Concordance of in vivo reflectance confocal microscopy and horizontal-sectioning histology in skin tumours.

BACKGROUND: In vivo reflectance confocal microscopy (RCM) enables the study of architectural and cytological aspects in horizontal sections, which closely correlate with histologic features. However, traditional histopathological vertical sections cannot totally reproduce the image of the in vivo RCM horizontal section. OBJECTIVE: To evaluate the concordance between in vivo RCM and histopathologic transverse sections for melanocytic lesions, basal cell carcinoma and seborrheic keratoses. METHODS: Prospectively collected benign melanocytic and non-melanocytic tumours diagnosed by dermoscopy were evaluated for common RCM features and compared to histopathology in horizontal sections with haematoxylin and eosin staining. RESULTS: A total of 44 skin tumours including 19 melanocytic lesions (nine compound, five junctional and five intradermal nevi), 12 basal cell carcinomas and 13 seborrheic keratoses were collected in the Department of Dermatology of Hospital Clinic of Barcelona. The RCM features that had statistically significant agreement with the histopathological horizontal sections were the preserved and visible honeycomb pattern, well defined DEJ, small bright particles, dermal nests, tumour islands and dark silhouettes, clefting, collagen bundles, thickened collagen bundles and cytologic atypia. CONCLUSIONS: Histopathology evaluation of horizontal sections of skin tumours can be correlated with main RCM findings. The results of this study have improved the understanding and interpretation of RCM features in relation to skin tumours, thus reinforcing the utility of RCM as a diagnostic tool.

Criteria for melanocytic lesions in LC-OCT.

BACKGROUND: Line-field confocal optical coherence tomography (LC-OCT) is an emerging diagnostic tool with imaging depth reaching ~400 µm and a novel three-dimensional (3D) cube providing cellular resolution. As far as we are aware, there are only a limited number of papers that have reported diagnostic criteria for melanocytic lesions using this technique, and none of them have been multicentric. OBJECTIVES: Our aim was to establish the diagnostic criteria for melanocytic lesions using LC-OCT and identify the most significant architectural and cytologic features associated with malignancy. METHODS: A retrospective evaluation of 80 consecutive melanocytic lesions from a prospective multicentric data set spanning three European centres was conducted. We excluded facial, acral and mucosal lesions from the study. Dermoscopic and LC-OCT images were evaluated by a consensus of four observers. Multivariate logistic regression with backward elimination was employed. RESULTS: The main melanoma diagnostic criteria include detecting >10 pagetoid cells in 3D acquisition, irregular 3D epidermal architecture, disrupted dermoepidermal junction (DEJ) and clefting. Significant risk factors were irregular 3D epidermal architecture, >10 pagetoid cells, dendritic cells at DEJ without underlying inflammation. Novel malignancy criteria in vertical view were DEJ disruption and clefting around atypical melanocyte nests. Exclusive melanoma features were epidermal nests, epidermal consumption, dense dermal nests with atypia. Protective features in the absence of any malignancy indicators were DEJ ring pattern, cobblestone, elongated rete ridges (vertical), well-defined DEJ and wave pattern (vertical). CONCLUSIONS: A series of diagnostic criteria for the identification of melanocytic lesions with LC-OCT have been established. Validation of these criteria in clinical practice through future studies is essential to further establish their utility.

Understanding the anatomy of dermoscopy of melanocytic skin tumours: Correlation in vivo with line-field optical coherence tomography.

BACKGROUND: Early melanoma detection is the main factor affecting prognosis and survival. For that reason, non-invasive technologies have been developed to provide a more accurate diagnosis. Recently, line-field confocal optical coherence tomography (LC-OCT) was developed to provide an in vivo, imaging device, with deep penetration and cellular resolution in three dimensions. Combining the advantages of conventional OCT and reflectance confocal microscopy, this tool seems to be particularly suitable for melanocytic lesions. OBJECTIVES: The objective of this study was to identify and describe the correlation between specific dermoscopic criteria and LC-OCT features in three dimensions associated with melanocytic lesions. METHODS: Dermoscopic and LC-OCT images of 126 melanocytic lesions were acquired in three different centres. The following dermoscopic criteria have been considered: reticular pattern, dots and globules, structureless areas, blue-whitish veil, regression structures, negative network, homogeneous pattern, streaks and blotches. RESULTS: 69 (55%) benign and 57 (45%) malignant lesions were analysed. A regular reticular pattern was found associated in the 75% of the cases with the presence of elongated rete ridges with pigmented cells along the basal layer, while atypical reticular pattern showed an irregular organization of rete ridges with melanocytic hyperplasia, broadened and fused ridges and elongated nests. Both typical and atypical dots and globules were found associated with melanocytic nests in the dermis or at the dermoepidermal junction (DEJ), as well as with keratin cysts/pseudocysts. Grey globules corresponded to the presence of melanin-containing dermal inflammatory cells (melanophages) within the papillae. Structureless brown/black areas correlated with alterations of the DEJ. We observed the same DEJ alterations, but with the presence of dermal melanophages, in 36% of the cases of blue/white/grey structureless areas. A description of each LC-OCT/dermoscopy correlation was made. CONCLUSIONS: LC-OCT permitted for the first time to perform an in vivo, 3D correlation between dermoscopic criteria and pathological-like features of melanocytic lesions.

Exposure to UV Radiation in Lifeguards on Barcelona's Beaches: An Underestimated Occupational Risk. / [Artículo traducido] Exposición a radiación ultravioleta en socorristas de las playas de Barcelona: un riesgo laboral infravalorado.

BACKGROUND: The development of skin cancer is closely related to high exposure to UV radiation. Lifeguards are at an increased risk of excessive sun exposure. OBJECTIVES: The main objective of this study was to measure the exposure of Barcelona's beach lifeguards to UV radiation. METHODS: Measurements in the work chair were taken every 30min on a typical working day from 10:45 am to 19:15 pm. These measurements were carried out on four different days. These data were used to calculate the erythematous doses received during working hours, as well as those potentially received throughout the summer season. Vitamin D production was also estimated for the four days that the radiation received was measured, and the amount generated was calculated for the entire summer season. RESULTS: Exposure to UV radiation among Barcelona lifeguards far exceeds safety limits. In some locations, the exposure to UVB radiation is more than 16 times the minimum erythematous dose for phototype II skin. LIMITATIONS: This study assessed the radiation received during only four days. However, is a much higher number than most of the published papers. CONCLUSION: Although the health risks of excessive exposure to UV radiation are known, Barcelona's beach lifeguards are insufficiently protected.

Reflectance Confocal Microscopy Terminology in Spanish: A Delphi Consensus Study. / Consenso de terminología en microscopia confocal de reflectancia en español mediante método Delphi.

The terminology used to describe reflectance confocal microscopy (RCM) findings in both melanocytic and nonmelanocytic lesions has been standardized in English. We convened a panel of Spanish-speaking RCM experts and used the Delphi method to seek consensus on which Spanish terms best describe RCM findings in this setting. The experts agreed on 52 terms: 28 for melanocytic lesions and 24 for nonmelanocytic lesions. The resulting terminology will facilitate homogenization, leading to a better understanding of structures, more standardized descriptions in clinical registries, and easier interpretation of clinical reports exchanged between dermatologists.

[Translated article] Melanoma Registry of the Spanish Academy of Dermatology and Venereology (REGESMEL): Description and Data in its First Year of Operation.

INTRODUCTION: The incidence of melanoma is rising in Spain. The prognostic stages of patients with melanoma are determined by various biological factors, such as tumor thickness, ulceration, or the presence of regional or distant metastases. The Spanish Academy of Dermatology and Venereology (AEDV) has encouraged the creation of a Spanish Melanoma Registry (REGESMEL) to evaluate other individual and health system-related factors that may impact the prognosis of patients with melanoma. The aim of this article is to introduce REGESMEL and provide basic descriptive data for its first year of operation. METHODS: REGESMEL is a prospective, multicentre cohort of consecutive patients with invasive cutaneous melanoma that collects demographic and staging data as well as individual and healthcare-related baseline data. It also records the medical and surgical treatment received by patients. RESULTS: A total of 450 cases of invasive cutaneous melanoma from 19 participant centres were included, with a predominance of thin melanomas≤1mm thick (54.7%), mainly located on the posterior trunk (35.2%). Selective sentinel lymph node biopsy was performed in 40.7% of cases. Most cases of melanoma were suspected by the patient (30.4%), or his/her dermatologist (29.6%). Patients received care mainly in public health centers (85.2%), with tele-dermatology resources being used in 21.6% of the cases. CONCLUSIONS: The distribution of the pathological and demographic variables of melanoma cases is consistent with data from former studies. REGESMEL has already recruited patients from 15 Spanish provinces and given its potential representativeness, it renders the Registry as an important tool to address a wide range of research questions.

Melanoma Registry of the Spanish Academy of Dermatology and Venereology (REGESMEL): Description and Data in its First Year of Operation. / Registro de Melanoma de la Academia Española de Dermatología y Venereología (REGESMEL): descripción y datos en el primer año de funcionamiento.

INTRODUCTION: The incidence of melanoma is rising in Spain. The prognostic stages of patients with melanoma are determined by various biological factors, such as tumor thickness, ulceration, or the presence of regional or distant metastases. The Spanish Academy of Dermatology and Venereology (AEDV) has encouraged the creation of a Spanish Melanoma Registry (REGESMEL) to evaluate other individual and health system-related factors that may impact the prognosis of patients with melanoma. The aim of this article is to introduce REGESMEL and provide basic descriptive data for its first year of operation. METHODS: REGESMEL is a prospective, multicentre cohort of consecutive patients with invasive cutaneous melanoma that collects demographic and staging data as well as individual and healthcare-related baseline data. It also records the medical and surgical treatment received by patients. RESULTS: A total of 450 cases of invasive cutaneous melanoma from 19 participant centres were included, with a predominance of thin melanomas≤1mm thick (54.7%), mainly located on the posterior trunk (35.2%). Selective sentinel lymph node biopsy was performed in 40.7% of cases. Most cases of melanoma were suspected by the patient (30.4%), or his/her dermatologist (29.6%). Patients received care mainly in public health centers (85.2%), with tele-dermatology resources being used in 21.6% of the cases. CONCLUSIONS: The distribution of the pathological and demographic variables of melanoma cases is consistent with data from former studies. REGESMEL has already recruited patients from 15 Spanish provinces and given its potential representativeness, it renders the Registry as an important tool to address a wide range of research questions.

Development and validation of a minimally invasive and image-guided tape stripping method to sample atopic skin in children.

BACKGROUND: Molecular skin profiling techniques, typically performed on skin samples taken by punch biopsy, have enhanced the understanding of the pathophysiology of atopic dermatitis (AD), thereby enabling the development of novel targeted therapeutics. However, punch biopsies are not always feasible or desirable, and novel minimally invasive methods such as skin tape stripping have been developed. AIM: To develop, optimize and validate a novel tape stripping method guided by noninvasive in vivo skin imaging to sample atopic skin in children. METHODS: Skin tape stripping-based procedures were compared and optimized using data from 30 healthy controls (HCs: 5 adults, 25 children) and 39 atopic children. Evaluations were guided by high-resolution photography, reflectance confocal microscopy, optical coherence tomography and transepidermal water loss measurements. We assessed and compared adverse events (AEs), the time needed to perform the sampling and the cDNA levels obtained from the tapes. RESULTS: Tape stripping methods based on previously described protocols resulted in erosions in all participants and required a median time of 65 min to perform (range 60-70 min), but provided good cDNA yield. Shorter durations appeared less invasive but provided lower cDNA yield. The final optimized tape stripping protocol, using 11 tapes of 22 mm in diameter, each applied twice for 5 s with 90° rotation, did not produce significant AEs, was completed within a median time of 7 min (range 5-15 min) and provided good cDNA yield both in HCs and atopic children. CONCLUSION: Our minimally invasive method is safe and reliable, and provides reproducible acquisition of cDNA in atopic children. In addition, it enables rapid sample collection, a crucial factor in clinical practice.

High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Exposure to UV Radiation in Lifeguards on Barcelona's Beaches: An Underestimated Occupational Risk.

BACKGROUND: The development of skin cancer is closely related to high exposure to UV radiation. Lifeguards are at an increased risk of excessive sun exposure. OBJECTIVES: The main objective of this study was to measure the exposure of Barcelona's beach lifeguards to UV radiation. METHODS: Measurements in the work chair were taken every 30min on a typical working day from 10:45 am to 19:15 pm. These measurements were carried out on four different days. These data were used to calculate the erythematous doses received during working hours, as well as those potentially received throughout the summer season. Vitamin D production was also estimated for the four days that the radiation received was measured, and the amount generated was calculated for the entire summer season. RESULTS: Exposure to UV radiation among Barcelona lifeguards far exceeds safety limits. In some locations, the exposure to UVB radiation is more than 16 times the minimum erythematous dose for phototype II skin. LIMITATIONS: This study assessed the radiation received during only four days. However, is a much higher number than most of the published papers. CONCLUSION: Although the health risks of excessive exposure to UV radiation are known, Barcelona's beach lifeguards are insufficiently protected.

M-CSF as a therapeutic target in BRAFV600E melanoma resistant to BRAF inhibitors.

BACKGROUND: Disseminated BRAFV600E melanoma responds to BRAF inhibitors (BRAFi) but easily develops resistance with poor prognosis. Secretome plays a pivotal role during tumour progression causing profound effects on therapeutic efficacy. Secreted M-CSF is involved in both cytotoxicity suppression and tumour progression in melanoma. We aimed to analyse the M-CSF contribution in resistant metastatic melanoma to BRAF-targeted therapies. METHODS: Conditioned media from melanoma cells were analysed by citoarray. Viability and migration/invasion assays were performed with paired melanoma cells and tumour growth in xenografted SCID mice. We evaluated the impact of M-CSF plasma levels with clinical prognosis from 35 metastatic BRAFV600E-mutant melanoma patients. RESULTS: BRAFi-resistant melanoma cells secretome is rich in pro-tumour cytokines. M-CSF secretion is essential to induce a Vemurafenib-resistant phenotype in melanoma cells. Further, we demonstrated that M-CSF mAb in combination with Vemurafenib and autophagy blockers synergistically induce apoptosis, impair migration and reduce tumour growth in BRAFi-resistant melanoma cells. Interestingly, lower M-CSF plasma levels are associated with better prognosis in metastatic melanoma patients. CONCLUSIONS: Secreted M-CSF induces a BRAFi-resistant phenotype and means worse prognosis in BRAFV600E metastatic melanoma patients. These results identify secreted M-CSF as a promising therapeutic target toward BRAFi-resistant melanomas.

Synchronous primary cutaneous melanomas: a descriptive study of their clinical features, histology, genetic background of the patients and clinical outcomes.

BACKGROUND: Around 0.5% of cutaneous melanoma (CM) patients will present with synchronous melanomas when first seen. Moreover, 26-40% of patients with multiple primary melanomas present with synchronous lesions. OBJECTIVES: To assess the prevalence, clinical and histopathological characteristics, germline mutations and outcome in patients with synchronous melanoma. METHODS: Clinical and histopathological data from 4703 melanoma patients were included. Clinical, histological and genetic mutational status information was analysed. Kaplan-Meier curves were used to investigate survival outcomes. RESULTS: A total of 144 patients (3.06%) presented simultaneously with two or more primary melanomas. During follow-up, 25.7% of patients with synchronous melanoma developed a new primary melanoma compared to 8.6% of patients diagnosed with single melanoma (P < 0.001). Germinal CDKN2A mutations were identified in 10.7% of patients with synchronous melanomas and genetic variants in MC1R in 72%. No significant differences in all survival outcomes between patients with synchronous melanomas and single melanomas were found. CONCLUSION: Synchronous melanomas are more frequent than previously reported and are more frequent in older patients compared to single melanomas. Moreover, these patients have a higher risk of developing a new primary melanoma during follow-up and have higher rates of germline susceptibility variants. Nevertheless, these findings were not associated with worse outcomes.

Line-field confocal optical coherence tomography of basosquamous carcinoma: a case series with histopathological correlation.

BACKGROUND: Basosquamous carcinoma (BSC) is a rare and potentially aggressive cutaneous neoplasm combining histopathological features of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Line-field confocal optical coherence tomography (LC-OCT) is a new, non-invasive imaging technique featuring excellent resolution and penetration. To date, studies about the use of LC-OCT in the BCC and SCC fields are available, but similar investigations are lacking in the BSC field. OBJECTIVE: The goal of the present study was to identify/describe LC-OCT criteria of BSC. METHODS: Consecutively enrolled BSCs were imaged with dermoscopy and LC-OCT prior to surgical excision. Dermoscopic and LC-OCT images were evaluated, and histopathological slides were reviewed. RESULTS: Six BSCs from six patients [four (66.7%) males and two (33.3%) females; mean age 76.5 (62-96) years] were included. Identified LC-OCT criteria for BSC included BCC-associated (dermal lobules with millefeuille pattern, dilated vessels, bright cells within the epidermis, bright cells within lobules, stromal stretching, stromal brightness) and SCC-associated features (acanthosis, hyperkeratosis, disarranged epidermal architecture, broad strands, elastosis and glomerular vessels). Interruption of the dermal-epidermal junction and ulceration represented overlapping criteria. CONCLUSION: Line-field confocal-OCT is a new promising technique that may support the non-invasive recognition of BSC through the simultaneous detection of BCC-associated and SCC-associated features. We hypothesize that the use of LC-OCT might be helpful not only in the diagnostic setting but also in the follow-up surveillance for an early identification of recurrences. Further larger studies are needed to prove this hypothesis.

Sinonasal mucosal melanomas: defining profiles for better survival outcomes.

BACKGROUND: Sinonasal mucosal melanoma is an aggressive malignancy with a 5-year survival rate ranging from 20% to 39%. Despite the evolving surgical and radiotherapy techniques, and introduction of immune-checkpoint inhibitor therapy, overall survival rates remain poor. METHODOLOGY: A retrospective cohort study was conducted at the Hospital Clinic de Barcelona and the Hospital de la Santa Creu i Sant Pau between 1984 and 2020; primary outcome measures were 3 and 5-year melanoma-specific survival (MSS). Kaplan-Meier survival analysis and Cox proportional hazards model were performed to identify predictors of survival. RESULTS: Fifty patients were included, the mean age was 70.4, MSS at 3 and 5 years was 51.2%, and 29.5%, respectively. The median follow-up was 39.6 months during which 46% presented locoregional recurrence and 36%, metastasis. The univariate and multivariate analyses found as survival predictors the N category, the treatment received, the surgical margins and the mitotic index. CONCLUSIONS: We found an overall 5-year MSS of 29.5%. Those patients with intention-to-cure (stages III and IVa) treated by surgery that were N0 at diagnosis, with < 10 mitoses per HPF showed a 5-year MSS rate of 74.1%. More studies will be needed to adequately define the patients' profiles that will benefit from a better survival outcome.

Epidemiology of Melanoma in Spain: Estimation of Number of Patients With Stage III Disease Eligible for Adjuvant Therapies. / Epidemiología del melanoma en España: estimación de los pacientes con melanoma con estadio III candidatos al tratamiento adyuvante.

BACKGROUND AND OBJECTIVE: Accurate information on the incidence of melanoma by stage and a better understanding of transition between stages are important for determining the burden of disease and assessing the impact of new adjuvant therapies on recurrence and survival. The aim of this study was to estimate the incidence rates of the various stages of melanoma in Spain and to estimate the number of patients with stage III disease who are eligible for adjuvant systemic therapies. MATERIALS AND METHOD: We built an epidemiological model using prospectively collected data from patients diagnosed with de novo or recurrent melanoma between 2012 and 2016 in the melanoma units of 4 public hospitals. RESULTS: The estimated crude incidence rates for stage I and II melanoma were 7 and 2.9 cases per 100,000 person-years, respectively. The corresponding rates for stage III and IV melanoma were 1.9 and 1.3 cases per 100,000 person-years; 25.8% of patients with stage III melanoma were stage IIIA, 47% were stage IIIB, and 27.3% were stage IIIC. The respective estimated incidence rates for recurrent stage III and IV melanoma were 1.1 and 0.9 cases per 100,000 person-years. Overall, 54% of patients with recurrent stage III melanoma had progressed from stage I or II; the other cases corresponded to changes in substage. Of the patients with stage III melanoma, 85% of those with a de novo diagnosis and 80% of those who had relapsed had resectable disease, meaning they were eligible for adjuvant therapy; 47% of these patients had a BRAF mutation. CONCLUSIONS: The above estimates could have a major impact on health care resource planning. Assessing the number of patients with melanoma who are eligible for adjuvant therapies in melanoma could help decision-makers and clinicians anticipate future needs for the management of this disease.

Incidence of Melanoma in the Basque Province of Álava, Spain, From 2015 to 2018: A Descriptive Study. / Estudio descriptivo de los pacientes diagnosticados de melanoma en la provincia de Álava (País Vasco) entre los años 2015 y 2018.

INTRODUCTION: The incidence of cutaneous melanoma is rising fast, and its prevalence has doubled in the past 3 decades. Detailed local epidemiological information is essential for informing community-based prevention strategies and optimizing hospital resources. MATERIAL AND METHODS: We included all patients diagnosed with cutaneous melanoma at Hospital Universitario Araba in the Basque province of Álava, Spain, between January 2015 and December 2018. We described clinical and pathologic characteristics and calculated annual incidence rates adjusted to the European standard population. RESULTS: A total of 242 new cases of melanoma were diagnosed between 2015 and 2018. The age-standardized annual incidence rose from 12.92 cases per 100 000 population in 2015 to 18.30 cases per 100 000 population in 2018. CONCLUSIONS: The incidence of melanoma in our area is higher than that reported for Spanish series in 2017 and 2018. Lentigo maligna accounted for a high proportion of cases and was the second largest histologic subgroup.

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear. METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set. RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018). CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection.

BACKGROUND: One of the challenging aspects of SARS-CoV-2 infection is its diverse multisystemic disease presentation. OBJECTIVES: To evaluate the diagnostic value of cutaneous manifestations of SARS-CoV-2 infection and investigate their duration and timing in relation to other COVID-19 symptoms. METHODS: We used data from 336 847 UK users of the COVID Symptom Study app to assess the diagnostic value of body rash or an acral rash in SARS-CoV-2 infection, and data from an independent online survey of 11 544 respondents to investigate skin-specific symptoms and collect their photographs. RESULTS: Using data from the app, we show significant association between skin rashes and a positive swab test result (odds ratio 1·67, 95% confidence interval 1·42-1·97). Strikingly, among the respondents of the independent online survey, we found that 17% of SARS-CoV-2-positive cases reported skin rashes as the first presentation, and 21% as the only clinical sign of COVID-19. Together with the British Association of Dermatologists, we have compiled a catalogue of images of the most common skin manifestations of COVID-19 from 400 individuals (https://covidskinsigns.com), which we have made publicly available to assist clinicians in recognition of this early clinical feature of COVID-19. CONCLUSIONS: Skin rashes cluster with other COVID-19 symptoms, are predictive of a positive swab test, and occur in a significant number of cases, either alone or before other classical symptoms. Recognizing rashes is important in identifying new and earlier cases of COVID-19.

Dermoscopy comparative approach for early diagnosis in familial melanoma: influence of MC1R genotype.

BACKGROUND: MC1R polymorphisms interact with CDKN2A mutations modulating melanoma risk and contribute to a less suspicious clinical and dermoscopic appearance of melanomas. Different strategies, including dermoscopic comparative approach and digital monitoring, are used for the melanoma diagnosis in this context. OBJECTIVE: To analyse the diagnostic accuracy of the morphologic approach and comparative approach in dermoscopy, and to detect melanoma in familial melanoma (FamMM) patients according to different genetic backgrounds. METHODS: Two independent readers evaluated 415 lesions belonging to 25 FamMM: 26 melanomas (62% in situ, 36% early invasive) and 389 naevi, blinded for dermoscopic and histopathologic diagnosis, following two different steps. First step-Randomized: all lesions were randomly located in one single folder. Second step-Comparative approach: the lesions were clustered by patient. Sensitivity, specificity and number needed to excise (NNE) for melanoma diagnosis were calculated for both diagnostic strategies. Sensitivity and specificity were also assessed regarding the genetic background. RESULTS: The comparative approach showed lower sensitivity compared to the morphologic approach (69.2 and 73.1 vs. 76.9 both readers) but better specificity (95.9 and 95.1 vs. 84.3 and 90.2, respectively). NNE was better in the comparative approach. The readers had more difficulties diagnosing lesions from CDKN2A mutation carriers with red hair colour (RHC) MC1R variants. CONCLUSION: The comparative approach can be useful in high-risk patients to decrease the NNE. Early melanomas in CDKN2A carriers with RHC polymorphisms are more difficult to diagnose even with the comparative approach and benefit from the detection of changes during digital dermoscopy monitoring for early diagnosis.

Dermatoscopy of combined blue nevi: a multicentre study of the International Dermoscopy Society.

BACKGROUND: Combined blue nevi (CBN) may mimic melanoma and are relatively often biopsied for diagnostic reasons. OBJECTIVE: To better characterize CBN and to compare it with melanoma. METHODS: We collected clinical and dermatoscopic images of 111 histologically confirmed CBN and contrasted their dermatoscopic characteristics with 132 partly blue coloured melanomas. Furthermore, we compared the accuracy of human experts using pattern analysis with a computer algorithm based on deep learning. RESULTS: Combined blue nevi are usually flat or slightly elevated and, in comparison with melanoma, more frequent on the head and neck. Dermatoscopically, they are typified by a blue structureless part in combination with either brown clods (n = 52, 46.8%), lines (n = 28, 25.2%) or skin-coloured or brown structureless areas (n = 31, 27.9%). In contrast with melanoma, the blue part of CBN is more often well defined (18.9% vs. 4.5%, P < 0.001) and more often located in the centre (22.5% vs. 5.3%, P < 0.001). Melanomas are more often chaotic (OR: 28.7, 95% CI: 14.8-55.7, P < 0.001), have at least one melanoma clue (OR: 10.8, 95% CI: 5.2-22.2 P < 0.001) in particular white lines (OR: 37.1, 95% CI: 13.4-102.9, P < 0.001). Using simplified pattern analysis (chaos and clues), two raters reached sensitivities of 93.9% (95% CI: 88.4-97.3%) and 92.4% (95% CI: 86.5-96.3%) at corresponding specificities of 59.5% (95% CI: 49.7-68.7%) and 65.8% (95% CI: 56.2-74.5%). The human accuracy with pattern analysis was on par with a state-of-the-art computer algorithm based on deep learning that achieved an area under the curve of (0.92, 95% CI: 0.87-0.96) and a specificity of 85.3% (95% CI: 76.5-91.7%) at a given sensitivity of 83.6% (95% CI: 72.5-91.5%). CONCLUSION: CBN usually lack melanoma clues, in particular white lines. The accuracy of pattern analysis for combined nevi is acceptable, and histopathologic confirmation may not be necessary in exemplary cases.