Cutaneous tissue samples show significant shrinkage during histopathological work-up: a real-world study.

BACKGROUND: Excision and histological examination of cutaneous neoplasms are very common diagnostic and therapeutic procedures in dermatological practice. There are often discrepancies between tissue seize in vivo and after histopathological work-up. This may raise questions according to tumor sizes or safety margins. METHODS: To investigate the effect of excision and histological processing on the properties of cutaneous neoplasms in real-life 401 specimens in 324 patients were prospectively investigated. Delineated excision margins of cutaneous neoplasms were documented prior to (T0) and post excision (T1). Length, width and thickness were measured after ≥48 h of formalin fixation (T2) and after sectioning (T3) on final histological slices. Accompanying parameters such as patient age, gender, anatomical site, and tumor entity were evaluated. RESULTS: All post-processed tissue exhibited a significant (P<0.001) median (interquartile range) reduction in length, width and thickness of 21.0% (9.5-30.0), 30.7% (20.0-40.0), and 28.0% (4.8-46.7), respectively, irrespective of site, patient age or tumor entity. Maximum median (IQR) reduction for the length and the width was observed right after excision (17.0% [4.3-25.0] and 14.0% [11.1-28.6] reduction). No significant median (IQR) tissue changes between T1 and T2 were observed (length: 4.8% (-4.3-13.3); width: 0% (-17.6-11.1); thickness 0% (-32.0-20.0). Subgroup analyses showed significantly greater tissue shrinkage in younger patients and for tissue sample sites (trunk or lower extremities). CONCLUSIONS: Most relevant shrinkage of cutaneous samples occurs right after excision. Age- and site-depended tissue contractility can influence these effects. Formalin fixation does not affect tissue shrinkage. Smaller tissue sizes on histopathological reports are to be expected.

S2k guideline: Diagnosis and therapy of localized scleroderma.

The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoS represents a spectrum of sclerotic skin diseases in which, depending on the subtype and localisation, structures such as adipose tissue, muscles, joints, and bones may also be affected. Involvement of internal organs or progression to systemic sclerosis does not occur. LoS can be classified into four main forms: limited, generalized, linear, and mixed forms, with some additional subtypes. For cases of limited skin involvement, the guideline primarily recommends therapy with topical corticosteroids. UV therapy can also be recommended. In subtypes with severe skin or musculoskeletal involvement, systemic therapy with methotrexate is recommended. During the active phase of the disease, systemic glucocorticosteroids can be used additionally. In cases of methotrexate and steroid refractory courses, contraindications, or intolerance, mycophenolate mofetil, mycophenolic acid, or abatacept can be considered as second-line systemic therapies. In the case of linear LoS, autologous adipose-derived stem cell transplantation can also be performed for correcting soft tissue defects.

Deep learning based histological classification of adnex tumors.

BACKGROUND: Cutaneous adnexal tumors are a diverse group of tumors arising from structures of the hair appendages. Although often benign, malignant entities occur which can metastasize and lead to patients´ death. Correct diagnosis is critical to ensure optimal treatment and best possible patient outcome. Artificial intelligence (AI) in the form of deep neural networks has recently shown enormous potential in the field of medicine including pathology, where we and others have found common cutaneous tumors can be detected with high sensitivity and specificity. To become a widely applied tool, AI approaches will also need to reliably detect and distinguish less common tumor entities including the diverse group of cutaneous adnexal tumors. METHODS: To assess the potential of AI to recognize cutaneous adnexal tumors, we selected a diverse set of these entities from five German centers. The algorithm was trained with samples from four centers and then tested on slides from the fifth center. RESULTS: The neural network was able to differentiate 14 different cutaneous adnexal tumors and distinguish them from more common cutaneous tumors (i.e. basal cell carcinoma and seborrheic keratosis). The total accuracy on the test set for classifying 248 samples into these 16 diagnoses was 89.92 %. Our findings support AI can distinguish rare tumors, for morphologically distinct entities even with very limited case numbers (< 50) for training. CONCLUSION: This study further underlines the enormous potential of AI in pathology which could become a standard tool to aid pathologists in routine diagnostics in the foreseeable future. The final diagnostic responsibility will remain with the pathologist.

Deep learning detection of melanoma metastases in lymph nodes.

BACKGROUND: In melanoma patients, surgical excision of the first draining lymph node, the sentinel lymph node (SLN), is a routine procedure to evaluate lymphogenic metastases. Metastasis detection by histopathological analysis assesses multiple tissue levels with hematoxylin and eosin and immunohistochemically stained glass slides. Considering the amount of tissue to analyze, the detection of metastasis can be highly time-consuming for pathologists. The application of artificial intelligence in the clinical routine has constantly increased over the past few years. METHODS: In this multi-center study, a deep learning method was established on histological tissue sections of sentinel lymph nodes collected from the clinical routine. The algorithm was trained to highlight potential melanoma metastases for further review by pathologists, without relying on supplementary immunohistochemical stainings (e.g. anti-S100, anti-MelanA). RESULTS: The established method was able to detect the existence of metastasis on individual tissue cuts with an area under the curve of 0.9630 and 0.9856 respectively on two test cohorts from different laboratories. The method was able to accurately identify tumour deposits>0.1 mm and, by automatic tumour diameter measurement, classify these into 0.1 mm to -1.0 mm and>1.0 mm groups, thus identifying and classifying metastasis currently relevant for assessing prognosis and stratifying treatment. CONCLUSIONS: Our results demonstrate that AI-based SLN melanoma metastasis detection has great potential and could become a routinely applied aid for pathologists. Our current study focused on assessing established parameters; however, larger future AI-based studies could identify novel biomarkers potentially further improving SLN-based prognostic and therapeutic predictions for affected patients.

Cutaneous Lupus Erythematosus: An Update on Pathogenesis and Future Therapeutic Directions.

Lupus erythematosus comprises a spectrum of autoimmune diseases that may affect various organs (systemic lupus erythematosus [SLE]) or the skin only (cutaneous lupus erythematosus [CLE]). Typical combinations of clinical, histological and serological findings define clinical subtypes of CLE, yet there is high interindividual variation. Skin lesions arise in the course of triggers such as ultraviolet (UV) light exposure, smoking or drugs; keratinocytes, cytotoxic T cells and plasmacytoid dendritic cells (pDCs) establish a self-perpetuating interplay between the innate and adaptive immune system that is pivotal for the pathogenesis of CLE. Therefore, treatment relies on avoidance of triggers and UV protection, topical therapies (glucocorticosteroids, calcineurin inhibitors) and rather unspecific immunosuppressive or immunomodulatory drugs. Yet, the advent of licensed targeted therapies for SLE might also open new perspectives in the management of CLE. The heterogeneity of CLE might be attributable to individual variables and we speculate that the prevailing inflammatory signature defined by either T cells, B cells, pDCs, a strong lesional type I interferon (IFN) response, or combinations of the above might be suitable to predict therapeutic response to targeted treatment. Therefore, pretherapeutic histological assessment of the inflammatory infiltrate could stratify patients with refractory CLE for T-cell-directed therapies (e.g. dapirolizumab pegol), B-cell-directed therapies (e.g. belimumab), pDC-directed therapies (e.g. litifilimab) or IFN-directed therapies (e.g. anifrolumab). Moreover, Janus kinase (JAK) and spleen tyrosine kinase (SYK) inhibitors might broaden the therapeutic armamentarium in the near future. A close interdisciplinary exchange with rheumatologists and nephrologists is mandatory for optimal treatment of lupus patients to define the best therapeutic strategy.

Lupus erythematosus.

Cutaneous lupus erythematosus can manifest with or without systemic involvement resulting in a broad clinical spectrum. Disease pathogenesis is often characterized by a loss of tolerance to endogenous antigens and a chronic relapsing activation of the innate and adaptive immune system. Research in recent years has expanded our pathogenic understanding of the disease. However, therapeutic options remain limited. Biologics directed against BLyS or the type I interferon receptor can be used for patients with cutaneous involvement and systemic lupus erythematosus, sometimes with an excellent response. Clinical trials are difficult to conduct due to the symptomatic variability of the disease. However, as cutaneous manifestations are increasingly recorded as a primary endpoints, we hope that multiple therapeutic targets will lead to better treatment options for SLE in the near future.

Efficacy and Safety of Methotrexate in Psoriasis Vulgaris Long-Term Treatment: A Real-World Observation Study.

Background: Methotrexate (MTX) in the therapy of psoriasis vulgaris (PV) is a well and long-established treatment option. Aims: To assess the long-term experience of individual patients in the real world with regard to the efficacy and safety of MTX in PV therapy. Patients and Methods: In a retrospective study, MTX as a weekly used monotherapy in PV was examined. Clinical data including the Psoriasis Area Severity Index (PASI), prevalence of psoriatic-arthritis (PsA), Investigator Global Assessment (IGA), laboratory parameters, occurrence of adverse events (AEs), dosing of MTX and characteristics of patients treated for at least 24 months were collected. Results: A total of 55 patients with 247 patient-years under MTX therapy were included. The mean PASI reduction was 51.2% with a significant (P < 0.001) improvement in the skin condition in the first 6 months of treatment, remaining stable thereafter. The mean MTX dose increased from 11.8 ± 3.7 mg to 12.9 ± 3.8 mg in the first year of therapy, with a constant mean dose in the following years. In 247 patient-years, no serious AE was documented. Gastrointestinal side effects or fatigue were commonly detected. The liver parameter alanine aminotransferase/ glutamate-pyruvate transaminase (ALT/GPT) (baseline 35.8 ± 22.0 U/L) increased after 3 years of therapy (42.0 ± 22.4 U/L; P = 0.013) without clinical significance. Conclusion: In this patient collective, MTX in low doses was effective and safe in long-term therapy. The improved skin condition was steady and reached by an unvarying dose. New data showed a better efficacy of MTX in higher doses; however, additional data must be collected on the long-term efficacy and safety of MTX with a higher dose regime.

Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.

Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1.

Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency.

Intercellular transmission of the second messenger 2',3'-cGAMP, synthesized by the viral DNA sensor cGAMP synthase (cGAS), is a potent mode of bystander activation during host defense. However, whether this mechanism also contributes to cGAS-dependent autoimmunity remains unknown. Here, using a murine bone marrow transplantation strategy, we demonstrate that, in Trex1 -/- -associated autoimmunity, cGAMP shuttling from radioresistant to immune cells induces NF-κB activation, interferon regulatory factor 3 (IRF3) phosphorylation, and subsequent interferon signaling. cGAMP travel prevented myeloid cell and lymphocyte death, promoting their accumulation in secondary lymphoid tissue. Nonetheless, it did not stimulate B cell differentiation into autoantibody-producing plasmablasts or aberrant T cell priming. Although cGAMP-mediated bystander activation did not induce spontaneous organ disease, it did trigger interface dermatitis after UV light exposure, similar to cutaneous lupus erythematosus. These findings reveal that, in Trex1-deficiency, intercellular cGAMP transfer propagates cGAS signaling and, under conducive conditions, causes tissue inflammation.