Search Results (199)

Nicotinamide (NAM), the amide form of vitamin B3, has gained increasing attention in dermatology due to its potential role in both skin aging and non-melanoma skin cancer (NMSC) prevention. This review summarizes the biological rationale and current clinical evidence supporting the use of NAM and other NAD⁺ precursors in photoaging and cutaneous carcinogenesis. Chronic ultraviolet exposure induces DNA damage, oxidative stress, inflammation, immune dysregulation, and extracellular matrix remodeling, linking photoaged skin to increased susceptibility to actinic keratoses (AKs), squamous cell carcinoma (SCCs), and basal cell carcinoma (BCCs). Through the NAD⁺ salvage pathway, NAM contributes to the maintenance of intracellular NAD⁺ pools, thereby influencing energy metabolism, DNA repair, mitochondrial function, redox homeostasis, and the activity of NAD⁺-dependent enzymes. Preclinical studies indicate that NAM enhances DNA repair, reduces oxidative stress and inflammatory signaling, supports autophagy and mitophagy, and improves epidermal barrier function and extracellular matrix integrity. Clinically, the strongest evidence for anti-aging effects concerns topical NAM, which consistently improves wrinkles, texture irregularities, pigmentation, and barrier function. Oral NAM has demonstrated chemopreventive activity in high-risk patients with previous NMSC, particularly by reducing the incidence of new SCCs and AKs during active treatment. However, despite a strong mechanistic rationale, current evidence remains heterogeneous, and additional long-term, skin-focused clinical trials are needed to better define efficacy, safety, optimal dosing strategies, and patient selection. Full article

Background: Tirbanibulin 1% ointment has demonstrated short-term efficacy and excellent tolerability in the treatment of actinic keratosis (AK) on the face and scalp. However, data on long-term efficacy are still lacking. Materials and Methods: This prospective, single-center, 12-month extension study included patients with facial and scalp AKs previously treated with tirbanibulin 1% ointment once daily for 5 consecutive days. Long-term analysis was restricted to lesions that had achieved complete clinical and dermoscopic clearance at the 2-month follow-up. At 12 months, the treated areas were reassessed clinically and dermoscopically. High-resolution images obtained at baseline, 2 months, and 12 months were compared lesion by lesion to distinguish sustained clearance, recurrence at the same anatomical site, and the development of new AKs within the treated field. Results: Thirty-seven patients were reassessed at 12 months. Of the 228 AKs treated at baseline, 116 lesions had achieved complete clearance at 2 months and were therefore eligible for long-term evaluation. At 1 year, 70/116 lesions (60.3%) remained free of recurrence, whereas 46/116 (39.7%) relapsed. Sustained clearance was observed in 35/51 grade 1 lesions (68.6%), 32/57 grade 2 lesions (56.1%), and 3/8 grade 3 lesions (37.5%). In addition, 35 new AKs developed within the previously treated field. No delayed local or systemic adverse events and no progression to invasive cSCC were observed during follow-up. Patient-reported satisfaction was high, and 94% of patients stated they would be willing to repeat the treatment. Conclusions: Tirbanibulin was associated with sustained lesion clearance at one year, particularly in lower-grade AKs. While recurrence remains relatively common—especially in thicker lesions—the treatment was well tolerated and associated with no delayed adverse effects. Its short application regimen and excellent safety profile support tirbanibulin’s role in the long-term management of field cancerization. Full article

Background/Objectives: The efficacy of topical therapies in dermatology is often limited by the barrier function of the stratum corneum, which restricts drug penetration. Iontophoresis is a non-invasive transdermal delivery technique that uses a low-intensity electrical current to enhance the transport of charged and polar molecules across the skin. It has emerged as a strategy to improve local drug bioavailability while minimizing systemic exposure. We systematically reviewed the clinical evidence on the efficacy, safety, and pharmacologic performance of iontophoresis-assisted topical drug delivery in dermatologic diseases. Methods: This systematic review followed PRISMA guidelines and was prospectively registered in PROSPERO (CRD420251234877). PubMed, Embase, Web of Science, CENTRAL, and ClinicalTrials.gov were searched through 19 November 2025 without language restrictions. Records were screened against predefined eligibility criteria, and data were extracted on study design, participants, dermatologic indications, intervention/comparator, iontophoresis parameters, efficacy outcomes, and adverse events. The risk of bias was assessed using RoB 2 for randomized trials and the JBI checklist for non-randomized studies. Because of substantial clinical and methodological heterogeneity, the findings were synthesized narratively and no meta-analysis was performed. Results: Twenty-one studies published between 1990 and 2025 met the inclusion criteria, including 15 randomized and 6 non-randomized studies. Investigated conditions included psoriasis, eczema, melasma, post-inflammatory hyperpigmentation, herpes labialis, onychomycosis, chronic ulcers, systemic sclerosis-related digital ulcers, acne scarring, and actinic keratosis. Across studies, findings were mixed. The most consistent signals of benefit were observed in pigmentary disorders and infectious diseases, whereas results were more heterogeneous in inflammatory dermatoses and some studies did not show superiority over active comparators. Tolerability was generally favorable, with adverse events limited to mild, reversible local reactions such as erythema, tingling, burning, or transient irritation. No serious treatment-related adverse events were reported. Conclusions: Iontophoresis may represent a useful non-invasive delivery-enhancement strategy in selected dermatologic settings, particularly when topical efficacy is limited by anatomical or physicochemical barriers. However, heterogeneity in protocols, formulations, outcomes, and clinical indications limits direct comparison and does not support broad conclusions of efficacy across all dermatologic conditions. Larger, standardized trials are needed to clarify its therapeutic role, long-term efficacy, and indication-specific benefit. Full article

Background: Angiogenesis is critical for tumor progression. Microvessel density (MVD) is commonly assessed using CD31 and CD34, which detect both mature and newly formed vessels and therefore cannot distinguish active neoangiogenesis from stable, quiescent vasculature. Nestin, an intermediate filament protein expressed preferentially in proliferating endothelial cells, has been proposed as a complementary marker of active angiogenesis and has been investigated in several solid tumor types, including pancreatic, colorectal, and breast carcinomas. However, no studies have quantitatively compared nestin-positive MVD across AK, BCC, and SCC using standardized methods. Methods: Immunohistochemistry for nestin, CD31, and CD34 was performed on 118 patient samples collected in 2015–2019 and diagnosed with AK, BCC, or SCC. MVD was quantified by averaging vessel counts in three representative “hot spot” areas. Results: Nestin-positive MVD was significantly lower in patients with AK compared to patients with BCC and SCC (p < 0.001). The mean MVD of nestin-positive vessels was significantly lower in AK than in BCC and SCC (p < 0.0001). In all three groups, nestin-positive MVD demonstrated a strong, positive correlation with both CD34 and CD31. Conclusions: Nestin-positive MVD was significantly elevated in BCC and SCC compared to AK lesions and demonstrated strong correlations with standard angiogenic markers. These findings suggest that nestin may warrant further investigation as a complementary marker of angiogenesis in non-melanoma skin cancer. Whether nestin-positive MVD offers independent diagnostic or prognostic value in this context remains to be determined in larger, prospective, multicentre studies. Full article

Background and Objectives: Invasive cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK) are growing burdens on ageing societies and mainly arise from chronic sun exposure. Distinguishing between carcinoma and carcinoma in situ is often clinically challenging but essential for decision-making with respect to targeted therapy. Ex vivo confocal laser scanning microscopy (CLSM) allows histologic examination of native tissue using tissue reflection and nuclear fluorescence staining. The digital staining process almost perfectly mimics conventional haematoxylin and eosin (HE) staining. While the use of CLSM for basal cell carcinoma (BCC) diagnosis is well described, data on cSCC remain scarce. The aim of this study was to compare CLSM with conventional histology in diagnosing and distinguishing cSCC and AK in routine clinical practice. Materials and Methods: Between August 2022 and March 2024, 63 patients with clinically suspected invasive cSCC or AK were enrolled. Biopsy or excision specimens were examined by ex vivo confocal laser scanning microscopy (VivaScope^® 2500 M-G4) followed by acridine orange staining. All samples underwent subsequent routine histopathology, which served as the reference. Two dermatologists independently compared the CLSM findings with the histopathological diagnoses. Results: Eighty-one lesions suspected to be cSCC were assessed using CLSM. The diagnostic accuracy was high across specimen types: cSCC was correctly identified in 24/26 cases (92.3%), AK/Morbus Bowen in 16/17 cases (94.1%), cSCC filia (cutaneous squamous cell carcinoma metastases) in 3/3 cases (100%), and basal cell carcinoma in 9/9 cases (100%). The absence of a tumour was correctly recognized in 19/21 cases (90.5%). In five cases (6.2%), AK and early invasive cSCC could not be differentiated, reflecting the histopathological results. Conclusions: CLSM with digital HE staining is well suited for rapid cSCC and AK diagnosis and differentiation in clinical practice. Full article

Photodynamic therapy (PDT) is a minimally invasive treatment choice whose clinical success in dermatology relies on the interaction between a photosensitizer, light of an appropriate wavelength, and tissue oxygen, leading to reactive oxygen species generation and selective cytotoxicity. This narrative review summarizes contemporary mechanisms and clinical evidence supporting PDT across neoplastic, inflammatory, infectious, and esthetic indications. A comprehensive literature search included randomized trials when available, systematic reviews, meta-analyses, and guideline and consensus documents, complemented by mechanistic and translational studies relevant to clinical outcomes. In premalignant and neoplastic disease, strongest evidence supports field-directed PDT for actinic keratosis and high efficacy in Bowen’s disease, with favorable cosmetic outcomes and acceptable recurrence patterns. PDT plays a more selective role in basal cell carcinoma, particularly superficial and selected nodular lesions, while its routine use as monotherapy in squamous cell carcinoma remains limited by higher recurrence. Beyond oncology, PDT shows expanding utility in acne via sebomodulatory and immunomodulatory effects, and in infectious dermatoses through broad antimicrobial activity and biofilm disruption with low resistance potential. Cosmetic applications, including photorejuvenation, benefit from protocol tailoring and combination strategies that enhance penetration and remodeling. Overall, PDT is evolving into an adaptable therapeutic framework best positioned within mechanism-oriented, multimodal algorithms. Full article

Background: Actinic keratoses (AKs) are considered early in situ forms of cutaneous squamous cell carcinoma (cSCC). However reliable histopathological or molecular markers for predicting the risk of progression are still lacking. The aim of this study was to investigate the relationship between immunohistochemical markers and basal proliferation patterns of AKs in order to identify histopathological associations that may be relevant for malignant transformation. Methods: A total of 97 AK samples from facial and scalp areas were retrospectively analyzed and classified according to their basal proliferation pattern (Pro I: non-proliferative and Pro III: proliferative). Immunohistochemical staining was performed for Ki-67, p53, p16 and podoplanin. In addition, histopathological parameters such as Röwert-Huber grade, inflammatory infiltrate, parakeratosis, elastosis and the presence of acantholysis were evaluated. Results: Pro III lesions were significantly more frequently associated with higher Röwert-Huber grades (AK III: 47.9% vs. 14.3%; p = 0.0004) and with acantholysis (p = 0.0004). No significant differences between the groups were found for Ki-67, p53 and p16. Podoplanin expression, however, was significantly higher in Pro III lesions (93.7% vs. 57.1%, p < 0.0001) and was predominantly localized basally. The combination of a PRO III pattern and podoplanin positivity identified a distinct histopathological subgroup associated with features linked to progression. Conclusions: Podoplanin expression, especially in combination with PRO III pattern and acantholysis, characterizes a histologically and biologically distinct AK subgroup. In contrast, Ki-67, p53 and p16 showed no additional discriminative value in this cohort. Podoplanin could therefore be a useful addition to existing classification systems and in the future support risk-adapted treatment decision. However, prospective longitudinal studies are required to determine its prognostic value. Full article

Background: In actinic keratosis (AK), clinical clearance after field-directed therapies does not necessarily correspond to histological resolution, resulting in subclinical persistence and risk of recurrence. Objective: To provide a practical, up-to-date framework for non-invasive monitoring of treatment response in AK, integrating clinical assessment and dermoscopy with high-resolution imaging techniques, reflectance confocal microscopy (RCM), line-field confocal optical coherence tomography (LC-OCT), and high-frequency ultrasound (HFUS), and to discuss emerging optical biomarkers based on Raman spectroscopy. Results: For each modality, we summarize pre- and post-treatment imaging patterns, proposed response criteria, recommended follow-up timing, and correlations with clinical outcomes (including clearance and AKASI) and, when available, histological findings. The available evidence is derived from a limited number of observational studies, predominantly involving RCM and LC-OCT, whereas data on HFUS and Raman spectroscopy remain comparatively scarce. RCM and LC-OCT allow in vivo assessment of epidermal architectural normalization and reduction of intraepidermal keratinocyte atypia. HFUS captures quantitative trajectories of superficial dermal remodeling, including changes in the subepidermal low-echogenic band (SLEB) and dermal echogenicity after photodynamic therapy and other field treatments. Dermoscopy remains the first-line tool for routine follow-up but may fail to detect minimal subclinical persistence. Finally, we discuss the potential role of in vivo Raman spectroscopy for dynamic molecular endpoints and its possible integration with artificial intelligence–based analytical approaches. Conclusions: A standardized multimodal follow-up strategy improves the accuracy of treatment-response assessment compared with clinical evaluation alone. We propose a technique-specific checklist of minimal response criteria and a pragmatic temporal assessment scheme, and outline a research roadmap to support validation and clinical implementation of non-invasive imaging-guided monitoring in actinic keratosis. Full article

Background: Accurate and timely diagnosis of skin lesions, including Melanoma (MEL), Basal Cell Carcinoma (BCC), Squamous Cell Carcinoma (SCC), Actinic Keratosis (ACK), Seborrheic Keratosis (SEK), and Nevus (NEV), is often hindered by the severe class imbalance and high morphological similarity among pathologies in clinical practice. Although multimodal learning has shown potential in resolving these issues, existing approaches often fail to address predictive uncertainty or effectively integrate heterogeneous clinical metadata. Therefore, this study proposes DermaCalibra, a robust and explainable multimodal framework optimized for small-scale, imbalanced clinical datasets. Methods: The proposed framework integrates three essential modules: First, the Attention-Based Multimodal Channel Recalibration (AMCR) module introduces a probabilistic Bayesian uncertainty estimation mechanism via Monte Carlo dropout to adjust focal loss weights, prioritizing features from underrepresented classes. Second, the Metadata-Driven Dynamic Feature Modulation and Cross-Attention Fusion (MDFM-CAF) module, designed to resolve inter-class visual ambiguity, dynamically rescales dermoscopic feature maps using non-linear clinical context transformations. Lastly, the Gradient Feature Attribution (GFA) module is implemented to provide pixel-level diagnostic heatmaps and metadata importance scores. Results: Evaluated on the PAD-UFES-20 dataset, DermaCalibra achieves a balanced accuracy (BACC) of 84.2%, outperforming current state-of-the-art (SOTA) methods by 3.6%, and a Macro Area Under the Receiver Operating Characteristic Curve (Macro AUC) of 96.9%. Extensive external validation on unseen hospital and synthetic datasets confirms robust generalizability across diverse clinical settings without the need for retraining. Conclusions: DermaCalibra effectively bridges the gap between deep learning complexity and clinical intuition through uncertainty-aware reasoning and transparent interpretability. The framework provides a reliable and scalable computer-aided diagnostic tool for early skin lesion detection, particularly in resource-limited clinical environments. Full article

Cellular senescence is a stress-induced cell-cycle arrest that constrains expansion of ultraviolet-damaged keratinocytes yet can remodel the microenvironment. This systematic review evaluated histological and genetic or epigenetic senescence markers in actinic keratosis (AK), cutaneous squamous cell carcinoma (cSCC), and basal cell carcinoma (BCC). PubMed, Scopus, and Web of Science were searched (January 2005–May 2025); 34 human studies were included. AK showed an early senescent signature with frequent cyclin-dependent kinase inhibitor p21 (p21CIP1) expression (82.1%) and DNA damage signaling, including phosphorylated histone H2AX (gamma-H2AX) positivity (77%). In invasive cSCC, p21^CIP1 fell to 43.9% and tumor suppressor p53 immunoreactivity often declined, whereas cyclin-dependent kinase inhibitor p16 (p16INK4a) commonly accumulated without arrest, including cytoplasmic staining at invasion fronts. Reported escape pathways involved c-Jun N-terminal kinase 2 activity and long noncoding RNA PVT1–dependent repression of p21. Telomerase reverse transcriptase (TERT) promoter mutations were prevalent in cSCC (about 50%) and BCC (up to 78%) but uncommon in AK, consistent with late telomerase activation. Study heterogeneity, variable antibody scoring, and limited assessment of senescence-associated beta-galactosidase and secretory mediators restricted cross-study comparability. Standardized, spatially resolved profiling may refine risk stratification and support senescence-targeted prevention and therapy in keratinocyte cancers. Full article

Basement membrane (BM) breaching is a critical hallmark of cutaneous squamous cell carcinoma (cSCC) invasion. This study aimed to identify novel BM-related genes (BMRGs) to effectively distinguish invasive cSCC from actinic keratosis (AK) and Bowen’s disease (BD), and to identify potential therapeutic targets. Single-cell RNA sequencing was used for BMRGs identification within keratinocytes and fibroblasts clusters. Protein–protein interaction network analysis and Lasso regression were performed for hub BMRGs screening, together with nomogram model construction and validation. In this study, 6–9 central hub BMRGs were identified for each stage during cSCC progression with a good AUC value (>0.8). In keratinocytes, BMRGs such as integrins (ITGB1, ITGA3, ITGA6), laminins (LAMA3, LAMC1), CD44, and FN1 were upregulated in cSCC compared to AK or BD (adjusted p < 0.05); in fibroblasts, BMRGs including ITGB1, ITGAV, LUM, BGN, SDC1, and FN1 were upregulated in cSCC (adjusted p < 0.05), suggesting their collective role in BM breaching and invasion, as well as a higher risk of BD. This study provides novel biological insights into the differentiation of progression pathways from AK or BD to cSCC, as well as potential targets for therapeutic intervention. Full article

The incidence of melanoma and non-melanoma skin cancers (NMSCs) is increasing worldwide. While NMSCs are more common, melanoma remains the most challenging because of its higher aggressiveness. Although the use of sunscreens is key in high-risk populations, it provides limited protection, which highlights the need for alternative solutions. In this review, we discuss current evidence on chemopreventive therapies, as well as their efficacy and adverse events, including immunocompetent and immunosuppressed patients. Acitretin, nicotinamide, 5-fluorouracil, and photodynamic therapy have shown overall promising results in actinic keratosis and squamous cell carcinoma. Nevertheless, more research is needed to establish their efficacy, particularly in melanoma, Merkel cell carcinoma, and cutaneous lymphoma, due to their higher mortality rates. Full article

Background/Objectives: Actinic keratoses (AKs), also known as solar keratoses, are considered premalignant skin lesions that can evolve into squamous cell carcinoma (SCC). Among the available options, 5-fluorouracil (5-FU) remains a cornerstone. Methods: This study is a retrospective analysis of our database of the non-melanoma skin cancer outpatient clinic. The main objective was to evaluate patients treated with 4% 5-FU cream for AK lesions. The efficacy of 4% 5-FU was evaluated retrospectively by measuring the percentage of patients who achieved complete clearance. A secondary efficacy measure was the percentage of partial clearance, defined as at least a 75% reduction in lesion count. Additionally, the study aimed to assess the safety of 4% 5-FU cream. Results: We included 150 patients clinically diagnosed with AK, treated with 4% 5-FU cream and evaluated 432 lesions. Complete clearance of lesions was observed in 138 patients (92%) with partial clearance in 12 patients (8%). At 12 months, the recurrence rate was 11%. Conclusions: Based on our analysis, 4% 5-FU cream is an effective and well-tolerated treatment for AKs, particularly in patients with extensive field cancerization. While local skin reactions are a natural part of its mechanism, they are manageable and do not outweigh clinical benefits. Full article

MicroRNAs (miRNAs) have emerged as critical post-transcriptional regulators in melanoma and non-melanoma skin cancers (NMSCs), yet their full biological and clinical significance remains incompletely defined. This review synthesizes current evidence on miRNA dysregulation across basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), Merkel cell carcinoma (MCC), and melanoma, emphasizing their diagnostic, prognostic, and therapeutic relevance. In BCC, distinct miRNA expression signatures differentiate tumor tissue from normal skin and correlate with histopathological subtypes. miR-383-5p, miR-4705, miR-145-5p, and miR-18a show strong diagnostic potential, while downregulation of miR-34a is consistently associated with greater tumor aggressiveness. Subtype-specific profiles further delineate superficial versus infiltrative lesions, highlighting miRNAs as markers of tumor behavior. cSCC similarly demonstrates characteristic miRNA alterations. miR-31 is markedly upregulated during the transition from actinic keratosis to invasive carcinoma, whereas high miR-205 and low miR-203 levels correlate with poor and favorable prognosis, respectively. Regarding MCC, many miRNAs such as miR-375 and miR-182 may present a clinical value for potential biomarkers, as they are upregulated in MCC. Merkel cell carcinoma has also been linked with Merkel cell polyomavirus (MCPyV). Melanoma exhibits a complex miRNA landscape, including oncogenic miR-18a-5p and miR-146a, and tumor-suppressive miR-128-3p. Several miRNAs correlate with metastatic potential, BRAF mutation status, and therapeutic resistance, particularly miR-181a/b, underscoring their potential as predictive biomarkers. Overall, current evidence supports miRNAs as promising diagnostic, prognostic, and predictive biomarkers in cutaneous oncology. Standardized methodologies and large-scale validation remain essential for their integration into routine clinical practice. Full article

Background/Objectives: Actinic keratosis (AK) is a precancerous lesion that may progress into cutaneous cancer. However, the progression potential of individual lesions remains unpredictable. The histological basal proliferation pattern of AKs may serve as a risk marker for progression, yet it cannot be assessed clinically. The objective was to evaluate whether Olsen grading (hyperkeratosis of AKs) and pain as clinical markers correlate with the histological basal proliferation (PRO) and different histological aspects. Methods: In this retrospective two-center study, 380 clinically diagnosed AKs were graded according to the clinical Olsen classification (I–III) and assessed for pain upon palpation. Histologically, they were classified based on their basal- (PRO I–III) and upward-directed (AK I–III) growth patterns, and additional histopathological features, such as acantholysis, were documented. Results: Olsen grading showed weak correlation with the PRO classification (Spearman’s rho = 0.136, p = 0.008), with exact agreement of 36.3% (κ = 0.07). Pain was significantly associated with higher PRO grades (p = 0.005) and acantholysis (p = 0.023) but not with Olsen grades or upward-directed growth (AK I–III). Conclusions: Olsen grading does not allow reliable prediction of basal proliferation patterns in AKs. Its use as a clinical severity scale may suggest progression relevance; however, no substantiated association with histological indicators of transformation could be demonstrated in this study. The presence of pain, however, correlated with high PRO grades and the presence of acantholysis. Full article