A 3-dimensional histology computer model of malignant melanoma and its implications for digital pathology.

BACKGROUND: Historically, cancer diagnoses have been made by pathologists using two-dimensional histological slides. However, with the advent of digital pathology and artificial intelligence, slides are being digitised, providing new opportunities to integrate their information. Since nature is 3-dimensional (3D), it seems intuitive to digitally reassemble the 3D structure for diagnosis. OBJECTIVE: To develop the first human-3D-melanoma-histology-model with full data and code availability. Further, to evaluate the 3D-simulation together with experienced pathologists in the field and discuss the implications of digital 3D-models for the future of digital pathology. METHODS: A malignant melanoma of the skin was digitised via 3 µm cuts by a slide scanner; an open-source software was then leveraged to construct the 3D model. A total of nine pathologists from four different countries with at least 10 years of experience in the histologic diagnosis of melanoma tested the model and discussed their experiences as well as implications for future pathology. RESULTS: We successfully constructed and tested the first 3D-model of human melanoma. Based on testing, 88.9% of pathologists believe that the technology is likely to enter routine pathology within the next 10 years; advantages include a better reflectance of anatomy, 3D assessment of symmetry and the opportunity to simultaneously evaluate different tissue levels at the same time; limitations include the high consumption of tissue and a yet inferior resolution due to computational limitations. CONCLUSIONS: 3D-histology-models are promising for digital pathology of cancer and melanoma specifically, however, there are yet limitations which need to be carefully addressed.

Lives of Skin Lesions in Monkeypox: Histomorphological, Immunohistochemical, and Clinical Correlations in a Small Case Series.

Monkeypox (mpox), a former rare viral zoonosis, has increasingly made it into the public eye since the major outbreak that started in May 2022. Mpox presents with skin lesions that change over time and go through different stages (macular, papular, pustular, and early and late ulceration). In this study, we evaluated skin biopsies of all stages. Therefore, five biopsies from four patients were analyzed histologically, immunohistochemically with anti-Vaccinia virus antibodies, and electron-microscopically. Notably, the early macular stage only showed subtle viropathic changes; it did not express of Orthopoxvirus proteins in immunohistochemistry and therefore can easily be missed histologically. In later stages, immunohistochemistry with anti-Vaccinia virus antibodies might be useful to distinguish mpox from differential diagnoses such as herpes virus infections. In the ulcerative stages, the identified occlusive vasculopathic changes could be an explanation for the severe pain of the lesions reported by some patients. Despite the small number of samples examined, our analysis suggests that the histological findings of mpox are highly dependent on the stage of the biopsied lesion. Therefore, knowledge of all different stages of histology is necessary to reliably diagnose mpox histologically, especially when molecular testing is not available.

Comparison of Complication Rates Between Subpectoral vs Prepectoral Techniques in Prosthetic Breast Reconstruction.

BACKGROUND: The location of tissue expanders in implant-based breast reconstruction remains controversial due to variation in surgical techniques and devices. OBJECTIVES: The aim of this study was to provide a comprehensive assessment of early and late complication rates between prepectoral and subpectoral placement of tissue expanders. METHODS: A retrospective cohort study was conducted of all adult female patients who had undergone 2-stage implant-based breast reconstruction between 2013 and 2019 in our institution. Early complication was defined as complications that occurred within 30 days after surgery. Time-to-event analyses were performed and Cox proportional hazard models were used to adjust for confounders. RESULTS: In total, 854 patients were included; 76% of patients underwent a subpectoral tissue expander placement. After the first-stage procedure, the early complication rate was 34% and the late complication rate was 36.4%. After the second-stage procedure, the early complication rate was 16.3% and the late complication rate was 16.1%. Location of the tissue expander did not predict either overall early or late complication rates, regardless of the stages of reconstruction, after adjusting for confounders. Tissue expanders placed in prepectoral plane were associated with a higher hazard ratio (HR) for developing early and late infection after the first stage of reconstruction (HR, 2.1 and 2.4, respectively) as well as late infection after the second stage of reconstruction (HR, 5.3; all P < .05). CONCLUSIONS: Location of tissue expanders did not predict risk of complication. However, the prepectoral group was associated with an increased risk of developing infection.

Immunothrombotic Mechanisms Induced by Ingenol Mebutate Lead to Rapid Necrosis and Clearance of Anogenital Warts.

Ingenol mebutate (IM) is highly effective in the treatment of human papillomavirus (HPV)-induced anogenital warts (AGW) leading to fast ablation within hours. However, the exact mode of action is still largely unknown. We performed dermoscopy, in vivo confocal microscopy (CLM), histology, immunohistochemistry, and immunofluorescence to gain insights in mechanisms of IM treatment in AGW. In addition, we used in vitro assays (ELISA, HPV-transfection models) to further investigate in vivo findings. IM treatment leads to a strong recruitment of neutrophils with thrombosis of small skin vessels within 8 h, in a sense of immunothrombosis. In vivo and in vitro analyses showed that IM supports a prothrombotic environment by endothelial cell activation and von Willebrand factor (VWF) secretion, in addition to induction of neutrophil extracellular traps (NETosis). IM superinduces CXCL8/IL-8 expression in HPV-E6/E7 transfected HaCaT cells when compared to non-infected keratinocytes. Rapid ablation of warts after IM treatment can be well explained by the observed immunothrombosis. This new mechanism has so far only been observed in HPV-induced lesions and is completely different from the mechanisms we see in the treatment of transformed keratinocytes in actinic keratosis. Our initial findings indicate an HPV-specific effect, which could be also of interest for the treatment of other HPV-induced lesions. Larger studies are now needed to further investigate the potential of IM in different HPV tumors.

[Digitalization in dermatopathology]. / Digitalisierung in der Dermatopathologie.

The histomorphological analysis of tissue sections by specially trained dermatopathologists is a central component for making the dermatological diagnosis. It is the foundation for the understanding of clinical aspects, pathophysiology and not least the treatment of skin diseases and is therefore an essential part of modern dermatology. New technological developments in recent years offer a variety of possibilities to digitalize dermatopathology, which could significantly change and even revolutionize the work of dermatopathologists in the coming years; however, like any new development there are limiting factors and open questions that need to be discussed. This article is intended to provide an overview of the current state of the art and to highlight the corresponding opportunities and risks on the road to digital dermatopathology.

[Skin manifestations of COVID-19 and after COVID-19 vaccination]. / Hautveränderungen bei COVID-19 und nach COVID-19-Impfung.

Coronavirus disease 2019 (COVID-19) is a systemic disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that frequently presents with skin manifestations. The five most common skin lesions are pseudo-chilblain and maculopapular, urticarial, vesicular, and livedo/necrotizing skin lesions. These skin lesions are of diagnostic and prognostic relevance. For example, in children, typical skin lesions may indicate a life-threatening inflammatory syndrome, which rarely occurs after corona infection. Skin lesions have also been described after COVID-19 vaccination. These usually show an uncomplicated, self-limiting course and therefore do not represent a contraindication for completing the vaccination status in the vast majority of cases.

Skin cancer classification via convolutional neural networks: systematic review of studies involving human experts.

BACKGROUND: Multiple studies have compared the performance of artificial intelligence (AI)-based models for automated skin cancer classification to human experts, thus setting the cornerstone for a successful translation of AI-based tools into clinicopathological practice. OBJECTIVE: The objective of the study was to systematically analyse the current state of research on reader studies involving melanoma and to assess their potential clinical relevance by evaluating three main aspects: test set characteristics (holdout/out-of-distribution data set, composition), test setting (experimental/clinical, inclusion of metadata) and representativeness of participating clinicians. METHODS: PubMed, Medline and ScienceDirect were screened for peer-reviewed studies published between 2017 and 2021 and dealing with AI-based skin cancer classification involving melanoma. The search terms skin cancer classification, deep learning, convolutional neural network (CNN), melanoma (detection), digital biomarkers, histopathology and whole slide imaging were combined. Based on the search results, only studies that considered direct comparison of AI results with clinicians and had a diagnostic classification as their main objective were included. RESULTS: A total of 19 reader studies fulfilled the inclusion criteria. Of these, 11 CNN-based approaches addressed the classification of dermoscopic images; 6 concentrated on the classification of clinical images, whereas 2 dermatopathological studies utilised digitised histopathological whole slide images. CONCLUSIONS: All 19 included studies demonstrated superior or at least equivalent performance of CNN-based classifiers compared with clinicians. However, almost all studies were conducted in highly artificial settings based exclusively on single images of the suspicious lesions. Moreover, test sets mainly consisted of holdout images and did not represent the full range of patient populations and melanoma subtypes encountered in clinical practice.

Delayed skin reaction after mRNA-1273 vaccine against SARS-CoV-2: a rare clinical reaction.

BACKGROUND: The coronavirus disease 2019 (COVID-19) is associated with a wide clinical spectrum of skin manifestations, including urticarial, vesicular, vasculitic and chilblain-like lesions. Recently, delayed skin reactions have been reported in 1% individuals following mRNA vaccination against SARS-CoV-2. The exact pathophysiology and the risk factors still remain unclear. PATIENTS AND METHODS: 6821 employees and patients were vaccinated at our institutions between February and June 2021. Every patient received two doses of the mRNA-1273 vaccine in our hospitals, and reported back in case of any side effects which were collected in our hospital managed database. RESULTS: Eleven of 6821 vaccinated patients (0.16%) developed delayed skin reactions after either the first or second dose of the mRNA-1273 vaccine against SARS-CoV-2. Eight of 11 patients (73%) developed a rash after the first dose, while in 3/11 (27%), the rash occurred after the second dose. More females (9/11) were affected. Four of 11 patients required antihistamines, with two needing additional topical steroids. All the cutaneous manifestations resolved within 14 days. None of the skin reactions after the first dose of the vaccine prevented the administration of the second dose. There were no long-term cutaneous sequelae in any of the affected individuals. CONCLUSION: Our data suggests that skin reactions after the use of mRNA-1273 vaccine against SARS-CoV-2 are possible, but rare. Further studies need to be done to understand the pathophysiology of these lesions.

Psoriasis on the Leg: Site-specific Histopathological and Immuno-histochemical Features and Diagnostic Difficulties.

The histopathology of psoriasis can lack classical features on certain anatomical sites. The aim of this study was to detail the histopathology and immunophenotype of psoriasis on the legs, in order to differentiate it from other inflammatory dermatoses, such as stasis dermatitis. The histopathology of psoriasis on the legs was retrospectively compared with psoriasis on the trunk and stasis dermatitis. Statistically, psoriasis on the legs was significantly less likely to show typical histological criteria of psoriasis, such as regular hyperplasia, suprapapillary thinning, and "kissing vessels". The most valuable criteria to distinguish psoriasis on the legs from stasis dermatitis were the presence of neutrophils in the cornified layer and staggered parakeratosis. In addition, an immunohistochemical panel (Ki-67, Bcl-2alpha, S100A7, CD3, MPO, CK10, CK16) revealed that staining with Ki-67 and MPO could be diagnostically useful. Since the cornified layer contains important histopathological clues to differentiate psoriasis on the legs from stasis dermatitis, clinicians should refrain from unnecessary rubbing during disinfection before taking a biopsy.

Histopathological Spectrum and Immunophenotypic Characterization of Symmetrical Drug-Related Intertriginous and Flexural Exanthema.

INTRODUCTION: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a clinically very well-defined drug eruption, but the histopathological findings are still considered to be nonspecific. OBJECTIVES: To characterize the histopathological and immunophenotypical features of SDRIFE. MATERIAL AND METHODS: We performed a retrospective study that identified 11 biopsies from 9 patients with SDRIFE. The histopathological features were analyzed in conjunction with the immunohistochemical findings. RESULTS: The most common histopathological feature was basal cell vacuolization, which was often associated with necrotic keratinocytes and focal spongiosis. TIA1+ T cells and neutrophils were frequently detected in the epidermis and at the dermoepidermal junction. The dermal inflammatory infiltrate was mixed, consisting of CD3+ T cells, macrophages, granulocytes, low numbers of CD20+ B cells, and plasma cells. A combination of histopathological patterns was observed in 5 cases. The most frequent combined histopathological patterns were interface dermatitis, spongiotic dermatitis, and psoriasiform dermatitis. Other histopathological patterns found in different combinations were pustular dermatitis, perivascular and interstitial neutrophilic dermatitis, and interstitial granulomatous dermatitis. In the other 4 cases, a single histopathological pattern predominated, such as psoriasiform dermatitis, vacuolar interface dermatitis of erythema multiforme-like type, or superficial and deep perivascular and interstitial dermatitis with eosinophils and neutrophils. CONCLUSIONS: SDRIFE is characterized histologically by a vacuolar interface dermatitis induced by cytotoxic T lymphocytes and neutrophilic granulocytes. This pattern may be obscured by accompanying spongiotic, psoriasiform, or pustular features combined with a mixed superficial and sometimes deep dermal infiltrate.

Correction to: The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Vemurafenib acts as an aryl hydrocarbon receptor antagonist: Implications for inflammatory cutaneous adverse events.

BACKGROUND: In recent years, the BRAF inhibitor vemurafenib has been successfully established in the therapy of advanced melanoma. Despite its superior efficacy, the use of vemurafenib is limited by frequent inflammatory cutaneous adverse events that affect patients' quality of life and may lead to dose reduction or even cessation of anti-tumor therapy. To date, the molecular and cellular mechanisms of vemurafenib-induced rashes have remained largely elusive. METHODS: In this study, we deployed immunohistochemistry, RT-qPCR, flow cytometry, lymphocyte activation tests, and different cell-free protein-interaction assays. RESULTS: We here demonstrate that vemurafenib inhibits the downstream signaling of the canonical pathway of aryl hydrocarbon receptor (AhR) in vitro, thereby inducing the expression of proinflammatory cytokines (eg, TNF) and chemokines (eg, CCL5). In line with these results, we observed an impaired expression of AhR-regulated genes (eg, CYP1A1) and an upregulation of the corresponding proinflammatory genes in vivo. Moreover, results of lymphocyte activation tests showed the absence of drug-specific T cells in respective patients. CONCLUSION: Taken together, we obtained no hint of an underlying sensitization against vemurafenib but found evidence suggesting that vemurafenib enhances proinflammatory responses by inhibition of canonical AhR signaling. Our findings contribute to our understanding of the central role of the AhR in skin inflammation and may point toward a potential role for topical AhR agonists in supportive cancer care.

Interest in Skin Cancer in Urban Populations: A Retrospective Analysis of Google Search Terms in Nine Large German Cities.

Skin cancer is a major public health issue, which could be reduced through prevention programmes. How-ever, prevention utilization is not very prevalent. It is therefore important to understand individuals' interest in skin cancer. Google AdWords Keyword Planner was used to identify the search volume of terms relating to skin cancer in 9 German cities between July 2014 and June 2018. From a total of 1,203 identified keywords, 1,047 search terms were related to skin cancer, which had a search volume of 3,460,980 queries for the study period. Most terms referred to "identifying skin cancer". For melanoma, the number of Google searches per 100,000 inhabitants correlated with the cancer registry data for melanoma incidence rates (men: r = 0.810, women: r = 0.569). Assessment of this data for the different cities further enabled identification of regional variations, which could help to identify areas with a high need for targeted prevention campaigns.

The AHR represses nucleotide excision repair and apoptosis and contributes to UV-induced skin carcinogenesis.

Ultraviolet B (UVB) radiation induces mutagenic DNA photoproducts, in particular cyclobutane pyrimidine dimers (CPDs), in epidermal keratinocytes (KC). To prevent skin carcinogenesis, these DNA photoproducts must be removed by nucleotide excision repair (NER) or apoptosis. Here we report that the UVB-sensitive transcription factor aryl hydrocarbon receptor (AHR) attenuates the clearance of UVB-induced CPDs in human HaCaT KC and skin from SKH-1 hairless mice. Subsequent RNA interference and inhibitor studies in KC revealed that AHR specifically suppresses global genome but not transcription-coupled NER. In further experiments, we found that the accelerated repair of CPDs in AHR-compromised KC depended on a modulation of the p27 tumor suppressor protein. Accordingly, p27 protein levels were increased in AHR-silenced KC and skin biopsies from AHR-/- mice, and critical for the improvement of NER. Besides increasing NER activity, AHR inhibition was accompanied by an enhanced occurrence of DNA double-strand breaks triggering KC apoptosis at later time points after irradiation. The UVB-activated AHR thus acts as a negative regulator of both early defense systems against carcinogenesis, NER and apoptosis, implying that it exhibits tumorigenic functions in UVB-exposed skin. In fact, AHR-/- mice developed 50% less UVB-induced cutaneous squamous cell carcinomas in a chronic photocarcinogenesis study than their AHR+/+ littermates. Taken together, our data reveal that AHR influences DNA damage-dependent responses in UVB-irradiated KC and critically contributes to skin photocarcinogenesis in mice.

Fast Ablation of Anogenital Warts of the Urinary Meatus by Low-dose Ingenol Mebutate Gel.

Therapeutic options of anogenital warts (AGW) at the urethral meatus are limited and often require effortful and time-consuming procedures under general anesthesia. Here, we present two cases of AGW at the urethral meatus, which we have successfully treated with low-dose topical ingenol mebutate gel.