A Protocol for the Automated Assessment of Cutaneous Pathology in a Mouse Model of Hemichannel Dysfunction.

In this chapter, we provide detailed instructions to perform quantitative reflectance imaging in a mouse model of a rare epidermal disorder caused by hyperactive connexin 26 hemichannels. Reflectance imaging is a versatile and powerful tool in dermatology, offering noninvasive, high-resolution insights into skin pathology, which is essential for both clinical practice and research. This approach offers several advantages and applications. Unlike traditional biopsy, reflectance imaging is noninvasive, allowing for real-time, in vivo examination of the skin. This is particularly valuable for monitoring chronic conditions or assessing the efficacy of treatments over time, enabling the detailed examination of skin morphology. This is crucial for identifying features of skin diseases such as cancers, inflammatory conditions, and infections. In therapeutic applications, reflectance imaging can be used to monitor the response of skin lesions to treatments. It can help in identifying the most representative area of a lesion for biopsy, thereby increasing the diagnostic accuracy. Reflectance imaging can also be used to diagnose and monitor inflammatory skin diseases, like psoriasis and eczema, by visualizing changes in skin structure and cellular infiltration. As the technology becomes more accessible, it has potential in telemedicine, allowing for remote diagnosis and monitoring of skin conditions. In academic settings, reflectance imaging can be a powerful research tool, enabling the study of skin pathology and the effects of novel treatments, including the development of monoclonal antibodies for therapeutic applications.

Assessment of specificity of dermatopathologic criteria for IgG4-related skin disease.

BACKGROUND: IgG4-related disease (IgG4-RD) represents a recently characterized multisystemic fibroinflammatory condition that can manifest a spectrum of skin findings (IgG4-related skin disease; IgG4-RSD). Histopathologic and immunohistochemical criteria have been proposed; however, the specificity of these criteria merits scrutiny given the potential histopathologic overlap of IgG4-RSD and both neoplastic and inflammatory skin conditions featuring lymphoplasmacytic infiltrates (IgG4-RSD mimics). This study sought to assess the specificity of the criteria by quantifying the frequency by which an expanded spectrum of IgG4-RSD mimics meet proposed thresholds. METHODS: Following IRB approval, a total of 69 cases of IgG4-RD mimics, representing 14 different diagnoses featuring plasma cells, were reviewed and analyzed for the following histopathologic and immunohistochemical features: (i) maximum IgG4+ count/high-powered field (hpf) >200; (ii) IgG4/IgG ratio >0.4 averaged over 3 hpfs; (iii) IgG4+ count >10 per hpf. RESULTS: Screening for IgG4-RSD by histopathologic criteria demonstrated the high frequency of lymphoplasmacytic infiltrates, contrasted with the rarity of storiform fibrosis (only one case of erythema elevatum diutinum [EED]) and obliterative phlebitis (0 cases). By immunohistochemical criteria, the analysis revealed that no cases exceeded 200 IgG4+ cells; 13% (9/69) cases demonstrated an IgG4/IgG ratio of >0.4 averaged over 3 hpfs; and 23% (16/69) cases demonstrated a mean IgG4+ count of >10 per hpf. CONCLUSION: Application of proposed IgG4-RSD histopathologic criteria to an expanded spectrum of potential IgG4-RSD mimics (to include cutaneous marginal zone lymphoma, syphilis, necrobiosis lipoidica, lichen sclerosus, ALHE, psoriasis, lymphoplasmacytic plaque, EED, and erosive pustular dermatosis), highlights the relative nonspecificity of lymphoplasmacytic infiltrates contrasted with the stringency of storiform fibrosis and obliterative fibrosis. Furthermore, an IgG4+ cell count of >10 per hpf and an IgG4/IgG ratio of >0.4 are not specific to IgG4-RSD alone. In the appropriate clinical context for IgG4-RSD, histopathologic features still represent the entry threshold for diagnosis consideration, which then allows for further screening by immunohistochemical criteria.

Smartphone adapter time trial analysis: A low-cost, time-efficient method to disseminate quality photomicrographs at the microscope.

BACKGROUND: Within the field of pathology there is a need for a uniform low-cost option for securing high-quality photomicrographs. Advances in smartphone photography and 3D-printing technology allow for custom adapters to be designed for the purpose of photomicrograph capture. METHODS: Photomicrograph acquisition was performed using four core modalities: a novel 3D-printed smartphone-to-microscope adapter, freehand smartphone-to-microscope technique, a commercial adaptor (LabCam Pro), and a microscope-mounted digital camera. Eight skin diagnoses were photographed using each of the modalities and time to image capture was measured. The photomicrographs were blindly reviewed by two academic dermatopathologists and one pathologist using a side-by-side comparison technique to determine the image quality. Cost assessments were evaluated by obtaining free pricing information on manufacturer websites. RESULTS: The 3D-printed adapter was the most efficient method of capturing a high-quality photomicrograph in addition to being budget neutral. The microscope-mounted camera produced the highest quality photomicrographs followed by the 3D-printed adapter. CONCLUSIONS: The 3D-printed smartphone-to-microscope adapter offers a low-cost, time-efficient method of capturing high-quality photomicrographs.

Assessment of Clinical and Laboratory Use of the Cutaneous Direct Immunofluorescence Assay.

IMPORTANCE: Dermatologists submit direct immunofluorescence (DIF) biopsies on a daily basis, using an assay detecting immunoreactant deposition with a panel that has traditionally comprised immunoglobulin (Ig) G, IgA, IgM, C3, and fibrin, with or without albumin antibodies. OBJECTIVES: To evaluate and compare the frequency of immunoreactants in DIF biopsies submitted over an 8-year period and assess use by dermatologists based on clinical impression. DESIGN, SETTING, AND PARTICIPANTS: A quality improvement study was conducted in a community outreach reference laboratory associated with a large academic medical center. Results of 2050 consecutive DIF skin biopsies submitted to the laboratory between April 1, 2012, and June 12, 2020, were analyzed by final pathologic diagnosis and antibody subtype positivity, in comparison with clinical impression. Biopsies in which the submitting physician had not performed the biopsy were excluded. MAIN OUTCOMES AND MEASURES: Histopathologic findings and the results of DIF biopsies using the standard 6-antibody panel were evaluated in correlation with the submitted clinical diagnosis to assess immunoreactivity of the assay. RESULTS: Of 2050 DIF biopsies submitted, 367 (17.9%) were positive; IgG, IgA, and C3 alone identified all primary immunobullous disease cases (pemphigoid, pemphigus, linear IgA, and dermatitis herpetiformis), and IgA, C3, and fibrin antibodies alone identified all vasculitis cases. A panel of IgG, IgA, IgM, and fibrin identified all cases of lupus erythematosus. DIF results were positive in less than half of cases of hematoxylin and eosin biopsy-confirmed lupus erythematosus (23 of 47 [49%]). A total of 247 biopsies were submitted for clinical diagnoses not optimally supported on DIF: lichen planus, porphyria, and connective tissue disease. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that there is a knowledge gap among dermatologists relating to the opportunity for high-value, cost-conscious use of DIF. The practice of reflexive antibody testing using a 6-antibody panel for all DIF biopsies is likely unnecessary. DIF protocols tailored to the clinical diagnosis may enhance cost-effectiveness without loss of test sensitivity or specificity.

The utility of digital pathology in improving the diagnostic skills of pathology trainees in commonly encountered pigmented cutaneous lesions during the COVID-19 pandemic: A single academic institution experience.

Digital pathology has become an integral part of pathology education in recent years, particularly during the COVID-19 pandemic, for its potential utility as a teaching tool that augments the traditional 1-to-1 sign-out experience. Herein, we evaluate the utility of whole slide imaging (WSI) in reducing diagnostic errors in pigmented cutaneous lesions by pathology fellows without subspecialty training in dermatopathology. Ten cases of 4 pigmented cutaneous lesions commonly encountered by general pathologists were selected. Corresponding whole slide images were distributed to our fellows, along with two sets of online surveys, each composed of 10 multiple-choice questions with 4 answers. Identical cases were used for both surveys to minimize variability in trainees' scores depending on the perceived level of difficulty, with the second set being distributed after random shuffling. Brief image-based teaching slides as self-assessment tool were provided to trainees between each survey. Pre- and post-self-assessment scores were analyzed. 61% (17/28) and 39% (11/28) of fellows completed the first and second surveys, respectively. The mean score in the first survey was 5.2/10. The mean score in the second survey following self-assessment increased to 7.2/10. 64% (7/11) of trainees showed an improvement in their scores, with 1 trainee improving his/her score by 8 points. No fellow scored less post-self-assessment than on the initial assessment. The difference in individual scores between two surveys was statistically significant (p = 0.003). Our study demonstrates the utility of WSI-based self-assessment learning as a source of improving diagnostic skills of pathology trainees in a short period of time.

Assessing comfort level with pediatric skin specimens among dermatopathologists and pediatric pathologists: A national cross-sectional survey.

BACKGROUND: Cutaneous histopathologic diagnoses in children often differ from those in adults. Depending on practice setting, these specimens may be evaluated by dermatopathologists or pediatric pathologists. We sought to determine whether comfort level with pediatric dermatopathology is associated with prior training, pediatric dermatopathology exposure during fellowship, career duration, or specimen subtype. METHODS: We surveyed dermatopathologists and pediatric pathologists practicing in the United States. Training and practice variables were evaluated by multivariable regression for association with comfort level. RESULTS: Of the 156 respondents, 72% were dermatopathologists (response rate 11.6%) and 28% were pediatric pathologists (response rate 9.3%). Dermatopathologists reported higher comfort overall (P < .001); this was also true for inflammatory dermatoses and melanocytic neoplasms (P < .001). Thirty-four percent and 75% of dermatopathologists and pediatric pathologists, respectively, reported lower comfort with pediatric skin specimens than their usual cases. Pediatric pathologists were 28% more likely to refer these cases to colleagues. Among dermatopathologists, dermatology-trained were more comfortable than pathology-trained colleagues interpreting inflammatory dermatoses (P < .001). CONCLUSIONS: Pathologists' comfort with pediatric dermatopathology varied significantly based upon prior training, career duration, and specimen subtype. These results suggest opportunities for improving education in this domain.

Luna stain: a simple and cost-effective diagnostic tool helps in detecting eosinophilic granules deposition of flame figures and aids in diagnosing eosinophilic cellulitis "Wells Syndrome".

We report a rare case of Wells syndrome in which a 61-year-old Caucasian male presented with three distinct skin lesions including a cutaneous bulla, an erythematous plaque, and a linear streak located on the patient's left anterior thigh, left dorsal wrist, and left anterior forearm, respectively. Histologic examination revealed diffuse and interstitial eosinophilic infiltrate admixed with lymphocytes and macrophages that predominantly involve the dermis. Nodular aggregates of eosinophils surrounding dermal collagen fibers suggestive of 'flame figures' were identified. Luna histochemical stain was used and highlighted the deposition of eosinophilic granules over the collagen bundles confirming the presence of flame figures. Laboratory workup revealed peripheral eosinophilia, but a comprehensive clinical evaluation failed to reveal a systemic disease and ultimately the diagnosis of eosinophilic cellulitis 'Wells Syndrome' was rendered. After a short course of immunosuppressive therapy, the patient experienced a complete resolution of the skin lesions on his last follow-up visit several weeks from the initial diagnosis. This case highlights the various clinical forms that Wells syndrome may present with and may serve as a good example for the use of Luna stain as a simple and cost-effective diagnostic tool that can help to arrive at the accurate diagnosis and inform therapy.

Assessment of Acute Acral Lesions in a Case Series of Children and Adolescents During the COVID-19 Pandemic.

Importance: A novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been identified as the cause of a pandemic called coronavirus disease 2019 (COVID-19). In this context, some associated skin diseases have been described. Cutaneous lesions referred to as acute acro-ischemia have been reported as a possible sign of COVID-19 in adolescents and children. Objective: To evaluate the pathogenesis of these newly described acute acral lesions. Design, Setting, and Participants: This prospective case series was conducted at La Fe University Hospital, a tertiary referral hospital in Valencia, Spain, between April 9 and April 15, 2020. Among 32 referred patients, 20 children and adolescents with new-onset inflammatory lesions did not have a diagnosis. Exposures: Patients were not exposed to any drug or other intervention. Main Outcomes and Measures: We performed reverse transcriptase-polymerase chain reaction for SARS-CoV-2 and a range of blood tests for possible origins of the lesions. Skin biopsies were performed in 6 patients. Results: Of the 20 patients enrolled, 7 were female and 13 were male, with an age range of 1 to 18 years. Clinical findings fit into the following patterns: acral erythema (6 patients), dactylitis (4 patients), purpuric maculopapules (7 patients), and a mixed pattern (3 patients). None of the patients had remarkable hematologic or serologic abnormalities, including negative antibodies to SARS-CoV-2. Biopsies performed in 6 patients showed histologic findings characteristic of perniosis. Conclusions and Relevance: The clinical, histologic, and laboratory test results were compatible with a diagnosis of perniosis, and no evidence was found to support the implication of SARS-CoV-2 infection.

Validation of the suction device Nimble for the assessment of skin fibrosis in systemic sclerosis.

OBJECTIVES: Skin fibrosis is a main hallmark of systemic sclerosis (SSc). Clinical assessment is done semi-quantitatively using the modified Rodnan skin score (mRSS). Objective measurements for quantifying skin fibrosis could complement the mRSS to achieve higher reproducibility. The aim of this study was to explore the potential of suction measurements to detect structural changes in the skin that are associated with skin fibrosis. METHODS: This clinical trial included 30 SSc patients and 30 healthy volunteers (HC). We validated a novel suction device-the Nimble-to quantify skin stiffness in comparison to the Cutometer using the OMERACT filter. RESULTS: A significant difference (p < 0.05) between the skin stiffness of HC and SSc patient groups was found for each location measured. The correlation between the measurements of forearm skin stiffness and the mRSS values was high for the Nimble (r = 0.82) and moderate for the Cutometer (r = 0.58). A ROC analysis showed good ability for the Nimble to distinguish between SSc patients with and without skin involvement (AUC = 0.82). Both suction devices provided excellent reliability in all measurements on HC and SSc patients and proved face validity and feasibility. CONCLUSION: Suction devices assessing skin stiffness, such as the Nimble, show clear potential to objectively quantify skin fibrosis in SSc patients and might be promising outcome measures complementing established methods such as the mRSS. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03644225, Registered 23 August 2018-Retrospectively registered, http://www.clinicaltrials.gov.

A skin disease and needs assessment analysis of the displaced Rohingya population in the Kutupalong refugee camp, Bangladesh.

The physical, psychological and financial burden of skin disease in low- to middle-income countries, where access to skincare is limited, is poorly understood. A group that we know very little about in this regard are refugees. There are limited data on the range of skin diseases and skincare needs of this group. To better understand the skincare needs of the displaced Rohingya population residing in the Kutupalong refugee camp, Bangladesh, we collected data on demographics, living conditions and range of dermatoses. In the 380 patients assessed, fungal skin infections, predominantly dermatophytes, were by far the most common skin disease seen (n = 215), followed by dermatitis (n = 81). Skin disease can be the presenting feature in many systemic conditions and may cause significant secondary complications itself. Developing a better understanding of the skincare needs of the refugee population is essential for future healthcare planning for this vulnerable group.

The Potential Impact of Social Genomics on Wound Healing.

Significance: Human skin wounds carry an immense epidemiologic and financial burden, and their impact will continue to grow with an aging population and rising incidence of comorbid conditions known to affect wound healing. To comprehensively address this growing clinical issue, physicians should also be aware of how conditions of the human social environment may affect wound healing. Here we provide a review of the emerging field of social genomics and its potential impact on the wound healing. Recent Advances: Multiple studies using human and animal models have correlated social influences and their contributing effects to acute and chronic stress with delays in wound healing. Furthermore, observations between nongenetic factors such as nutrition, socioeconomic, and educational status have also shown to have a direct or indirect impact on clinical outcomes of wound healing. Critical Issues: Nutrition, financial burden, socioeconomic and education status, and acute and chronic stress are variables that have either direct (epigenetic) or indirect impact on wound healing and patients' quality of life. Wound care is costly and remains a challenge placing economic burden on patients. Furthermore, poor clinical outcomes and complications including loss of mobility and disability may lead to job loss, further contributing to socioeconomic related stress. Thus, the economic burden and inadequate wound healing are intertwined, making each other worse. Future Directions: Although some evidence regarding the specific changes in genetic pathways imparted by conditions of the social environment exists, further studies are warranted to identify potential mechanisms, interventions, and prevention approaches.

European Dermatology Forum guidelines on topical photodynamic therapy 2019 Part 2: emerging indications - field cancerization, photorejuvenation and inflammatory/infective dermatoses.

In addition to approved indications in non-melanoma skin cancer in immunocompetent patients, topical photodynamic therapy (PDT) has also been studied for its place in the treatment of, as well as its potential to prevent, superficial skin cancers in immune-suppressed patients, although sustained clearance rates are lower than for immune-competent individuals. PDT using a nanoemulsion of ALA in a daylight or conventional PDT protocol has been approved for use in field cancerization, although evidence of the potential of the treatment to prevent new SCC remained limited. High-quality evidence supports a strong recommendation for the use of topical PDT in photorejuvenation as well as for acne, refractory warts, cutaneous leishmaniasis and in onychomycosis, although these indications currently lack approvals for use and protocols remain to be optimized, with more comparative evidence with established therapies required to establish its place in practice. Adverse events across all indications for PDT can be minimized through the use of modified and low-irradiance regimens, with a low risk of contact allergy to photosensitizer prodrugs, and no other significant documented longer-term risks with no current evidence of cumulative toxicity or photocarcinogenic risk. The literature on the pharmacoeconomics for using PDT is also reviewed, although accurate comparisons are difficult to establish in different healthcare settings, comparing hospital/office-based therapies of PDT and surgery with topical ointments, requiring inclusion of number of visits, real-world efficacy as well as considering the value to be placed on cosmetic outcome and patient preference. This guideline, published over two parts, considers all current approved and emerging indications for the use of topical photodynamic therapy in Dermatology prepared by the PDT subgroup of the European Dermatology Forum guidelines committee. It presents consensual expert recommendations reflecting current published evidence.

How to prevent skin damage from air pollution. Part 1: Exposure assessment.

Both epidemiological and experimental studies have demonstrated the crucial connection between air pollution exposure and skin disorders. The exact mechanisms by which air pollutants mediate skin damage remain largely unknown. Therefore, it is very necessary to investigate the mechanism of air pollution-induced skin damage and explore some potential protective and therapeutic methods. In this review, we focus on the qualitative and quantitative skin exposure assessment methodologies-a relatively new field of interdisciplinary research.

A comprehensive assessment of cutaneous Rosai-Dorfman disease.

BACKGROUND: Cutaneous Rosai-Dorfman (CRD) disease is a rare entity that is characterized by histiocytic proliferation in the skin. The disease has been reported to exhibit different clinical profiles and occasionally confounding histologic features that may be challenging for a correct diagnosis. The purpose of this study was to assess the pathobiology and highlight the variance in clinical and histologic spectrum of the disease based on published literature. METHODS: A PUBMED search was performed to retrieve cases of cutaneous Rosai-Dorfman disease published in the literature. A PRISMA-guided review of the included articles was performed. Three interesting case reports from our institution are also described. RESULTS: A total of 263 patients, of which 220 with purely cutaneous disease were identified in 152 studies. The mean age at presentation was 45.2 years with a slight female preponderance, and East-Asian, Caucasian and African populations being largely affected. Majority of the patients presented with multiple lesions, predominantly on limbs and comprising of nodules, plaques and papules that were occasionally pigmented. The classis histologic findings included large foamy histiocytes, exhibiting emperipolesis and a specific immunophenotype (S100+, CD68+, CD1a-). Inconspicuous emperipolesis, fibrosis, increased vascularity, neutrophilic microabscesses and concurrent langerhans cell histiocytosis and lymphoma in few cases highlighted the importance of immunohistochemistry for a definitive diagnosis. The disease shows an indolent and benign course with excision and chemotherapy being most effective for extensive and refractory cases. CONCLUSIONS: This review of largest cohort of CRD patients provides an updated insight into the clinicopathologic features with possible diagnostic pitfalls and effective therapeutic options that should be useful in diagnosis, management and future research opportunities.