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.

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.

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.

[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.

Paraneoplastic pemphigus: Revised diagnostic criteria based on literature analysis.

BACKGROUND: Paraneoplastic pemphigus (PNP) is a rare autoimmune bullous disease classically associated with an underlying neoplasm. The heterogeneous clinical and histopathologic features of the disease make diagnosis challenging for clinicians. There are no formally accepted diagnostic criteria, and newer techniques for identifying antibodies directed against plakin proteins have largely replaced immunoprecipitation, the historic gold standard. METHODS: An analysis of 265 published cases of PNP was performed. The clinical, histopathologic, and immunologic features of PNP were assessed. RESULTS: Based on this review, we modified previous diagnostic criteria to capture 89.4% of PNP cases compared to 71.2% of cases captured by the most commonly referenced criteria devised by Camisa and Helm (p-value < 0.01, z-test; 95% CI [10.2, 33.6]). CONCLUSION: These revised diagnostic criteria address the variable clinical, histopathologic, and biochemical features of PNP, allowing physicians to have greater confidence in diagnosis of this rare and often fatal disease. The revised criteria include three major criteria and two minor criteria, whereby meeting either all three major criteria or two major and both minor criteria would fulfill a diagnosis of paraneoplastic pemphigus. The major criteria include (a) mucous membrane lesions with or without cutaneous involvement, (b) concomitant internal neoplasm, and (b) serologic evidence of anti-plakin antibodies. The minor criteria include (a) acantholysis and/or lichenoid interface dermatitis on histopathology and (b) direct immunofluorescence staining showing intercellular and/or basement membrane staining.

Case of Bullous Grover Disease.

ABSTRACT: Grover disease is an acquired acantholytic dermatosis affecting middle-aged men, with pruritus being the most commonly associated symptom. Grover disease tends to wax and wane and can last between several months to several years. Although Grover disease is usually papular, we report here a patient who presented with mainly vesicular and bullous lesions on his back originally concerning for folliculitis, contact dermatitis, or disseminated herpes simplex viral infection. Skin biopsy demonstrated acantholysis, suprabasal blisters, and a predominantly lymphocytic dermal infiltrate. Tzanck preparation for giant cells, immunohistochemistry for viral markers, and direct immunofluorescence staining were all negative. A diagnosis of bullous Grover disease was made based on clinicopathological correlation. Minocycline was recommended based on report of its efficacy. However, patient declined treatment and his rash self-resolved within a couple of months. This case brings awareness to this atypical variant of Grover disease and encourages physician to include Grover disease in their differential of vesiculobullous disorders.

Peristomal Punctate Pemphigus.

ABSTRACT: Cutaneous reactions surrounding abdominal stoma sites are typically irritant, allergic, infectious, traumatic or pathergic in etiology. Pemphigus, which encompasses a group of vesiculobullous autoimmune skin disorders, is seldom encountered as a peristomal dermatosis. Direct immunofluorescence (DIF) studies of pemphigus generally show continuous intercellular net-like depositions of IgG. However, punctate or dot-like intercellular deposition of IgG can also be seen in cases of pemphigus. The punctuate pattern is underreported in the literature and little is known about its implication. We describe a case of a 58-year-old Caucasian man with a history of bowel obstruction, status postcolostomy, who presented with a sharply demarcated, erythematous, crusted plaque surrounding his abdominal stoma. The patient endorsed persistent pruritus. A punch biopsy of the lesion was performed for clinical suspicion of fungal infection versus irritant dermatitis. Histopathology revealed a predominantly subcorneal acantholytic dermatitis. Periodic acid-Schiff with diastase and Grocott methenamine silver histochemical stains were negative for fungi. DIF was positive for IgG and C3 detected in a punctate intercellular pattern. In conjunction with the patient's clinical presentation and DIF, a diagnosis of peristomal pemphigus foliaceous was rendered. Herein, we describe a case of punctate pemphigus presenting as a peristomal dermatosis and include a review of the literature to raise awareness of this phenomenon.

Cutaneous acantholytic dyskeratotic acanthoma accompanying syringofibroadenomatous hyperplasia with proliferation of mature sebocytes: A case report.

Acantholytic dyskeratotic acanthoma is a rare variant of epidermal acanthoma. It has a flat, plaque-like structure and is characterized microscopically by acantholysis and dyskeratosis. Eccrine syringofibroadenomatous hyperplasia is benign and likely reactive. It has recently been considered as a hyperplastic process affecting the eccrine ducts rather than the neoplasm because of its pathological heterogeneity and wide clinical associations. In this article, we present the case of 97-year-old Japanese women with a 10-mm wide, painful acantholytic dyskeratotic acanthoma accompanied by syringofibroadenomatous hyperplasia in the right femoral region. Although syringofibroadenomatous hyperplasia is known to occur as a reactive process with various dermatoses and cutaneous tumors, to date, there have been no reports of cases of acantholytic dyskeratotic acanthoma accompanying syringofibroadenomatous hyperplasia. Moreover, this case also includes the unusual finding of an increase in the mature sebocytes in the area of the syringofibroadenomatous hyperplasia.

Erythrodermic Darier disease associated with metastatic lung adenocarcinoma.

We present a patient with erythrodermic Darier disease occurring in temporal association with diagnosis of metastatic lung adenocarcinoma. The patient presented with eroded and crusted keratotic papules and plaques over greater than 90% body surface area with extensive secondary impetiginization. Given a longstanding history of pruritic eruption, this presentation represents a paraneoplastic flare of an underlying genodermatosis. Near total resolution was achieved with chemotherapy and topical corticosteroids.

Dermatologic toxicities to immune checkpoint inhibitor therapy: A review of histopathologic features.

Antineoplastic agents that use the immune system have revolutionized cancer treatment. Specifically, implementation of immune checkpoint inhibitors, monoclonal antibodies that block cytotoxic T-lymphocyte-associated antigen-4, programmed cell death protein 1, or programmed cell death ligand 1 show improved and sustained responses in patients with cancer. However, these agents are associated with a plethora of adverse events, many manifesting in the skin. As the clinical application of cancer immunotherapies expands, understanding the clinical and histopathologic features of associated cutaneous toxicities becomes increasingly important to dermatologists, oncologists, and pathologists to ensure timely diagnosis and appropriate care. This review discusses cutaneous reactions to immune checkpoint inhibitors, focusing on histopathologic features.

ATP2A2 SINE Insertion in an Irish Terrier with Darier Disease and Associated Infundibular Cyst Formation.

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications. Histology of the excised tissue revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients. Whole genome sequencing of the affected dog was performed, and the functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease.

Transient acantholytic dermatosis in a patient with prostate cancer.

Transient acantholytic dermatosis (TAD) is a relatively common entity that has been also noted to occur in patients with cancer. Herein, we describe a case of transient acantholytic dermatosis occurring in a patient with a history of prostate cancer status post radiation, now being treated with combination therapy with pembrolizumab and carboplatin-pemetrexed for advanced lung adenocarcinoma. Our case emphasizes the importance of being cognizant of TAD and its associations, particularly in cancer patients.

BRAF inhibitor and hairy cell leukemia-related transient acantholytic dermatosis.

Grover disease (GD) is an acquired, nonfamilial, nonimmune mediated, transient or persistent acantholytic dermatosis. Herein, we present a 72-year-old man who had clinical and histopathologic findings of GD following two weeks of treatment with vemurafenib without MEK inhibitor. The patient was successfully treated with topical emollients and a high-potency corticosteroid. Meanwhile, vemurafenib was temporarily discontinued. Drug-induced GD has increasingly been reported in patients on BRAF inhibitor monotherapy as an immune-related adverse event. The cutaneous side effects seem to arise secondary to a paradoxical activation of the mitogen-activated protein kinase signaling of BRAF inhibitor treatment, leading to keratinocyte proliferation. Although the pathogenesis of GD has not been delineated, there is suggestion of activation of T lymphocytes, particularly helper cells under the action of pro-inflammatory cytokines, resulting in proliferation of keratinocytes. Combination therapy with a MEK inhibitor appears to prevent BRAF-induced GD. Given that there is a higher prevalence of GD in patients with hematologic malignancy, a direct causal relationship between the initiation of vemurafenib therapy and development of GD in this case may be difficult to establish.

Familial "benign" pemphigus? Erythroderma and fatal outcome

Abstract Hailey-Hailey disease, or familial benign pemphigus, is a rare bullous genodermatosis that usually presents with flaccid blisters, erosions, and maceration limited to flexural areas, resulting in increased morbidity and reduced quality of life for affected patients. The authors report an unusual case of generalized Hailey-Hailey disease with erythroderma and fatal outcome.