Clinical and direct immunofluorescence characteristics of cutaneous toxicity associated with enfortumab vedotin.

Enfortumab vedotin (EV), a novel antibody-drug conjugate approved for metastatic urothelial carcinoma, causes a variety of cutaneous adverse reactions. We present two cases of bullous eruptions following treatment with EV, both demonstrating IgG deposition on direct immunofluorescence (DIF) correlating to the location of nectin-4 in the epidermis. This suggests that the IgG component of EV binding to nectin-4 in keratinocytes is likely a primary contributor to the high rates of cutaneous toxicity.

Successful Outpatient Management of Diffuse Photosensitive Bullous Dermatitis Following Pembrolizumab Therapy.

Immune checkpoint inhibitors including programmed death protein 1 inhibitors show great therapeutic benefit for numerous advanced malignancies but can cause a spectrum of immune-related adverse events, with cutaneous toxicity being a common presentation. This report includes two cases of lung adenocarcinoma treated with pembrolizumab that developed rare presentations of diffuse bullous lichenoid dermatitis involving >50% total body surface area. These cases were successfully treated in the outpatient setting with oral dexamethasone and minimal interruption of pembrolizumab therapy, a more conservative approach than current guidelines suggest. J Drugs Dermatol. 2022;21(6):668-670. doi:10.36849/JDD.6715.

Cutaneous involvement by T-cell prolymphocytic leukemia presenting as livedoid vasculopathy.

T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive neoplasm derived from post-thymic T-cells. Patients are typically middle aged with a slight male predominance who present with a high white blood cell count, hepatosplenomegaly, lymphadenopathy, and other symptoms typically associated with leukemia. Although cutaneous involvement has been reported in up to 30% of cases of T-PLL, to our knowledge, none have presented with a presentation resembling livedoid vasculopathy. In the correct clinical context, an underlying hematolymphoid neoplasm should be included in the differential diagnosis of a patient presenting with livedoid vasculopathy.

Outcomes of adjunctive therapies post hedgehog inhibitors in the management of locally advanced basal cell carcinoma: A systematic review and pooled analysis.

Management of patients with locally advanced basal cell carcinoma (laBCC) with traditional strategies has yielded suboptimal outcomes. Targeted treatments including hedgehog inhibitor therapy (HHIT) present limitations when utilized as monotherapy. Herein, we report evidence-based outcomes from available literature on multimodality treatments adjuvant to HHIT in laBCC management. Utilizing a systematic search strategy in PubMed, we identified studies published from inception to April 15, 2020, screened for definitive inclusion/exclusion criteria, and performed individual study quality assessment and pooled analysis to assess impact of adjunctive treatment-based responses post-HHIT on clinical response and recurrence outcomes. Twenty-nine studies (n = 103) were included. Primary findings include a complete response (CR) rate of 90.5%, the median follow-up of 12 months post-HHIT completion. The recurrence rate was 10.8% with 12-month median time to recurrence. Mohs micrographic surgery (MMS) had 100% CR post-HHIT, while no difference was observed between surgery and radiation therapy (RT). MMS and surgery had comparable 2-year recurrence free rates (RFR) at 87% and 86% respectively, while RT had the lower 2-year RFR at 67%. Male gender portended a more advanced stage at diagnosis and worse outcomes. In a subset analysis, periorbital laBCCs with orbital involvement had a CR rate of 81.8% versus 100% in those without orbital involvement, with similar rates of recurrence. Limited available quantitative data and possible publication bias were limitations. Pooled analysis of observational data supports use of adjunctive therapies post-HHIT to improve treatment response in patients with laBCC. Longer-term follow-up is needed to study recurrence rates after combination therapy.

Resolution of Pembrolizumab-Associated Steroid-Refractory Lichenoid Dermatitis with Cyclosporine.

Checkpoint inhibitors such as pembrolizumab, an anti-PD-1 monoclonal antibody, are a promising new category of oncological therapeutics, associated with a higher risk of immune-related adverse events including dermatological, autoimmune and endocrine sequelae. Here, we present a case of a woman 76 years of age with stage IV lung adenocarcinoma who developed a severe and steroid-refractory lichenoid dermatitis associated with pruritus on pembrolizumab. This eruption resolved completely with a short course of oral cyclosporine. Cyclosporine is a promising and effective treatment option for checkpoint inhibitor-related severe cutaneous eruptions.

Role of imaging in low-grade cutaneous B-cell lymphoma presenting in the skin.

BACKGROUND: Whole-body imaging is the current standard of care for staging all patients presenting with skin lesions of B-cell lymphomas (BCLs), regardless of skin disease extent; however, supporting data are lacking. OBJECTIVE: To determine the clinical utility of imaging in the detection of systemic involvement in low-grade cutaneous BCLs in the skin. METHODS: Retrospective cohort analysis of patients presenting with cutaneous lesions of BCLs at Memorial Sloan Kettering Cancer Center and Stanford University during 1997-2016. RESULTS: At initial staging, of the 522 patients, extracutaneous disease was noted in 3.6% and 8.8% of patients with marginal zone lymphoma (MZL, n = 306) and follicle center lymphoma (FCL, n = 216) histology, respectively. In patients with systemic involvement, imaging alone identified 81.8% (9/11) of MZL cases and 89.4% of follicular lymphoma cases. In primary cutaneous MZL, 1.7% of patients subsequently had extracutaneous involvement (median follow-up 45 months), and in primary cutaneous FCL. 3.0% subsequently had extracutaneous involvement (median follow-up 47 months). LIMITATIONS: This was a retrospective study. CONCLUSION: Imaging is effective at identifying patients with systemic involvement in indolent BCLs present in the skin; however, incidence is low. After negative initial staging, primary cutaneous MZL patients may be followed clinically without routine imaging.

T-cell receptor-δ expression and γδ+ T-cell infiltrates in primary cutaneous γδ T-cell lymphoma and other cutaneous T-cell lymphoproliferative disorders.

AIMS: The diagnosis of cutaneous γδ T-cell lymphoma (GDTCL) requires the identification of γδ chains of the T-cell receptor (TCR). Our aim in this study was, by using a new monoclonal antibody (mAb) against TCRδ, to evaluate TCRδ expression in formalin-fixed paraffin-embedded (FFPE) skin tissue from TCRγ+ cutaneous T-cell lymphoma (CTCL), and to assess TCRδ expression within a spectrum of other cutaneous lymphoproliferative disorders (CLPDs). METHODS AND RESULTS: Twelve cases (10 patients) with TCRγ+ CTCL and 132 additional CLPD cases (127 patients) were examined, including mycosis fungoides (MF) (n = 60), cutaneous GDTCL (n = 15), subcutaneous panniculitis-like T-cell lymphoma (SPTCL) (n = 11), and CD30+ lymphoproliferative disorder (LPD) (n = 24). Clone H-41 against TCRδ was used on a Leica Bond-3 automated stainer to label FFPE slides. H-41 immunostaining was graded as percentage infiltrate: high (50-100%), moderate (10-49%), and low (0-9%). In TCRγ+ tumours, 12 of 12 (100%) patients showed TCRδ expression comparable to TCRγ expression. No (0%) TCRγ+ cases were negative for TCRδ. In all CLPDs, TCRδ expression was as follows: GDTCL, 16 of 20 cases (14 of 15 patients) high, two moderate, and two low; MF, 0 of 60 cases high, nine moderate, and 51 low; CD30+ LPD, one of 24 cases high, two moderate, and 21 low; and SPTCL, 0 of 11 cases (0 of 9 patients) high, two moderate, and two low. Three MF-like cases and one SPTCL-like case showed high expression; the remainder showed low expression. CONCLUSIONS: mAb H-41 against TCRδ matches TCRγ in immunostaining FFPE tissues from GDTCL, supporting H-41 as a replacement for mAb γ3.20. TCRδ expression in our study suggests that the true occurrence of γδ+ non-GDTCL CTCL/CLPD may be lower than suggested by the recent literature.

Unrelated immunodeficiency states may impact outcomes and immune checkpoint molecule expression in patients with mycosis fungoides: A clinicopathologic case-control study.

BACKGROUND: Immunodeficiency (ID) correlates with worse outcomes and decreased immune checkpoint molecule expression in melanoma. The impact of ID in mycosis fungoides (MF) is unknown. OBJECTIVE: Our goal was to evaluate the impact of ID in MF. METHODS: We conducted a case-control study of 17 patients with MF and ID versus age-, stage-, and race-matched controls as a subset of a comparative analysis of 23 patients with MF with ID (prior lymphoma, recent/current pregnancy, HIV, hypogammaglobulinemia, and prior chemotherapy) versus without ID. Programmed cell death 1 (PD1), programmed death ligand 1 (PDL1), forkhead box p3, and interleukin 17 immunohistochemistry was performed on 12 patients with ID and 10 controls. RESULTS: Patients with ID had more treatment failure (14 of 23 vs 5 of 17 [P = .028]), more treatment failure within 3 years of diagnosis (12 of 23 vs 4 of 17 [P = .050]), more angiocentrism (6 of 12 vs 0 of 10 [P = .005]), larger cells (1.92 ± 0.51 out of 3 vs 1.30 ± 0.48 out of 3 [P = .009]), more cases with at least 10% PD1 positivity (9 of 11 vs 4 of 10 [P = .031]) and at least 10% PDL1 positivity (7 of 12 vs 2 of 10 [P = .042]), and a higher average percentage of PD1+ cells (43.27 ± 40.22 vs 11.2 ± 13.62 [P = .028]). No differences in survival, forkhead box p3 expression, interleukin 17 expression, histologic depth, ulceration, granulomatous changes, or syringotropism were seen. LIMITATIONS: This was a small single-center study with heterogeneous immunodeficiencies. CONCLUSION: ID correlated with worse outcomes and increased PD1 and PDL1 expression in MF. Patients with MF and ID may be candidates for immune checkpoint inhibitor therapy, pending further investigation.

Low-Grade Cutaneous B-cell Lymphoma in African American Patients

Introduction: Cutaneous marginal zone lymphoma (CMZL) and cutaneous follicle center lymphoma (CFCL) are rare indolent cutaneous B-cell lymphomas (CBCL). Their incidence in African American (AA) patients is extremely low. While cutaneous T-cell lymphomas appear to be more aggressive in AA individuals, there is no data on the presentation and course of disease of CBCL in this group. In this study, we aimed to characterize CMZL/CFCL in AA patients. Methods: A retrospective chart review identified 10 AA patients with CMZL/CFCL. We compared demographics, clinical features, and systemic disease incidence between AA and white patients. Results: Of 288 patients with CMZL/CFCL, 10 patients were AA (3.5%), and 266 were white. AA patients trended toward diagnosis at a younger age compared to white individuals (median age of 41 vs 54 years; P=0.07). AAs presented with more regional and generalized cutaneous disease (T2-T3 in 70%), while most white patients presented with a solitary lesion (T1 in 55%). Head and neck involvement was more common in AA patients. Extracutaneous systemic disease at initial staging was not significantly different between the groups. One AA patient with primary CMZL developed extracutaneous MZL after16 years. No deaths were reported among AAs. Discussion: CMZL/ CFCL in this series of AA patients had an earlier age of onset with preferential head and neck involvement and a higher T classification at presentation. Despite these features, systemic involvement was uncommon, and no deaths were recorded. This data supports an indolent course of CMZL and CFCL in the AA population; larger studies are needed to confirm these findings. J Drugs Dermatol. 2018;17(12):1334-1337.

Evaluation of the Tolerability of Hedgehog Pathway Inhibitors in the Treatment of Advanced Basal Cell Carcinoma: A Narrative Review of Treatment Strategies.

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response.

Deep Learning in Dermatology: A Systematic Review of Current Approaches, Outcomes, and Limitations.

Artificial intelligence (AI) has recently made great advances in image classification and malignancy prediction in the field of dermatology. However, understanding the applicability of AI in clinical dermatology practice remains challenging owing to the variability of models, image data, database characteristics, and variable outcome metrics. This systematic review aims to provide a comprehensive overview of dermatology literature using convolutional neural networks. Furthermore, the review summarizes the current landscape of image datasets, transfer learning approaches, challenges, and limitations within current AI literature and current regulatory pathways for approval of models as clinical decision support tools.

Teledermatology May Benefit Marginalized Populations: National and Institutional Trends during the COVID-19 Pandemic.

INTRODUCTION: Limited data exist regarding demographic-specific teledermatology (TD) utilization during the coronavirus disease 2019 (COVID-19) pandemic. This study aimed to determine TD utilization trends during the pandemic. METHODS: A retrospective cohort study for national and institutional populations was conducted. Patient encounters in the American Academy of Dermatology's DataDerm registry (DataDerm) were analyzed from 1 April 2020 through 30 June 2021. All dermatological patients seen by Duke University Health Systems (DUHS) were analyzed from 1 March 2020 through 30 April 2021. In-person clinic visits versus TD encounters (national and institutional) and no-show rates (institutional only) were collected for visit type (i.e., TD versus in-person), sex, race, age/generation, and in- versus out-of-state location (national only). TD utilization is defined as the cohort of interest using TD (e.g., females, whites) within a demographic group (i.e., sex, race) as a percentage of total TD users. This was compared with in-person utilization during the identical timeframe. RESULTS: For US national data, 13,964,816 encounters were analyzed. Sex, race, age, and location each had a significant association with TD utilization (adjusted p < 0.001). For institutional data, 54,400 encounters were analyzed. Sex, race, and age had a significant association with TD utilization (adjusted p < 0.001). Both datasets revealed majority female populations for telehealth visits (DataDerm 66.0%; DUHS 61.7%). Non-white populations accounted for a higher percentage of TD utilizers (DataDerm 15.0%; DUHS 37.3%) when compared with in-person utilizers (DataDerm 11.7%; DUHS 22.3%). Younger patients utilized TD (DataDerm 63.6%; DUHS 62.6%) more than in-person services (DataDerm 26.3%; DUHS 43.8%). Institutional no-show rates between telehealth and in-person visits were lower for Black patients (11.8% versus 19.2%), other non-white races (10.6% versus 13.6%), and younger ages/generations (9.8% versus 12.8%), respectively. TD utilization decreased over time nationally as a percentage of total visits (2.9% versus 0.3%) in 2020 versus 2021, respectively. CONCLUSIONS AND RELEVANCE: During the COVID-19 pandemic, certain populations (females, younger patients, non-white races) showed higher TD utilization. Understanding TD utilization trends is critical in defining the role of virtual care for improving universal care access, optimizing resources, and informing future healthcare models for all patient populations.

Implementation Evaluation of a Teledermatology Virtual Clinic at an Academic Medical Center.

Background: Teledermatology (TD) is an evidence-based practice that may increase access to dermatologic care. We sought to evaluate implementation of TD at four Duke primary care practices. Methods: We implemented a hybrid TD program where trained primary care providers (PCPs) sent referrals with clinical and dermatoscopic images to dermatology. Patients were seen by dermatologists over video visit within days, and dermatologists managed the patient plan. We evaluated implementation using the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) framework using electronic health record data. Implementation barriers and facilitators were collected through surveys (n = 24 PCPs, n = 10 dermatologists, n = 10 dermatology residents). Results: At four PCP clinics throughout 9/1/2021-4/30/2022 there were 218 TD referrals. Video visits occurred on average 7.5 days after referral and 18/18 patients completing the post-visit survey were satisfied. Adoption varied between clinics, with one placing 22% of all dermatology referrals as TD and another placing 2%. The primary PCP barriers to TD were time burdens, lack of fit in clinic flow, and discomfort with image taking. Top-endorsed potential facilitating interventions included allowing for rash referrals without dermoscopy and assurance for clinical evaluation within 3 days. Conclusions: Addressing TD process fit into PCP clinic flow and reducing time burdens may increase PCP uptake of TD.

Implementation evaluation of a teledermatology virtual clinic at an academic medical center.

BACKGROUND: Teledermatology (TD) is an evidence-based practice that may increase access to dermatologic care. We sought to use the Exploration, Preparation, Implementation, and Sustainment (EPIS) and the Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM) frameworks to evaluate implementation of TD at Duke. METHODS: The EPIS and RE-AIM frameworks were deployed to design and implement a TD program that leveraged the strengths of the Duke University Health System and addressed previously reported barriers to implementation of store-and-forward and synchronous TD models. In the resultant hybrid TD model, trained primary care providers (PCPs) sent e-comm referrals with clinical and dermatoscopic images to dermatology. These e-consults were reviewed asynchronously and patients were scheduled for a synchronous video visit with dermatology within days. Dermatologists managed the patient plan. This hybrid TD model was piloted at four primary care clinics. Pertinent outcomes from a TD-adapted RE-AIM framework were tracked using electronic health record data. Patient satisfaction was assessed using a post-video visit survey (n = 18). Implementation barriers and facilitators were also collected through provider surveys (n = 24 PCPs, n = 10 dermatologists, n = 10 dermatology residents). RESULTS: At four PCP clinics throughout 9/1/2021-4/30/2022, there were 218 TD referrals. Video visits occurred on average 7.5 ± 0.5 days after referral and 18/18 patients completing the post-visit survey were satisfied. Adoption varied between clinics, with one placing 22% of all dermatology referrals as TD and another placing 2%. The primary PCP barriers to TD were time burdens, lack of fit in clinic flow, and discomfort with image taking. Top-endorsed potential facilitating interventions included allowing for rash referrals without dermoscopy and assurance for clinical evaluation within 3 days. CONCLUSIONS: The use of implementation science frameworks allowed for identification of system and contextual strengths which informed the hybrid TD pilot. Barriers and facilitating interventions will provide guidance for expansion and ongoing maintenance of TD.

Early Detection and Prognostic Assessment of Cutaneous Melanoma: Consensus on Optimal Practice and the Role of Gene Expression Profile Testing.

Importance: Therapy for advanced melanoma has transformed during the past decade, but early detection and prognostic assessment of cutaneous melanoma (CM) remain paramount goals. Best practices for screening and use of pigmented lesion evaluation tools and gene expression profile (GEP) testing in CM remain to be defined. Objective: To provide consensus recommendations on optimal screening practices and prebiopsy diagnostic, postbiopsy diagnostic, and prognostic assessment of CM. Evidence Review: Case scenarios were interrogated using a modified Delphi consensus method. Melanoma panelists (n = 60) were invited to vote on hypothetical scenarios via an emailed survey (n = 42), which was followed by a consensus conference (n = 51) that reviewed the literature and the rationale for survey answers. Panelists participated in a follow-up survey for final recommendations on the scenarios (n = 45). Findings: The panelists reached consensus (≥70% agreement) in supporting a risk-stratified approach to melanoma screening in clinical settings and public screening events, screening personnel recommendations (self/partner, primary care provider, general dermatologist, and pigmented lesion expert), screening intervals, and acceptable appointment wait times. Participants also reached consensus that visual and dermoscopic examination are sufficient for evaluation and follow-up of melanocytic skin lesions deemed innocuous. The panelists reached consensus on interpreting reflectance confocal microscopy and some but not all results from epidermal tape stripping, but they did not reach consensus on use of certain pigmented lesion evaluation tools, such as electrical impedance spectroscopy. Regarding GEP scores, the panelists reached consensus that a low-risk prognostic GEP score should not outweigh concerning histologic features when selecting patients to undergo sentinel lymph node biopsy but did not reach consensus on imaging recommendations in the setting of a high-risk prognostic GEP score and low-risk histology and/or negative nodal status. Conclusions and Relevance: For this consensus statement, panelists reached consensus on aspects of a risk-stratified approach to melanoma screening and follow-up as well as use of visual examination and dermoscopy. These findings support a practical approach to diagnosing and evaluating CM. Panelists did not reach consensus on a clearly defined role for GEP testing in clinical decision-making, citing the need for additional studies to establish the clinical use of existing GEP assays.

Hedgehog inhibitors with and without adjunctive therapy in treatment of locally advanced basal cell carcinoma.

BACKGROUND: Hedgehog inhibitor therapy (HHIT) is considered first-line treatment for locally advanced, unresectable basal cell carcinoma (laBCC). HHIT often results in a partial response, which requires adjunctive therapy (AT) post HHIT. We present real-world data for laBCCs undergoing HHIT ± AT. METHODS: Retrospective review at Duke University from 11/01/2007 through 5/20/2020 revealed 13 patients treated with systemic HHIT (sonidegib or vismodegib) for laBCC. RESULTS: Fourteen laBCCs were identified in 13 patients. LaBCCs were treated with sonidegib (n = 10, 71%) or vismodegib (n = 4, 29%) for a median (IQR) of 9.4 (9.3) or 9.8 (8.5) months, respectively. The median (IQR) follow-up time from HHIT initiation was 15.5 (8.7) months. Tumors were most often located on the trunk (43%), followed by head and neck (29%), extremities (21%), and orbit/periorbital area (7%). Nine laBCCs (64%) were treated with HHIT alone, of which five (36%) achieved complete response (CR), four (29%) achieved partial response (PR), and five (36%) achieved CR with combined HHIT and AT post-HHIT. Duration of HHIT treatment (IQR) was 7.5 (3.5) months in the 10 CR patients, versus 15.1 (6.3) months in the four PR patients (P = 0.024). Nine patients (69%) experienced adverse events from HHIT, most commonly ageusia/dysgeusia, muscle spasms, and alopecia. CONCLUSION: As a single institutional experience, we report 10/14 laBCCs (71%) with CRs without recurrence and 4/14 laBCCs (29%) with PRs with HHIT ± AT over median follow-up of 15.5 months. Longer follow-up and larger cohorts evaluating responses with HHIT followed by AT are needed to substantiate our findings.