Dermatopathology

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

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

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. Full article

Desmosomes are specialized cell–cell junctions that play a crucial role in maintaining the structural integrity of both cornifying and non-cornifying epithelium. Disruption of desmosomal cohesion in autoimmune, infectious, and other diseases is typically associated with acantholysis, often leading to intraepidermal blisters and erosions. In recent decades, genetic mutations have been identified that impair desmosomal integrity to varying degrees, giving rise to a spectrum of genodermatoses. These conditions, which include palmoplantar keratoderma, epidermolysis bullosa, and ichthyoses, can range from mild to severe, with some forms being syndromic and life-threatening. We investigated dermatopathologic changes in patients with mutations in genes encoding desmosomal proteins seen in consultations at our genodermatoses unit. A series of cases, including keratosis palmoplantaris areata et striata (striated palmoplantar keratoderma type 1), Carvajal–Huerta syndrome, severe dermatitis–multiple allergies–metabolic wasting (SAM) syndrome, ectodermal dysplasia–skin fragility syndrome, and inflammatory peeling skin disease, was examined histologically and, when necessary, immunohistochemically. Findings from our cohort were compared with histopathological consultation cases from our dermatopathology laboratory and previously published cases in the literature. Through these observations, we defined a distinct form of acantholysis associated with desmosomal protein mutations, which we term “desmosomal-type acantholysis.” We outline the spectrum of this newly characterized pattern and highlight its differences from conventional forms of acantholysis. Furthermore, for the first time, we describe incidental cases where “desmosomal-type acantholysis” appears sporadically in solitary acanthoma and in association with a melanocytic nevus. Full article

Blastomycosis-like pyoderma (BLP) is a rare chronic inflammatory dermatosis characterized by exuberant vegetative and verrucous plaques, most frequently associated with bacterial colonization, particularly Staphylococcus aureus. Owing to its striking clinical and histopathological resemblance to squamous cell carcinoma (SCC) and other granulomatous or hyperplastic dermatoses, BLP represents a well-recognized diagnostic pitfall, often leading to delayed diagnosis or unnecessary surgical management. We report an unusual case of bilateral auricular BLP in a 58-year-old apparently immunocompetent woman, initially misdiagnosed as SCC. Comprehensive clinicopathological reassessment revealed pseudoepitheliomatous hyperplasia, intraepidermal neutrophilic microabscesses, and a dense mixed inflammatory infiltrate, findings consistent with a reactive rather than neoplastic process. Microbiological cultures confirmed Staphylococcus aureus, supporting the final diagnosis of BLP and guiding effective antimicrobial therapy. To better contextualize this rare presentation, we reviewed all previously reported cases of BLP, summarizing available clinical, histopathological, microbiological, and therapeutic data. This case further raises the possibility of an association between BLP and systemic inflammatory conditions, as the patient subsequently developed severe colitis, highlighting the potential role of immune dysregulation and the gut–skin axis in disease pathogenesis or a possible temporal association, without allowing causal inference. Beyond inflammatory bowel disease, blastomycosis-like pyoderma has been reported in association with a variety of systemic and immune-mediated conditions, including diabetes mellitus, hematologic malignancies, HIV infection, chronic renal failure, autoimmune disorders, and prolonged immunosuppressive therapies. These associations support the concept that BLP represents a hyperinflammatory reaction pattern occurring in the setting of altered immune surveillance rather than a purely infectious disease. Accurate recognition and management of BLP require careful integration of clinical features, histological findings, and microbiological results. Increased awareness of its diverse presentations is essential to avoid misdiagnosis and to ensure appropriate, conservative treatment. Full article

Cutaneous adnexal carcinomas (CACs) comprise a diverse group of malignant tumors that show morphological differentiation toward one of the four main adnexal structures in normal skin: hair follicles, sebaceous glands, sweat-apocrine glands, and sweat-eccrine glands. These tumors can arise sporadically or may be associated with rare genetic syndromes. A total of 276 CACs cases underwent hybrid capture-based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA). Sequencing data were used to determine microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), genomic ancestry, and COSMIC mutational signatures. PD-L1 expression was evaluated by immunohistochemistry (TPS; Dako 22C3). Statistical analyses were performed using Fisher’s exact test, with false discovery rate correction via the Benjamini–Hochberg method. Sequencing was performed on primary cutaneous tumors in 131 cases (47.4%) and on local recurrence or metastatic site biopsies in 145 cases (52.5%). Across all groups, there was a male predominance (64–81%) and similar mean ages (59–63 years), with apocrine (APO) tumors occurring in older patients than eccrine (ECC) tumors (72 vs. 62 years; p = 0.001). Histologically, 173 tumors (62.7%) were sweat gland-derived (SWT), 55 (19.9%) sebaceous gland-derived (SEB), 14 (5.1%) hair follicle-derived (HRF), and 34 (12.3%) unclassified (UNK). Among SWT tumors, 150 (86.7%) were eccrine and 23 (13.3%) apocrine. SWT tumors included digital papillary adenocarcinomas (DPA, 6.9%), mucinous carcinomas (MC, 6.3%), porocarcinomas (POR, 11.0%), spiradenocarcinomas (SPR, 8.1%), syringoadenocarcinomas (SRNG, 5.8%), and 77 (44.5%) unclassified cases. The number of GA per tumor was highest in SEB compared with SWT tumors (7.9 vs. 4.9; p = 0.005) and lowest in DPA (2.1 vs. 5.0 in non-DPA; p = 0.03). No differences in ancestry distribution were observed. Compared with SWT tumors, SEB tumors exhibited higher frequencies of RB1 (38.2% vs. 8.1%; p < 0.0001) and TP53 alterations (76.4% vs. 43.4%; p = 0.0002), suggesting potential neuroendocrine differentiation. MC tumors showed significantly higher PTCH1 alterations than non-MC tumors (36.4% vs. 1.8%; p = 0.044). MSI-high status was most frequent in SEB tumors compared with all other groups (15.7% vs. 1.2%; p = 0.005), and gLOH > 16% was also more common in SEB than SWT tumors (19.6% vs. 7.2%; p = 0.081). The MMR signature occurred more frequently in SEB than SWT tumors (32.0% vs. 2.1%; p = 0.005). Mean TMB was elevated across most CACs types, ranging from 10.4 mutations/Mb in HRF to 38.8 mutations/Mb in MC, with the exceptions of APO (2.7 mut/Mb; p = 0.001) and DPA (1.4 mut/Mb; p = 0.003). PD-L1 expression was generally low and did not differ significantly between SWT and SEB tumors (37.0% vs. 33.3%; NS). Given the limited data on CAC treatment, this study provides a catalog of commonly observed GA. SEB tumors exhibited the highest frequency of genomic alterations. Prospective clinical trials are needed to determine the prognostic and predictive value of CAC-specific biomarkers for immune checkpoint inhibitor (ICI) response, which is essential for integrating novel therapies into the evolving treatment landscape. Full article

PRAME (Preferentially Expressed Antigen in Melanoma) is increasingly used as an immunohistochemical marker in the evaluation of melanocytic lesions; however, its expression in benign melanocytic proliferations remains incompletely characterized. This study investigated PRAME expression in melanoacanthomas, with particular emphasis on its relationship with ultraviolet exposure and chronic solar damage. A consecutive series of melanoacanthomas was retrospectively analyzed. Melanocytes were identified and quantified using SOX10 immunohistochemistry, while PRAME-positive melanocytes were counted and graded semiquantitatively according to nuclear staining intensity. PRAME expression was correlated with lesion site (photoexposed versus non-photoexposed skin) and with the degree of solar elastosis. Eighty-four cases were evaluated, of which 25 (29.8%) showed at least focal PRAME positivity in melanocytes. Overall melanocytic density assessed by SOX10 did not differ significantly between photoexposed and non-photoexposed lesions. Similarly, stratification based on total PRAME-positive melanocyte counts, irrespective of staining intensity, revealed no significant association with photoexposure. In contrast, analysis restricted to melanocytes with strong nuclear PRAME expression demonstrated a significant enrichment in photoexposed lesions compared with non-photoexposed sites (p < 0.01). Moreover, high-intensity PRAME expression showed a positive association with increasing grades of solar elastosis. These findings indicate that strong PRAME expression in melanoacanthoma could be associated with chronic sun damage and may reflect non-specific, ultraviolet-related modulation rather than malignant transformation, underscoring the importance of contextual interpretation of PRAME immunohistochemistry in diagnostic practice. Full article

Longitudinal melanonychia (LM) results from the deposition of pigment in the nail plate due to increased melanocytic activity within the nail matrix. Recent publications on this topic have helped clarify the main clinical, histological, and evolutionary characteristics of pediatric LM and provide guidance for its appropriate management. In this review, we will examine the literature on the subject. LM is far less common in children than in adults and is most often caused by benign nail matrix lesions. Pediatric LM has specific clinical and histopathologic features, and many of the clinical warning signs used in adults are not applicable to children. Pediatric lesions may show atypical cytologic and even architectural features yet still follow a benign clinical course. Spontaneous regression of LM is common in children, with fading and narrowing of the pigmented band, or even complete disappearance. The vast majority of pediatric LM cases can be managed conservatively with regular follow-up, including clinical photography and onychoscopy. Full article

Biopsies are only performed in less than 1% of all consultations dedicated to paediatric genital dermatology. The objectives of this paper are to review and clarify the histopathological features of the conditions most often biopsied: first, lichen sclerosus, which has a peak incidence in childhood and progresses over years; secondly, pigmented lesions, including atypical genital naevi and common naevi in the context of lichen sclerosus, both histologically differential diagnoses of melanoma, which probably does not present in childhood. And finally, Crohn’s disease, which is a cause of vulval oedema or genital ulceration. Full article