Cladribine Use in Xanthoma Disseminatum: A Rare Case Presentation and Brief Updated Literature Review.

Xanthoma disseminatum (XD) is a rare, non-Langerhans cell histiocytosis. While treatment is notoriously difficult, 2-chlorodeoxyadenosine (cladribine) has recently emerged as a potential effective therapeutic option. Here, we describe the case of a 65-year-old male with XD who experienced significant cutaneous improvement after cladribine treatment. We also provide an updated literature review on cladribine use in patients with XD in light of reported adverse effects (AEs). While the efficacy of cladribine in XD is clear, no consensus exists for treatment duration and AE management. Hence, we strongly encourage interdisciplinary discourse involving dermatology and oncology in these cases.

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.

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.

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.

Use of convolutional neural networks in skin lesion analysis using real world image and non-image data.

Background: Understanding performance of convolutional neural networks (CNNs) for binary (benign vs. malignant) lesion classification based on real world images is important for developing a meaningful clinical decision support (CDS) tool. Methods: We developed a CNN based on real world smartphone images with histopathological ground truth and tested the utility of structured electronic health record (EHR) data on model performance. Model accuracy was compared against three board-certified dermatologists for clinical validity. Results: At a classification threshold of 0.5, the sensitivity was 79 vs. 77 vs. 72%, and specificity was 64 vs. 65 vs. 57% for image-alone vs. combined image and clinical data vs. clinical data-alone models, respectively. The PPV was 68 vs. 69 vs. 62%, AUC was 0.79 vs. 0.79 vs. 0.69, and AP was 0.78 vs. 0.79 vs. 0.64 for image-alone vs. combined data vs. clinical data-alone models. Older age, male sex, and number of prior dermatology visits were important positive predictors for malignancy in the clinical data-alone model. Conclusion: Additional clinical data did not significantly improve CNN image model performance. Model accuracy for predicting malignant lesions was comparable to dermatologists (model: 71.31% vs. 3 dermatologists: 77.87, 69.88, and 71.93%), validating clinical utility. Prospective validation of the model in primary care setting will enhance understanding of the model's clinical utility.

Lesion identification and malignancy prediction from clinical dermatological images.

We consider machine-learning-based lesion identification and malignancy prediction from clinical dermatological images, which can be indistinctly acquired via smartphone or dermoscopy capture. Additionally, we do not assume that images contain single lesions, thus the framework supports both focal or wide-field images. Specifically, we propose a two-stage approach in which we first identify all lesions present in the image regardless of sub-type or likelihood of malignancy, then it estimates their likelihood of malignancy, and through aggregation, it also generates an image-level likelihood of malignancy that can be used for high-level screening processes. Further, we consider augmenting the proposed approach with clinical covariates (from electronic health records) and publicly available data (the ISIC dataset). Comprehensive experiments validated on an independent test dataset demonstrate that (1) the proposed approach outperforms alternative model architectures; (2) the model based on images outperforms a pure clinical model by a large margin, and the combination of images and clinical data does not significantly improves over the image-only model; and (3) the proposed framework offers comparable performance in terms of malignancy classification relative to three board certified dermatologists with different levels of experience.

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.

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.

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.

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.

Key Clinical Adverse Events in Patients with Advanced Basal Cell Carcinoma Treated with Sonidegib or Vismodegib: A Post Hoc Analysis.

INTRODUCTION: Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. METHODS: This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. RESULTS: Over 18 treatment cycles, the most common all-grade AEs for sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. CONCLUSION: This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence.

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.

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.

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.

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.