Skin biopsy is one of the most valuable diagnostic procedures in dermatology, particularly when clinical findings alone are insufficient to establish a diagnosis. However, obtaining an accurate histopathological diagnosis depends on multiple steps, and errors at any stage of the biopsy pathway may compromise the final result. This review synthesizes current evidence and available guidelines on best practices for skin biopsy, integrating the practical experience of four internationally recognized dermatopathologists to address areas where evidence is limited or poorly standardized. The review covers biopsy planning, selection of the optimal biopsy site and technique, specimen handling and fixation, grossing and laboratory processing, prevention of technical artifacts, the use of ancillary diagnostic techniques, and clinicopathological correlation, with particular attention to challenging anatomical sites and complex diseases. Diagnostic accuracy depends on obtaining a representative specimen, maintaining high technical standards throughout tissue processing, providing adequate clinical information, and ensuring close communication between the clinician and the dermatopathologist. In selected cases, multidisciplinary review is required to reach a definitive diagnosis. Adherence to these principles can optimize diagnostic yield, reduce avoidable errors, and ultimately improve patient care.
We are grateful for the commentary by Ángel Fernández-Flores on our concept of “desmosomal-type acantholysis”, a distinct histologic form of acantholysis associated with mutations in genes encoding desmosomal proteins [...]
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.
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.
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.
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.
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.
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.
Cutaneous pseudolymphomas are benign reactive lymphoid proliferations that often mimic cutaneous lymphomas both clinically and histologically. A diverse array of inflammatory, infectious, and drug-induced dermatoses can closely resemble cutaneous T-cell lymphomas (CTCLs), particularly mycosis fungoides (MFs), posing significant diagnostic challenges. These mimickers may show histopathological features such as epidermotropism, dense lymphocytic infiltrates, or even clonality, making accurate differentiation crucial to avoid overtreatment. This review endeavors to comprehensively discuss the clinicopathologic features of the various inflammatory and infectious dermatoses that may simulate CTCL, drawing on illustrative examples across disease categories. By highlighting important comparative features and emphasizing the importance of clinicopathologic correlation, this review outlines practical strategies for distinguishing true lymphoma from its inflammatory mimics.
AIM:This study aimed to identify the clinical and pathological features of primary cutaneous melanomas in young patients, comparing them with those of older patients. MATERIALS AND METHODS:We performed a retrospective study observing the differences with respect to clinical and pathological features in young patients versus older patients. We distributed the cases into two groups: patients < 40 years diagnosed with cutaneous melanoma and patients ≥ 40 years diagnosed with cutaneous melanoma. RESULTS:From the total number of primary cutaneous melanomas diagnosed, 11% of cases were represented by young patients. The clinical and pathological features more frequently associated with cutaneous melanomas in AYAs (adolescents and young adults) were represented by the superficial spreading subtype (p = 0.0003), a brisk inflammatory infiltrate (p = 0.0061), a pT1-pT2 pathological stage (p = 0.0183), decreased mitotic activity (p = 0.0186), decreased Breslow index (p = 0.0301), and female sex (p = 0.022). CONCLUSIONS:The most important features of cutaneous melanomas diagnosed in AYA patients were represented by the superficial spreading subtype, the presence of a brisk inflammatory infiltrate, and a pT1-pT2 pathological stage.
Melanocytic nevi exhibiting perineuriomatous differentiation are rare and pose significant diagnostic challenges due to their low incidence and morphological resemblance to other cutaneous spindle-cell lesions, including desmoplastic melanoma. In this report, we describe the clinical, dermoscopic, microscopic, and immunohistochemical features of a perineuriomatous melanocytic nevus on the right mid-forearm of a 73-year-old Caucasian man. Given the scarcity of reported cases, documenting additional examples is crucial for refining clinicopathological diagnostic criteria. Accurate identification relies on thorough histopathological and immunohistochemical assessment. By presenting the current case, we aim to enhance diagnostic accuracy and raise awareness of this uncommon nevus. A clearer understanding of these characteristics will help dermatologists and dermatopathologists identify this nevus and distinguish it from other cutaneous spindle-cell proliferations.
Cutaneous hematologic neoplasms in children are relatively rare and encompass a wide range of lymphoproliferative and myeloproliferative disorders. This review explores and updates the classification, clinical presentation, diagnostic challenges, histopathology, and management of pediatric lymphomas, lymphoproliferations, and leukemias that may be seen in the skin. The most frequent of them are lymphomatoid papulosis (LyP) and mycosis fungoides (MF), and are discussed first, with a particular focus on differential diagnosis and overlaps with benign lesions-mainly pityriasis lichenoides-which raises questions regarding the delineation of these entities and their potential interconnection. It is important to underline that most cutaneous lymphoproliferations are indolent in children: primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder, subcutaneous panniculitis-like T-cell lymphoproliferation (non-associated with HAVCR2 mutations), primary cutaneous marginal zone lymphoproliferative disorder, and EBV-related lymphoproliferative disorders. However, aggressive hematologic malignancies, although rarer, must not be missed; these are mostly leukemias (but not all forms) and blastic plasmacytoid dendritic cell neoplasm. We emphasize the importance of clinical-pathological correlation, with clonality studies playing a crucial role in some cases. Management strategies are briefly reviewed, ranging from skin-directed therapies like phototherapy and corticosteroids to systemic treatments for more aggressive forms of leukemia cutis and lymphomas.
A 23-year-old man reported a 3-year history of slowly growing, slightly itchy, flesh-colored papules on the distal glans penis. He denied any history of trauma or previous treatment. Additionally, he experienced no difficulties with urination, discharge, or erectile function. Upon examination, three firm, dome-shaped papules were found to be attached to the skin but mobile over the underlying tissues. There was no regional lymph node enlargement, hardening, or fluctuation observed. Histopathological analysis revealed a well-defined, encapsulated tumor in the dermis, consisting of spindle cells interspersed with varying numbers of axons.
Granuloma annulare is a non-infectious granulomatous dermatosis with a probable pathogenic mechanism of delayed-type hypersensitivity, in which the dermal histiocytic granulomatous infiltrate is usually accompanied by a lesser component of lymphocytes. Although there are more common clinical and histopathological patterns of presentation, there are less well-known variants that may pose significant diagnostic challenges by mimicking other inflammatory cutaneous processes or even neoplastic conditions. One of the rarest forms of granuloma annulare is the pseudolymphomatous variant, in which the lymphocytic component is not only highly prominent but may, in some cases, partially or completely obscure the histiocytic component itself. This feature, together with the fact that the clinical presentation of this variant is often atypical—frequently lacking the characteristic annular morphology of conventional granuloma annulare—renders the diagnosis particularly challenging. From an immunohistochemical standpoint, the infiltrates described are predominantly composed of T cells, with only a sparse and scattered B-cell component. In this article, we present a case of granuloma annulare with a pseudolymphomatous B-cell component (PAX5+, CD79+) and minimal T-cell involvement, observed in a 4 mm skin nodule located on the shoulder of a 48-year-old male. This case therefore broadens the concept of pseudolymphomatous granuloma annulare to include infiltrates predominantly composed of B lymphocytes.
Background and Objectives: Sentinel lymph node biopsy (SLNB) is increasingly used for high-risk, clinically node-negative cutaneous squamous cell carcinoma (cSCC), yet pathological reporting remains binary, lacking morphological stratification. The prognostic relevance of nodal tumor burden subtypes-isolated tumor cells (ITC), micrometastases, and macrometastases-is well established in melanoma and breast cancer but remains uncharacterized in cSCC. We aimed to describe the morphological spectrum of sentinel lymph node involvement in a consecutive institutional cohort and determine whether primary tumor characteristics predict the extent of nodal colonization. Materials and Methods: We conducted a retrospective-observational study at Clinical Center Niš (Serbia) including 35 consecutive clinically N0 high-risk cSCC patients who underwent SLNB using a dual-tracer protocol (99mTc-labeled albumin and methylene blue). Sentinel nodes were processed by serial sectioning with hematoxylin-eosin and pancytokeratin (AE1/AE3) immunohistochemistry. Deposits were classified as ITC (≤0.2 mm), micrometastases (>0.2-2.0 mm), or macrometastases (>2.0 mm). Clinicopathologic predictors were evaluated using the Mann-Whitney U test, Fisher's exact test, the Kruskal-Wallis test, and the Spearman rank correlation test. Results: SLN involvement was identified in 12 of 35 patients (34.3%). Among positive cases, ITC accounted for 6 patients (50.0%), micrometastases for 5 (41.7%), and macrometastasis for 1 (8.3%)-minimal nodal disease constituting 91.7% of positive findings. No primary tumor feature-including diameter, thickness, grade, perineural invasion, or lesion multiplicity-significantly distinguished ITC from overt metastatic deposits. Patients with ITC showed numerically higher median tumor thickness (8.0 mm) than those with micrometastases (4.0 mm), though this did not reach significance (Kruskal-Wallis p = 0.065). Conclusions: SLN positivity in high-risk cSCC is morphologically heterogeneous, with minimal nodal disease predominating. Primary tumor features do not reliably stratify the extent of nodal colonization. Structured tumor-burden reporting-distinguishing ITC, micrometastases, and macrometastases-should be adopted as standard practice to enable meaningful prognostic comparisons and inform individualized management.
Inflammatory skin diseases are characterized by complex interactions between immune pathways, epidermal barrier function, and environmental triggers, leading to distinct clinical and histopathological features. This narrative review aims to integrate current knowledge on the cutaneous immune microenvironment across major inflammatory skin diseases, including atopic dermatitis, psoriasis, hidradenitis suppurativa, and vitiligo. A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus, focusing on studies published between 2021 and early 2026. The findings highlight disease-specific immune signatures, such as Th2-driven inflammation in atopic dermatitis, IL-23/Th17 axis activation in psoriasis, neutrophil-dominated responses in hidradenitis suppurativa, and cytotoxic T-cell-mediated melanocyte destruction in vitiligo. These molecular pathways are closely reflected in histopathological patterns, emphasizing the link between morphology and immunopathogenesis. Advances in targeted therapies, including biologics and Janus kinase inhibitors, demonstrate the clinical relevance of these pathways and support a transition toward mechanism-based treatment strategies. Dermatopathology is increasingly contributing to precision medicine approaches by supporting correlations between tissue features, immune pathways, and potential therapeutic targets. This review provides a framework for improved disease stratification and for the development of personalized treatment strategies in inflammatory skin diseases.
The authors would like to make the following corrections to this published paper [...]
An 86-year-old man presented with a slowly enlarging, subject to chronic mechanical irritation, pedunculated keratotic papule on the plantar tip of the right hallux in the setting of severe peripheral arterial disease. Excision was deferred until after endovascular revascularization to reduce the risk of nonhealing and limb complications, after which the lesion was removed without wound sequelae. Histopathology demonstrated a conical papule with a central collagenous core and an overlying cap of compact hyperkeratosis. This case highlights key clinicopathologic features that distinguish acral keratotic tumors and underscores the importance of perfusion optimization when planning elective excision on an ischemic limb.
