Aging is the primary risk factor for chronic disease and is characterized by profound structural and architectural remodeling of human tissues. Here, we present a comprehensive assessment of these changes using 25,712 whole-slide histopathological images from 40 tissue types across 983 individuals in the Genotype-Tissue Expression cohort. By leveraging deep learning, we quantified nuanced morphological alterations to develop 'tissue clocks', predictors of biological age that reflect tissue structural integrity and physiological fitness. These clocks correlate with established aging markers, such as telomere attrition, subclinical pathologies and comorbidities. Through a systematic evaluation of biological aging rates across organs, we identified associations of tissue-specific age acceleration with demographic, lifestyle and medical factors, highlighting potentially modifiable risk factors that affect tissue aging. Furthermore, by integrating paired histology and transcriptomic data, we developed a strategy to predict tissue-specific age gaps directly from blood samples. We validated this approach by identifying disease-relevant organ aging across independent cohorts for eight prevalent diseases, including Alzheimer's disease, stroke and Crohn's disease. This work positions tissue architecture as a critical integrator of molecular and cellular changes over the course of aging, demonstrates that histopathological imaging provides a robust framework for monitoring tissue-specific aging and offers a scalable foundation for understanding organ-level physiological decline in health and disease.

Optical imaging technologies are increasingly reshaping the interface between clinical dermatology and dermatopathology. In vivo reflectance confocal microscopy (IV-RCM), line-field confocal optical coherence tomography (LC-OCT), and ex vivo confocal microscopy (EV-CM) provide tissue-level morphological information without the need for conventional histopathologic processing or with substantially reduced processing times. These technologies have enabled the concept of the “virtual biopsy” and are increasingly integrated into diagnostic workflows. However, their clinical value cannot be understood solely through conventional diagnostic performance metrics such as sensitivity and specificity. Rather, their impact depends on how the information they generate is incorporated into sequential diagnostic pathways and clinical decision-making processes. This review summarizes the principles, current applications, diagnostic performance, limitations, and future prospects of IV-RCM, LC-OCT, and EV-CM. We discuss the complementary strengths of these modalities and propose a systems perspective in which imaging technologies are viewed as components of diagnostic ecosystems linking clinical examination, dermatoscopy, pathology, surgery, and computational decision support. Emerging developments in artificial intelligence, multimodal imaging, and digital pathology are likely to further strengthen these connections and expand the role of optical imaging in dermatology and dermatopathology.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare lymphoma primarily linked to textured breast implants. Symptoms are often non-specific (e.g., breast swelling, pain, or fluid collection). When imaging detects fluid around the implant, cytological examination is the first diagnostic approach. However, this method has limited sensitivity and may yield false-negative results. In this case, a 41-year-old woman presented with swelling, pain, and itching in her left breast six years after bilateral textured breast implant placement. Ultrasonography (US) revealed peri-implant fluid collection around the left implant. A following magnetic resonance imaging (MRI) scan ruled out an implant rupture. Due to persistent pain and the peri-implant effusion on the left side, open surgery was performed. During implant removal, the seroma was drained, and multiple suspicious masses were found on the left side. The cytology of the seroma fluid was negative and intraoperative frozen sections of the excised masses were inconclusive. A complete capsulectomy was conducted due to the suspicion of malignancy. Histological examination ultimately confirmed the diagnosis of BIA-ALCL. This case highlights the diagnostic challenges associated with this rare condition. Therefore, BIA-ALCL should always be considered in the differential diagnosis of breast implant-associated seroma.

Chlamydia trachomatis (Ct) is the most common cause for bacterial sexually transmitted infections (STIs) worldwide with a tremendous impact on public health. With the aim to unravel novel targets of the chlamydia life cycle, we screen a compound library and identify 28 agents to significantly reduce Ct growth. The known anti-infective agent pentamidine-one of the top candidates of the screen-shows anti-chlamydia activity in low concentrations by changing the metabolism of host cells impairing chlamydia growth. Furthermore, it effectively decreases the Ct burden upon local or systemic application in mice. Pentamidine also inhibits the growth of Neisseria gonorrhea (Ng), which is a common co-infection of Ct. The conducted compound screen is powerful in exploring antimicrobial compounds against Ct in a medium-throughput format. Following thorough in vitro and in vivo assessments, pentamidine emerges as a promising agent for topical prophylaxis or treatment against Ct and possibly other bacterial STIs.

Autoinflammatory diseases (AIDs) arise from disturbances that alter interactions of immune cells and tissues. They give rise to prominent (auto)inflammation in the absence of aberrant autoantibodies and/or autoreactive T cells. AIDs that are predominantly caused by changes in the inflammasome pathways, such as the NLRP3- or pyrin-associated inflammasome, have gained substantial attention over the last years. However, AIDs resulting primarily from other changes in the defense system of the innate immune system are less well-studied. These noninflammasome-mediated AIDs relate to, for example, disturbance in the TNF or IFN signaling pathways or aberrations in genes affecting the IL-1RA. The spectrum of clinical signs and symptoms of these conditions is vast. Thus, recognizing early cutaneous signs constitutes an important step in differential diagnoses for dermatologists and other physicians. This review provides an overview of the pathogenesis, clinical presentation, and available treatment options highlighting dermatologic aspects of noninflammasome-mediated AIDs.

The emerging group of autoinflammatory diseases (AIDs) is caused by a dysregulation of the innate immune system while lacking the typical footprint of adaptive immunity. A prominent subgroup of AIDs are inflammasomopathies, which are characterised by periodic flares of cutaneous signs as well as systemic organ involvement and fever. The range of possible skin lesions is vast, ranging from urticarial, erysipelas-like and pustular rashes to erythematous patches, violaceous plaques and eventual necrosis and ulceration. This review provides a structured overview of the pathogenesis and the clinical picture with a focus on dermatological aspects of inflammasomopathies. Current treatment options for these conditions are also discussed.

Primary cutaneous B-cell lymphomas (CBCL) comprise a group of extranodal non-Hodgkin lymphomas that are primarily confined to the skin. Primary cutaneous marginal zone lymphoma (MZL) and follicle center lymphoma (FCL) are associated with a rather indolent tumor behavior, while diffuse large B-cell lymphoma, leg type (DLBCL-LT) shows an aggressive clinical course. Besides distinct clinical and immune-histological features, the underlying molecular tumor biology is still only insufficiently understood. Therefore, we performed single-cell RNA sequencing combined with B-cell receptor sequencing in different CBCL entities and B-cell pseudolymphoma. We observed the expansion of a single B-cell clone in CBCL only. So-called pseudolymphoma was identified to be polyclonal as expected. Expanded clones of MZL showed terminal differentiation along a physiological trajectory from unswitched towards switched immunoglobulin phenotypes that included large numbers of plasma cells. Overall transcriptomic profiles were indistinguishable from benign polyclonal B cells, in line with its indolent clinical course. FCL clones also exhibited a canonical B-cell marker profile, but only of proliferating and non-proliferating germinal center B cells. By contrast, DLBCL-LT cells uniquely exhibited multiple aberrant marker profiles including proliferative activity beyond conventional germinal center-like phenotypes, pursuant of aggressive clinical behavior. Moreover, the TME comprising polyclonal T- and B-cells decreased in number and diversity from MZL over FCL to DLBCL-LT as confirmed through multiplex in situ IF. Our data revealed that while FCL and DLBCL-LT show a transcriptionally distinct expanded clone, MZL tumor cells only differentiate along physiological B-cell trajectories, suggestive of a lymphoproliferative disorder rather than an overt lymphoma.

Primary cutaneous T-cell lymphomas (CTCL) are a group of incurable extranodal non-Hodgkin lymphomas that usually develop from skin-homing CD4+ T cells, with mycosis fungoides (MF) as their most frequent entity. Due to clinical and histopathological similarities to benign inflammatory conditions, it takes a median of 3 years from the initial appearance of a skin lesion until a definitive diagnosis of MF can be made, and there are currently no specific diagnostic biomarkers available. To better define cellular and molecular characteristics of CTCL in comparison to its potential imitators, we profiled skin biopsies of early MF vs.

The diagnosis of early mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is often delayed due to clinical and histopathological similarities with benign inflammatory dermatoses. Moreover, its clear delineation from the spectrum of so-called "parapsoriasis" is still controversial. For further insight on a molecular level, we performed single-cell RNA sequencing to profile skin biopsies from patients presenting clinically with small- or large-patch dermatitis and compared them to atopic dermatitis (AD) lesions and healthy control (HC) individuals. Respective histological diagnoses of early MF, parapsoriasis/fingerprint dermatitis or AD were assigned by a dermatopathologist in a blinded fashion. We found 6 out of 7 large-patch lesions to harbor either an expanded alpha/beta or gamma/delta T-cell clone, constituting 17.3-53.6% of all TCR+ cells, consistent with early MF. By contrast, 6 out of 7 small-patch lesions contained a highly polyclonal T-cell pattern, indistinguishable from AD and HC skin. However, only AD harbored so-called "Th2A" cells, a CD3+CD4+IL17RB+CRTH2+ IL13-expressing cell type, previously associated with allergic sensitization and tissue-resident disease memory formation in atopic individuals. Expanded MF clones were deficient for CD7 expression, in line with a lymphomatous phenotype, and overexpressed LGALS3, PGK1, IL26, OSTF1, and LDHA in comparison to polyclonal T cells. On a stromal cell level, AD uniquely harbored COL6A5+CCL19+COL18A1+ inflammatory fibroblasts, while MF showed elevated frequencies of a CD36+IL6+ fibroblast population, that was largely absent in HC, parapsoriasis or AD samples. In sum, we found Th2A cells and specific fibroblast subpopulations to distinguish AD from early MF and parapsoriasis, with the presence of noticeable clonal T-cell expansion only in MF.

Cutaneous B-cell lymphomas (CBL) comprise a diverse group of diseases with variable clinical course and prognosis. The cellular and molecular mechanisms underlying the pathogenesis of CBL remain ill-defined. Here we performed single-cell RNA sequencing combined with B-cell and T-cell receptor sequencing in three distinct CBL entities. In contrast to benign cutaneous pseudolymphomas and healthy skin, each CBL variant contained a single dominant B-cell clone. In marginal zone lymphoproliferative disorder (MZLPD), expanded clones generally showed terminal differentiation along a physiological trajectory towards plasma cells and displayed transcriptomic profiles indistinguishable from the benign polyclonal bystander B-cells. Follicle center lymphoma (FCL) clones also exhibited a canonical B-cell marker profile but consisted of more homogeneous populations of proliferating and nonproliferating germinal center (GC) B-cell-like phenotypes. In the most aggressive CBL, diffuse large B-cell lymphoma, leg type (DCBCL-LT), cells revealed multiple non-physiological marker profiles as well as aberrant proliferative activity beyond conventional GC-like cells. Fibroblasts in MZLPD, FCL and pseudolymphomas, but not DLBCL-LT, expressed the classical chemotactic chemokine CXCL13 . These data suggest that in cutaneous B-cell disorders other than DLBCL-LT, physiological immune circuits are primarily operative, consistent with their overall indolent behavior. Key Points This is the first comprehensive molecular map of primary cutaneous B-cell lymphoproliferative disorders. Differences between entities were primarily geared by the expanded B-cell clone and less by other immune or stromal cells.

Background Though patient needs are key drivers of treatment decisions, they are rarely systematically investigated in routine care. Objective This study aimed at analysing needs and expectations from the patient perspective in the German and Swiss psoriasis registries PsoBest and Swiss Dermatology Network of Targeted Therapies (SDNTT) with respect to treatment choice, age and gender. Methods The German and Swiss psoriasis registries observe patients recruited at first-time use of systemic drugs. Within 10 years, clinical [Psoriasis Area Severity Index (PASI), Body Surface Area (BSA)] and patient-reported outcomes are documented, including the Dermatology Quality of Life Index (DLQI) and the Patient Benefit Index (PBI), characterizing patient needs for treatment. The analysis data set includes n = 4894 patients from PsoBest and n = 449 from SDNTT with mean follow-up time of 7.5 months. Results A total of 5343 patients registered between 2008 and 2016 were included in the analyses (at baseline: 59.6% male, mean age 47.6 years +/- 14.5, PASI 14.2 +/- 9.7, BSA 22.7 +/- 19.7, DLQI 11.3 +/- 7.2). The most important patient needs were to 'get better skin quickly' and to 'be healed of all skin defects'. Subgroup analyses by age revealed significant differences in needs, especially higher needs regarding social impairments in patients younger than 65 years. Patients 65 years or older attributed more importance to sleep quality, less dependency on medical visits, fewer side-effects and confidence in the therapy. Out of 25 items reflecting patient needs, 20 items were rated significantly more important by women than men, with the greatest differences regarding feeling of depression, sleep quality and everyday productivity. Divided by treatment, needs were rated differently, recommending individualized and targeted choice of therapy. Conclusion Age and gender stratify patient needs. Women showed higher expectations and rated specific needs in psoriasis treatment higher than men. Analysing the patient needs on an individual level will facilitate shared decisions by patient and physician in finding the optimal personalized treatment.

Primary melanoma ulceration is an unfavourable prognostic factor included in current staging systems. Yet, the immunological and molecular alterations responsible for this adverse outcome have not been fully elucidated.

Physicians can treat psoriasis patients with several effective treatments, however the response is individual and even the most effective therapies do sometimes not lead to a success of treatment. Currently, possible genetic markers that can predict individual therapy response are investigated. Up to now 45 genes have been identified to be associated with psoriasis [1].