Numerous multinucleated giant cells in cutaneous epithelioid angiosarcoma and pulmonary metastasis: A unique observation with potential diagnostic pitfalls.

The histopathologic diagnosis of poorly differentiated cutaneous angiosarcoma can be challenging. We report a case of cutaneous epithelioid angiosarcoma with numerous multinucleated giant cells (MGCs) developing pulmonary metastasis. A 79-year-old man presented with a red-purple plaque on the scalp. A skin biopsy revealed epithelioid cell proliferation, admixed with numerous MGCs, and background hemorrhage. Vascular spaces were focally present and lined by atypical endothelial cells, including MGCs. Immunohistochemically, tumor cells, including MGCs, were positive for CD31, D2-40, and ERG. The patient received radiation therapy and chemotherapy, after which a follow-up CT scan revealed symptomless pneumothorax and pulmonary metastases. The patient received palliative partial lung resection, and the specimen revealed histopathological and immunohistochemical features similar to the primary cutaneous lesion. Our report expands the morphologic spectrum of cutaneous epithelioid angiosarcoma. Cutaneous angiosarcoma is an aggressive neoplasm; thus, awareness of this rare manifestation is important.

Clinical Profiles of Japanese Patients with Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Collected by a Nationwide System from 2006 to 2023.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening severe cutaneous adverse drug reactions. These diseases are rare, and their onset is difficult to predict because of their idiosyncratic reactivity. The Japan Severe Adverse Reactions Research Group, led by the National Institute of Health Sciences, has operated a nationwide to collect clinical information and genomic samples from patients with SJS/TEN since 2006. This study evaluated the associations of clinical symptoms with sequelae and specific causative drugs/drug groups in Japanese patients with SJS/TEN to identify clinical clues for SJS/TEN treatment and prognosis. Acetaminophen, antibiotics, and carbocisteine were linked to high frequencies of severe ocular symptoms and ocular sequelae (p < 0.05). For erythema and erosion areas, antipyretic analgesics had higher rates of skin symptom affecting <10% of the skin than the other drugs, suggesting narrower lesions (p < 0.004). Hepatic dysfunction, was common in both SJS and TEN, and antiepileptic drugs carried higher risks of hepatic dysfunction than the other drug groups (p = 0.0032). This study revealed that the clinical manifestations of SJS/TEN vary according to the causative drugs.

Longitudinal changes in cell-mediated immunity after varicella-zoster virus skin test in the general population; Shozu Herpes Zoster Study: SHEZ study.

Varicella-zoster virus-specific cell-mediated immunity has been associated with the onset and severity of herpes zoster (HZ), and the administration of the HZ vaccine enhanced the immunity. However, limited data is available on the duration of cell-mediated immunity enhancement by soluble antigen of varicella-zoster virus (VZV) skin test. A prospective, community-based cohort study was conducted in Shozu County, Kagawa Prefecture, Japan. Repeated VZV skin tests containing inactivated VZV antigen and blood tests were performed on 365 subjects aged 60 years and older at baseline, 1, 2, and 3 years later. The differential immunity indices of VZV over time for cell-mediated and humoral immunity were evaluated. VZV skin test reaction and ELISpot counts increased significantly at 1, 2, and 3 years later compared to the baseline. However, humoral immunity indices did not change materially over time. Soluble antigen by VZV skin test enhanced VZV-specific cell-mediated immunity, and it persisted for at least 1 year. In addition, the inoculation with inactivated antigens every year by VZV skin test continued to enhance VZV-specific cell-mediated immunity after 2 and 3 years.

YAP1::MAML2 fusions in poromatosis: A report of two patients.

Poromatosis is a rare condition characterized by the development of multiple poromas, mainly reported in patients with a history of malignancy. Recently, frequent YAP1::MAML2 and YAP1::NUTM1 fusions have been described in poromas and porocarcinomas. To date, the molecular features of poromatosis have been investigated in one patient only, wherein the poromas harbored YAP1::MAML2 fusions. Herein, we present two additional cases of poromatosis with YAP1::MAML2 fusions. Case 1: An 81-year-old woman presented with nine papules on the scalp, trunk, and extremities persisting for a year. She had a history of breast cancer, with no information on the treatment. Seven papules were excised. Case 2: A 65-year-old woman presented with 21 lesions on her trunk and lower extremities persisting for 2 years. She had been diagnosed with breast cancer 11 years prior and had undergone partial mastectomy, radiotherapy, chemotherapy, and endocrine therapy. Four lesions were excised. All 11 lesions in both patients were histopathologically similar: anastomosing cords and strands extending from the epidermis, and poroid and cuticular cell proliferation with interspersed small ducts. The tumors showed diffuse nuclear expression of YAP1 N-terminus and loss of YAP1 C-terminus expression. No lesions showed NUT immunopositivity. Sanger sequencing identified YAP1::MAML2 fusions in the poromas of both patients.

Mucosal Fixed Drug Eruption with Oral, Conjunctival, Nasal, and Anal Lesions: A Case Report.

is missing (Short communication).

Monogenic causes of pigmentary mosaicism.

Pigmentary mosaicism of the Ito type, also known as hypomelanosis of Ito, is a neurocutaneous syndrome considered to be predominantly caused by somatic chromosomal mosaicism. However, a few monogenic causes of pigmentary mosaicism have been recently reported. Eleven unrelated individuals with pigmentary mosaicism (mostly hypopigmented skin) were recruited for this study. Skin punch biopsies of the probands and trio-based blood samples (from probands and both biological parents) were collected, and genomic DNA was extracted and analyzed by exome sequencing. In all patients, plausible monogenic causes were detected with somatic and germline variants identified in five and six patients, respectively. Among the somatic variants, four patients had MTOR variant (36%) and another had an RHOA variant. De novo germline variants in USP9X, TFE3, and KCNQ5 were detected in two, one, and one patients, respectively. A maternally inherited PHF6 variant was detected in one patient with hyperpigmented skin. Compound heterozygous GTF3C5 variants were highlighted as strong candidates in the remaining patient. Exome sequencing, using patients' blood and skin samples is highly recommended as the first choice for detecting causative genetic variants of pigmentary mosaicism.

Trichilemmal cysts with proteinaceous material: A potential diagnostic pitfall.

BACKGROUND: Cysts of the skin are observed frequently and their diagnoses are generally straightforward. However, atypical cystic lesions for which differentiation is indistinct have been noted. METHODS: We examined five cases of trichilemmal cyst with proteinaceous material (TCPM), which required differentiation from sweat duct/gland tumors. We investigated the histopathological findings of TCPMs and evaluated the immunohistochemical expression of cytokeratin (CK) 10, CK13, CK17, CK19, CD8, and CD117. Immunohistochemical analysis was performed on the 5 TCPMs, 10 trichilemmal cysts (TCs), 5 clear-cell hidradenomas, 5 poroid hidradenomas, and cutaneous normal adnexa. RESULTS: Apoptotic cells were present in the cyst wall with a small amount of keratin or calcification in the cavity of TCPMs. The TCPMs and TCs were negative for CK19 and CD117, on the other hand clear-cell hidradenoma and poroid hidradenoma were positive for CK19 and CD117. The restricted positivity for CK10 was detected in the suprabasal layers of the cyst walls of TCPMs and TCs. The immunostaining patterns of TCPMs and TCs were similar to those of normal follicular isthmus. CONCLUSIONS: The histopathological findings with characteristics of TCs and a panel of immunohistochemical antibodies including CD117, CK19, and CK10 contributed to a correct diagnosis of TCPM.

Risk of Herpes Zoster in Relation to Body Mass Index Among Residents Aged ≥50 Years: The Shozu Herpes Zoster Study.

BACKGROUND: The impact of body mass index on incidence of herpes zoster is unclear. This study investigated whether body mass index was associated with a history of herpes zoster and incidence during a 3-year follow-up, using data from a prospective cohort study in Japan. METHODS: In total, 12,311 individuals were included in the cross-sectional analysis at baseline, of whom 1,818 with a history of herpes zoster were excluded from the incidence analysis, leaving 10,493 individuals. Body mass index (kg/m2) was classified into three categories (underweight: <18.5; normal: 18.5 to <25; and overweight: ≥25). To evaluate the risk of herpes zoster, we used a logistic regression model for prevalence and a Cox proportional hazard regression model for incidence. RESULTS: Being overweight or underweight was not associated with herpes zoster prevalence at baseline. The multivariate hazard ratios of herpes zoster incidence for overweight versus normal-weight groups were 0.67 (95% confidence interval, 0.51-0.90) in all participants, and 0.57 (95% confidence interval, 0.39-0.83) in women, with no significant difference for men. CONCLUSION: Being overweight was associated with a lower incidence of herpes zoster than being normal weight in older Japanese women.

Patch testing with the Japanese baseline series 2015: A 4-year experience.

BACKGROUND: The Japanese baseline series (JBS), established in 1994, was updated in 2008 and 2015. The JBS 2015 is a modification of the thin-layer rapid-use epicutaneous (TRUE) test (SmartPractice Denmark, Hillerød, Denmark). No nationwide studies concerning the TRUE test have previously been reported. OBJECTIVES: To determine the prevalence of sensitizations to JBS 2015 allergens from 2015 to 2018. METHODS: We investigated JBS 2015 patch test results using the web-registered Skin Safety Care Information Network (SSCI-Net) from April 2015 to March 2019. RESULTS: Patch test results of 5865 patients were registered from 63 facilities. The five allergens with the highest positivity rates were gold sodium thiosulfate (GST; 25.7%), nickel sulfate (24.5%), urushiol (9.1%), p-phenylenediamine (PPD; 8.9%), and cobalt chloride (8.4%). The five allergens with the lowest positivity rates were mercaptobenzothiazole (0.8%), formaldehyde (0.9%), paraben mix (1.1%), mercapto mix (1.1%), and PPD black rubber mix (1.4%). CONCLUSIONS: Nickel sulfate and GST had the highest positivity rates. The JBS 2015, including a modified TRUE test, is suitable for baseline series patch testing.

The association of family history of herpes zoster and the risk of incident herpes zoster: the SHEZ Study.

BACKGROUND: We investigated whether family histories of herpes zoster (HZ) are associated with the risk of incident HZ in a Japanese population. METHODS: A total of 12,522 Japanese residents aged ≥50 years in Shozu County participated in the baseline survey between December 2008 and November 2009 (the participation rate = 72.3%). They were interviewed at baseline by research physicians regarding the registrants' history of HZ. A self-administered questionnaire survey was conducted to evaluate the potential confounding factors. 10,530 participants without a history of HZ were followed up to ascertain the incidence of HZ during 3-years follow-up until the end of November 2012 with Japanese nationals. We estimated hazard ratios (HRs) of incident HZ according to first-degree family histories using the Cox proportional hazard regression after adjusting for age, sex, and other potential confounding factors. RESULTS: Compared to no HZ history of each family member, a history of brother or sister was associated with a higher risk of incident HZ while histories of father and mother were not. The multivariable HR (95%CI) of incident HZ for a history of brother or sister was 1.67 (1.04-2.69). When comparing to no family histories of all first-degree relatives, the multivariable HRs (95%CIs) were 1.34 (0.77-2.34) for a history of brother or sister alone, but 4.81 (1.78-13.00) for a history of mother plus brother or sister. As for the number of family histories, the multivariable HRs (95%CIs) were 1.08 (0.76-1.54) for one relative (father, mother, or brother or sister) and 2.75 (1.13-6.70) for two or more relatives. CONCLUSION: Family histories of mother plus brother or sister and two or more first-degree relatives were associated with a higher risk of incident HZ.

Multicenter 1-month follow-up study of the patch-test reaction to the gold sodium thiosulfate of the TRUE Test and its association with piercings and dental metal history.

BACKGROUND: There is controversy over late and long-lasting reactions to gold sodium thiosulfate (GST). OBJECTIVES: To study the GST patch-test reaction by observing the application site after 1 month, and to clarify the relevance of GST sensitization by piercings and dental metals. PATIENTS: A retrospective analysis was performed on 746 patients (143 male; 603 female) who were patch tested using GST of the TRUE Test. We conducted a questionnaire on the presence of piercings or dental metals in these patients. RESULTS: The GST positive rate was 27.9% at day (D)3 and/or D7 and 40.3% up to the 1-month reading. The positive rate was significantly higher in female patients and increased with age. Sixty-two percent of cases with a positive reaction at D7 continued to show a positive reaction after 1 month. Eleven percent of cases with a negative reaction at D3 and D7 showed a late reaction. Both piercings and dental metals were related to gold sensitization. CONCLUSIONS: The GST of the TRUE Test had a high positive and low false-negative rate. The 1-month reading after the patch test was important for identifying late reactions. Piercing history and dental metal were associated with gold sensitization.

Current Perspective Regarding the Immunopathogenesis of Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms (DIHS/DRESS).

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a severe type of adverse drug eruption associated with multiorgan involvement and the reactivation of human herpesvirus 6, which arises after prolonged exposure to certain drugs. Typically, two waves of disease activity occur during the course of DIHS/DRESS; however, some patients experience multiple waves of exacerbation and remission of the disease. Severe complications, some of which are related to cytomegalovirus reactivation, can be fatal. DIHS/DRESS is distinct from other drug reactions, as it involves herpes virus reactivation and can lead to the subsequent development of autoimmune diseases. The association between herpesviruses and DIHS/DRESS is now well established, and DIHS/DRESS is considered to arise as a result of complex interactions between several herpesviruses and comprehensive immune responses, including drug-specific immune responses and antiviral immune responses, each of which may be mediated by distinct types of immune cells. It appears that both CD4 and CD8 T cells are involved in the pathogenesis of DIHS/DRESS but play distinct roles. CD4 T cells mainly initiate drug allergies in response to drug antigens, and then herpesvirus-specific CD8 T cells that target virus-infected cells emerge, resulting in tissue damage. Regulatory T-cell dynamics are also suggested to contribute to the diverse symptoms of DIHS/DRESS. However, the pathomechanisms of this complex disease remain largely unknown. In particular, how viral infections contribute to the pathogenesis of DIHS/DRESS and why autoimmune sequelae arise in DIHS/DRESS are yet to be elucidated. This review describes the clinical features of DIHS/DRESS, including the associated complications and sequelae, and discusses recent advances in our understanding of the immunopathogenic mechanisms of DIHS/DRESS.

Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.

Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.

Sleep Shortage Is Associated With Postherpetic Neuralgia Development Through Hyperesthesia and Acute Pain Intensity: A Community-Based Prospective Cohort Study.

OBJECTIVES: There have been no community-based studies investigating the association between sleep duration and postherpetic neuralgia (PHN) development. The aim of the current study was to examine the association of sleep with herpes zoster (HZ) incidence and PHN. METHODS: In total, 12,329 residents (ages 50 to 103 years) of Shozu County, Japan, participated in our study from December 2009 to November 2010 and were followed up for 3 years. At baseline, the participants completed self-administered health questionnaires, including those on usual sleep duration. Three dermatologists diagnosed HZ on the basis of clinical symptoms and virus identification testing by polymerase chain reaction and serological tests, and evaluated pain using a modified Zoster Brief Pain Inventory survey form via telephone. We used a Cox proportional hazard regression model to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident HZ and PHN. We also performed mediation analysis to examine whether hyperesthesia and acute pain intensity mediated the association between sleep shortage and chronic pain intensity. RESULTS: During follow-up, 400 cases of HZ were identified. Of these, 55 participants developed PHN. Sleep duration was not associated with HZ incidence. Sleep shortage increased the risk for PHN (HR 2.02 [95% CI: 1.06 to 3.85]). Hyperesthesia and acute pain intensity mediated the association between sleep shortage and chronic pain intensity (indirect/total effect ratio = 50% mediation). CONCLUSIONS: Sleep shortage was associated with increased risk for PHN, and hyperesthesia and acute pain intensity appeared to mediate this association. Sleep shortage may be a novel risk factor for PHN.

Associations of Perceived Mental Stress, Sense of Purpose in Life, and Negative Life Events With the Risk of Incident Herpes Zoster and Postherpetic Neuralgia: The SHEZ Study.

In the present population-based prospective study, we examined the associations of psychosocial factors with the incidence of herpes zoster (HZ) and postherpetic neuralgia (PHN). Data were collected from 12,359 participants (≥50 years of age) who answered a self-completed health questionnaire in the Shozu County of Kagawa Prefecture in Japan. During a 3-year follow-up between December 2008 and November 2012, HZ and PHN were diagnosed in 400 and 79 subjects, respectively. We used Cox regression analysis to estimate hazard ratios of incident HZ and PHN according to psychosocial factors, adjusting for age, sex, histories of HZ, cancer, and diabetes, smoking and drinking habits, and time from disease onset to treatment. Men with high levels of mental stress were twice as likely to be at risk for incident HZ. The risk of incident HZ was approximately 60% lower among men and women who reported a high sense of purpose in life. Women who experienced negative life events-particularly changes in their work, living environment, and relationships-had a 2- to 3-fold higher risk of incident PHN. Psychosocial factors such as perceived mental stress, sense of purpose in life, and negative life events may contribute to the development of HZ and PHN in the general population.

Essential Requirement for IFN Regulatory Factor 7 in Autoantibody Production but Not Development of Nephritis in Murine Lupus.

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of autoantibodies against nuclear components. Recent genetic studies of SLE patients have revealed that IFN regulatory factor (IRF) 7 gene polymorphisms are associated with an increased risk of SLE, but the precise role of IRF7 in SLE development is not fully understood. We investigated the role of IRF7 in the pathogenesis of SLE using a mouse model and saw a curious dissociation of autoantibody production and development of glomerulonephritis. SLE was chemically induced into IRF7-deficient mice, and glomerulonephritis with deposits of IgG and lipogranulomas were observed after 10 mo. However, these mice failed to produce anti-dsDNA, ssDNA, ribonucleoprotein, and Sm autoantibodies. Following the chemical induction, IRF7-deficient mice expressed substantially lower levels of IFN-stimulated genes than did wild-type mice, but NF-κB target genes were equally upregulated in both strains. Therefore, the type I IFN pathway seems critical for the autoantibody production, but the NF-κB activation is sufficient for the development of glomerulonephritis in this model. Our study thus demonstrates a specific requirement for IRF7 in autoantibody production and uncovers a new layer of complexity in the pathogenesis of SLE.

Relationship between cell-mediated immunity to Varicella-Zoster virus and aging in subjects from the community-based Shozu Herpes Zoster study.

Age-related declines in cell-mediated immunity (CMI) are associated with the incidence and severity of Herpes Zoster (HZ) infection. However, the level of Varicella-Zoster virus (VZV)-specific CMI associated with disease onset is unclear. This study aimed to examine factors associated with VZV-specific CMI, as measured by an interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISPOT) assay, in a Japanese cohort. The study enrolled 365 subjects aged 60 years and over, all of whom were taking part in the Shozu Herpes Zoster (SHEZ) study and had undergone four sets of blood and intradermal reaction tests during a 3 year follow-up period. The VZV-specific immunity profile of each subject was assessed, and linear mixed effects models were constructed to analyze IFN-γ ELISPOT results in association with a combination of factors. The model that best explained the IFN-γ ELISPOT results was selected using the Akaike Information Criteria. The best-fit model consisted of age group as the only explanatory fixed-effect variable. The model showed that VZV-specific CMI, quantified as numbers of spots on the ELISPOT assay, among subjects aged 70-79 was on average 10.30 points lower than that among subjects aged 60-69. There was no statistically significant difference between subjects aged 70-79 and those aged 80-89. Age was the only factor significantly associated with the level of VZV-specific CMI, as measured by the IFN-γ ELISPOT assay. These results may represent an important step towards quantifying the relationship between VZV-specific CMI and the onset of HZ. J. Med. Virol. 89:313-317, 2017. © 2016 Wiley Periodicals, Inc.