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IMPORTANCE: Somatic variants in the RAS/MAPK pathway genes are commonly associated with melanocytic nevi and melanoma, whereas germline variants in these genes are associated with RASopathies, syndromes involving multiple organs, including the skin. Nevi counts may be higher in some RASopathies, but studies on features observed through dermoscopy are limited. OBJECTIVE: To determine the distinguishing dermoscopic features of melanocytic nevi and how the RAS pathway influences them by comparing nevi in patients with cardiofaciocutaneous syndrome (CFC) and Costello syndrome (CS). DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, patients with CFC and CS, 2 RASopathies caused by variants in the downstream and upstream components of the RAS/MAPK pathway, were recruited from the international CFC and CS family conferences. Some patients with CFC also elected to participate in a longitudinal follow-up study. MAIN OUTCOMES AND MEASURES: The main outcomes were dermoscopic features and, in the longitudinal follow-up study, nevi counts, which were recorded over time. RESULTS: A total of 39 patients, 16 with CFC and 23 with CS, were enrolled (overall cohort: 26 [66.7%] female; median [IQR] age, 13.0 [7.6-22.0] years). The 112 nevi overall frequently displayed an organized dermoscopic pattern (CFC, 61 [84.7%]; CS, 34 [85.0%]) rather than a disorganized pattern (CFC, 6 [8.3%]; CS, 1 [2.5%]). Of the organized nevi, homogenous brown was the most common pattern (CFC, 41 [67.2%]; CS, 22 [64.7%]), followed by reticular (CFC, 11 [18.0%]; CS, 7 [20.6%]) and globular (CFC, 9 [14.8%]; CS, 5 [14.7%]). Pigmented networks occurred in 12 nevi in CFC (16.7%) and 6 nevi in CS (15%; P > .99). Of these, 6 CFC-associated nevi (50%) and no CS-associated nevi had atypical networks (P = .05). Six patients with CFC in the follow-up study developed significantly more nevi within 5 years (median [IQR] increase, 24.5 [10-120] nevi; P = .04). CONCLUSIONS AND RELEVANCE: In this cohort study, the findings suggest that nevi in patients with CFC and CS commonly display organized homogenous brown dermoscopic patterns, and the number of nevi may significantly increase over time in those with CFC. A disorganized pattern and atypical networks may be more frequent in patients with CFC. Future studies are needed to determine the risk of melanoma in individuals with CFC or CS.

On the basis of the clinical impression and current knowledge, acquired melanocytic nevi and melanomas may not occur in random localizations. The goal of this study was to identify whether their distribution on the back is random and whether the location of melanoma correlates with its adjacent lesions. Therefore, patient-level and lesion-level spatial analyses were performed using the Clark‒Evans test for complete spatial randomness. A total of 311 patients with three-dimensional total body photography (average age of 40.08 [30‒49] years; male/female ratio: 128/183) with 5,108 eligible lesions in total were included in the study (mean sum of eligible lesions per patient of 16.42 [3‒199]). The patient-level analysis revealed that the distributions of acquired melanocytic neoplasms were more likely to deviate toward clustering than dispersion (average z-score of ‒0.55 [95% confidence interval = ‒0.69 to ‒0.41; P< 0.001]). The lesion-level analysis indicated a higher portion of melanomas (n = 57 of 72, 79.2% [95% confidence interval = 69.4‒88.9%]) appearing in proximity to neighboring melanocytic neoplasms than to nevi (n = 2,281 of 5,036, 45.3% [95% confidence interval = 43.9‒46.7%]). In conclusion, the nevi and melanomas’ distribution on the back tends toward clustering as opposed to dispersion. Furthermore, melanomas are more likely to appear proximally to their neighboring neoplasms than to nevi. These findings may justify various oncogenic theories and improve diagnostic methodology.

Skin cancers are the most common form of malignancy. Early diagnosis and treatment provides the best chance for survival and reduced morbidity. However, some patients have recurrent or resistant lesions. [...]

Background. This study was designed to determine the risk of developing malignant melanoma (MM) in patients with a history of basal cell and/or squamous cell skin cancer (BCC/SCC) and to determine whether surveillance efforts can be directed toward these patients for the detection of early MMs. Methods. The study cohort was followed by annual total cutaneous examination (TCE). Controls consisted of individuals from the United States population matched for age, sex, and length of follow-up. The anatomic locations of the study cohorts' newly diagnosed MMs were plotted on an anatomic chart. The setting was a private dermatology practice. Two hundred, ninety consecutive white patients with a history of BCC/SCC but with no personal or family history of MM were followed by annual TCEs. The main outcome measures were the relative risk of developing MM and their prognosis. Results. Ten of the 290 patients developed an MM within an average of 109 months of follow-up (range, 3--17 years). All MMs were less than 0.70 mm in Breslow thickness and 80% occurred on usually clothed cutaneous sites. The expected number of MMs in the control population was 0.59 (P = 0.006), resulting in a relative risk of 17. Conclusion. Patients with BCC/SCC skin cancer are at substantial increased risk for developing MM. Regular and life-long surveillance TCE is an inexpensive and effective method for detecting curable MMs in such patients.

Skin cancers are the most common cancers in humans. The American Cancer Society estimates that in the United States more than 700,000 new skin cancers are diagnosed annually. Although the majority of nonmelanoma skin cancers occur on visibly exposed anatomic areas, most malignant melanomas occur on body sites obscured by clothing. The high mortality associated with advanced melanomas emphasizes the importance of performing regular total cutaneous examinations in all patients to detect early, easily curable lesions. A number of techniques aid in these examinations: (1) physical and psychologic preparation of the patient; (2) appropriate lighting and a suitable examination table; (3) when indicated, use of Wood's light, dermoscopy, and photography. In addition, any suspicious lesion should be biopsied promptly either in parte or in toto. Lastly, the patient should be educated about the signs and symptoms of skin cancer, the role of sunlight in causing skin cancers, and the need for sun avoidance and/or protection. By heightening public awareness of the high incidence of cancers of the skin and by emphasizing the need for routine examination of the entire cutaneous surface, most cutaneous malignancies can be diagnosed early when they can be cured by simple surgical procedures.

IMPORTANCE: Dermoscopy education in US dermatology residency programs varies widely, and there is currently no existing expert consensus identifying what is most important for resident physicians to know. OBJECTIVES: To identify consensus-based learning constructs representing an appropriate foundational proficiency in dermoscopic image interpretation for dermatology resident physicians, including dermoscopic diagnoses, associated features, and representative teaching images. Defining these foundational proficiency learning constructs will facilitate further skill development in dermoscopic image interpretation to help residents achieve clinical proficiency. DESIGN, SETTING, AND PARTICIPANTS: A 2-phase modified Delphi surveying technique was used to identify resident learning constructs in 3 sequential sets of surveys—diagnoses, features, and images. Expert panelists were recruited through an email distributed to the 32 members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group. Twenty-six (81%) opted to participate. Surveys were distributed using RedCAP software. MAIN OUTCOMES AND MEASURES: Consensus on diagnoses, associated dermoscopic features, and representative teaching images reflective of a foundational proficiency in dermoscopic image interpretation for US dermatology resident physicians. RESULTS: Twenty-six pigmented lesion and dermoscopy specialists completed 8 rounds of surveys, with 100% (26/26) response rate in all rounds. A final list of 32 diagnoses and 116 associated dermoscopic features was generated. Three hundred seventy-eight representative teaching images reached consensus with panelists. CONCLUSIONS AND RELEVANCE: Consensus achieved in this modified Delphi process identified common dermoscopic diagnoses, associated features, and representative teaching images reflective of a foundational proficiency in dermoscopic image interpretation for dermatology residency training. This list of validated objectives provides a consensus-based foundation of key learning points in dermoscopy to help resident physicians achieve clinical proficiency in dermoscopic image interpretation.

IMPORTANCE: The development of new primary cutaneous melanoma (CM) after starting immune checkpoint inhibitor (ICI) therapy is poorly characterized. OBJECTIVE: To determine the incidence of new CM in patients treated with ipilimumab, nivolumab, and/or pembrolizumab for metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: Single-center, retrospective, observational cohort study using an institutional database to identify patients diagnosed with melanoma at a tertiary care cancer hospital in New York, New York. EXPOSURES: Ipilimumab, nivolumab, and/or pembrolizumab treatment for metastatic melanoma. MAIN OUTCOMES AND MEASURES: Primary outcomes were the incidence proportion, the incidence rate, and the 5-year cause-specific cumulative risk. RESULTS: A total of 2251 patients were included in the study; mean (SD) age at the time of ICI start was 62.8 (14.4) years. The majority were male (63.8%, n = 1437), White (92.7%, n = 2086), and non-Hispanic (92.1%, n = 2073). Forty-two of 2251 patients who received ipilimumab, nivolumab, and/or pembrolizumab were diagnosed with 48 new CMs at a median (range) of 397.5 (39-2409) days after ICI initiation. The median age of affected patients at the time of ICI first dose was 66.5 years. The majority were male (66.7%, n = 28), White (92.9%, n = 39), and non-Hispanic (100.0%, n = 42). There were no differences in age, sex, race, and ethnicity among patients who did and did not develop a new CM. Patients who developed a new CM were more likely to have a family history of melanoma (23.8% vs 16.3%, P = .02). Most new CMs (n = 30, 62.5%) were diagnosed after the last date of ICI administration. Twenty-seven (56.3%) new CMs were in situ and 21 (43.8%) were invasive. Of the invasive CMs with a reported Breslow thickness (n = 20), the median (range) thickness was 0.4 (0.1-8.4) mm. The overall incidence proportion of new CM was 1.9% (95% CI, 1.4%-2.5%) and the incidence rate was 1103 cases per 100 000 person-years (95% CI, 815-1492). The 5-year cumulative cause-specific risk of new CM was 4.9% (95% CI, 3.3%-7.4%). CONCLUSIONS AND RELEVANCE: Patients treated with ICI therapy for metastatic melanoma remain at risk for the development of new CM.

IMPORTANCE: Use of prognostic gene expression profile (GEP) testing in cutaneous melanoma (CM) is rising despite a lack of endorsement as standard of care. OBJECTIVE: To develop guidelines within the national Melanoma Prevention Working Group (MPWG) on integration of GEP testing into the management of patients with CM, including (1) review of published data using GEP tests, (2) definition of acceptable performance criteria, (3) current recommendations for use of GEP testing in clinical practice, and (4) considerations for future studies. EVIDENCE REVIEW: The MPWG members and other international melanoma specialists participated in 2 online surveys and then convened a summit meeting. Published data and meeting abstracts from 2015 to 2019 were reviewed. FINDINGS: The MPWG members are optimistic about the future use of prognostic GEP testing to improve risk stratification and enhance clinical decision-making but acknowledge that current utility is limited by test performance in patients with stage I disease. Published studies of GEP testing have not evaluated results in the context of all relevant clinicopathologic factors or as predictors of regional nodal metastasis to replace sentinel lymph node biopsy (SLNB). The performance of GEP tests has generally been reported for small groups of patients representing particular tumor stages or in aggregate form, such that stage-specific performance cannot be ascertained, and without survival outcomes compared with data from the American Joint Committee on Cancer 8th edition melanoma staging system international database. There are significant challenges to performing clinical trials incorporating GEP testing with SLNB and adjuvant therapy. The MPWG members favor conducting retrospective studies that evaluate multiple GEP testing platforms on fully annotated archived samples before embarking on costly prospective studies and recommend avoiding routine use of GEP testing to direct patient management until prospective studies support their clinical utility. CONCLUSIONS AND RELEVANCE: More evidence is needed to support using GEP testing to inform recommendations regarding SLNB, intensity of follow-up or imaging surveillance, and postoperative adjuvant therapy. The MPWG recommends further research to assess the validity and clinical applicability of existing and emerging GEP tests. Decisions on performing GEP testing and patient management based on these results should only be made in the context of discussion of testing limitations with the patient or within a multidisciplinary group.

IMPORTANCE: Basal cell carcinoma (BCC) is the most common skin cancer. Dermoscopic imaging has improved diagnostic accuracy; however, diagnosis of nonpigmented BCC remains limited to arborizing vessels, ulceration, and shiny white structures. OBJECTIVE: To assess multiple aggregated yellow-white (MAY) globules as a diagnostic feature for BCC. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective, single-center, case-control study, nonpigmented skin tumors, determined clinically, were identified from a database of lesions consecutively biopsied during a 7-year period (January 1, 2009, to December 31, 2015). A subset of tumors was prospectively diagnosed, and reflectance confocal microscopy, optical coherence tomography, and histopathologic correlation were performed. Data analysis was conducted from July 1 to September 31, 2019. EXPOSURES: Investigators evaluated for the presence or absence of known dermoscopic criteria. MAY globules were defined as aggregated, white-yellow structures visualized in polarized and nonpolarized light. MAIN OUTCOMES AND MEASURES: The primary outcome was the diagnostic accuracy of MAY globules for the diagnosis of BCC. Secondary objectives included the association with BCC location and subtype. Interrater agreement was estimated. RESULTS: A total of 656 nonpigmented lesions from 643 patients (mean [SD] age, 63.1 [14.9] years; 381 [58.1%] male) were included. In all, 194 lesions (29.6%) were located on the head and neck. A total of 291 (44.4%) were BCCs. MAY globules were seen in 61 of 291 BCC cases (21.0%) and in 3 of 365 other diagnoses (0.8%) (P &lt; .001). The odds ratio for diagnosis of BCC was 32.0 (96% CI, 9.9-103.2). The presence of MAY globules was associated with a diagnosis of histologic high-risk BCC (odds ratio, 6.5; 95% CI, 3.1-14.3). The structure was never seen in cases of superficial BCCs. CONCLUSIONS AND RELEVANCE: The findings suggest that MAY globules may have utility as a new BCC dermoscopic criterion with a high specificity. MAY globules were negatively associated with superficial BCC and positively associated with deeper-seated, histologic, higher-grade tumor subtypes.

IMPORTANCE: Although various treatments have been found in clinical trials to be effective in treating actinic keratosis (AK), researchers often report different outcomes. Heterogeneous outcome reporting precludes the comparison of results across studies and impedes the synthesis of treatment effectiveness in systematic reviews. OBJECTIVE: To establish an international core outcome set for all clinical studies on AK treatment using systematic literature review and a Delphi consensus process. EVIDENCE REVIEW: Survey study with a formal consensus process. The keywords actinic keratosis and treatment were searched in PubMed, Embase, CINAHL, and the Cochrane Library to identify English-language studies investigating AK treatments published between January 1, 1980, and July 13, 2015. Physician and patient stakeholders were nominated to participate in Delphi surveys by the Measurement of Priority Outcome Variables in Dermatologic Surgery Steering Committee members. All participants from the first round were invited to participate in the second round. Outcomes reported in randomized controlled clinical trials on AK treatment were rated via web-based e-Delphi consensus surveys. Stakeholders were asked to assess the relative importance of each outcome in 2 Delphi survey rounds. Outcomes were provisionally included, pending the final consensus conference, if at least 70% of patient or physician stakeholders rated the outcome as critically important in 1 or both Delphi rounds and the outcome received a mean score of 7.5 from either stakeholder group. Data analysis was performed from November 5, 2018, to February 27, 2019. FINDINGS: A total of 516 outcomes were identified by reviewing the literature and surveying key stakeholder groups. After deduplication and combination of similar outcomes, 137 of the 516 outcomes were included in the Delphi surveys. Twenty-one physicians and 12 patients participated in round 1 of the eDelphi survey, with 17 physicians (81%) retained and 12 patients (100%) retained in round 2. Of the 137 candidate outcomes, 9 met a priori Delphi consensus criteria, and 6 were included in the final outcomes set after a consensus meeting: complete clearance of AKs, percentage of AKs cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and recurrence rate. It was recommended that treatment response be assessed at 2 to 4 months and recurrence at 6 to 12 months, with the AK rate of progression to cutaneous squamous cell carcinoma reported whenever long-term follow-up was possible. CONCLUSIONS AND RELEVANCE: Consensus was reached regarding a core outcome set for AK trials. Further research may help determine the specific outcome measures used to assess each of these outcomes.

Dermoscopy aids in melanoma detection; however, agreement on dermoscopic features, including those of high clinical relevance, remains poor. In this study, we attempted to evaluate agreement among experts on exemplar images not only for the presence of melanocytic-specific features but also for spatial localization. This was a cross-sectional, multicenter, observational study. Dermoscopy images exhibiting at least 1 of 31 melanocytic-specific features were submitted by 25 world experts as exemplars. Using a web-based platform that allows for image markup of specific contrast-defined regions (superpixels), 20 expert readers annotated 248 dermoscopic images in collections of 62 images. Each collection was reviewed by five independent readers. A total of 4,507 feature observations were performed. Good-to-excellent agreement was found for 14 of 31 features (45.2%), with eight achieving excellent agreement (Gwet’s AC >0.75) and seven of them being melanoma-specific features. These features were peppering/granularity (0.91), shiny white streaks (0.89), typical pigment network (0.83), blotch irregular (0.82), negative network (0.81), irregular globules (0.78), dotted vessels (0.77), and blue–whitish veil (0.76). By utilizing an exemplar dataset, a good-to-excellent agreement was found for 14 features that have previously been shown useful in discriminating nevi from melanoma. All images are public (www.isic-archive.com) and can be used for education, scientific communication, and machine learning experiments.