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Background: A portion of approximately 2-20% of cutaneous melanoma (CM) are diagnosed as amelanotic/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis., Objectives: Since the degree to which somatic mutations and copy number aberrations (CNA) in genes associated with skin-lightening or albinism may contribute to the loss of tumour pigmentation in AHM samples has not yet been addressed, we have investigated loss of function mutations of key pigmentation genes in matched germline and AHM as well as pigmented melanoma (PM) tumour DNA samples., Methods: An analysis of clinical and histopathological characteristics together with whole exome sequencing data of 34 fresh frozen primary CM, graded according to the amount of pigmentation present was performed. Together with germline and somatic variant analysis, 30 samples were previously analysed for CNA changes. This study focussed on germline and somatic variants in the coding region of 16 genes known to be associated with albinism/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain., Results: The finding that red hair related MC1R and TYR R402Q loss of activity gene variant alleles and genotypes are associated with AHM was validated in this study. Germline AHM-related gene variants were enriched in 70% (n=7 of 10) of AHM patients vs 8.3% (n=2 of 24) of PM patients. This surprisingly high frequency of rare germline variants in AHM patients constitutes the "first hit" and confirms that AHM patients are more likely to be albinism allele carriers than patients with PM. Next, in CNA analysis of each tumour sample, 50% (n=4 of 8) AHM samples with a pigmentation gene variant had LOH in the region containing the corresponding gene, and 25% (=2 of 8) had loss-of-heterozygosity (LOH) in chromosomal regions of two AHM-related genes., Conclusions: This study proposes that the likely molecular mechanism for development of amelanogenesis in AHM is carriage of an albinism/hypopigmentation allele followed by LOH of the corresponding gene in the tumour., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality., Objectives: Our study aim was to perform a rare-variant allele (RVA) analysis of whole-exome sequencing of patients with NM and non-NM (minor allele frequency ≤ 1% non-Finnish European) for a set of 500 candidate genes potentially implicated in melanoma., Methods: This study recruited 131 participants with NM and 194 with non-NM from South-east Queensland and patients with NM from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts., Results: Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores was similar in patients with NM and non-NM, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high-penetrant melanoma gene and loss-of-function variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared with non-NM cases. The genes with RVAs of greatest frequency in NM included PTCH1, ARID2 and GHR. Rare variants in the SMO gene, which interacts with PTCH1 as ligand and receptor, were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM-associated genes. A 14.8-fold increased ratio for NM compared with non-NM was seen when two RVAs of the 39 genes were carried by a patient., Conclusions: This study highlights the importance of considering frequency of RVA to identify those at risk of NM in addition to known high penetrance genes., Competing Interests: Conflicts of interest H.P.S. is a shareholder of MoleMap NZ Limited and e-derm consult GmbH and undertakes regular teledermatological reporting for both companies. H.P.S. is a medical consultant for Canfield Scientific Inc. and MoleMap Australia Pty Ltd, and a medical advisor for First Derm. V.J.M. has received speaker fees from Bristol Myers Squibb, Janssen, Merck and Novartis, and has participated in advisory boards for L’Oreal and MSD. The other authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored., Objectives: To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals., Materials and Methods: Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank)., Results: The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals., Conclusions: RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals., Competing Interests: Conflicts of interest H.P.S. is a shareholder of MoleMap NZ Limited and e-derm consult GmbH, and undertakes regular teledermatological reporting for both companies; he is also a Medical Consultant for Canfield Scientific Inc., Blaze Bioscience Inc., MoleMap Australia Pty Limited, and a Medical Advisor for First Derm and Revenio Research Oy. The other authors state no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest H.P.S. is a shareholder of MoleMap NZ Limited and e-derm consult GmbH, and undertakes regular teledermatological reporting for both companies. H.P.S. is a medical consultant for Canfield Scientific Inc., MoleMap Australia Pty Ltd, Blaze Bioscience Inc. and a medical advisor for First Derm.

Background: Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown., Objectives: To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients., Methods: A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records., Results: During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up); however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer., Conclusions: Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020; 183:416-417., (© 2020 British Association of Dermatologists.)

Background: Skin phenotype, host genotype and ultraviolet (UV) damage play a role in the development of melanoma., Objectives: To ascertain whether the level of UV damage at the site of melanomas was associated with genetic polymorphisms., Methods: Deep phenotyping was performed on 1244 individuals; 281 with multiple primary melanomas (MPMs), 304 with single primary melanoma (SPM) and 659 convenience controls. Genotype data was generated using the Illumina CoreExome microarray platform, assaying over 500 000 single-nucleotide polymorphisms. A subset of variants were combined to assess a polygenic risk score (PRS) for melanoma., Results: Most MPM cases were diagnosed in patients aged > 40 years, in sites with visible chronic UV damage. Women and those diagnosed at age ≤ 40 years were less likely to have perilesional UV damage. Patients with MPM had higher frequencies of MITF E318K, MC1R R-alleles and the ASIP risk haplotype. Individuals who had melanoma in a visibly UV-damaged site were more likely to carry MC1R rs75570604 [odds ratio (OR) 2·5], 9q31.2 rs10816595 (OR 1·4) and MTAP rs869329 (OR 1·4). These same alleles were more common in patients with MPM who were diagnosed at age ≤ 40 years. The mean PRS was significantly higher in MPM than in SPM and controls. Naevus count was comparable in early-onset MPM cases and those diagnosed at age > 40 years., Conclusions: Our cohort demonstrated higher frequencies of previously reported alleles associated with melanoma. MPM melanomas more commonly occur in UV-damaged areas, and these individuals are more likely to carry MC1R red hair colour alleles. Awareness of the interplay of genetic vulnerability with UV damage can stratify risk and guide recommendations for melanoma screening. What's already known about this topic? Skin phenotype, host genotype and ultraviolet (UV) damage all play a role in melanoma development. One of the main risk factors is a personal history of melanoma; second and subsequent primary melanomas account for over 20% of all melanomas registered in Queensland. Multiple loci are associated with melanoma risk, including many low-penetrance loci, which may have a cumulatively significant risk. Population-wide screening programmes for melanoma are not yet economically viable. What does this study add? Patients diagnosed with melanoma at age ≤ 40 years were more likely than older patients to have melanomas in non-UV-damaged sites. Patients with multiple melanomas had higher frequencies of MITF E318K, MC1R R-alleles, and the ASIP extended risk haplotype than patients with single melanoma. CDKN2A, MC1R and MTAP variants were more frequent in patients who developed melanomas at a younger age, but also in those whose melanomas were all on visibly UV-damaged sites. What is the translational message? Incorporating these genetic findings into the known risk factors of skin phenotype and visible UV damage may allow for a more customized and economically feasible approach to early detection of melanoma, particularly in younger patients. Plain language summary available online., (© 2019 British Association of Dermatologists.)

Background: Thin cutaneous melanomas (≤ 1·00 mm) are increasing worldwide, causing around a quarter of all melanoma deaths in the U.S.A. and Australia. Identification of predictive factors for potentially fatal thin melanomas could allow better use of resources for follow-up., Objectives: To identify the clinicopathological factors associated with fatal thin melanomas., Methods: This large, nested case-case study extracted data from the population-based Queensland Cancer Registry, Australia. Our cohort consisted of Queensland residents aged 0-89 years who were diagnosed with a single, locally invasive thin melanoma (≤ 1·00 mm) between 1995 and 2014. Fatal cases (eligible patients who died from melanoma) were individually matched to three nonfatal cases (eligible patients who were not known to have died from melanoma) according to sex, age, year of diagnosis and follow-up interval. Using conditional logistic regression, we calculated odds ratios (ORs) for melanoma-specific death, adjusting for all collected clinicopathological variables., Results: In the cohort, 27 660 eligible patients were diagnosed with a single, thin melanoma. The final case-case series included 424 fatal cases and 1189 nonfatal cases. Fatal cases were sixfold as likely to arise on the scalp as on the back [OR 6·39, 95% confidence interval (CI) 2·57-15·92] and six times as likely to be of thickness 0·80-1·00 mm as of < 0·30 mm (OR 6·00, 95% CI 3·55-10·17)., Conclusions: Scalp location is a strong prognostic factor of death from thin melanoma. Further, this study provides support that melanomas with a thickness of 0·80-1·00 mm are the more hazardous thin lesions. Patients with these tumour characteristics require specific attention during follow-up. What's already known about this topic? Thin invasive melanomas (≤ 1·00 mm) contribute a substantial proportion of melanoma fatalities, owing to the high volume of disease. There is a need to find prognostic factors that will better identify fatal thin melanomas at the time of diagnosis. What does this study add? In this large population-based study, fatal thin tumours were sixfold as likely to be located on the scalp as on the back. Thin melanomas of 0·80-1·00 mm thickness were six times as likely to be associated with death as tumours < 0·30 mm. Scalp location and increasing thickness are strong predictive factors of fatal thin melanomas, indicating that patients with these tumour characteristics require close follow-up., (© 2019 British Association of Dermatologists.)

Background: A high total body naevus count is the highest risk factor for melanoma; the phenotype of red hair colour, freckling and pale skin that burns easily, produced by MC1R R alleles, also predisposes to melanoma., Objectives: To determine whether the known melanoma risk factors of high naevus count and red hair or MC1R R alleles act synergistically to increase melanoma risk., Methods: The Brisbane Naevus Morphology Study involved 1267 participants from volunteers presenting at a melanoma unit, dermatology outpatient clinic, private dermatology clinics, the Brisbane Longitudinal Twin Study and the QSkin Study. We examined pigmentation characteristics, total body naevus ≥ 5 mm count, and MC1R, ASIP and CDKN2A genotype in participants with and without a personal history of melanoma, living in Queensland, Australia, which is an area of high ultraviolet radiation., Results: Cases were older than controls (median 57 vs. 33 years). Compared with individuals with dark brown hair and zero to four naevi, individuals with red hair and ≥ 20 naevi had a melanoma odds ratio of 10·0 (95% confidence interval 4·2-24·3). Individuals with MC1R R/R genotype and ≥ 20 naevi (≥ 5 mm diameter) had a melanoma odds ratio of 25·1 (95% confidence interval 8·4-82·7) compared with wild-type (WT)/WT individuals with zero to four naevi. The highest risk group is Australian men with the MC1R R/R genotype and ≥ 20 moles, who have an absolute risk of melanoma to age 75 years of 23·3%, compared with 0·8% for men with the WT/WT genotype and zero to four naevi., Conclusions: Patients who live in areas of high ultraviolet radiation, and have many large naevi and the red hair colour phenotype, particularly those with the MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers. Therefore, they should undergo intensive physician-led surveillance. What's already known about this topic? A high number of acquired melanocytic naevi, the red hair phenotype and MC1R R alleles all independently increase melanoma risk. Women with atypical naevi have an increasing melanoma risk gradient from darker hair to lighter hair. Women with many naevi have an increasing melanoma risk gradient from those with no elements of the red hair phenotype, to those with freckles but not red hair, to those with red hair. What does this study add? In Queensland, Australia, people with ≥ 20 naevi (≥ 5 mm diameter) and MC1R R/R genotype have a 25-fold increased melanoma risk, relative to people with zero to four naevi and the MC1R WT/WT genotype. In Queensland, individuals with ≥ 20 naevi and the MC1R R/R genotype have an absolute melanoma risk to age 75 years of 23·3% for men and 19·3% for women. This effect is independent of CDKN2A genotype. Further research is required to determine the effect of areas of lower ultraviolet radiation, as this study took place in the Queensland, Australia, which is an area of high ultraviolet radiation. MC1R R/r genotype is associated with increased total body naevus count but this is not the case for R/R. What is the translational message? Patients with many large naevi and the red hair colour phenotype, particularly those with an MC1R R/R genotype, have an unusually high risk of melanoma. In a high ultraviolet environment, this risk exceeds the threshold recommended for screening in other cancers, and such individuals should undergo intensive, regular, physician-led surveillance. Patients with many large naevi but with non-red colour hair may benefit further from clinical MC1R genotyping., (© 2019 British Association of Dermatologists.)

Background: Iris naevi and iris freckles have a frequency of 4% and 50% in the European population, respectively. They are associated with dysplastic naevi, but few studies have examined their link to cutaneous melanoma., Objectives: To assess whether iris pigmented lesions are a predictive indicator for cutaneous melanoma., Methods: This is a melanoma case-control study of 1254 European-background Australians. Sun exposure and melanoma history, a saliva sample for DNA analysis and eye photographs taken with a digital camera were collected from 1117 participants. Iris images were assessed by up to four trained observers for the number of iris pigmented lesions. The data were analysed for correlations between iris pigmented lesions and melanoma history., Results: Case participants over the age of 40 had similar numbers of iris pigmented lesions to age matched controls (mean 5·7 vs. 5·2, P = 0·02), but in younger case and control participants there was a greater difference (mean 3·96 vs. 2·19, P = 0·004). A logistic regression adjusted for age, sex, skin, hair and eye colour, skin freckling and naevus count found that the presence of three or more iris pigmented lesions increases the melanoma risk 1·45-fold [95% confidence interval (CI) 1·07-1·95]. HERC2/OCA2 rs12913832 and IRF4 rs12203592 influenced both eye colour and the number of iris pigmented lesions. On the HERC2/OCA2 A/A and A/G genotype background there was an increasing proportion of blue eye colour when carrying the IRF4 T allele (P = 3 × 10 -4 ) and a higher number of iris pigmented lesions with the IRF4 T/T homozygote (P = 3 × 10 -9 )., Conclusions: Iris pigmented lesion count provides additional predictive information for melanoma risk above that from conventional risk factors., (© 2018 British Association of Dermatologists.)

Background: Acquired naevi can have unique dermoscopic patterns that correspond to distinct microanatomical growth patterns. Previous studies on acquired naevi stratified according to dermoscopic pattern focused on the frequency of somatic BRAF mutations, whereas NRAS mutations remained to be elucidated., Objectives: To investigate the BRAF and NRAS mutation prevalence and activation of the mitogen-activated protein kinase (MAPK) pathway in distinct dermoscopic subtypes of acquired naevi., Methods: Common mutations present in BRAF and NRAS were assessed in 40 globular, reticular and peripheral rim of globules (PG) subtypes of acquired naevi from 27 participants (19 male, 8 female; mean age 46·7 years) selected from 1261 eligible volunteers. Mutations were determined using the highly sensitive and quantitative QX200 droplet digital™ polymerase chain reaction (ddPCR) system., Results: The BRAF V600E (c.1799T>A or c.1799&#95;1800delTGinsA) and BRAF V600K mutations were detected in 85% (n = 34/40) of naevi. All BRAF wild-type naevi (15%; n = 6/40) harboured an NRAS codon 12/13 or 61 mutation. BRAF mutations were present in 92% (n = 12/13) of globular and 100% (n = 12/12) of PG naevi, whereas reticular naevi were 67% (n = 10/15) BRAF- and 33% (n = 5/15) NRAS-mutant (P = 0·037)., Conclusions: We discovered that 100% of the assessed acquired naevi had either a BRAF or NRAS mutation. Using sensitive techniques capable of single-cell mutation detection, it is likely that all acquired naevi will be mutated for BRAF or NRAS. Because both of these mutations are prevalent in distinct dermoscopic naevus subsets, our study supports the role of the MAPK pathway in the development of benign melanocytic proliferations, indicating that additional genomic events besides somatic mutations in BRAF or NRAS are required for melanoma development., (© 2017 British Association of Dermatologists.)

Background: Squamous cell carcinoma (SCC) and intraepidermal carcinoma (IEC) commonly arise in actinically damaged skin., Objectives: To identify clinical features of actinic change that correlate with an increased risk of SCC or IEC in the short-to-medium term as guidance for prioritizing field treatment., Methods: In a nested case-control study, cases were renal transplant recipients who developed an incident SCC or IEC within 18 months following baseline examination and photography. Controls without SCC or IEC were matched to cases on age, sex and duration of immunosuppression. Predefined skin sites on the head, neck and upper limbs were examined using baseline photographs to assess objectively the following features of actinic damage: presence of actinic keratosis (AK) patch (defined as AK > 1 cm 2 ), number of AK patches, number of AKs and area affected by AK. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using McNemar's test to identify differences in SCC/IEC risk combined and SCC risk alone between case and control skin sites., Results: Thirty-nine cases were matched to 39 controls. Significant associations with the presence of an AK patch, number of AK patches, number of AKs and area affected by AKs were identified. The presence of an AK patch conferred an 18-fold increased risk of SCC (OR 18·00, 95% CI 2·84-750) and more than a sixfold increased risk of SCC/IEC combined (OR 6·60, 95% CI 2·56-21·66)., Conclusions: AK patches are predictive of SCC/IEC development within 18 months. This can be used to guide site selection for field treatment in patients with widespread actinic damage., (© 2016 British Association of Dermatologists.)

Background: Mobile teledermoscopy allows consumers to send images of skin lesions to a teledermatologist for remote diagnosis. Currently, technology acceptance of mobile teledermoscopy by people at high risk of melanoma is unknown., Objectives: We aimed to determine the acceptance of mobile teledermoscopy by consumers based on perceived usefulness, ease of use, compatibility, attitude/intention, subjective norms, facilitators and trust before use. Consumer satisfaction was explored after use., Methods: Consumers aged 50-64 years at high risk of melanoma (fair skin or previous skin cancer) were recruited from a population-based cohort study and via media announcements in Brisbane, Australia in 2013. The participants completed a 27-item questionnaire preteledermoscopy modified from a technology acceptance model. The first 49 participants with a suitable smartphone then conducted mobile teledermoscopy in their homes for early detection of melanoma and were asked to rate their satisfaction., Results: The preteledermoscopy questionnaire was completed by 228 participants. Most participants (87%) agreed that mobile teledermoscopy would improve their skin self-examination performance and 91% agreed that it would be in their best interest to use mobile teledermoscopy. However, nearly half of participants (45%) were unsure about whether they had complete trust in the telediagnosis. The participants who conducted mobile teledermoscopy (n = 49) reported that the dermatoscope was easy to use (94%) and motivated them to examine their skin more often (86%). However, 18% could not take photographs in hard-to-see areas and 35% required help to submit the photograph to the teledermatologist., Conclusions: Mobile teledermoscopy consumer acceptance appears to be favourable. This new technology warrants further assessment for its utility in the early detection of melanoma or follow-up., (© 2016 British Association of Dermatologists.)

Background: When used correctly, dermoscopy is an essential tool for helping clinicians in the diagnosis of skin diseases and the early detection of skin cancers. Despite its proven benefits, there is a lack of data about how European dermatologists use dermoscopy in everyday practice., Objectives: To identify the motivations, obstacles and modifiable factors influencing the use of dermoscopy in daily dermatology practice across Europe., Methods: All registered dermatologists in 32 European countries were invited to complete an online survey of 20 questions regarding demographic and practice characteristics, dermoscopy training and self-confidence in dermoscopic skills, patterns of dermoscopy use, reasons for not using dermoscopy and attitudes relating to dermoscopy utility., Results: We collected 7480 valid answers, of which 89% reported use of dermoscopy. The main reasons for not using dermoscopy were lack of equipment (58% of nonusers) and lack of training (42%). Dermoscopy training during residency was reported by 41% of dermoscopy users and by 12% of nonusers (P < 0·001). Dermatologists working in public hospitals were the least likely to use dermoscopy. High use of dermoscopy across the spectrum of skin diseases was reported by 62% of dermoscopy users and was associated with dermoscopy training during residency, the use of polarized light and digital dermoscopy devices, longer dermoscopy practice, younger age and female gender., Conclusions: Expanding access to dermoscopy equipment, especially in public healthcare facilities and establishing dermoscopy training during dermatology residency would further enhance the substantially high dermoscopy use across European countries., (© 2016 British Association of Dermatologists.)

Background: LEO 43204 is a novel ingenol derivative in development for the treatment of actinic keratosis., Objectives: To compare the safety and preliminary efficacy of three doses of LEO 43204 with ingenol mebutate in actinic keratoses (AKs)., Methods: Patients with at least three visible, discrete, nonkeratotic AKs on four separate selected treatment areas on the forearms received LEO 43204 gel (0·025%, 0·05% and 0·075%) and ingenol mebutate 0·05% gel, by investigator-blinded, randomized allocation, for 2 consecutive days. Patients were assessed at 8 weeks. Primary outcomes included maximum composite local skin response (LSR) score and adverse events (AEs). Secondary outcomes included a reduction in the number of visible AKs., Results: Forty patients completed the trial. For all treatments, mean LSR scores peaked at week 1, and were below baseline by week 8. Mean maximum composite LSR scores for LEO 43204 0·025%, 0·05% and 0·075% were 9·2 (Dunnett adjusted P = 0·02), 10·1 (Dunnett adjusted P = 0·90) and 11·2 (Dunnett adjusted P < 0·01), respectively, vs. ingenol mebutate 0·05% gel (10·0). The most frequent AEs across all treatments were application site pruritus, burning sensation and tenderness. Mean reduction in the number of AKs was comparable for ingenol mebutate and the two lowest doses of LEO 43204 (71·9-73·1%), but LEO 43204 0·075% gave a significantly larger reduction (81·8%; Dunnett adjusted P = 0·04)., Conclusions: LEO 43204 had a similar safety profile to ingenol mebutate and a dose-response relationship for LSRs was demonstrated. The highest LEO 43204 dose (0·075%) significantly reduced the AK count when compared with ingenol mebutate., (© 2015 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Heritability of naevi counts is widely acknowledged as a potential surveillance parameter for prevention purposes. The contribution of heritability to the changes seen in naevus number and morphology over time and their corresponding dermoscopic characteristics is unknown, but is important to understand in order to account for adequate prevention measures., Objectives: To identify naevus characteristics that are strongly influenced by heritability., Methods: This cross-sectional study included 220 individuals [76 monozygotic (MZ), 144 dizygotic (DZ)], recruited from the Brisbane Twin Naevus Study. Participants received full body imaging and dermoscopy of naevi ≥ 5 mm in diameter. Dermoscopic type, total naevus count (TNC), change in TNC with age, and naevus distribution, size, colour and profile were compared between MZ and DZ twins. Heritability of these traits was assessed via Falconer's estimate., Results: Significant differences were found in comparing MZ and DZ twins for TNC, numbers of naevi 5·0-7·9 mm in diameter, counts of light-brown naevi, naevi on the back and sun-protected sites, and naevi with the 'nonspecific' dermoscopic pattern., Conclusions: This study strongly supports a heritable component to TNC, as well as changes in TNC, and the number of medium-sized naevi, light-brown naevi, specific sites and certain dermoscopic features in adults. These characteristics should be taken into account by naevus surveillance programmes and further studied to identify candidate gene associations for clinical and dermoscopic patterns in conjunction with melanoma risk stratification., (© 2015 British Association of Dermatologists.)

Background: Early detection by skin self-examination (SSE) could improve outcomes for melanoma. Mobile teledermoscopy may aid this process., Objectives: To establish the clinical accuracy of SSE plus mobile teledermoscopy vs. clinical skin examination (CSE) and to test whether providing people with detailed SSE instructions improves accuracy., Methods: Men and women aged 50-64 years (n = 58) performed SSE plus mobile teledermoscopy in their homes between May and November 2013 and were given technical instructions plus detailed SSE instructions (intervention) or technical instructions only (control). Within 3 months, they underwent a CSE. Outcome measures included (i) body sites examined, lesions photographed, and missed; (ii) sensitivity of SSE plus mobile teledermoscopy vs. in-person CSE using either patients or lesions as denominator; and (iii) concordance of telediagnosis with CSE., Results: Overall 49 of 58 randomized participants completed the study, and submitted 309 lesions to the teledermatologist. Intervention-group participants were more likely to submit lesions from their legs compared with controls (P = 0·03), with no other differences. Eleven participants (22%) did not photograph 14 pigmented lesions that the dermatologist considered worthwhile photographing or monitoring. The sensitivity of SSE plus mobile teledermoscopy was 82% using the patient as denominator and 42% using the lesion as denominator. There was substantial agreement between telediagnosis and CSE (κ = 0·90), accounting for differential diagnoses., Conclusions: SSE plus mobile teledermoscopy is promising for surveillance of particular lesions even without detailed SSE instructions. However, in the format tested in this study, consumers may overlook lesions and send many nonpigmented lesions. This investigation demonstrates that high-quality dermoscopic images can be taken by patients at home with high accuracy., (© 2014 British Association of Dermatologists.)

Background: Most melanomas are first recognized by patients themselves or by their friends and family., Objectives: To assess the ability of laypersons to identify melanomas using dermoscopy images., Methods: This is an image-based study using laptop computers in the community. Seventeen laypersons were given a one-page educational brochure on the AC Rule for melanoma (asymmetry, colour variation). These laypersons and three expert dermoscopists completed two image sets, each containing a series of 100 pigmented skin lesions. Set 1 contained five melanomas, while set 2 contained 20 melanomas. Participants viewed a clinical image followed by a dermoscopy image for each lesion. For each image a score of 0-10 was assigned for asymmetry and colour, and then an overall assessment was made for suspicion of melanoma. Mean estimates have been calculated for sensitivity and specificity., Results: Laypersons achieved a clinical sensitivity of 91·2% and a significantly higher dermoscopy sensitivity of 94·0%, P = 0·013. This improvement was not associated with a significant change in overall specificity, which for the clinical image was 64·2% and with dermoscopy was 62·0%, P = 0·97., Conclusions: These results indicate that laypersons may be able to use dermoscopy to identify more melanomas than naked eye examination alone. Further study into the practice of dermoscopy by laypersons is warranted., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

Background: Skin ageing is a complex process due to intrinsic chronological factors (chronoageing) and extrinsic environmental factors. The primary extrinsic factor is cumulative ultraviolet (UV) exposure, and is therefore termed photoageing. The current standards for measuring cumulative sun damage are biopsy histology and skin microtopography. However, skin biopsies are too invasive for population studies and skin replicas render only superficial skin architecture data. Reflectance confocal microscopy (RCM) is a noninvasive imaging tool that allows for in vivo imaging of the skin at quasihistological resolution., Objectives: To define and identify RCM features associated with chronological ageing and photoageing on the forearm in two age groups with different skin phototypes and to assess whether these results agree with previous findings., Methods: We obtained RCM images of dorsal and volar nonlesional skin of the lower forearm of 75 individuals with skin Fitzpatrick phototypes I-III in two age groups (20-30 years and 50-60 years). From each participant and body site, 21 RCM features were assessed and statistically significant differences between the two age groups and different forearm sites determined., Results: RCM enabled identification of changes in architecture, cell morphology and extracellular matrix (collagen) at the level of the epidermis, dermoepidermal junction and papillary dermis. Changes that were correlated with chronological ageing and which were aggravated on the UV-exposed dorsal forearm were: loss of small skin furrows resulting in wider and less intersecting furrows; irregularity of the epidermal honeycomb pattern; irregularly distributed (mottled) pigmented keratinocytes/melanocytes; irregularity of the papillary rings and/or effacement of the rete ridges; and loss of thin collagen fibres and presence of collagen clods., Conclusion: We have tested previously reported and new parameters for skin ageing evaluation by RCM, and identified 15 statistically significant RCM features that can be used to quantify ageing and photoageing in forearm skin noninvasively., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

As our understanding of the role of ultraviolet (UV) radiation exposure in causing skin cancer continues to be enhanced, it is important that clinicians and researchers are familiar with the various methods for assessing photodamage to skin. This paper provides a systematic review of the published literature on invasive and noninvasive methods used to quantify lifetime UV exposure ('photoageing'). Clinical examination, histopathology, immunohistochemistry, skin surface topography and ultrasound, in addition to newer technologies such as reflectance confocal microscopy, optical coherence tomography and multiphoton tomography, are reviewed. It is concluded that histopathological solar elastosis alone should not be viewed as a 'gold standard' diagnostic test and that there is no single method available to give accurate quantification of the degenerative changes associated with photodamage. Although additional research into sensitivity and specificity is still needed, skin surface topography currently has the most support in the literature as a valid and reliable noninvasive tool for the assessment of photoageing., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.)

Background: The ability to diagnose malignant skin tumours accurately and to distinguish them from benign lesions is vital in ensuring appropriate patient management. Little is known about the effects of mobile teledermatology services on diagnostic accuracy and their appropriateness for skin tumour surveillance., Objective: To evaluate the diagnostic accuracy of clinical and dermoscopic image tele-evaluation for mobile skin tumour screening., Methods: Over a 3-month period up to three clinical and dermoscopic images were obtained of 113 skin tumours from 88 patients using a mobile phone camera. Dermoscopic images were taken with a dermatoscope applied to the camera lens. Clinical and dermoscopic images of each lesion together with clinical information were separately teletransmitted for decision-making. Results were compared with those obtained by face-to-face examination and histopathology as the gold standard., Results: A total of 322 clinical and 278 dermoscopic images were acquired; two (1%) clinical and 18 (6%) dermoscopic pictures were inadequate for decision-making. After excluding inadequate images, the majority of which were dermoscopic pictures, only 104 of the 113 skin tumours from 80 of 88 patients could be tele-evaluated. Among these 104 lesions, 25 (24%) benign nonmelanocytic, 15 (14%) benign melanocytic, 58 (56%) malignant nonmelanocytic and six (6%) malignant melanocytic lesions were identified. Clinical and dermoscopic tele-evaluations demonstrated strong concordance with the gold standard (κ = 0·84 for each) and similar high sensitivity and specificity for all diagnostic categories. With regard to the detailed diagnoses, clinical image tele-evaluation was superior to teledermoscopy resulting in 16 vs. 22 discordant cases., Conclusions: Clinical image tele-evaluation might be the method of choice for mobile tumour screening., (© 2011 The Authors. BJD © 2011 British Association of Dermatologists.)

Background: Teledermoscopy is a rapidly developing field of dermatology with studies demonstrating excellent agreement with face-to-face diagnosis. However, we are unaware of studies evaluating interobserver variability in diagnosis between dermatologists from different continents. This evaluation is important to determine the robustness of teledermoscopy and allow comparisons to be made between different studies., Objectives: To assess the interobserver diagnostic variability between five independent experienced dermatologists (A-E) in New Zealand, Australia and the U.S.A., Methods: Images from 979 lesions from 206 patients were distributed to five dermatologists. The lesions were viewed and diagnoses recorded using MoleMap Diagnose (MoleMap, Auckland, New Zealand) software. The diagnoses were analysed for interobserver variability., Results: There was excellent agreement between four of five dermatologists (A-D) for lesions that were agreed upon as melanoma (κ = 0·81-0·97) and benign naevus (κ = 0·77-0·82).The fifth dermatologist (E) made a more frequent diagnosis of atypical naevus and melanoma than the others. For nonmelanocytic lesions, there was moderate to very good agreement for seborrhoeic keratosis (κ = 0·64-0·80) and basal cell carcinoma (κ = 0·55-0·67), but poor agreement for invasive squamous cell carcinoma (SCC) (κ = 0·05-0·15). Agreement for actinic keratosis (κ = 0·32-0·67) and SCC in situ (κ = 0·15-0·32) was only moderate. When atypical and benign naevi were grouped together and actinic keratosis and SCC in situ grouped together, there was better agreement among all dermatologists. There was good ability to distinguish malignant from benign lesions (κ = 0·57-0·93)., Conclusions: There was good agreement among dermatologists A-D but dermatologist E varied from the group with more frequent diagnosis of melanoma and atypical naevus. This difference could be due to different definition of terms with lack of consensus guidelines in definition of atypical naevus, lack of familiarity with the specific patient population and/or diagnostic drift., (© 2010 The Authors. BJD © 2010 British Association of Dermatologists.)

The lack of consensus among clinicians and pathologists due to the mixture of clinical and histopathological features used to define the various melanocytic naevi underscores the need of a better classification system for these benign lesions. We describe a dermoscopic classification system for melanocytic naevi that is directed to clinicians dealing with the early diagnosis of melanoma, as well to pathologists, in order to promote better communication between these different specialists.

Background: The accuracy of clinical diagnosis of nonpigmented, facial actinic keratosis (AK) is often suboptimal, even for experienced clinicians., Objectives: To investigate the dermoscopic features of nonpigmented AK located on the head/neck that may assist the clinical diagnosis., Methods: Forty-one nonpigmented AKs on facial sites were examined by dermoscopy for any consistent underlying features. Lesions were gathered from skin cancer centres in Australia, Austria, Italy and the U.S.A. All cases were diagnosed histopathologically., Results: Four essential dermoscopic features were observed in facial AK: (i) erythema, revealing a marked pink-to-red 'pseudonetwork' surrounding the hair follicles (95%); (ii) white-to-yellow surface scale (85%); (iii) fine, linear-wavy vessels surrounding the hair follicles (81%); and (vi) hair follicle openings filled with yellowish keratotic plugs (66%) and/or surrounded by a white halo (100%). These features combined, in 95% of cases, to produce a peculiar 'strawberry' appearance., Conclusions: A dermoscopic model of 'strawberry' pattern is presented, which may prove helpful in the in vivo diagnosis of nonpigmented, facial AK. A limitation of this study is the lack of testing of the specificity of the described dermoscopic criteria in differentiating nonpigmented AKs from other nonpigmented skin lesions at this site.

Background: A variety of pigmented skin tumours can lead to diagnostic difficulties in dermatopathology., Objectives: To investigate whether the interobserver agreement between histopathological diagnoses of equivocal pigmented tumours made by two referral centres can be improved by additional use of dermoscopic images., Material and Methods: Retrospective study using 160 tumours excised in the pigmented skin lesions clinic in Graz and 141 from Tübingen. Tumours were diagnosed in the referring centres using clinical data, histopathology and, if required, immunohistochemistry. The tumours were initially diagnosed as 74 melanomas, 218 melanocytic naevi and nine nonmelanocytic tumours. Haematoxylin and eosin sections, patients' age and sex, tumour localization and digital dermoscopic images were then exchanged between the participating centres. Then, diagnoses were made initially based solely on dermatopathology and clinical information. After a washout phase, the same sections were reevaluated with the additional use of dermoscopic images. The main outcome measures were the Cohen's kappa-coefficients of the initial diagnoses of the centre submitting the cases and the diagnoses of the other centre without and with dermoscopy., Results: The kappa-coefficient between the initial diagnoses with those made by the second centre without dermoscopy was 0.90 in Graz, 0.73 in Tübingen, and 0.81 overall. With the additional use of dermoscopy the kappa-value was invariably high with 0.89 in Graz, and improved to 0.87 in Tübingen, and to 0.88 overall., Conclusions: The additional use of digital dermoscopic images further improved the overall very good agreement of histopathological diagnoses between two referral centres.

Background: In a pilot study, the three-point checklist of dermoscopy has been shown to represent a valid and reproducible tool with high sensitivity for the diagnosis of skin cancer in the hands of a small group of nonexperts., Objectives: To re-evaluate these preliminary results in a large number of observers independently from their profession and expertise in dermoscopy., Methods: The study was conducted via the internet to provide worldwide access for participants. After a short web-based tutorial, the participants evaluated dermoscopic images of 165 (116 benign and 49 malignant) skin lesions (15 training and 150 test lesions). For each lesion participants scored the presence of the three-point checklist criteria (asymmetry, atypical network and blue-white structures). Kappa values, odds ratios, sensitivity, specificity and likelihood ratios were estimated., Results: Overall, 150 participants joined the study. The three-point checklist showed good interobserver reproducibility (kappa value: 0.53). Sensitivity for skin cancer (melanoma and basal cell carcinoma) was 91.0% and this value remained basically uninfluenced by the observers' professional profile. Only 20 participants lacking any experience in dermoscopy performed significantly more poorly, but the sensitivity was still remarkably high (86.7%) when considering that they were untrained novices in dermoscopy. The specificity was 71.9% and was significantly influenced by the profession, with dermatologists performing best., Conclusions: Our study confirms that the three-point checklist is a feasible, simple, accurate and reproducible skin cancer screening tool.

Background: Based on the dermoscopic classification of acquired melanocytic naevi, six different dermoscopic types can be distinguished by morphology (globular, globular-reticular, globular-homogeneous, reticular, reticular-homogeneous, homogeneous) and by pigment distribution (uniform, central hyperpigmentation, central hypopigmentation, peripheral hyperpigmentation, peripheral hypopigmentation, multifocal hyper/hypopigmentation). It has been suggested that most individuals harbour one predominant dermoscopic type among their naevi., Objectives: To evaluate whether the age of the patient influences the predominant naevus pattern observed in individuals with multiple acquired melanocytic naevi., Methods: Individuals were recruited from the pigmented skin lesion clinic in Graz between July 2000 and February 2001. Individuals with at least 10 melanocytic naevi were selected consecutively until a total of 10 individuals in each of five age groups was obtained. Age groups were: 0-15 years, 16-30 years, 31-45 years, 46-60 years and > 60 years. Digitized images of acquired melanocytic naevi, defined as benign melanocytic proliferations having a diameter of at least 5 mm with a macular component and which were not apparent within the first year of life, were evaluated by dermoscopic criteria. The associations of dermoscopic features as a function of patient age were analysed. We calculated absolute numbers and frequencies, given as percentages, as well as predominance of the dermoscopic types of naevi in the different age groups., Results: Analysis of 1268 naevi revealed that the globular pattern predominated in the youngest age group. By contrast, the reticular and/or homogeneous patterns were increasingly exhibited in naevi from older individuals (older than 15 years). Uniform pigmentation was most common in melanocytic naevi in the youngest age group, while central hyperpigmentation was predominantly seen in the group of individuals aged 16-30 years., Conclusions: The predominance of dermoscopic types of melanocytic naevi varies according to the individual's age. Awareness of the age-related dermoscopic predominance of melanocytic naevi might allow more accurate recognition of dermoscopic patterns of melanocytic skin lesions that are unusual with respect to the individual's age. This observation may help in the early recognition of some 'banal'-appearing melanomas. Furthermore, the observations made in this study raise interesting questions regarding naevus evolution.

Background: Large, asymmetrical and irregularly pigmented naevi in patients with epidermolysis bullosa (EB) have been reported often to mimic cutaneous melanoma clinically., Objectives: As the biological course of these peculiar moles is benign, we assessed EB naevi with a dermatoscope to determine whether they could be reliably differentiated from cutaneous melanoma., Methods: We evaluated digital dermoscopic images of 23 EB naevi from 11 patients with EB and analysed these pigmented lesions according to pattern analysis, ABCD rule of dermoscopy and the seven-point checklist., Results: Melanoma-associated dermoscopic criteria such as multicomponent pattern (20 of 23), atypical pigment network (17 of 23), irregular dots/globules (16 of 23), irregular pigmentation (22 of 23) and an atypical vascular pattern (seven of 23) were frequently seen in EB naevi. In contrast, other criteria frequently associated with melanoma progression, such as irregular streaks, blue-whitish veil, regression structures (blue-whitish areas) or black dots, were rarely seen. Most lesions gave false-positive results when the scores of the dermoscopic diagnostic algorithms were calculated., Conclusions: Recurring dermoscopic structures in EB naevi reveal a distinctive dermoscopic pattern of this recently defined entity. Although EB naevi represent an exception to dermoscopic diagnostic algorithms, their dermoscopic evaluation most often allows us to estimate their benign nature. Nevertheless, as an unequivocal discrimination from malignant melanoma in vivo is sometimes not possible, regular clinical follow up of EB naevi with histopathological evaluation of highly suspicious lesions is mandatory.

Background: Dermoscopy improves the diagnostic accuracy in pigmented skin lesions, but it is also useful in the evaluation of nonpigmented skin tumours as it allows the recognition of vascular structures that are not visible to the naked eye. Bowen's disease (BD) or squamous cell carcinoma in situ is usually nonpigmented, but may also rarely be pigmented. Objective To describe the dermoscopic features in a series of pigmented and nonpigmented BD., Methods: Dermoscopic images of 21 histopathologically proven BD were evaluated for the presence of various dermoscopic features. Each lesion was photographed using the Dermaphot (Heine Optotechnik, Herrsching, Germany), at 10-fold magnification, and the colour slides were scanned to digital format using a Kodak Photo CD system., Results: The majority of cases of BD revealed a peculiar dermoscopic pattern characterized by glomerular vessels (90%) and a scaly surface (90%). In addition, in pigmented BD small brown globules regularly packed in a patchy distribution (90%), and structureless grey to brown pigmentation (80%) were observed., Conclusions: Dermoscopy can be helpful for diagnosing BD because of the presence of repetitive morphological findings such as glomerular vessels and a scaly surface. In pigmented BD, small brown globules and/or homogeneous pigmentation can be seen as well.

Background: Amelanotic malignant melanoma is a subtype of cutaneous melanoma with little or no pigment on visual inspection. It may mimic benign and malignant variants of both melanocytic and nonmelanocytic lesions., Objectives: To evaluate whether dermoscopy is also a useful technique for the diagnosis of amelanotic/hypomelanotic melanoma (AHM)., Methods: We conducted a retrospective clinical study of 151 amelanotic/hypomelanotic skin lesions from 151 patients with a mean age of 47 years (+/- 17.5 SD). Digitized images of amelanotic/hypomelanotic skin lesions were converted to JPEG format and sent by e-mail from the five participating centres. Lesions included 55 amelanotic/hypomelanotic nonmelanocytic lesions (AHNML), 52 amelanotic/hypomelanotic benign melanocytic lesions (AHBML), and 44 AHM, 10 (23%) of which were nonpigmented, truly amelanotic melanomas (AM). The 44 AHM lesions were divided into thin melanomas (TnM) 1 mm (15 cases), according to the Breslow index. Five clinical features (elevation, ulceration, shape, borders and colour) as well as 10 dermoscopic criteria (pigment network, pigmentation, streaks, dots/globules, blue-whitish veil, regression structures, hypopigmentation, leaf-like areas, multiple grey-bluish globules, central white patch) and eight vascular patterns (comma, arborizing, hairpin, dotted, linear irregular, dotted and linear irregular vessels, and milky-red areas) were evaluated in order to achieve clinical and dermoscopic diagnoses. Statistical analyses were performed with the chi2-test and Fisher's exact test, when appropriate., Results: The most frequent and significant clinical features for TnM and TkM were asymmetry and ulceration (the latter only for TkM) compared with AHBML. Irregular dots/globules (62% vs. 35%; P