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Malignant melanoma continues to present a significant public health problem as its incidence is rising faster than that of any other cancer in the US. At current rates, 1 in 74 Americans will develop melanoma during his or her lifetime. Management of melanoma is a complex issue requiring a multidisciplinary approach. The most effective method of protection against the development of melanoma is minimization of ultraviolet exposure from sunlight. Early detection and treatment are critical and result in improved patient survival rates. Surgical excision remains the mainstay of treatment but many new promising therapies are being investigated. It is hoped that increased public and professional awareness and education in all areas relating to the prevention, detection, and treatment of malignant melanoma will contribute to decreasing trends in the incidence and mortality from this cancer in the future. [ABSTRACT FROM AUTHOR]

Competing Interests: Conflicts of interest Dr Ruiz serves is a consultant for Regeneron, Checkpoint Therapeutic, Feldan Pharmaceuticals. She serves as a Principal Investigator/Co-Investigator for the following companies: Regeneron (PI/Co-I), Merck (Co-I), Castle Biosciences (Co-I) and is the Executive Officer of Skin Cancer Outcomes Consortium (SCOUT) Skin Cancer Champions. Dr Carr is an investigator for Regeneron (no direct funds). Dr Cañueto has the following disclosures: grants to institution: Sanofi/Regeneron, Castle Biosciences; Lectures honoraria: Sanofi, Almirall, AbbVie, Regeneron, Sun Pharma; Payment for expert testimony: Sanofi, Regeneron, Almirall; Support for attending meetings: Pfizer, Almirall, Lilly, Castle Biosciences; Advisory board: Almirall, Sanofi, Regeneron, Kyowa, Roche, InflaRx; Funding: support by the Gerencia Regional de Salud de Castilla y León (GRS2549/A/22) and by the Instituto de Salud Carlos III (PI21/01207), co-financed by European Union. Dr Mangold has patent Methods and Materials for assessing and treating cutaneous squamous cell carcinoma (provisional 63-423254) and Regeneron Consulting with payments to the institution. He has consulted for Kyowa, Eli Lilly, Momenta, UCB, and Regeneron in the past, greater than 24 months ago. He has consulted for PHELEC in the past, great than 12 months. He has consulted for Incyte, Soligenix, Clarivate, and Bristol Myers Squibb in the past, less than 12 months ago. He consults for Nuvig, Argenyx, Boehringer, Janssen, and Ingelheim currently. He consults for Pfizer currently with payments to the institution. He has grant support from Kyowa, Miragen, Regeneron, Corbus, Pfizer, Incyte, Eli Lilly, Aregenx, Palbella, AbbVie, Priovant, Merck in the last 24 months. Beyond 24 months, grant support has come from Sun Pharma, Elorac, Novartis, and Janssen. His current patents include the use of oral JAKi in Lichen Planus (provisional 63/453,065), and Topical Ruxolitinib in Lichen Planus (WO2022072814A1). Dr Carucci receives funding for investigator initiated basic science research from Regeneron and is a PI for a clinical trial sponsored by Regeneron. Dr Koyfman has the following disclosures: Advisory board (paid): Merck, BMS, Regeneron, Galera therapeutics; Advisory board (unpaid): Castle Biosciences; Research support: Castle biosciences, merck, BMS, Regeneron; Honoraria: UpToDate. Dr Vidimos has the following dicslosures: Research Support – Castle; Advisory Board - Inhibitor Therapeutics; Honoraria - Up to Date. Dr Wysong has received an institutional research grant from Castle Biosciences. Drs Granger, Ran, Groover, Shahwan, Hirotsu, Carter, Girardi, Brodland, Sruvastava, Zitelli, and Willenbrink have no conflicts of interest to declare.

There is a paucity of information on racial and ethnic disparities relating to barriers to care in healthcare access and utilization in patients with cutaneous malignancies. We conducted a cross-sectional analysis of adults with melanoma, basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) in the National Institutes of Health (NIH) All of Us Research Program collected between May 2018 and July 2022. Participants included adults (aged 18 or older) with cutaneous malignancy who completed the Health Care Access and Utilization survey. We identified 5,817 adults who were diagnosed with BCC (67%), cSCC (28.9%), and melanoma (23.9%). Non-Hispanic Black (NHB) and Hispanic patients were more likely than non-Hispanic White (NHW) patients to delay a primary care visit due to cost (p = 0.005 and p = 0.015, respectively). NHB patients were also more likely to delay care due to lack of transportation (p < 0.001). NHB and Hispanic patients were more likely to place importance on seeing a provider from the same background (NHB p < 0.002; Hispanic p = 0.002) and also were more likely to report never being able to see such a provider (NHB p < 0.001; Hispanic p = 0.002). Medicaid/Medicare patients, non-college graduates, and those with lower incomes also faced increased barriers to care, including delays due to cost and transportation issues. People of color with cutaneous malignancies are more likely to delay care in seeing primary care providers due to cost or transportation issues. This study provides important insights on disproportionate healthcare usage among racial/ethnic groups that may help mitigate healthcare disparities., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: A deeper understanding of acute rejection in vascularized composite allotransplantation is paramount for expanding its utility and longevity. There remains a need to develop more precise and accurate tools for diagnosis and prognosis of these allografts, as well as alternatives to traditional immunosuppressive regimens., Methods: Twenty-seven skin biopsies collected from 3 vascularized composite allotransplantation recipients, consisting of face and hand transplants, were evaluated by histology, immunohistochemistry staining, and gene expression profiling., Results: Biopsies with clinical signs and symptoms of rejection, irrespective of histopathological grading, were significantly enriched for genes contributing to the adaptive immune response, innate immune response, and lymphocyte activation. Inflammation episodes exhibited significant fold change correlations between the face and hands, as well as across patients. Immune checkpoint genes were upregulated during periods of inflammation that necessitated treatment. A gene signature consisting of CCL5 , CD8A , KLRK1 , and IFNγ significantly predicted inflammation specific to vascularized composite allografts that required therapeutic intervention., Conclusions: The mechanism of vascularized composite allograft-specific inflammation and rejection appears to be conserved across different patients and skin on different anatomical sites. A concise gene signature can be utilized to ascertain graft status along with a continuous scale, providing valuable diagnostic and prognostic information to supplement current gold standards of graft evaluation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Limited access to dermatologic care may pose an obstacle to the early detection and intervention of cutaneous malignancies. The role of artificial intelligence (AI) in skin cancer diagnosis may alleviate potential care gaps., Objective: The aim of this systematic review was to offer an in-depth exploration of published AI algorithms trained on dermoscopic and macroscopic clinical images for the diagnosis of melanoma, basal cell carcinoma, and cutaneous squamous cell carcinoma (cSCC)., Methods: Adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, a systematic review was conducted on peer-reviewed articles published between January 1, 2000, and January 26, 2023., Results and Discussion: Among the 232 studies in this review, the overall accuracy, sensitivity, and specificity of AI for tumor detection averaged 90%, 87%, and 91%, respectively. Model performance improved with time. Despite seemingly impressive performance, the paucity of external validation and limited representation of cSCC and skin of color in the data sets limits the generalizability of the current models. In addition, dermatologists coauthored only 12.9% of all studies included in the review. Moving forward, it is imperative to prioritize robustness in data reporting, inclusivity in data collection, and interdisciplinary collaboration to ensure the development of equitable and effective AI tools., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited., Objective: To define standardized reporting measures for retrospective CSCC studies., Findings: An expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses., Conclusions and Relevance: The recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

Background: Mohs micrographic surgery (MMS) is a promising treatment modality for melanoma in situ (MIS). However, variations in surgical technique limit the generalizability of existing data and may impede future study of MMS in clinical trials., Methods: A modified Delphi method was selected to establish consensus on optimal MMS techniques for treating MIS in future clinical trials. The Delphi method was selected due to the limited current data, the wide range of techniques used in the field, and the intention to establish a standardized technique for future clinical trials. A literature review and interviews with experienced MMS surgeons were performed to identify dimensions of the MMS technique for MIS that (1) likely impacted costs or outcomes of the procedure, and (2) showed significant variability between surgeons. A total of 8 dimensions of technical variation were selected. The Delphi process consisted of 2 rounds of voting and commentary, during which 44 expert Mohs surgeons across the United States rated their agreement with specific recommendations using a Likert scale., Results: Five of eight recommendations achieved consensus in Round 1. All 3 of the remaining recommendations achieved consensus in Round 2. Techniques achieving consensus in Round 1 included the use of a starting peripheral margin of ≤5 mm, application of immunohistochemistry, frozen tissue processing, and resecting to the depth of subcutaneous fat. Consensus on the use of Wood's lamp, dermatoscope, and negative tissue controls was established in Round 2., Conclusions: This study generated 8 consensus recommendations intended to offer guidance for Mohs surgeons treating MIS. The adoption of these recommendations will promote standardization to facilitate comparisons of aggregate data in multicenter clinical trials.

Background: Impaired immunity may drive the increased incidence and aggression of cutaneous squamous cell carcinoma (cSCC) in patients with hematologic malignancy; however, precise mechanisms and prognostic biomarkers remain undefined. CD73 maintains elevated immunosuppressive adenosine levels and is associated with poor prognosis in several tumor microenvironments., Objective: Identify poor outcome biomarkers in patients with cSCC and hematologic malignancy., Materials and Methods: Differentially expressed genes in tumors from patients with hematologic malignancy experiencing good (n = 8) versus poor (n = 7) outcomes were identified by NanoString analysis. Results were validated at the protein level using CD73 immunohistochemistry in cSCC patients with (n = 38) and without (n = 29) hematologic malignancy., Results: Forty-eight genes were differentially expressed in tumors from patients with hematologic malignancy experiencing good versus poor outcomes. CD73 gene expression was >2-fold higher in patients with poor versus good outcomes or normal skin. Significantly increased CD73 protein levels were observed in cSCC tumors with poor versus good outcomes from patients with hematologic malignancies (p < .01), whereas no differences were noted in tumors with poor versus good outcomes from patients without hematologic malignancies (p = .49)., Conclusion: CD73 is highly expressed in poor prognosis cSCC from patients with hematologic malignancy and may represent a useful biomarker and potential therapeutic target., (Copyright © 2024 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Competing Interests: Conflicts of interest None disclosed.

Merkel cell carcinoma (MCC) is a neuroendocrine skin cancer with a high rate of mortality. While still relatively rare, the incidence of MCC has been rapidly rising in the US and around the world. Since 2017, two immunotherapeutic drugs, avelumab and pembrolizumab, have been FDA-approved for the treatment of metastatic MCC and have revolutionized outcomes for MCC. However, real-world outcomes can differ from clinical trial data, and the adoption of novel therapeutics can be gradual. We aimed to characterize the treatment practices and outcomes of patients with metastatic MCC across the US. A retrospective cohort study of adult cases of MCC in the National Cancer Database diagnosed from 2004 to 2019 was performed. Multivariable logistic regressions to determine the association of a variety of patient, tumor, and system factors with likelihood of receipt of systemic therapies were performed. Univariate Kaplan-Meier and multivariable Cox survival regressions were performed. We identified 1017 cases of metastatic MCC. From 2017 to 2019, 54.2% of patients received immunotherapy. This increased from 45.1% in 2017 to 63.0% in 2019. High-volume centers were significantly more likely to use immunotherapy (odds ratio 3.235, p = 0.002). On univariate analysis, patients receiving systemic immunotherapy had significantly improved overall survival (p < 0.001). One-, 3-, and 5-year survival was 47.2% (standard error [SE] 1.8%), 21.8% (SE 1.5%), and 16.5% (SE 1.4%), respectively, for patients who did not receive immunotherapy versus 62.7% (SE 3.5%), 34.4% (SE 3.9%), and 23.6% (SE 4.4%), respectively, for those who did (Fig. 1). In our multivariable survival regression, receipt of immunotherapy was associated with an approximately 35% reduction in hazard of death (hazard ratio 0.665, p < 0.001; 95% CI 0.548-0.808). Our results demonstrate that the real-world survival advantage of immunotherapy for metastatic MCC is similar to clinical trial data. However, many patients with metastatic disease did not receive this guideline-recommended therapy in our most recent study year, and use of immunotherapy is higher at high-volume centers. This suggests that regionalization of care to high-volume centers or dissemination of their practices, may ultimately improve patient survival., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Vulvar squamous cell carcinoma (vSCC) is a rare tumor with a good prognosis when treated at a localized stage. However, once regional/distant metastasis occurs, vSCC can be rapidly fatal. Thus, it is important to identify tumor prognostic features so that high-risk cases can be prioritized for further diagnostic workup and treatment., Objective: To estimate the risk of regional/distant metastasis at presentation and sentinel lymph node status for vSCC based on histopathologic characteristics., Methods: A retrospective cohort study of 15,188 adult vSCC cases from the National Cancer Database diagnosed from 2012 to 2019., Results: We provide specific estimates of the risk of clinically positive nodes and metastatic disease at presentation and sentinel lymph node positivity according to tumor size, moderate/poor tumor differentiation, and lymph-vascular invasion. These histopathologic factors were all significantly associated with the tested clinical outcomes in a multivariable analysis. Moderate (hazard ratio, 1.190; P < .001) and poor differentiation (hazard ratio, 1.204; P < .001) and lymph-vascular invasion (hazard ratio, 1.465; P < .001) were also associated with significantly poorer overall survival., Limitations: Data on disease-specific survival not available in the data set., Conclusions: We demonstrate the association of the histopathologic characteristics of vSCC with clinically important outcomes. These data may provide individualized information when discussing diagnostic/treatment recommendations, particularly regarding sentinel lymph node biopsy. These data may also guide future staging and risk stratification efforts for vSCC., Competing Interests: Conflicts of interest None disclosed., (Copyright © 2023. Published by Elsevier Inc.)

Background: It is recommended to excise adnexal neoplasms with standard local excision or Mohs micrographic surgery (MMS), although many occur on high-risk sites such as the head and neck (H&N) and exhibit subclinical extension. Minimal evidence exists on the efficacy of standard excisions for these tumors., Objective: To evaluate the rate of positive surgical margins after standard excision of adnexal tumors., Methods: Retrospective cohort study of cutaneous adnexal malignancies from the National Cancer Database diagnosed from 2004 to 2019., Results: The authors identified a total of 4,402 cases treated with standard excision. Tumors on the H&N were approximately twice as likely as those on the trunk and extremities (T&E) to be excised with positive margins (odds ratio 2.146, p < .001), with the highest estimated rate for eccrine adenocarcinoma (12.1%, SE: 2.3%). The subtype with the highest positive margin rate on the T&E was microcystic adnexal carcinoma (8.0%, SE: 2.9). Positive margins were associated with poorer overall survival on multivariable survival analysis (hazard ratio 1.299, p = .015)., Conclusion: The authors present subtype- and site-specific positive margin rates for adnexal tumors treated with standard excision, which suggest that tumors on the H&N and some T&E subtypes, should be considered for MMS., (Copyright © 2023 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Merkel cell carcinoma (MCC) is a rare cutaneous malignant neoplasm with increasing incidence and high mortality. Although it is accepted that the optimal treatment for localized tumors is surgical, the data surrounding the optimal surgical approach are mixed, and current National Comprehensive Cancer Network guidelines state that Mohs micrographic surgery (MMS) and wide local excision (WLE) can both be used. The current National Comprehensive Cancer Network guidelines do not advocate a preference for MMS or WLE and suggest that they can be used interchangeably., Objective: To evaluate the association of surgical approach with overall survival after excision of localized T1/T2 MCC., Design, Setting, and Participants: This retrospective cohort study used the National Cancer Database to assess adults with T1/T2 MCC who were diagnosed between January 1, 2004, and December 31, 2018, with pathologically confirmed, negative regional lymph nodes and treated with surgery. The National Cancer Database includes all reportable cases from Commission on Cancer-accredited facilities. Data analysis was performed from October 2022 to May 2023., Exposure: Surgical approach., Main Outcomes and Measures: Overall survival., Results: A total of 2313 patients (mean [SD] age, 71 [10.6] years; 1340 [57.9%] male) were included in the study. Excision with MMS had the best unadjusted survival, with mean (SE) survival rates of 87.4% (3.4%) at 3 years, 84.5% (3.9%) at 5 years, and 81.8% (4.6%) at 10 years vs 86.1% (0.9%) at 3 years, 76.9% (1.2%) at 5 years, and 60.9% (2.0%) at 10 years for patients treated with WLE. Patients treated with narrow-margin excision had similar survival as those treated with WLE, with mean (SE) survival rates of 84.8% (1.4%) at 3 years, 78.3% (1.7%) at 5 years, and 60.8% (3.6%) at 10 years. On multivariable survival analysis, excision with MMS was associated with significantly improved survival compared with WLE (hazard ratio, 0.59; 95% CI, 0.36-0.97; P = .04). High-volume MCC centers were significantly more likely to use MMS over WLE compared with other centers (odds ratio, 1.99; 95% CI, 1.63-2.44; P < .001)., Conclusions and Relevance: In this cohort study, the use of MMS (compared with WLE) was associated with significantly improved survival for patients with localized MCC with pathologically confirmed negative lymph nodes treated with surgery. These data suggest that Mohs surgery may provide a more effective treatment for MCC primary tumors than conventional WLE, although the lack of randomization and potential for selection bias in this study highlight the need for future prospective work evaluating this issue.

Competing Interests: Conflicts of interest None disclosed.

It is well established that immunosuppressed patients are at increased risk for poor outcomes (PO) from cutaneous squamous cell carcinoma (cSCC), including local recurrence (LR), nodal metastasis (NM), distant metastasis (DM), and disease-specific death (DSD). Defining PO risk is challenging but may be beneficial in guiding management. We aimed to define PO risk factors and evaluated their importance in immunosuppressed versus immunocompetent patients. We conducted a 4-year single-center retrospective review of patients with cSCC. Patient and tumor characteristics were evaluated in those that experienced PO. Immunosuppressed patients were ~ 11-fold more likely than immunocompetent patients to develop PO (10/85 vs. 15/1332, p < 0.0001). Among those with PO, immunosuppressed patients had diminished relapse free (p = 0.026) and progression free (p < 0.001) survival compared to immunocompetent. Immunosuppression was significantly associated with LR (p < 0.00001). Immunosuppressed patients were also more likely to develop NM, DM and experience DSD (p = 0.027). Mohs Appropriate Use Criteria was associated with NM, DM and DSD (p = 0.029), with area H tumors more likely to result in metastasis and death. In conclusion, immunosuppressed patients are more likely to develop LR, metastasis, and DSD from cSCC compared to immunocompetent patients. Immunosuppressed status was an independent risk factor for PO in this cohort and further considered for its inclusion in prognostication schema is warranted., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Vulvar melanoma is a rare malignancy with frequent recurrence and poor prognosis. National guidelines recommend wide local excision of these tumors with allowances for narrower margins for anatomic and functional limitations, which are common on specialty sites. There is presently a lack of data of margin positivity after standard excision of vulvar melanomas., Objective: We aim to evaluate the rate of positive margins after standard excision of vulvar melanomas., Materials and Methods: Retrospective cohort study of surgically excised vulvar melanomas from the NCDB diagnosed from 2004 to 2019., Results: We identified a total of 2,226 cases. Across surgical approaches and tumor stages, 17.2% (Standard Error [SE]: 0.8%) of cases had positive surgical margins. Among tumor stages, T4 tumors were most commonly excised with positive margins (22.9%, SE: 1.5%). On multivariable survival analysis, excision with positive margins was associated with significantly poorer survival (Hazard Ratio 1.299, p = .015)., Conclusion: We find that positive margin rates after standard excision of vulvar malignancies are higher than for other specialty site melanomas. Our data suggest that use of surgical approaches with complete margin assessment may improve local control and functional outcomes for patients with vulvar melanoma as they have for patients with other specialty site melanomas., (Copyright © 2023 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

There is controversy regarding the optimal surgical modality and ideal recommended margins for treating melanoma in situ (MIS) and invasive melanoma (IM). Although wide local excision is recommended, staged excision offers excellent margin control and low recurrence rates. In this manuscript, we reviewed a 10-year experience of staged excisions for the treatment of MIS and IM. A retrospective review was performed of 130 MIS and 32 IM cases treated with staged excision from April 2012 to April 2022. Staged excision was performed on the head and neck in 102 (79%) MIS and 23 (72%) IM cases. Approximately 10% of cases required surgical margins above the current recommendations (11 (9%) MIS and 6 (19%) IM). Twenty-three (19%) MIS and 7 (22%) IM cases required more than one excision to obtain clearance. Recurrence rates among MIS and IM were 0.0% and 0.6%, respectively. Upstaging occurred in 5 (4%) MIS and 7 (22%) IM cases. Complex repairs were performed on 82 (63%) MIS and 17 (53%) IM cases. Our findings revealed that staged excision provides effective margin control and low recurrence rates. Approximately 10% of patients required margins greater than the current recommendations, leading to larger defects and more complex repairs., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nasal reconstruction has important functional and cosmetic considerations, as proper repair of nasal defects is necessary to maintain function of the nasal airway and to recreate the normal appearance of this central facial structure. Cheek advancement flaps provide matched, mobile, and highly vascularized tissue for the reconstruction of nasal defects, allowing for the concealment of incisions within natural creases in a one-stage approach. However, cheek advancement flaps are often underutilized for nasal reconstruction because of their difficulty in restoring nasal contour. We describe reconstruction of 19 nasal dorsal and sidewall defects 0.8 to 3 cm in size. We incorporated a periosteal anchoring suture to maintain/restore nasal contour and additionally removed a half standing cone inferior to the defect to prevent encroachment of the nasal ala or alar crease. All patients were evaluated at least 3 months postoperatively. In all patients, we were able to restore concavity of the nasofacial sulcus, preserve the biconvex nasal tips, prevent alar flaring and retraction, and conserve the alar groove. All patients had excellent functional and cosmetic outcomes. We believe this modified cheek advancement flap provides functionally and aesthetically superior results and can be considered as a first-line approach for repair of nasal dorsal and sidewall defects in subselected patients., Competing Interests: None declared., (Thieme. All rights reserved.)

Primary cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with a rising incidence of about 1.8 million in the United States annually. Primary cSCC is usually curable by surgery; however, in some cases, cSCC eventuates in nodal metastasis and death from disease specific death. cSCC results in up to 15,000 deaths each year in the United States. Until recently, non-surgical options for treatment of locally advanced or metastatic cSCC were largely ineffective. With the advent of checkpoint inhibitor immunotherapy, including cemiplimab and pembrolizumab, response rates climbed to 50%, representing a vast improvement over chemotherapeutic agents used previously. Herein, we discuss the phenotype and function of SCC associated Langerhans cells, dendritic cells, macrophages, myeloid derived suppressor cells and T cells as well as SCC-associated lymphatics and blood vessels. Possible role(s) of SCC-associated cytokines in progression and invasion are reviewed. We also discuss the SCC immune microenvironment in the context of currently available and pipeline therapeutics., Competing Interests: JC has been the recipient of funding for investigator initiated basic science research from Regeneron and GlaxoSmithKline. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saeidi, Doudican and Carucci.)

Competing Interests: Conflicts of interest Dr Carucci has performed clinical and basic research funded by Regeneron and has consulted for Incyte Pharmaceuticals and Genentech. Drs Canavan, Doudican, and Stevenson and Authors Celen and Frazzette have no conflicts of interest to declare.

Competing Interests: Conflicts of interest None disclosed.

Deliberate practice-based medical education has demonstrated superiority in trainee acquisition and maintenance of skills in several surgical subspecialties. In an effort to highlight the impact of a deliberate practice-based surgical curriculum on the technical proficiency of dermatology residents, a prospective cohort study including first- and second-year dermatology residents was performed. A total of 87.5% (7 of 8) first-year dermatology residents completed three hands-on simulations at 6-week intervals. Additionally, six of eight (75.0%) second-year dermatology residents at the same institution were evaluated at a single point-in-time session without accessing the surgical curriculum prior. A 5-point global rating scale (GRS) was used to assess resident performance on six core surgical techniques. Nonparametric ANOVA statistical methods using the Kruskal-Wallis test was performed. The residents' overall GRS increased from a median of 1-2.75 after completion of the curriculum (p < 0.01). There was a significant improvement in the median scores of each tested surgical technique. The first-year residents had a greater overall GRS after completion of the curriculum compared to the second-year residents (median of 2.13 versus 1.88, p < 0.001). Limitations include the small sample size and lack of a synchronized control group. Our study highlights the use of deliberate practice-based strategies as an effective modality in teaching surgical skills to dermatology residents., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Conflicts of interest None disclosed.

Importance: There is a paucity of evidence to guide physicians regarding prevention strategies for cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTRs)., Objective: To examine the development and results of a Delphi process initiated to identify consensus-based medical management recommendations for prevention of CSCC in SOTRs., Evidence Review: Dermatologists with more than 5 years' experience treating SOTRs were invited to participate. A novel actinic damage and skin cancer index (AD-SCI), consisting of 6 ordinal stages corresponding to an increasing burden of actinic damage and CSCC, was used to guide survey design. Three sequential web-based surveys were administered from January 1, 2019, to December 31, 2020. Pursuant to Delphi principles, respondents thoroughly reviewed all peer responses between rounds. Supplemental questions were also asked to better understand panelists' rationale for their responses., Findings: The Delphi panel comprised 48 dermatologists. Respondents represented 13 countries, with 27 (56%) from the US. Twenty-nine respondents (60%) were Mohs surgeons. Consensus was reached with 80% or higher concordance among respondents when presented with a statement, question, or management strategy pertaining to prevention of CSCC in SOTRs. A near-consensus category of 70% to less than 80% concordance was also defined. The AD-SCI stage-based recommendations were established if consensus or near-consensus was achieved. The panel was able to make recommendations for 5 of 6 AD-SCI stages. Key recommendations include the following: cryotherapy for scattered actinic keratosis (AK); field therapy for AK when grouped in 1 anatomical area, unless AKs are thick in which case field therapy and cryotherapy were recommended; combination lesion directed and field therapy with fluorouracil for field cancerized skin; and initiation of acitretin therapy and discussion of immunosuppression reduction or modification for patients who develop multiple skin cancers at a high rate (10 CSCCs per year) or develop high-risk CSCC (defined by a tumor with approximately ≥20% risk of nodal metastasis). No consensus recommendation was achieved for SOTRs with a first low risk CSCC., Conclusions and Relevance: Physicians may consider implementation of panel recommendations for prevention of CSCC in SOTRs while awaiting high-level-of-evidence data. Additional clinical trials are needed in areas where consensus was not reached.

Standard histopathology is currently the gold standard for assessment of margin status in Mohs surgical removal of skin cancer. Ex vivo confocal microscopy (XVM) is potentially faster, less costly and inherently 3D/digital compared to standard histopathology. Despite these advantages, XVM use is not widespread due, in part, to the need for pathologists to retrain to interpret XVM images. We developed artificial intelligence (AI)-driven XVM pathology by implementing algorithms that render intuitive XVM pathology images identical to standard histopathology and produce automated tumor positivity maps. XVM images have fluorescence labeling of cellular and nuclear biology on the background of endogenous (unstained) reflectance contrast as a grounding counter-contrast. XVM images of 26 surgical excision specimens discarded after Mohs micrographic surgery were used to develop an XVM data pipeline with 4 stages: flattening, colorizing, enhancement and automated diagnosis. The first two stages were novel, deterministic image processing algorithms, and the second two were AI algorithms. Diagnostic sensitivity and specificity were calculated for basal cell carcinoma detection as proof of principal for the XVM image processing pipeline. The resulting diagnostic readouts mimicked the appearance of histopathology and found tumor positivity that required first collapsing the confocal stack to a 2D image optimized for cellular fluorescence contrast, then a dark field-to-bright field colorizing transformation, then either an AI image transformation for visual inspection or an AI diagnostic binary image segmentation of tumor obtaining a diagnostic sensitivity and specificity of 88% and 91% respectively. These results show that video-assisted micrographic XVM pathology could feasibly aid margin status determination in micrographic surgery of skin cancer., Competing Interests: Dr. Gareau is an inventor of a patent with claims related to the colorization of confocal images to mimic the appearance of histopathology and holds equity in a company that holds an exclusive license to that patent., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves. Perineural invasion is associated with aggressive disease and a greater likelihood of poor outcomes. In this study, 3 of 9 patients with cutaneous squamous cell carcinoma and perineural invasion exhibited poor clinical outcomes. Tumors from these patients expressed high levels of MAGE-A3, a cancer testis antigen that may contribute to key processes of tumor development. In addition to perineural invasion, the tumors exhibited poor differentiation and deep invasion and were subsequently classified as Brigham and Women's Hospital tumor stage 3. Cyclin E, A and B mRNA levels were increased in these tumors compared with normal skin tissues (102.93±15.03 vs. 27.15±4.59, 36.83±19.41 vs. 11.59±5.83, 343.77±86.49 vs. 95.65±29.25, respectively; p<0.05). A431 cutaneous squamous cell carcinoma cells pretreated with MAGE-A3 antibody exhibited a decreased percentage S-phase cells (14.13±2.8% vs. 33.97±1.1%; p<0.05) and reduced closure in scratch assays (43.88±5.49% vs. 61.17±3.97%; p = 0.0058). In a syngeneic animal model of squamous cell carcinoma, immunoblots revealed overexpression of MAGE-A3 and cyclin E, A, and B protein in tumors at 6 weeks. However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3) compared with parental cells. These results suggest that MAGE-A3 is a key mediator in cancer progression. Moreover, elevated collagen XI and matrix metalloproteases 3, 10, 11, and 13 mRNA levels were observed in poorly differentiated cutaneous squamous cell carcinoma with perineural invasion compared with normal skin tissue (1132.56±882.7 vs. 107.62±183.62, 1118.15±1109.49 vs. 9.5±5, 2603.87±2385.26 vs. 5.29±3, 957.95±627.14 vs. 400.42±967.66, 1149.13±832.18 vs. 19.41±35.62, respectively; p<0.05). In summary, this study highlights the potential prognostic value of MAGE-A3 in clinical outcomes of cutaneous squamous cell carcinoma patients., Competing Interests: Jean-Philippe Therrien and James Lee were employees and shareholders of GlaxoSmithKline while these studies were being performed. This does not alter our adherence to Plos One policies on sharing data and materials.

Significance: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics., Aim: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration., Approach: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves., Results: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs., Conclusions: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology.

Cutaneous squamous cell carcinoma (cSCC) causes approximately 10,000 deaths annually in the U. S. Current therapies are largely ineffective against metastatic and locally advanced cSCC. There is a need to identify novel, effective, and less toxic small molecule cSCC therapeutics. We developed a 3-dimensional bioprinted skin (3DBPS) model of cSCC tumors together with a microscopy assay to test chemotherapeutic effects in tissue. The full thickness SCC tissue model was validated using hematoxylin and eosin (H&E) and immunohistochemical histological staining, confocal microscopy, and cDNA microarray analysis. A nondestructive, 3D fluorescence confocal imaging assay with tdTomato-labeled A431 SCC and ZsGreen-labeled keratinocytes was developed to test efficacy and general toxicity of chemotherapeutics. Fluorescence-derived imaging biomarkers indicated that 50% of cancer cells were killed in the tissue after 1μM 5-Fluorouracil 48-hour treatment, compared to a baseline of 12% for untreated controls. The imaging biomarkers also showed that normal keratinocytes were less affected by treatment (11% killed) than the untreated tissue, which had no significant killing effect. Data showed that 5-Fluorouracil selectively killed cSCC cells more than keratinocytes. Our 3DBPS assay platform provides cellular-level measurement of cell viability and can be adapted to achieve nondestructive high-throughput screening (HTS) in bio-fabricated tissues., Competing Interests: CONFLICTS OF INTEREST The authors state no conflicts of interest., (Copyright: © 2020 Browning et al.)

T-cell landscape differences between cutaneous squamous cell carcinoma (cSCC) tumors in immune competent (SCC in IC) and immunocompromised organ transplant recipients (TSCC in OTR) are unclear. We developed an analytical method to define tumor infiltrating lymphocyte (TIL) phenotype in cSCC from immune competent and immune suppressed patients using single-cell TCR sequencing and gene expression data. TSCC exhibits reduced proportions of cytotoxic and naïve TILs and similar numbers of regulatory TILs. Fewer, more heterogeneous TCR clonotypes are observed in TIL from OTR. Most TCR sequences for top ten clonotypes correspond to known antigens, while 24% correspond to putative neoantigens. OTR show increased cSCC events over 12 months possibly due to reduced cytotoxic T-cells. Our novel method of barcoding CD8+ T-cells is the first providing gene expression and TCR sequences in cSCC. Knowledge regarding putative antigens recognized by TCRs with phenotypic function of T-cells bearing those TCRs could facilitate personalized cSCC treatments., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2020.)

There have been several significant advances in cancer treatment in the last decade that are applicable to the treatment of melanoma and advanced nonmelanoma skin cancers. Among these are the development of immune checkpoint inhibitors targeting the programmed death protein-1 (PD-1)/programmed death legand-1 (PDL-1) axis, as well as targeted inhibitors of the BRAF/MEK signaling cascade in melanoma, and the hedgehog signaling pathway in basal cell carcinoma (BCC). These immune-based and targeted therapies have dramatically changed the treatment options for locally advanced and metastatic melanoma, Merkel's cell carcinoma, cutaneous squamous cell carcinoma (cSCC), and BCC. In this article, we will briefly review the currently approved targeted and immunotherapy-based treatments for locally advanced and metastatic melanoma, Merkel's cell carcinoma, and cSCC and discuss various combinations of approved therapies, as well as emerging therapeutic candidates that are currently in clinical trials, including novel checkpoint inhibitors in development, intratumoral oncolytic agents (viral and nonviral), and various immune-based therapies such as toll-like receptor (TLR) agonists, adoptive T-cell therapy, T-cell costimulation, and innate immune cell therapy. For advanced BCC, we will discuss trials investigating the currently approved smoothened (SMO) inhibitors for neoadjuvant use, emerging SMO inhibitors in development, topical SMO inhibitors, alternative targets in the hedgehog signaling pathway, and the use of anti-PD-1 agents for advanced BCC both alone and in combination with SMO inhibitors., Competing Interests: J.A.C. reports grants from Regeneron, outside the submitted work. M.L.S. reports and coinvestigator on intralesional cepilipumab for recurrent SCC. All the other authors report no conflict of interest., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Opioid overprescribing is a major contributor to the opioid crisis. The lack of procedure-specific guidelines contributes to the vast differences in prescribing practices., Objective: To create opioid-prescribing consensus guidelines for common dermatologic procedures., Methods: We used a 4-step modified Delphi method to conduct a systematic discussion among a panel of dermatologists in the fields of general dermatology, dermatologic surgery, and cosmetics/phlebology to develop opioid prescribing guidelines for some of the most common dermatologic procedural scenarios. Guidelines were developed for opioid-naive patients undergoing routine procedures. Opioid tablets were defined as oxycodone 5-mg oral equivalents., Results: Postoperative pain after most uncomplicated procedures (76%) can be adequately managed with acetaminophen and/or ibuprofen. Group consensus identified no specific dermatologic scenario that routinely requires more than 15 oxycodone 5-mg oral equivalents to manage postoperative pain. Group consensus found that 23% of the procedural scenarios routinely require 1 to 10 opioid tablets, and only 1 routinely requires 1 to 15 opioid tablets., Limitations: These recommendations are based on expert consensus in lieu of quality evidence-based outcomes research. These recommendations must be individualized to accommodate patients' comorbidities., Conclusions: Procedure-specific opioid prescribing guidelines may serve as a foundation to produce effective and responsible postoperative pain management strategies after dermatologic interventions., (Copyright © 2019 American Academy of Dermatology, Inc. All rights reserved.)

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer., (© 2019 Steunstichting ESOT.)

Background: Staging systems for cutaneous squamous cell carcinoma (CSCC) include Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer staging system, eighth edition (AJCC-8)., Objective: To evaluate and compare AJCC-8 and BWH staging systems for CSCC in immunosuppressed patients., Materials and Methods: A retrospective cohort study of immunosuppressed patients diagnosed with primary CSCC from 2012 to 2016. The main end point was any poor outcome (PO), which included local recurrence, nodal metastasis, and disease-specific death., Results: Fifty-eight immunosuppressed patients had 263 CSCCs. Fifty percent of tumors were AJCC-8 T1, 44.7% T2, and 4.8% T3. Fifty percent of tumors were BWH T1, 48.5% T2a, 1.3% T2b, and 0.4% T3. Risk of PO for AJCC-8 was 1.7%, 8.8%, and 36.4% for T1, T2, and T3, respectively (p < .01). Risk of PO for BWH was 1.8%, 9.9%, 33.3%, and 100.0% for T1, T2a, T2b, and T3, respectively (p < .01). Thirty-six percent of AJCC-8 T3/T4 tumors had POs compared with 5.1% in low T1/T2 stages (p = .002). Fifty percent of BWH T2b/T3 tumors had POs compared with 5.3% in low T1/T2a stages (p = .01)., Conclusion: AJCC-8 and BWH staging systems stratify CSCC with similar distinctiveness, homogeneity, and monotonicity for immunosuppressed patients.

Background: The management of skin cancers has evolved with the development of Mohs micrographic surgery and a greater emphasis on surgical training within dermatology. It is unclear whether these changes have translated into innovations and contributions to the reconstructive literature., Objective: To assess contributions from each medical specialty to the cutaneous head and neck oncologic reconstructive literature., Methods: The authors conducted a systematic review of the head and neck reconstructive literature from 2000 through 2015 based on a priori search terms relating to suture technique, linear closure, advancement, rotation, transposition and interpolation flaps, and identified the specialty of the senior authors., Results: The authors identified 74,871 articles, of which 1,319 were relevant. Under suture technique articles, the senior authors were primarily dermatologists (58.2%) and plastic surgeons (20.3%). Under linear closure, the authors were dermatologists (48.1%), plastic surgeons (22.2%), and otolaryngologists (20.4%). Under advancement and rotation flaps, the senior authors were plastic surgeons (40.5%, 38.9%), dermatologists (38.1%, 34.2%), and otolaryngologists (14.4%, 21.6%). Under transposition and interpolation flaps, the senior authors were plastic surgeons (47.3%, 39.4%), dermatologists (32.3%, 27.0%), and otolaryngologists (15.3%, 23.4%)., Conclusion: The primary specialties contributing to the cutaneous head and neck reconstructive literature are plastic surgery, dermatology, and otolaryngology.