC risk related to lifetime UVR dose and skin phototype was estimated. RESULTS: A positive association was found between SL and lifetime UVR dose (p=0.060). Skin phototype (p=0.001) and SL (p<0.001) were associated with SC. Combined SC risk increased 1.23 by doubling the average lifetime UVR dose and was 34.9 times higher for those with very fair skin compared to dark Mediterranean skin. CONCLUSION: The estimate of SC risk shows that skin phototype is of greater relative importance than lifetime UVR dose.

A cross-sectional analysis of skin cancer risk in patients receiving narrow-band ultraviolet B phototherapy: an evaluation of 100 patients.

Narrow-band ultraviolet B (NB-UVB) phototherapy is an effective and widely used treatment modality for psoriasis and other inflammatory skin diseases. The carcinogenic effect of PUVA treatment has been investigated extensively, but there is very scarce data about the role of NB-UVB in the development of skin cancer. The aim of this study was to investigate the potential carcinogenic risk of NB-UVB therapy in various skin disorders. In this cross-sectional study, we evaluated 100 patients who had received whole-body NB-UVB treatment and 100 age- and sex-matched controls. Phototherapy unit database was used to identify patients. A total of 100 patients (53 males and 47 females) treated with NB-UVB and 100 controls were included in the study. The patient group revealed no cases of melanoma or non-melanoma skin cancer, while ten of them were found to have solar lentigines. Basal cell carcinoma in a patient and nine patients with solar lentigines were detected in the control group. There was no statistically significant difference between patient and control groups in terms of skin cancer and solar lentigines. This study does not provide evidence for an increased skin cancer risk in patients treated with NB-UVB phototherapy. However, we have detected the occurence of 10 cases of solar lentigines. Still, definitive prospective longitudinal studies with a greater number of patients and prolonged follow-up are required to specifically address skin cancer risk in relation to NB-UVB phototherapy.

Melanoma, past severe sunburns and multiple solar lentigines of the upper back and shoulders.

BACKGROUND: Multiple solar lentigines of the upper back and shoulders (MSLBS) have recently been demonstrated as being associated with intense sunburns in the past. OBJECTIVE: To determine the prevalence of MSLBS among patients with cutaneous melanoma. METHODS: Thisprevalence study was conducted prospectively from October 2003 to November 2004 in a single department of dermatology (Reims University Hospital, north of France). One hundred and twenty-five adult patients, followed up for a cutaneous melanoma, were included, and the prevalence of MSLBS was determined, with comparison of clinical characteristics of patients with and without these lesions. RESULTS: The prevalence of MSLBS among patients with cutaneous melanoma was 37.6%. MSLBS were significantly and independently associated with cutaneous melanoma of the back in multivariate analysis (adjusted odds ratio, OR = 4.3, 95% confidence interval, CI = 1.5-12.3) and with recalled episodes of severe sunburn before the age of 28 (OR = 3.4, 95% CI = 1.3-9.4). CONCLUSION: Large irregularly shaped brown macules of the upper back and shoulders or MSLBS are frequent among adult patients with cutaneous melanoma. They are associated with melanoma located on the upper back. This topographical association further illustrates the relation between past intense sunburns and cutaneous melanoma. MSLBS should be evaluated as an easily recognizable clinical marker of the risk of cutaneous melanoma.

Melanoma markers in marathon runners: increase with sun exposure and physical strain.

BACKGROUND: Marathon runners seem to have an increased melanoma risk. OBJECTIVE: To identify potential melanoma markers. METHODS: 150 marathon runners volunteered to take part in the skin cancer screening campaign. After the runners completed a questionnaire about melanoma risk factors, types of sportswear and training programs, they received a total skin examination. The number of lentigines and nevi on the left shoulder and the left buttock were counted in each participant using templates in standardized positions. The potential association of training sportswear and training parameters with the number of lentigines and nevi on the left shoulder was evaluated. RESULTS: The mean number of lentigines on the left shoulder was 19.6 +/- 18.2 (SD), whereas no lentigines were found on the left buttock (p = 0.000). The number of nevi also differed significantly between the 2 localizations with higher numbers on the left shoulder (p = 0.000). While lifetime sunburn history and type of sportswear correlated with the number of lentigines, training parameters had an impact on the number of nevi. Independent of their mean weekly running time, runners with higher heart rates while training, higher training velocities and higher physical strain indexes showed more nevi on the shoulder than the other runners (p = 0.029, 0.046, 0.038, respectively). CONCLUSION: Sun exposure and high physical strain lead to an increase in melanoma markers such as lentigines and nevi in marathon runners.

Contributions by MC1R Variants to Melanoma Risk in Males and Females.

Importance: Recently, the red hair variants of MC1R were found to contribute differently to pigmentation phenotype in males and females. Objective: To investigate the role of these variants in melanoma risk in males and females separately because carriers of the red hair variants of MC1R are at increased risk of melanoma. Design, Setting, and Participants: In this hospital-based, case-control study, we evaluated the effect of MC1R and melanoma risk for males and females separately by performing multivariate logistic regression analyses. Main Outcomes and Measures: Association of MC1R variants and melanoma risk in males and females. Results: A total of 905 females (473 melanoma cases, 432 controls) and 886 males (518 melanoma cases, 368 controls) were included in the analyses. The mean (SD) age of the study population was 59.2 (15.6). In females, carrying any MC1R red hair variants remained an independent risk factor of melanoma in a multivariable analysis (adjusted odds ratio [OR], 2.19 [95% CI, 1.60-2.99]), whereas in males, only signs of actinic skin damage (lentigines on the back [OR, 2.56; 95% CI, 1.47-4.45; P = .001] and the hands [OR, 2.31; 95% CI, 1.24-4.29; P = .008] and wrinkling on the neck [OR, 2.17; 95% CI, 1.23-3.82; P = .007]) and sunburns (OR, 1.65; 95% CI, 1.12-2.42; P = .01) remained significant risk factors. Conclusions and Relevance: MC1R variants contribute differently to melanoma risk in males and females. This could be helpful to better classify melanoma risk factors between the sexes.

Carney complex, a familial multiple neoplasia and lentiginosis syndrome. Analysis of 11 kindreds and linkage to the short arm of chromosome 2.

Carney complex is an autosomal dominant syndrome characterized by multiple neoplasias, including myxomas at various sites and endocrine tumors, and lentiginosis. The genetic defect(s) responsible for the complex remain(s) unknown. We studied 101 subjects, including 51 affected members, from 11 North American kindreds with Carney complex. Blood samples were collected from patients and their family members. Hospital records, photographs, and tissue specimens of deceased individuals were reviewed. DNA was extracted from blood samples, patient-derived cell lines, and/or paraffin-embedded tissues. Linkage analysis was performed with highly polymorphic microsatellite markers, distributed over areas of the human genome harboring the most likely candidate genes. The most prevalent clinical manifestation in patients with Carney complex was spotty skin pigmentation, similar to that observed in Peutz-Jeghers and other lentiginosis syndromes. Skin and cardiac myxomas, Cushing syndrome, and acromegaly were present in 62, 30, 31 and 8 percent of the patients, respectively. Linkage was obtained for three markers on the short arm of chromosome 2 (2p16), with a maximum two-point lod score of 5.97 at theta = 0.03 for the marker CA-2 (odds in favor of linkage 10(6):1. The flanking markers CA7 and D2S378 defined a region of approximately 6.4 cM that is likely to contain the gene(s) associated with Carney complex. Candidate genes in the proximity, including the propiomelanocortin and the DNA-mismatch repair hMSH2 genes, were excluded. We conclude that the genetic defect(s) responsible for Carney complex map(s) to the short arm of chromosome 2 (2p16). This region has exhibited cytogenetic aberrations in atrial myxomas associated with the complex, and has been characterized by microsatellite instability in human neoplasias.

Xeroderma pigmentosum at a tertiary care center in Saudi Arabia.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder caused by defective DNA repair that results in extreme sensitivity to ultraviolet (UV) rays. Depending on the type of XP, the disease may affect the skin, eyes and nervous system. OBJECTIVES: Describe the dermatologic manifestations in patients suffering from XP. DESIGN: Retrospective, descriptive review of medical records. SETTING: Dermatology clinic at tertiary care center in Riyadh. PATIENTS AND METHODS: This study included Saudi patients with clinically confirmed XP. MAIN OUTCOME MEASURE(S): Demographic and clinical data including pathology and associated conditions and outcomes. RESULTS: Of 21 patients with XP, the most common manifestation was lentigines, affecting 18 patients (86%). The most common skin cancer was basal cell carcinoma followed by squamous cell carcinoma (SCC) affecting 15 (71.4%) and 9 (42.8%), respectively. Other skin findings included neurofibroma, trichilemmoma and seborrheic keratosis. Ocular involvement included photophobia, which was the most common finding followed by dryness and ocular malignancies. Two patients showed neurological involvement, which correlated with the type of mutation. CONCLUSION: Considering that XP is a rare genetic disease, this description of our patient population will aid in early recognition and diagnosis. LIMITATIONS: Retrospective and small number of patients. Genetic analyses were done for only 5 of the 21 patients.

The epidemiology of nevi and signs of skin aging in the adult general population: Results of the KORA-survey 2000.

Nevi can approximate the melanoma risk and demographic changes will increase the meaning of signs of skin aging (SSA). However, little is known about the epidemiology of nevi and SSA in the general adult population. We aimed to estimate the prevalence and age distribution of common and atypical nevi and SSA as well as gender differences in a large population-based sample. Within the Cooperative Health Research in the Augsburg Region (KORA) in Germany, a population-based survey was performed. Data were gathered by interview and the number of pigmented lesions and presence of SSA were obtained by dermatological examination. A total of 2,823 adults (mean age 49 years, 50% women) participated (response 67%). Most subjects (60.3%) exhibited 11 to 50 common nevi and 5.2% had at least one atypical nevus. 51.9% were diagnosed with elastosis (Cutis rhomboidalis nuchae, 18.3%; Morbus Favre Racouchot 1.4%). Ephelides were seen in 16%, lentigines solaris in 62.4%, and lentigines seniles in 33.2%. All signs of skin aging increased significantly with age and so did lentigines solaris, seniles, and actinic keratoses. In contrast, common and atypical nevi and ephelides decreased significantly with age. Signs of skin aging are frequent and increase, in contrast to common and atypical nevi, with age.

Etiological differences between subtypes of cutaneous malignant melanoma: Western Canada Melanoma Study.

From newly incident cases in Western Canada, 415 patients with superficial spreading melanoma (SSM), 128 with nodular melanoma (NM), and 56 with lentigo maligna melanoma (LMM) were interviewed, with age- and sex-matched controls chosen from the general population. The associations of these 3 subtypes with pigmentation, skin reaction to sun, different types of sun exposure, sunburn, and suntan were assessed. Compared to the other types, LMM occurred in older patients, and 75% of lesions occurred on the head and neck: It was less strongly related to pigmentation factors, intermittent sun exposure, and skin reaction to sun. The associations of SSM and NM with pigmentation, chronic sun exposure, skin reaction, and suntan were very similar: Both were associated with intermittent sun exposure, but SSM was more strongly related to vacation exposures than was NM. These results were compared with those from a similar Australian study. While LMM appears different in its etiology from SSM and NM, there is no strong evidence of major etiological differences between SSM and NM.

A genome-wide association study in Caucasian women suggests the involvement of HLA genes in the severity of facial solar lentigines.

Solar lentigines are a common feature of sun-induced skin ageing. Little is known, however, about the genetic factors contributing to their development. In this genome-wide association study, we aimed to identify genetic loci associated with solar lentigines on the face in 502 middle-aged French women. Nine SNPs, gathered in two independent blocks on chromosome 6, exhibited a false discovery rate below 25% when looking for associations with the facial lentigine score. The first block, in the 6p22 region, corresponded to intergenic SNPs and also exhibited a significant association with forehead lentigines (P = 1.37 × 10(-8) ). The second block, within the 6p21 HLA region, was associated with decreased HLA-C expression according to several eQTL databases. Interestingly, these SNPs were also in high linkage disequilibrium with the HLA-C*0701 allele (r(2)  = 0.95). We replicated an association recently found by GWAS in the IRF4 gene. Finally, a complementary study on 44 selected candidate SNPs revealed novel associations in the MITF gene. Overall, our results point to several mechanisms involved in the severity of facial lentigines, including HLA/immunity and the melanogenesis pathway.