Dermatopathology, Volume 13, Issue 3 (September 2026) – 14 articles

Background: Psoriasis is a chronic inflammatory skin disease due to genetic susceptibility and multiple environmental factors. Transient receptor potential vanilloid 4 (TRPV4) is a calcium channel extensively expressed throughout the body with multiple functions. However, the role of TRPV4 in imiquimod (IMQ)-induced -psoriasis progression remains unclear although it is ubiquitously expressed in skin tissues and participates in cutaneous mechano- and thermo-sensation. Methods: Both in vivo and in vitro studies were performed in murine skin tissue and isolated cells. TRPV4 expression, autophagy, and Akt/mTOR phosphorylation were assessed by Western blot and reactive oxygen species (ROS) generation was examined by MitoSOX staining. Cytokine levels were measured by ELISA and cell proliferation was determined by CCK staining. The severity of psoriasis was also checked by psoriasis severity index (PSI), scale and thickness scoring and microscopic observations. Results: IMQ-induced psoriasis was remarkably attenuated in TRPV4 knockout mice compared with their wild-type counterparts, accompanied by reduced expression of several inflammatory cytokines. Deletion of TRPV4 diminished ROS production and Akt/mTOR phosphorylation. In vitro experiments showed that IMQ caused a concentration-dependent increase in autophagy, characterized by an initial increasing phase followed by a declining phase in primary keratinocytes. IMQ-induced autophagic activity was enhanced via Calmodulin/Akt pathway suppression while weakened by CaMKKβ/AMPK pathway inhibition. Moreover, blockade of the Calmodulin/Akt pathway significantly reduced IMQ-induced ROS production and psoriasis severity, whereas inhibition of the CaMKKβ/AMPK pathway exacerbated IMQ-induced psoriasis progression through ROS accumulation. Conclusions: Both CaMKKβ/AMPK and Calmodulin/Akt signaling pathways, as downstream components of TRPV4, are involved in IMQ-induced psoriasis: lower IMQ dosage activates AMPK, thereby preventing psoriasis by ROS clearance, whereas higher IMQ dosage activates Calmodulin and exacerbates psoriasis. Our findings reveal the potential values of targeting TRP-related channels in IMQ-induced psoriasis. Full article

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. Full article

Vasculitis encompasses a heterogeneous group of diseases characterized by the inflammation of blood vessels. In children, the diagnosis of vasculitis with cutaneous involvement relies on a combination of clinical evaluation, histopathological examination, and, in some cases, genetic investigations. Diagnosing pediatric vasculitis remains particularly challenging due to overlapping clinical manifestations, variable disease courses, and the evolving nature of histological features. Histopathological assessment aims to confirm inflammation of the vessel walls—either readily visible at low magnification or requiring serial sections—and to characterize the inflammatory infiltrate and other key features that aid in classifying the vasculitis subtype. Accurate diagnosis requires ongoing dialog and collaboration among multiple specialists. In this article, we present the clinical and histopathological features of the most common pediatric vasculitides—including IgA vasculitis and polyarteritis nodosa—as well as newly recognized entities such as COVID-19-associated vasculitis and monogenic vasculitides. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer (NMSC) and represents the leading cause of NMSC-related deaths. Despite its growing global burden, comprehensive epidemiological and clinicopathological data from Easter Europe remains limited. This study aimed to evaluate the epidemiological, clinical, histopathological, and surgical characteristics of cSCC diagnosed before, during and after the COVID-19 pandemic. Methods: We conducted a retrospective, descriptive observational study including 332 lesions diagnosed between January 2017 and December 2025 at the Clinical Pathology Department of the Mureș Clinical County Hospital. Demographic, epidemiological, topographic, histopathologic, surgical, and volumetric parameters were analyzed. Tumours were stratified into low-, high-, and very-high-risk categories according to the National Comprehensive Cancer Network (NCCN) criteria. Results: The cohort demonstrated a significant male predominance (n = 193 vs. n = 139; p = 0.0355), with females presenting a higher median age (77 vs. 75; p = 0.0489). Lesions were predominantly located in the head and neck region (n = 216; p < 0.0001), which was significantly associated with very-high-risk tumours (p = 0.0051). Low-risk tumours accounted for 62.35% of cases, while high-risk and very-high-risk lesions comprised 19.88% and 17.77%, respectively (p < 0.0001). Ulcerations were strongly associated with very-high-risk tumours (p < 0.0001). Poor differentiation was more frequent outside the head and neck region (p < 0.0001) and varied significantly across the pandemic periods (p = 0.0349). Tumoral and excision volumes were higher in very-high-risk (p = 0.0070; p = 0.0004) and ulcerated tumours (p < 0.001), with a peak in volume during the COVID-19 period (p < 0.0001). A decrease through the years of diagnosis was observed in tumoral volumes (r = −0.2295; p < 0.0001) and patients showed a weak positive correlation with diagnosis year (r = +0.13; p = 0.019). Conclusions: The study provides an epidemiological and clinicopathological characterization of cSCC within one of the largest Romanian cohorts to date. Tumour aggressiveness was primarily driven by histopathological and topographical features rather than demographic factors. While the COVID-19 pandemic did not induce persistent changes in tumour risk profiles or surgical outcomes, it influenced diagnosis timing and tumour burden. These findings highlight the importance of incorporating temporal and emerging systemic factors, such as pandemics, and infectious events, into future epidemiological models to improve preparedness, early detection, future treatment schemes, and risk stratification in cSCC. Full article

The integration of immunohistochemical biomarkers like PRAME (Preferentially Expressed Antigen in Melanoma) into the histomorphological assessment of melanocytic lesions is gaining prominence. While PRAME’s diagnostic value is widely recognized, its independent weight compared directly to classical morphology remains underexplored in large, challenging cohorts. This retrospective study quantifies the diagnostic utility of PRAME alongside traditional histomorphology in a high-risk cohort of 954 primary melanocytic lesions (335 nevi, 215 melanomas in situ, 404 invasive melanomas) where PRAME was clinically requested to resolve diagnostic ambiguity. Using Firth’s penalized likelihood regression, a baseline diagnostic model utilizing 13 histomorphological features was established and subsequently integrated with PRAME expression. The pure morphology baseline model demonstrated a high cross-validated area under the curve (AUC) of 0.969. As a standalone marker, PRAME achieved an AUC of 0.895, with a diffuse expression score of 4+ yielding peak specificity (94.3%) and moderate sensitivity (77.9%). Integrating PRAME into the morphological model significantly enhanced diagnostic accuracy (AUC: 0.980; p < 0.001), establishing PRAME as a dominant independent predictor of malignancy alongside core features like junctional atypia and upward melanocytes (Odds Ratio 19.08 for Score 4+). Analysis of discordant cases revealed that completely PRAME-negative melanomas were morphologically indistinguishable from typical PRAME-positive melanomas. Conversely, diffusely PRAME-positive (4+) nevi exhibited significantly higher rates of upward migrating melanocytes, constituting a critical diagnostic pitfall. In conclusion, while classic histomorphology remains the indispensable gold standard in dermatopathology, PRAME functions as a highly objective, reproducible tie-breaker. The synergistic integration of PRAME with morphological assessment effectively resolves diagnostic ambiguity and maximizes diagnostic confidence in challenging melanocytic lesions. Full article

Halo nevus (HN), also known as Sutton nevus or leukoderma acquisitum centrifugum, is a melanocytic lesion characterized by a depigmented halo surrounding a central nevus. Although HN is a benign dermatological condition, increasing evidence indicates that HN represents a dynamic in vivo model of melanocyte-directed immune response with relevant implications for autoimmunity, pigmentary disorders, melanoma regression, and tumor immunosurveillance. The pathogenesis is primarily mediated by CD8+ cytotoxic T lymphocytes via interferon-γ-driven pathways, leading to targeted destruction of melanocytes. However, recent studies have highlighted the importance of immune regulatory mechanisms, including PD-L1-expressing neutrophils and FOXP3+ regulatory T cells, which limit excessive immune-mediated damage and may contribute to the self-limited course and repigmentation observed in some lesions. Additional cytotoxic mediators, particularly granulysin, appear to strengthen melanocyte-directed cytotoxicity, while dendritic cells, macrophages, Langerhans cells, neutrophils, and natural killer cells contribute to antigen presentation, tissue remodeling, and immune resolution. HN shares key immunopathogenic features with vitiligo and melanoma regression but differs from both conditions due to its localized, tightly regulated behavior. Moreover, the halo phenomenon is not restricted to melanocytic lesions, supporting the view that it reflects a broader immune pattern rather than a disease-specific entity. This review provides a comprehensive synthesis of the clinical, histopathological, immunological, diagnostic, and translational aspects of halo nevus. Based on the available evidence, we propose a self-limited melanocyte autoimmunity model to explain the characteristic balance between melanocyte destruction, immune regulation, and spontaneous resolution observed in halo nevi. Full article

Histopathologic melanoma diagnosis extends beyond melanocytic cytology to encompass non-melanocytic features: solar elastosis patterns, stromal regression, adnexal relationships, epidermal reaction patterns, and the host inflammatory response. These “old school” low-power clues are particularly valuable on sun-damaged skin, where benign nevi, reactive melanocytic hyperplasia, and melanoma in situ share overlapping features. Quantitative data support two elastosis-based signs: the “umbrella sign” (reduced elastosis beneath the lesion’s central third; PPV (Positive Predictive Value) for nevus, 96%, and NPV (Negative predictive Value) for melanoma, 74%; calculated from raw cohort data) and the “purple fiber sign” (100% specificity, 30% sensitivity for nevus), both from a cohort of 81 actinically damaged lesions. Regression—identified by compressed elastic layers displaced to the reticular dermis, fibrosis, melanophages, and inflammation—aids diagnosis but complicates distinction from surgical scar. The maturation state of tertiary lymphoid structures (TLSs) within the regression zone, ranging from immunosuppressive immature aggregates to anti-tumoral mature structures with germinal centers, may explain the variable prognostic significance of histologic regression. Epidermal hyperplasia over thick melanomas reflects angiogenesis-related changes, while effacement is a practical red flag in spitzoid lesions. Ancillary tests are most productive when morphology has already framed the differential. These non-melanocytic clues remain indispensable as the foundation for rational ancillary testing. Full article

Background: Melanoma incidence is rising rapidly worldwide and stands out due to its high lethality. Despite advances in clinical treatment and in understanding melanoma-sensitive genes and molecular pathogenesis, a specific area of ongoing research is the connection between stress-related β-adrenergic receptors (ARs), hypoxia, and neovascularization in melanoma tumor progression. This exploratory study aimed to investigate the expression of β3-AR, HIF-1α, and CD31 in several cellular subsets of atypical melanocytic lesions and their interplay in promoting melanoma malignancy. Methods: Twenty-seven patients with melanocytic lesions at different stages that were surgically removed were retrospectively selected; clinical-pathological and dermoscopic data were collected. Results: Immunohistochemical and digital evaluation revealed a significant upregulation of β3-AR in malignant melanoma melanocytes and in macrophages from invasive >pT1a melanomas compared to dysplastic nevi. Increased HIF-1α expression in malignant melanocytes and CD31 expression levels in >pT1a melanomas were observed. Ulcerated lesions exhibited a higher percentage of β3-AR, HIF-1α, and CD31 expression. Pearson correlation analysis revealed positive associations among these markers in human malignant melanoma, suggesting a potential relationship between adrenergic signaling, hypoxia, and tumor vascularization. Conclusions: These exploratory findings suggest that β3-AR, HIF-1α, and CD31 may represent interconnected components of the melanoma microenvironment. Unraveling these interactions in larger, independent cohorts and functional studies may provide additional insights into melanoma biology and help define their potential translational relevance. Full article

Background/Objectives: Hydroxychloroquine is widely used in the treatment of autoimmune and dermatologic diseases; however, it may rarely induce severe cutaneous adverse reactions. Acute Generalized Exanthematous Pustulosis is an uncommon, acute pustular eruption most frequently associated with antibiotics. Hydroxychloroquine-induced AGEP remains relatively rare and diagnostically challenging due to its atypical and prolonged clinical course. Case presentation: We report the case of a 45-year-old woman with rheumatoid arthritis and a complex medical history who developed generalized urticarial and pustular dermatosis following re-exposure to hydroxychloroquine. Notably, the patient had experienced a similar cutaneous reaction after previous exposure to the same medication several years earlier. Ten days after completing a treatment course of hydroxychloroquine, she developed rapidly progressive pruritic erythematous and urticarial plaques that evolved into generalized annular lesions with peripheral scaling and grouped sterile pustules. Laboratory evaluation demonstrated leukocytosis, intermittent eosinophilia, and elevated IgE levels, while the infectious workup was negative. Histopathological examination revealed subcorneal pustules with neutrophilic infiltration, mild spongiosis, and scattered individual eosinophils, perivascular inflammatory infiltrates, findings consistent with AGEP. Retrospective assessment using the EuroSCAR scoring system classified the reaction as probable AGEP, while the Naranjo adverse drug reaction scale supported a probable causal relationship with hydroxychloroquine. Clinical improvement was achieved after withdrawal of the drug and treatment with systemic corticosteroids and supportive therapy. Conclusions: This case highlights the importance of recognizing atypical presentations compatible with hydroxychloroquine-induced probable AGEP and emphasizes the diagnostic value of a positive rechallenge as supportive evidence of drug causality. Early recognition and prompt discontinuation of the offending agent are essential to prevent severe complications and recurrence. Full article

Syphilis remains one of the most prevalent sexually transmitted infections. Serology is the diagnostic gold standard, but skin biopsies aid in ambiguous cases. Treponemas can be detected in tissue by immunohistochemistry (IHC) and polymerase chain reaction (PCR); however, their comparative performance across disease stages has not been extensively studied. This retrospective study of 48 formalin-fixed, paraffin-embedded (FFPE) skin biopsies from syphilis cases compared Treponema pallidum IHC and PCR. Of 48 biopsies, 42 (88%) were positive by T. pallidum–specific PCR, whereas IHC identified 45 (94%; p = 0.04). Organisms were denser in primary syphilis (p = 0.03) and predominantly involved the lower third of the epidermis. In 7 of 45 biopsies (15%), treponemas were only detected in the dermis (all secondary syphilis). Therefore, Treponema pallidum IHC demonstrated a slight advantage over PCR, but low Treponema density in about 40% and epidermal absence in nearly 20% of secondary syphilis biopsies highlight a substantial risk of overlooking treponemas on IHC. Systematic assessment including endothelium and perivascular areas is essential. Full article

Proliferative nodules (PNs) are benign, well-limited melanocytic proliferations that can occur within congenital nevi, particularly larger ones. Although they may mimic melanoma clinically and histologically, PNs are characterized by a monomorphic, well-defined cell population with peripheral blending with the adjacent nevus cells, and a lack of severe atypias, numerous mitoses (in most instances), necrosis, or inflammation. They generally present at birth or early childhood, and even with cytological atypia, they do not undergo malignant transformation. The risk of malignancy associated with a large/giant congenital nevus is low but increases with size and the presence of multiple satellite lesions. Diagnostic tools, including immunohistochemistry and, in selected cases, molecular techniques such as CGH-array or RNA-seq, can help differentiate atypical PNs from melanoma. Awareness of this entity and its diverse histological features is crucial to avoid over-diagnosis of malignancy and unnecessary interventions. Here we report a case of atypical PNs in a giant congenital nevus and discuss the literature. Full article