Enigma of Acantholytic and Clear Cell Changes in Oral Squamous Cell Carcinoma.

Only limited cases have been reported about the clear cell variant of squamous cell carcinoma occurring in the oral cavity. The present study regards the case showing the histopathological features of both the clear cell and acantholytic variants of oral squamous cell carcinoma. A review of the literature has been done to understand the pathogenesis of those changes. Also, a hypothesis has been given that the clear cell changes could be the consequences of the cascades of the acantholytic process and not a separate entity. Therefore, more research is required to confirm this hypothesis and understand the prognosis of the lesion.

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models.

Pemphigus is a life-threatening, chronic, autoimmune bullous disease affecting both the skin and the mucous membranes. Based on the mainstream concept that blister formation occurs upon binding of autoantibodies to their antigen proteins (desmoglein1, DSG1 and desmoglein3, DSG3), current therapies mostly aim to suppress the immune system. To avoid the severe side effects associated with the chronic use of immunosuppressive treatments, we have developed PC111, a fully human monoclonal antibody targeting human Fas ligand (FasL). We have provided a number of in vitro and in vivo evidences showing that soluble FasL induces keratinocyte apoptosis followed by acantholysis. An anti-murine FasL prevents blister formation in the pemphigus neonatal mouse model. To confirm the mechanism of action (MoA) and the efficacy of PC111 in a human pemphigus context, we used the keratinocyte dissociation assay and two independent Human Skin Organ Cultures (HSOC) pemphigus models. PC111 reduced acantholysis in vitro, as shown by the dose-dependent reduction of fragments in the monolayer cultures. In the first HSOC model, normal human skin was subcutaneously injected with a scFv antibody fragment directed against DSG1 and DSG3, resulting in a severe acantholysis (70-100%) after 24 hours. PC111 inhibited blister formation to around 50% of control. In the second model, normal human skin was injected with a mixture of pemphigus patients' autoantibodies resulting in a less severe acantholysis (20-30%). PC111 significantly suppressed blister formation to more than 75% up to 72 hours. These results confirm PC111 MoA and demonstrates the efficacy of the anti-FasL antibody also in a pemphigus setting.

Acantholytic Nodular Basal Cell Carcinoma.

ABSTRACT: Acantholysis is a microscopic finding describing the breakdown of desmosomes of keratinocytes and the formation of intraepithelial clefts after the loss of cohesion of keratinocytes. It can be observed in keratinocytic neoplasms, typically actinic keratoses and squamous cell carcinomas, and defines the acantholytic variants of these entities. Acantholysis has so far been reported in only 4 cases of basal cell carcinomas (BCCs), mainly of the superficial type. A case of an otherwise typical nodular BCC showing features of acantholysis is presented here. Because BCCs are keratinocytic neoplasms, the finding of acantholysis in them is not totally surprising; however, the reason why it is only very exceptionally observed in BCCs is unclear.

Association of Somatic ATP2A2 Damaging Variants With Grover Disease.

Importance: Grover disease (GD), a truncal eruption that typically occurs in older individuals, is exacerbated by sweating, irradiation, cancers, medications, kidney failure, and organ transplantation. The pathobiology of GD remains unknown. Objective: To determine if damaging somatic single-nucleotide variants (SNVs) are associated with GD. Design, Setting, and Participants: In this retrospective case series, we identified consecutive patients from a dermatopathology archive over a 4-year period (January 2007 to December 2011) who had 1 biopsy with a clinical diagnosis of GD confirmed via histopathologic findings and another non-GD biopsy. Participant DNA was extracted from both biopsy tissues and sequenced to high depth with a 51-gene panel to screen for SNVs in genes previously associated with acantholysis and Mendelian disorders of cornification. Analysis took place between 2021 and 2023. Main Outcomes and Measures: Comparative analysis of sequencing data from paired GD and control tissue was employed to identify SNVs predicted to affect gene function, which were exclusive to, or highly enriched in, GD tissue. Results: Overall, 12 of 15 cases of GD (12 men and 3 women; mean [SD] age, 68.3 [10.0] years) were associated with C>T or G>A ATP2A2 SNVs in GD tissue; all were predicted to be highly damaging via combined annotation dependent depletion (CADD) scores, and 4 were previously associated with Darier disease. In 9 cases (75%), the GD-associated ATP2A2 SNV was absent from control tissue DNA, and in 3 cases (25%), ATP2A2 SNVs were enriched 4- to 22-fold in GD vs control tissue. Conclusions and Relevance: In this case series study of 15 patients, damaging somatic ATP2A2 SNVs were associated with GD. This discovery expands the spectrum of acantholytic disorders associated with ATP2A2 SNVs and highlights the role of somatic variation in acquired disorders.

Concomitant nivolumab-associated Grover disease and bullous pemphigoid in a patient with metastatic renal cell carcinoma.

Immune checkpoint inhibitor (ICI)-induced bullous pemphigoid (BP) and Grover disease (GD) are uncommon, and concomitant GD and BP is rarer still. We report a third case of concomitant BP and GD associated with nivolumab with emphasis on the clinical, histopathologic and immunofluorescence findings as well as differential diagnoses. A 73-year-old male with metastatic renal cell carcinoma on nivolumab developed erythematous scaly papules on the trunk with biopsy showing suprabasal acantholysis with dyskeratosis, consistent with GD. Subsequently, he developed widespread lesions on arms, legs, trunk, and scrotum with new vesiculobullae and urticarial lesions. Biopsy of a vesicle showed subepidermal blister with numerous eosinophils and neutrophils, and immunofluorescence and serological studies were supportive of BP. He continued to have clinically apparent GD that was confirmed on repeat biopsy. The patient was diagnosed with concomitant GD and BP induced by nivolumab and successfully treated with dupilumab. The relationship between ICI-induced GD and BP is not well understood; it has been suggested that T-cell activation against the BP180 antigen expressed on surface of tumor cells may predispose susceptible individuals to BP. Subsequent ICI-induced GD may create keratinocyte injury needed to expose additional proteins to reactivated and autoreactive T-cells, leading to autoimmunity. An important differential diagnosis is bullous GD, which can be distinguished by negative immunofluorescence and serological studies.

Assessment of Blue Light Phototherapy for Grover Disease: A Nonrandomized Controlled Trial.

This nonrandomized clinical trial assesses treatment of patients diagnosed with Grover disease with blue light phytotherapy for several weeks.

Anti-desmoglein 1 antibody-positive mother and antibody-negative child with Darier's disease.

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis.

Paraneoplastic Pemphigus Autoantibodies Against C-terminus of Desmoplakin Induced Acantholysis In Vitro and In Vivo.

Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease associated with underlying neoplasms and characterized by antibodies against desmoglein 3 (Dsg 3) and plakins. Autoantibodies against desmoglein 3 in sera of patients with PNP have been proven to cause acantholysis in vivo in neonatal mice. As a member of the plakin family, autoantibodies against desmoplakin were detected frequently by immunoprecipitation in the sera of PNP. The recombinant C-terminus of desmoplakin was expressed and purified to adsorb the specific autoantibodies against the C-terminus of desmoplakin. In vitro dispase-dependent keratinocyte dissociation assay and in vivo IgG passive transfer into neonatal mice assay were performed, followed by the electronic microscopy examination and TUNEL assay. We found that anti-C terminus of desmoplakin autoantibodies caused blisters and acantholysis in mice skin at a dose-dependent manner. Moreover, dissociated fragments were observed after incubation with the purified IgG against desmoplakin, compared with normal human IgG (P-value =0.0207). The electronic microscopy examination showed the disconnection of keratin intermediate filaments from desmosomes. Lastly, apoptosis of keratinocytes in the TUNEL assay was all detected in the skins of neonatal mice after injection of the anti-C terminus of desmoplakin autoantibodies. Taken together, the study suggests that autoantibodies against the C-terminus of desmoplakin might be pathogenic in PNP.

Low SOCS3 expression in CD4+ T cells from pemphigus vulgaris patients enhanced Th1- and Th17-cell differentiation and exacerbated acantholysis via STAT activation.

OBJECTIVE: Pemphigus vulgaris (PV) is a chronic inflammatory autoimmune blistering disease. Aberrant SOCS3/STAT pathway activation is associated with many autoimmune diseases. This study explored the relationship between activation of the SOCS3/STAT pathway and abnormally increased proportions of Th1 and Th17 cells in the peripheral blood of PV patients as well as the effect of CD4+ T cells with abnormal SOCS3/STAT pathway activation on acantholysis. METHODS: In PV patients, the proportions of Th1 and Th17 cells in peripheral blood, the levels of IFN-γ and IL-17 in serum and the mRNA levels of SOCS3 and STAT1/3 in CD4+ T cells were detected. Then, SOCS3-knockdown primary CD4+ T cells were prepared, and cocultured with HaCaT cells. Finally, after SOCS3 knockdown and coculture, CD4+ T cells were collected, and the proportions of Th1 and Th17 cells, the protein levels of STAT1/3 and p-STAT1/3, and the levels of IFN-γ and IL-17 were measured. After 2 days of coculture, HaCaT cells were collected, inflammatory factors mRNA expression and acantholysis were assessed. RESULTS: In PV patients, the proportions of Th1 (P = 0.016) and Th17 (P = 0.045) cells and the levels of IFN-γ (P = 0.010) were significantly increased. SOCS3 mRNA in CD4+ T cells was significantly decreased (P = 0.008), whereas STAT1 (P = 0.043) and STAT3 (P = 0.004) mRNA were significantly increased. After SOCS3 knockdown, the proportions of Th1 (P < 0.001) and Th17 (P = 0.006) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P = 0.001), and the protein levels of p-STAT1 (P = 0.001) and p-STAT3 (P = 0.003) were significantly increased in the CD4+ T-shSOCS3-1 group. In the coculture system, the proportions of Th1 (P < 0.001) and Th17 (P < 0.001) cells, the levels of IFN-γ (P < 0.001) and IL-17 (P < 0.001), and the number of cell fragments (P < 0.001) were significantly increased in the CD4+ T-shSOCS3-1+HaCaT-PV-IgG group, whereas the protein level of desmoglein3 (Dsg3) was significantly decreased. In addition, PV-IgG significantly increased IFN-γ and IL-6 mRNA in HaCaT cells. CONCLUSION: Low SOCS3 expression in CD4+ T cells from PV patients leads to overactivation of STAT, which causes CD4+ T cells to overdifferentiate into Th1 and Th17 cells. Additionally, PV-IgG-induced local inflammation in skin lesions, which is mediated by IFN-γ and IL-6, can aggravate this phenomenon. Furthermore, low SOCS3 expression in CD4+ T cells further exacerbates PV-IgG-induced acantholysis. Therefore, upregulating the expression of SOCS3 in CD4+ T cells of PV patients and maintaining the balance of the IFN-γ/STAT1/SOCS3 and IL-6/STAT3/SOCS3 pathways can alleviate acantholysis in patients with PV.

Darier disease: the use of dermoscopy in monitoring acitretin treatment.

Darier disease is an uncommon autosomal dominant inherited disease, caused by a mutation in the ATP2A2 gene. The clinical findings are hyperkeratotic papules on the trunk, scalp, face, and neck, maceration of intertriginous areas, palmar pits, whitish papules on the oral mucosa and nail abnormalities. The main histopathologic findings are acantholysis and dyskeratotic keratinocytes. Dermatoscopic features are comedo-like openings with a central polygonal yellowish/brownish structure, surrounded by a whitish halo. First-line treatment includes acitretin. Five reports have been published describing Darier disease dermatoscopic findings. Herein, we report for the first time a patient under acitretin treatment and dermatoscopic follow-up.

[A Case of Pemphigus Vulgaris Showing a Local Nose Erosion as the First Clinical Manifestation].

A 73-year-old male noticed a localized nose erosion that we thought was possibly an exacerbation of skin erosion due to the direct influence of friction from wearing a mask. Blood examination revealed a remarkable increase in serum anti-desmoglein-1 and anti-desmoglein-3 antibodies. A skin biopsy showed acantholysis in the epidermal granular layer. Based on the clinical manifestation and laboratory examination, we diagnosed his eruption as anti-desmoglein-1 and anti-desmoglein-3 antibody - positive pemphigus vulgaris. His skin eruption responded well to oral prednisolone and azathioprine and gradually improved. Pemphigus was a candidate as a differential diagnosis in this case, in which the direct mechanical friction from wearing a mask was thought to be an exacerbating factor of skin eruption.

Acantholytic Dyskeratosis Post-COVID Vaccination.

ABSTRACT: Acantholytic dyskeratosis mimicking Grover disease as a cutaneous manifestation of a side effect to the Moderna (mRNA-1273) COVID vaccine is rare with only one documented case in the literature to date. Herein, we present a case of an eruptive, erythematous, vesiculopapular rash developing in a patient after the Moderna vaccine. Histopathology of a representative biopsy [x2, done 8 weeks apart] of the rash revealed similar histopathologic findings of patchy suprabasal acantholysis with dyskeratotic keratinocytes and an underlying inflammatory infiltrate of lymphocytes and neutrophils. Direct immunofluorescence was negative. In contrast to the only case previously reported in the literature, a confounding feature in our case, was that patient had a medical history significant for Grover disease, which had been successfully treated with complete resolution and seemed to be in remission. Given the temporal relationship of the onset of the rash to vaccine administration, the changes were likely vaccine-related with the caveat that, in light of the medical history, the differential diagnosis includes reactivation of Grover disease by the vaccine as a trigger factor.

Drug-induced Grover's disease: a case report and review of the literature.

BACKGROUND: Grover's disease (GD) is a relatively rare transient dermatosis that can be idiopathic or acquired. Acquired GD may occur secondary to internal triggers such as medications and malignancies and external factors such as friction. OBJECTIVE: The purpose of this report is to describe the clinical and histological presentation of drug-induced Grover's disease (DIGD) and discuss potential pathogenic mechanisms. METHODS: A systemic review of the literature was performed to identify medications implicated in DIGD. RESULTS: We identified 13 reports of patients with DIGD. Most patients presented with a papular or papulovesicular morphology involving the trunk and extremities. Pruritus was the most common symptom. The majority of the offending agents were cancer therapeutics. Discontinuation of the culprit medication was sufficient for rash clearance and symptom resolution in most cases. CONCLUSION: The overlap in morphology and associated symptoms in DIGD and GD makes the diagnosis of DIGD challenging and has potentially led to underdiagnosis. However, in cases of more extensive involvement and treatment recalcitrance, a drug-induced eruption should be considered.

A Case of Segmental Darier Disease.

Darier disease (DD), also known as Darier-White disease, follicular keratosis, or dyskeratosis follicularis, is an uncommon autosomal dominant genodermatosis with complete penetrance and variable expressivity. This disorder is caused by mutations in the ATP2A2 gene and affects the skin, nails, and mucous membranes (1,2). A 40-year-old woman, without comorbidities, presented with pruritic, unilateral skin lesions on the trunk since she was 37 years old. Lesions had remained stable since onset, with physical examination revealing tiny scattered erythematous to light brown keratotic papules beginning at the patient's abdominal midline, extending over her left flank and onto her back (Figure 1, a, b). No other lesions were observed, and family history was negative. Skin punch biopsy revealed parakeratotic and acanthotic epidermis with foci of suprabasilar acantholysis and corps ronds in the stratum spinosum (Figure 2, a, b, c). Based on these findings, the patient was diagnosed with segmental DD - localized form type 1. DD usually develops between the ages of 6 and 20 and is characterized by keratotic, red to brown, sometimes yellowish, crusted, pruritic papules in a seborrheic distribution (3,4). Nail abnormalities, alternating red and/or white longitudinal bands, fragility, and subungual keratosis can be present. Mucosal whitish papules and palmoplantar keratotic papules are also frequently observed. Insufficient function of the ATP2A2 gene that encodes for the sarco/endoplasmic reticulum Ca2+ ATPase type 2 (SERCA2) leads to calcium dyshomeostasis, loss of cellular adhesion, and characteristic histological findings of acantholysis and dyskeratosis. The main pathological finding is the presence of two types of dyskeratotic cells, "corps ronds", present in the Malpighian layer, and "grains", mostly located in the stratum corneum (1). Approximately 10% of cases present as the localized form of disease, with two phenotypes of segmental DD having been observed. The more common, type 1, is characterized by a unilateral distribution along Blaschko's lines with normal surrounding skin, whereas the type 2 variant presents with generalized disease and localized areas of increased severity. Although generalized DD is associated with nail and mucosal involvement, as well as positive family history, these findings are rarely seen in localized forms (1). Family members with identical ATP2A2 mutations may have notable differences in clinical manifestations of the disease (5). DD is usually a chronic disease with reccurent exacerbations. Exacerbating factors include sun exposure, heat, sweat, and occlusion (2). Infection is a common complication (1). Associated conditions include neuropsychiatric abnormalities and squamous cell carcinoma (6,7). Increased risk of heart failure has also been observed (8). Type 1 segmental DD may be clinically and histologically hard to distinguish from acantholytic dyskeratotic epidermal nevus (ADEN). Age of onset plays an important role in differentiation, as ADEN is often congenital (3). However, some studies suggest ADEN is a localized form of DD (1). Other differential diagnoses include herpes zoster, lichen striatus, lichen planus (4), severe seborrheic dermatitis, and Grover disease. Our patient was treated with a topical retinoid, for the first two weeks in combination with a topical corticosteroid. She was advised on the use of proper daily skincare with antimicrobial cleansers and emollients, as well as behavioral measures such as avoiding triggering factors and wearing light clothing, resulting in substantial clinical improvement (Figure 1, c, d) and amelioration of pruritus. Other treatment options include salicylic and lactic acid as well as topical 5-fluorouracil, while oral retinoids are reserved for more severe disease (1-3). Doxycycline and pulsed dye laser have also been reported to be effective (2,9). One in vitro study showed that COX-2 inhibitors may reinstitute the dysregulated ATP2A2 gene (4). In summary, DD is a rare keratinization disorder that can present in a generalized or localized pattern. Although uncommon, segmental DD should be included in the differential diagnosis of dermatoses that follow Blaschko's lines. Treatment options include various topical and oral treatments, depending on disease severity.

Anti-Desmocollin Autoantibodies in Autoimmune Blistering Diseases.

The presence of anti-desmocollin (Dsc) antibodies is rarely described in autoimmune blistering diseases patients. Moreover, several clinical phenotypes of pemphigus may be associated with these antibodies. In this review we analyze clinicopathological, immunologic and outcome features of anti-Dsc autoimmune blistering diseases patients, to improve their diagnosis and management. We conducted a systematic search of PubMed and Embase (1990-present) for studies reporting cases of autoimmune blistering diseases with anti-Dsc antibodies. We classified the selected patients as patients with exclusively anti-Dsc autoantibodies, and patients with anti-Dsc and other autoantibodies. Of 93 cases with anti-Dsc autoantibodies included, 38 (41%) had exclusively these antibodies. Only 18% of patients presented with the typical clinicopathological phenotype of pemphigus vulgaris or pemphigus foliaceous. Mucosal involvement was seen in approximately half of the patients. Up to 18% of cases were associated with neoplasms. Acantholysis was described in 54% of cases with histopathological information. Treatments and outcomes vary in the different clinical phenotypes. The presence of anti-Dsc antibodies must be suspected mainly in those patients with either atypical pemphigus, in special with clinical pustules, or in cases showing intraepithelial or dermal neutrophilic/eosinophilic infiltrate on histological examination and dual pattern by direct immunofluorescence examination.