Search Results (28)

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

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

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

Darier′s disease (DD) is a rare, autosomal dominant genodermatosis caused by pathogenic variants in the ATP2A2 gene, which encodes the SERCA2 protein, an endoplasmic reticulum ATPase Ca²⁺ transporter. These mutations impair the intracellular calcium homeostasis leading to increased protein misfolding, endoplasmic reticulum (ER) stress response, and the activation of the unfolded protein response (UPR), culminating in keratinocyte apoptosis and anomalies in interfollicular epidermal stratification. Clinically, the disease is characterized by the presence of skin lesions with hyperkeratotic papules and an increased susceptibility to inflammatory reactions, bacterial and viral infections. The histological hallmarks include acantholysis, dyskeratosis, and increased apoptotic keratinocytes, referred to as “corp ronds”. The SERCA2b isoform is expressed not only in the epidermis but it is present ubiquitously in all tissues, suggesting that its alteration may have multi-organ effects. The review aims to provide a broad overview of the pathology, from intracellular dysfunction to the clinical manifestations, elucidating the molecular effects of SERCA2 variants found in DD patients and exploring the potential cell signaling pathways that may contribute to disease progression. Beginning with an examination of the cellular alterations, our work then shifts to exploring their impact in an organ-specific context, providing insights into new potential therapeutic strategies tailored to clinical manifestations. Full article

Background/Objectives: Hailey–Hailey disease (HHD) is an uncommon genodermatosis with autosomal dominant inheritance caused by loss-of-function mutations in the ATP2C1 gene, which lead to disruption in keratinocyte adhesion and intraepidermal acantholysis. The chronic nature of the disease, its frequent recurrences and the lack of specific treatment pose real challenges in the long-term management of these patients. Recent studies have evaluated the effect of dupilumab, a human monoclonal antibody that blocks interleukin-4 and -13 receptor in refractory HHD, with very promising results. The aim of this study was to review the published data on the use of dupilumab for the treatment of HHD, to present our own experience in the field, and to discuss the mechanisms underlying dupilumab’s beneficial effects in HHD and the future treatment perspectives. Methods: A search of the medical literature on the use of dupilumab in the treatment of HHD was conducted. The terms “Hailey–Hailey disease”, “benign familial pemphigus”, “benign chronic pemphigus”, and “dupilumab” were searched across multiple databases (Medline, Chrocane Library, EMBASE) from inception until 30 September 2024. Results: To date, six manuscripts describing 11 refractory HHD cases treated with dupilumab have been published. All the patients experienced significant clinical improvement. The authors reported sustained disease quiescence in seven patients (64%), monitored for 5 to 24 months. None of the patients experienced adverse effects related to dupilumab. To the existing evidence, we add a new case of recalcitrant HHD successfully treated with dupilumab. Conclusions: Mounting evidence indicates dupilumab as a safe and efficient therapeutic alternative in patients with severe, refractory HHD. However, the long-term efficacy of dupilumab and the optimal therapeutic regimen for HHD are yet to be determined. Full article

The diagnostic utility of immunohistochemistry on paraffin-embedded sections in bullous disorders is useful when frozen tissue is not available. In pemphigus vulgaris and pemphigus foliaceus, an intercellular lace-like staining pattern of IgG4 on lesional tissue by immunohistochemistry has been described, with a comparable sensitivity and specificity to direct immunofluorescence on perilesional tissue. This study aimed to evaluate the staining pattern of IgG4 in non-immunobullous disorders to highlight the potential pitfalls when using this stain. In this study, we conducted a retrospective review of our institution’s database of non-immunobullous disorders where immunohistochemistry of IgG4 was performed to rule out pemphigus. We identified 27 cases where IgG4 immunohistochemistry was performed and observed intercellular IgG4 staining in some cases of Grover disease, bullous impetigo, irritated dermal hypersensitivity reaction, acantholytic actinic keratosis, and graft versus host disease. Our results indicate that the interpretation of IgG4 staining by immunohistochemistry in cutaneous acantholytic disorders should be approached with caution. Confirmation on cryosections with direct immunofluorescence study results is important in these settings. Full article

Paraneoplastic pemphigus (PNP) is a rare autoimmune disorder associated with underlying neoplasms, predominantly Non-Hodgkin Lymphomas, affecting adults aged 45 to 70. This review analyzed 87 articles from MEDLINE/PubMed, Ovid and Scopus focusing on patients with oral manifestations of PNP, emphasizing histological and serological aspects and discussing recent updates on pathogenetic options. Key findings revealed that PNP is often diagnosed before the neoplasm, with Follicular variant Non-Hodgkin Lymphoma and Castleman Disease being the most common associations. Histopathological analysis showed suprabasal acantholysis and inflammation, and serological tests identify a comprehensive autoantibody panel, underscoring the need for standardized diagnostic criteria and improved serological testing. Full article

Better mechanistic understanding of desmosome disruption and acantholysis in Grover’s disease (GD) may improve management of this disease. Recent molecular studies highlighted promising pathways to be explored by directly comparing GD and selected features of associated skin diseases. The association between GD and cutaneous keratinocyte carcinomas, the most prevalent non-melanoma skin cancers (NMSC), is not completely characterized. To review the medical literature regarding GD-associated cutaneous keratinocyte cancers, focusing on molecular features, pathophysiological mechanisms, and disease associations, to help guide future research and patient management. GD has been associated with a variety of skin conditions, but its association with skin cancers has been rarely reported. Between 1983 and 2024, only nine scientific papers presented data supporting this association. Interestingly, we found that GD may mimic multiple NMSCs, as few authors reported GD cases misdiagnosed as multiple cutaneous squamous cell carcinomas for more than 4 years or the presence of superficial basal cell carcinoma-like areas associated with focal acantholysis. In conclusion: (a) GD may be an imitator of multiple NMSCs, and (b) the relationship between GD and NMSCs may reveal promising pathways for the mechanistic understanding of desmosome disruption and acantholysis in GD and may even lead to its reclassification as a distinctive syndrome. Full article

Pemphigus is an autoimmune disease that affects the skin and mucous membranes, induced by the deposition of pemphigus IgG, which mainly targets desmogleins 1 and 3 (Dsg1 and 3). This autoantibody causes steric interference between Dsg1 and 3 and the loss of cell adhesion, producing acantholysis. This molecule and its cellular effects are clinically reflected as intraepidermal blistering. Pemphigus vulgaris-IgG (PV-IgG) binding involves p38MAPK-signaling-dependent caspase-3 activation. The present work assessed the in vitro effect of PV-IgG on the adherence of HaCaT cells dependent on caspase-3. PV-IgG induced cell detachment and apoptotic changes, as demonstrated by annexin fluorescent assays. The effect of caspase-3 induced by PV-IgG was suppressed in cells pre-treated with caspase-3-shRNA, and normal IgG (N-IgG) as a control had no relevant effects on the aforementioned parameters. The results demonstrated that shRNA reduces caspase-3 expression, as measured via qRT-PCR and via Western blot and immunofluorescence, and increases cell adhesion. In conclusion, shRNA prevented in vitro cell detachment and the late effects of apoptosis induced by PV-IgG on HaCaT cells, furthering our understanding of the molecular role of caspase-3 cell adhesion dependence in pemphigus disease. Full article

Autoimmune bullous diseases (AIBDs) are characterized by the formation of vesicles, bullous lesions, and mucosal erosions. The autoantibodies target the cellular anchoring structures from the surface of epidermal keratinocyte named desmosomes, leading to a loss of cellular cohesion named acantholysis. AIBDs are classified into intraepidermal or subepidermal types based on clinical features, histological characteristics, and immunofluorescence patterns. Pemphigus foliaceus (PF) is an acquired, rare, autoimmune skin condition associated with autoantibodies that specifically target desmoglein-1, leading to a clinical presentation characterized by delicate cutaneous blisters, typically sparing the mucous membranes. Several factors, including genetic predisposition, environmental triggers, malignancies, medication use, and vaccination (for influenza, hepatitis B, rabies, tetanus, and more recently, severe acute respiratory syndrome Coronavirus 2 known as SARS-CoV-2), can potentially trigger the onset of pemphigus. With the advent of vaccines playing a pivotal role in combatting the 2019 coronavirus disease (COVID-19), extensive research has been conducted globally to ascertain their efficacy and potential cutaneous adverse effects. While reports of AIBDs post-COVID-19 vaccination exist in the medical literature, instances of PF following vaccination have been less commonly reported worldwide. The disease’s pathophysiology is likely attributed to the resemblance between the ribonucleic acid (RNA) antigen present in these vaccines and cellular nuclear matter. The protein produced by the BNT-162b2 messenger ribonucleic acid (mRNA) vaccine includes immunogenic epitopes that could potentially trigger autoimmune phenomena in predisposed individuals through several mechanisms, including molecular mimicry, the activation of pattern recognition receptors, the polyclonal stimulation of B cells, type I interferon production, and autoinflammation. In this review, we present a comprehensive examination of the existing literature regarding the relationship between COVID-19 and PF, delving into their intricate interactions. This exploration improves the understanding of both pemphigus and mRNA vaccine mechanisms, highlighting the importance of close monitoring for PF post-immunization. Full article

Pemphigus vegetans and pemphigus foliaceus are rare autoimmune blistering diseases characterized by the disruption of desmosomal adhesion proteins, particularly desmoglein 3 and desmoglein 1. We report the case of a 62-year-old male who presented initially with scaly red plaques posing several diagnostic challenges. A histopathological examination revealed subcorneal acantholysis, matching the suspected clinical diagnosis of pemphigus foliaceus. The patient progressed, developing vegetating plaques, and a new biopsy was performed. The new histopathological and direct immunofluorescence exams were consistent with pemphigus vegetans. This case highlights the diagnostic challenges posed by the transition of pemphigus foliaceus to its vegetating form. We discuss the role of desmogleins in the pathogenesis of pemphigus and explore potential therapeutic strategies targeting these specific autoantigens. Full article

Galli–Galli disease (GGD) is a rare genodermatosis that exhibits autosomal dominant inheritance with variable penetrance. GGD typically manifests with erythematous macules, papules, and reticulate hyperpigmentation in flexural areas. A distinct atypical variant exists, which features brown macules predominantly on the trunk, lower limbs, and extremities, with a notable absence of the hallmark reticulated hyperpigmentation in flexural areas. This review includes a detailed literature search and examines cases since GGD’s first description in 1982. It aims to synthesize the current knowledge on GGD, covering its etiology, clinical presentation, histopathology, diagnosis, and treatment. A significant aspect of this review is the exploration of the genetic, histopathological, and clinical parallels between GGD and Dowling-Degos disease (DDD), which is another rare autosomal dominant genodermatosis, particularly focusing on their shared mutations in the KRT5 and POGLUT1 genes. This supports the hypothesis that GGD and DDD may be different phenotypic expressions of the same pathological condition, although they have traditionally been recognized as separate entities, with suprabasal acantholysis being a distinctive feature of GGD. Lastly, this review discusses the existing treatment approaches, underscoring the absence of established guidelines and the limited effectiveness of various treatments. Full article

The mucosal-dominant variant of pemphigus vulgaris (MPV) is an autoimmune disease characterized by oral mucosal blistering and circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3), resulting in life-threatening bullae and erosion formation. Recently, microRNAs (miRNAs) have emerged as promising players in the diagnosis and prognosis of several pathological states. For the first time, we have identified a different expression profile of miRNAs isolated from plasma-derived exosomes (P-EVs) of MPV patients positive for antibodies against Dsg3 (Dsg3-positive) compared to healthy controls. Moreover, a dysregulated miRNA profile was confirmed in MPV tissue biopsies. In particular, a strong downregulation of the miR-148a-3p expression level in P-EVs of MPV patients compared to healthy controls was demonstrated. Bioinformatics prediction analysis identifies metalloproteinase-7 (MMP7) as a potential miR-148a-3p target. An in vitro acantholysis model revealed that the miR-148a-3p expression level was dramatically downregulated after treatment with Dsg3 autoantibodies, with a concomitant increase in MMP7 expression. The increased expression of MMP7 leads to the disruption of intercellular and/or extracellular matrix adhesion in an in vitro cellular model of MPV, with subsequent cell dissociation. Overexpression of miR-148a-3p prevented cell dissociation and regressed MMP7 upregulation. Our findings suggest a pivotal role of P-EV cargo in regulating molecular mechanisms involved in MPV pathogenesis and indicate them as potential MPV therapeutic targets. Full article

Histological risk factors of AKs cannot be directly determined. Recent studies indicate that AKs restricted to the lower third of the epidermis (AK I), with marked basal proliferation (PRO III) and acantholysis, are associated with an increased risk of progression to invasive squamous cell carcinoma (iSCC). To confirm the aforementioned histological risk factors, this study compared AKs from solid organ transplant recipients (sOTRs), known to carry an up to 250-fold higher risk for progression into iSCC, to a matched immunocompetent control group (ICG). In total, 111 AKs from 43 sOTRs showed more AKs (n = 54, 48.7%) graded as AK I compared to 35 AKs (31.5%) in the ICG (p = 0.009). In line with these findings, 89 AKs (80.2%) from sOTRs showed pronounced basal proliferation (PRO III) compared to 37 AKs (33.3%) in the ICG (p < 0.0001). Acantholysis was more frequent in sOTRs than the ICG (59.5% vs. 32.4%, p < 0.0001) and more frequently associated with advanced basal proliferation (p < 0.0001). In conclusion, this study showed that acantholytic AKs graded as AK I and PRO III are predominantly found in a population at high risk of iSCC. Thus, AKs with marked basal proliferation and acantholysis should be assumed to be histological high-risk factors for the progression into iSCC. Full article

The importance of acetylcholine (ACh) in keratinocyte adhesion and acantholysis has been investigated over the last three decades, particularly in the pathophysiology of autoimmune blistering dermatoses. Pemphigus vulgaris (PV) is an autoimmune blistering skin disease where autoantibody-mediated suprabasilar intraepidermal splitting causes flaccid blisters and non-healing erosions of the oral mucosa and sometimes also of the skin. Historically, acantholysis in PV was thought to be driven by anti-desmoglein (Dsg) antibodies. Herein, we describe the role of autoantibodies against keratinocyte muscarinic and nicotinic acetylcholine receptors, as well as the annexin-like molecule pemphaxin that also binds ACh, in the immunopathogenesis of PV. The identification of targets in this disease is important, as they may lead to novel diagnostic and therapeutic options in the future for this potentially deadly disease. Full article