Mikio Ohtsuka

The association of latent Epstein-Barr virus infection with hydroa vacciniforme.

Patients with hydroa vacciniforme (HV)‐like eruptions and malignant potential have been reported from Asia and Mexico, and those patients frequently had an associated latent Epstein–Barr virus (EBV) infection. In order to elucidate the association of latent EBV infection with HV, we studied six children with typical manifestations of HV by detection of EBV genes and EBV‐related RNAs in biopsy specimens from cutaneous lesions. Cutaneous lesions of all six children with typical HV contained EBV‐encoded small nuclear RNA (EBER)+ cells in 3–10% of the dermal infiltrates, whereas no Bam HI‐H, l‐fragment (BHLF) mRNA, or transcripts encoding EA‐D antigen, were detected. No EBER + cells were detected in other inflammatory or benign lymphoproliferative skin disorders tested. Polymerase chain reaction amplification confirmed the presence of EBV DNA sequences in five of six biopsy specimens from the patients. Latent EBV infection is associated with the development of cutaneous lesions of HV.

The latency pattern of Epstein-Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas.

The nasal type, extranodal natural killer or T(NK/T)-cell lymphoma is usually associated with latent Epstein–Barr virus (EBV) infection. In order to elucidate the EBV gene expression patterns in vivo, we examined eight patients with cutaneous EBV-related NK/T-cell lymphomas, including six patients with a NK-cell phenotype and two patients with a T-cell phenotype. The implication of EBV in the skin lesions was determined by the presence of EBV-DNA, EBV-encoded nuclear RNA (EBER) and a clonality of EBV-DNA fragments containing the terminal repeats. Transcripts of EBV-encoded genes were screened by reverse transcription- polymerase chain reaction (RT-PCR), and confirmed by Southern blot hybridization. The expression of EBV-related antigens was examined by immunostaining using paraffin-embedded tissue sections and cell pellets of EBV-positive cell lines. Our study demonstrated that all samples from the patients contained EBV nuclear antigen (EBNA)-1 mRNA which was transcribed using the Q promoter, whereas both the Q promoter and another upstream promoter (Cp/Wp) were used in EBV-positive cell lines, B95.8, Raji and Jiyoye. Latent membrane protein-1 (LMP-1) mRNA was detected in seven of eight patients and all cell lines, whereas EBNA-2 transcripts were found only in the cell lines. Immunostaining showed no LMP-1, EBNA-2 or ZEBRA antigens in the paraffin-embedded tissue sections, although they were positive in the cell line cells. Latent BHRF1 transcripts encoding bcl-2 homologue and BCRF1 transcripts encoding viral interleukin (vIL)-10 were detected in one and two of eight patients, respectively. A patient with NK-cell lymphoma expressing both transcripts died of rapid progression of the illness. Our results indicate that the restricted expression of the latency-associated EBV genes and the production of vIL-10 and bcl-2 homologue may favour tumour growth, evading the host immune surveillance.

CD56-positive (nasal-type T/NK cell) lymphoma arising on the skin. Report of two cases and review of the literature.

Several authors have reported cases of patients with malignant lymphoma with unique characteristics, designated nasal‐type T/NK cell lymphoma, which expresses the natural killer (NK) cell marker and shows frequent extra‐nodal involvement and poor prognosis. We report 2 cases of this type of lymphoma which were CD56‐positive and showed a histopathologically angiocentric pattern with cutaneous and subcutaneous tumorous lesions. Patient 1 had extensive invasion of skin, underlying skeletal muscle, spleen and bone marrow, and died of sepsis 34 months after onset. Patient 2 had multiple subcutaneous nodules and invasion to mammary gland, lung, lymph node and spleen at the time of her first visit. She died of a rapid invasion of lymphoma cells to the liver 5 months after onset. Both patients showed similar immunophenotypes of tumor cells (CD2+, CD3−, CD4−, CD8−, CD20−, CD56+) and germ line configuration of the heavy chain of immunoglobulin (JH), T‐cell receptor C beta‐1 subunit DNA and T‐cell receptor J gamma subunit DNA. Epstein‐Barr virus early regions RNA was demonstrated in the nuclei of tumor cells of both patients with in situ hybridization. The histopathological examination of the skin lesions of both patients revealed the features of angiocentric lymphoma. The detection of CD56 in the tumor cells of cutaneous lymphomas should be routinely performed for the early diagnosis of this type of lymphoma with extremely poor prognosis.

Cutaneous lymphoproliferative disorders associated with Epstein-Barr virus infection: a clinical overview

Epstein Barr virus (EBV) infection is implicated in various kinds of neoplasms including certain types of cutaneous T or natural killer (NK) cell proliferative disorders. Although a pathogenic role of EBV infection is not clear, some EBV gene products expressed during a latency phase were found to have biological properties leading to cellular gene expression and immortalization. Furthermore, EBV can use an array of strategies to evade host immune responses, and maintain the latent infection. EBV-associated cutaneous lymphoproliferative disorders are prevalent in Asia, and less frequent in western countries where infectious mononucleosis is common in adolescents and young adults. This review introduces recent advances on the mechanism of EBV infection, highlighting unique clinicopathologic manifestations of EBV-associated cutaneous lymphoproliferative disorders.

Exacerbation of Psoriasis During Nivolumab Therapy for Metastatic Melanoma

© 2016 The Authors. doi: 10.2340/00015555-2212 Journal Compilation

Occurrence of Psoriasiform Eruption During Nivolumab Therapy for Primary Oral Mucosal Melanoma

described in the Japanese population, several PP cases have also been reported in Western countries and, recently, in the Middle East.2,3 The pathogenesis of PP is not completely clear. In addition to being associated with several factors including exogenous (physical trauma, friction) and hormonal (pregnancy, menstruation), PP has classically been reported in association with metabolic derangements, especially ketotic states (dieting, fasting, diabetes mellitus).2,3 Actually, several studies have detected elevated urine and/or blood ketone levels in patients with PP.2,3 In such circumstances, it is believed that ketone bodies may distribute around blood vessels leading to perivascular inflammation or enter into cells modifying their intracytoplasmic processes. The inflammation is believed to be mainly mediated by neutrophils: PP usually responds well to medications with antineutrophil effect, such as dapsone and tetracyclines, which would support this neutrophil-mediated theory. A role for decreased insulin levels, which is reported to occur after bariatric surgery,4 has also been hypothesized as cause of PP.2 In addition to its effect in changing the course of many skin diseases such as psoriasis, bariatric surgery has been associated with several dermatoses including bowel-associated dermatosis–arthritis syndrome, nutritional deficiency dermatoses, and alopecia.5 However, PP has never been reported after bariatric surgery. Given that such surgery may easily replicate the metabolic disturbance associated with other ketotic states such as dieting or fasting,5,6 we believe that the association between PP and bariatric surgery may be underdiagnosed or underreported. In conclusion, to our knowledge, this report is the first to describe PP developing after bariatric surgery, adding PP to the cutaneous complications of such procedures. Increased awareness of this rare entity and this association is important because bariatric surgery is a common procedure nowadays, and the metabolic abnormalities accompanying it mimic those that occur with other ketotic states.

Internalization of constitutive desmogleins with the subsequent induction of desmoglein 2 in pemphigus lesions

Acantholytic blisters in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are caused by a dissociation of desmosomes mediated by autoantibodies against desmoglein (Dsg) 3 and Dsg 1, respectively. The blistering occurs at the suprabasilar level in PV and at the subcorneal level in PF, which corresponds to the distribution of target antigens in the epidermis: there is a more prominent expression of Dsg 1 in the upper layer, whereas Dsg 3 is more prominent in the lower layer. To elucidate the histogenesis of acantholysis, we studied the alterations of the desmosomal components and the expression pattern of Dsg isoforms in the lesional and perilesional epidermis of pemphigus patients. The results demonstrated an internalization of the desmosomes in the lower epidermis of PV, PF and pemphigus vegetans. A similar phenomenon was induced in monolayers of keratinocytes cultured with PV sera. However, little change was observed in E‐cadherin expression until acantholysis became manifest. This internalization occurred prior to overt acantholysis, and was frequently associated with the induction of Dsg 2 expression in the basilar or lower layers of the epidermis. These findings indicate an alteration of Dsg isoform expression in subclinical pemphigus lesions, which might be related to the characteristic acantholytic patterns: the suprabasilar layer in PV and the upper epidermis in PF.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid.

BACKGROUND Patients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. OBJECTIVE A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. METHODS We evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. RESULTS We enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. CONCLUSION IVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Over-Expression of the Testis-Specific Gene TSGA10 in Cancers and Its Immunogenicity

The TSGA10 gene was originally isolated in normal testis by differential mRNA display. TSGA10 is located on chromosome 2q11.2 and consists of 19 exons extending over 3 kb. TSGA10 mRNA expression was investigated in normal and malignant tissues using quantitative real‐time RT‐PCR. It was predominantly expressed in the testis in adult normal tissues. In malignant tissues, TSGA10 was over‐expressed in 4 of 20 hepatocellular carcinomas (HCC), 1 of 20 colon cancers, 7 of 20 ovarian cancers, 3 of 20 prostate cancers, 1 of 21 malignant melanomas, and 8 of 21 bladder cancers. Serological analysis revealed that 3 out of 346 patients with various types of cancer possessed antibody against recombinant TSGA10 protein. They included 2 patients with hepatocellular carcinoma and a patient with malignant melanoma.

Guidelines for the management of cutaneous lymphomas (2011): A consensus statement by the Japanese Skin Cancer Society - Lymphoma Study Group

In 2010, the first Japanese edition of guidelines for the management of cutaneous lymphoma was published jointly by the Japanese Dermatological Association (JDA) and the Japanese Skin Cancer Society (JSCS) – Lymphoma Study Group. Because the guidelines were revised in 2011 based on the most recent data, we summarized the revised guidelines in English for two reasons: (i) to inform overseas clinicians about our way of managing common types of cutaneous lymphomas such as mycosis fungoides/Sézary syndrome; and (ii) to introduce Japanese guidelines for lymphomas peculiar to Asia, such as adult T‐cell leukemia/lymphoma and extranodal natural killer/T‐cell lymphoma, nasal type. References that provide scientific evidence for these guidelines have been selected by the JSCS – Lymphoma Study Group. These guidelines, together with the degrees of recommendation, have been made in the context of limited medical treatment resources, and standard medical practice within the framework of the Japanese National Health Insurance system.