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Background/aims: The association of Epstein-Barr virus (EBV) with gastric malignancies has been proven by many studies in the literature. However, information about EBV-associated inflammation/gastritis remains limited. The aim of this study is to establish the prevalence of latent EBV infection in patients with chronic gastritis without H. pylori infection., Materials and Methods: In this study, 119 patients with gastritis without H. pylori infection were included. Furthermore, 28 patients with H. pylori gastritis were included in the study as a control group. Chromogenic in situ hybridization (EBV-encoded RNA) and immunohistochemistry (LMP-1 antibody) were performed in all 147 cases. The prevalence of EBV and its relationship with age, sex, the affected part of the stomach, the density of inflammation, inflammatory activity, intestinal metaplasia, and atrophy were analyzed., Results: In this study, 14 cases showed positive immunostaining for EBV. EBV positivity was seen mostly in the lymphoid tissue (13 cases), but it was also detected at the gastric epithelium (7 cases). The mean age of the patients was 44 years, which was slightly younger than that of the EBV-negative cases (48 years). The inflammation density was higher in EBV-positive cases than the EBV-negative gastritis cases (p=0.002). Intestinal metaplasia was detected in 7% of the cases. EBV-positive cases had a higher incidence of atrophy without intestinal metaplasia (21% vs 3.8% without EBV)., Conclusion: EBV was detected in 12% of the cases with gastritis without H. pylori infection. Endoscopic follow-up may be appropriate for patients with gastritis, who have atrophy without intestinal metaplasia and are H. pylori negative but EBV positive.

Herein, we describe an extremely rare case of gastritis due to concurrent infection with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) occurring in an immunocompetent adult. The patient was a 35-year-old man who presented with slight fever, nausea, anorexia, weight loss for 3 weeks, mild transaminitis, and leukocytosis with atypical lymphocytes in peripheral blood. The clinical presentation and elevated IgM titers to both EBV-VCA and CMV strongly suggested infectious mononucleosis syndrome caused by co-infection with EBV and CMV. A computed tomographic scan of the abdomen showed diffuse thickening of the gastric wall mimicking linitis plastica, and upper endoscopy revealed thickened and eroded mucosa throughout the stomach. Histologic examination of gastric biopsies showed a dense lymphoid and neutrophilic infiltrate in the lamina propria with erosion. In situ hybridization assay revealed many lymphocytes positive for EBV-encoded RNA. Moreover, immunohistochemistry using an anti-CMV monoclonal antibody identified some CMV-positive cells (i.e. foveolar epithelium and endothelium). We finally diagnosed this case as gastric involvement in infectious mononucleosis, and the patient recovered without the administration of antiviral drugs. To our knowledge, this is the first reported case of gastritis co-infected with EBV and CMV, as a manifestation of infectious mononucleosis in an immunocompetent adult.

The Epstein-Barr virus (EBV) is one of the infectious agents found in stomach tissue. Recently, EBV-associated gastric carcinoma (EBVaGC) was classified as a new subtype of gastric carcinoma. To date, there is a lack of knowledge about the distribution and prevalence of EBV infection in both the normal stomach and various gastric lesions, including EBVaGC, in the Thai population. In this study, we detected EBV in the normal stomach (NS; n = 19), chronic gastritis (CG; n = 36), intestinal metaplasia (IM; n = 40), gastric dysplasia (GD; n = 15), and gastric adenocarcinoma (GC; n = 33) by polymerase chain reaction (PCR) amplification of the latent membrane protein (LMP1) gene of EBV. EBV-PCR amplification was positive in 42.1%, 36.1%, 22.5%, 13.3%, and 33.3% of NS, CG, IM, GD, and GC, respectively. For further clarification in EBVaGC, we performed EBV-encoded small RNA in situ hybridization (EBER-ISH) in PCR-positive cases of GD and GC. Four GC cases were EBER-ISH positive (12.1%), while both GD cases were EBER-ISH negative. In addition, we determined the distribution of the EBV strain (type A or B) based on EBNA3C sequence and EBV variants based on LMP1 variation (wild-type and 30-bp deletion variants; wt-LMP1 or del-LMP1). The results showed that type A and wt-LMP1 were the most prevalent in all lesions. In conclusion, EBV is common in both the NS and gastric lesions, and the frequency of EBVaGC was 12.1% in Thai patients., (© 2018 Wiley Periodicals, Inc.)

Epstein-Barr virus-associated gastric cancer (EBVaGC) is a representative EBV-infected epithelial neoplasm, which is now included as one of the four subtypes of The Cancer Genome Atlas molecular classification of gastric cancer. In this review, we portray a gastritis-infection-cancer sequence of EBVaGC. This virus-associated type of gastric cancer demonstrates clonal growth of EBV-infected epithelial cells within the mucosa of atrophic gastritis. Its core molecular abnormality is the EBV-specific hyper-epigenotype of CpG island promoter methylation, which induces silencing of tumor suppressor genes. This is due to the infection-induced disruption of the balance between DNA methylation and DNA demethylation activities. Abnormalities in the host cell genome, including phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit α (PIK3CA), AT-rich interaction domain 1A (ARID1A), and programmed death-ligand 1 (PD-L1), are associated with the development and progression of EBVaGC. Furthermore, posttranscriptional modulation affects the transformation processes of EBV-infected cells, such as epithelial mesenchymal transition and anti-apoptosis, via cellular and viral microRNAs (miRNAs). Once established, cancer cells of EBVaGC remodel their microenvironment, at least partly, via the delivery of exosomes containing cellular and viral miRNAs. After exosomes are incorporated, these molecules change the functions of stromal cells, tuning the microenvironment for EBVaGC. During this series of events, EBV hijacks and uses cellular machineries, such as DNA methylation and the miRNA delivery system. This portrait of gastritis-infection-cancer sequences highlights the survival strategies of EBV in the stomach epithelial cells and may be useful for the integration of therapeutic modalities against EBV-driven gastric cancer.

Spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM) have been recognized as neoplastic precursors in gastric carcinogenesis. We explored the relationship between SPEM and IM in Epstein-Barr virus-associated (EBVaGC) and Epstein-Barr virus-negative (EBVnGC) gastric cancer. Sixty-four EBVaGC and one hundred and fifty-four EBVnGC patients were included. EBV positivity was identified using Epstein-Barr virus-encoded RNA-1 in situ hybridization. SPEM was subclassified into absent, early, and advanced SPEM. Acute and chronic inflammation was graded as absent, mild, moderate, and marked. Univariate and multivariate logistic regression analyses were conducted to analyze the correlation between SPEM, IM, and inflammation. Our study revealed that SPEM was detected in 87.5% EBVaGC and 85.1% EBVnGC patients. Distribution of patients according to the SPEM classification was significantly different between EBVaGC and EBVnGC groups (P=.038). IM was observed less frequently in EBVaGC when compared with EBVnGC patients (P<.001). No difference was observed between EBVaGC and EBVnGC in the levels of acute and chronic inflammation. A positive correlation between IM and SPEM status was observed in both EBVaGC and EBVnGC patients. Furthermore, advanced SPEM was an independent influential factor to IM in EBVnGC (P=.013). In conclusion, SPEM was associated with both EBVaGC and EBVnGC more frequently than IM. Moreover, advanced SPEM had a stronger association with IM than early SPEM in EBVnGC. These results suggest that identification of SPEM should be used as a high-risk indicator for detecting early gastric carcinoma, and should be brought to the attention of pathologists and clinicians., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Different lines of evidence support an association between Epstein-Barr virus (EBV) and gastric cancer (GC). The main understood risk factor to develop GC is infection by Helicobacter pylori (H. pylori), which triggers a local inflammatory response critical for progression from gastritis to GC. The role of EBV in early inflammatory gastric lesions has been poorly studied. A recent study proposed a cutoff value of 2000 EBV particles to identify patients with increased chances of infection of the gastric epithelium, which may favor the inflammatory process. To better understand the role of EBV in cancer progression, we analyzed 75 samples of GC, 147 control samples of non-tumor gastric tissue derived from GC patients and 75 biopsies from patients with non-atrophic gastritis (NAG). A first-round PCR was used for EBV detection in tumor and non-tumor controls and a more sensitive nested PCR for gastritis samples; both PCRs had lower detection limits above the proposed cutoff value. With this strategy 10.67% of GC, 1.3% of non-tumor controls and 8% of gastritis samples were found positive. An EBER1 in situ hybridization showed EBV infection of epithelial cells in GC and in a third of NAG samples, while in the other NAGs infection was restricted to the mononuclear cell infiltrate. EBV-positive GCs were enriched in lace and cribriform patterns, while these rare patterns were not observed in EBV negative samples. Our results support a role for EBV in GC and early precursor lesions, either as directly oncogenic infecting epithelial cells or indirectly as an inflammatory trigger.

The article describes a clinical case of chronic gastritis associated with Helicobacter pylori infection and Epstein-Barr virus. The authors draw attention to the peculiarities of dyspepsia syndrome, on the characteristics of this disease in the endoscopic and morphological study.

The article contains the results of studies of clinical and morphological features of chronic gastritis of viral and bacterail etiology in age aspects. Chronic gastritis when infected with Epstein-Barr virus in elderly patients has clinical and morphological differences from chronic gastritis associated with Helicobacter pylori infection, consisting in significantly lower severity of regenerative changes in the cervical epithelium of the mucous membrane of the body and antrum of the stomach, cervical mucosal epithelium of the body, antrum, bottom mucosal epithelium of the stomach body; and significantly more rare intestinal metaplasia in the stomach and the absence of stromal fibrosis antrum.

Background: H. pylori infection is acquired during childhood and causes a chronic inflammatory response in the gastric mucosa, which is considered the main risk factor to acquire gastric cancer (GC) later in life. More recently, infection by Epstein-Barr virus (EBV) have also been associated with GC. The role of EBV in early inflammatory responses and its relationship with H. pylori infection remains poorly studied. Here, we assessed whether EBV infection in children correlated with the stage of gastritis and whether co-infection with H. pylori affected the severity of inflammation., Methodology/principal Findings: 333 pediatric patients with chronic abdominal pain were studied. From them, gastric biopsies were taken and inflammation graded according to the Sydney system; peripheral blood was drawn and antibodies against EBV (IgG and IgM anti-VCA) and H. pylori (IgG anti-whole bacteria and anti-CagA) were measured in sera. We found that children infected only by EBV presented mild mononuclear (MN) and none polymorphonuclear (PMN) cell infiltration, while those infected by H. pylori presented moderate MN and mild PMN. In contrast, patients co-infected with both pathogens were significantly associated with severe gastritis. Importantly, co-infection of H. pylori CagA+/EBV+ had a stronger association with severe MN (PR 3.0) and PMN (PR 7.2) cells than cases with single H. pylori CagA+ infection., Conclusions/significance: Co-infection with EBV and H. pylori in pediatric patients is associated with severe gastritis. Even single infections with H. pylori CagA+ strains are associated with mild to moderate infiltration arguing for a cooperative effect of H. pylori and EBV in the gastric mucosa and revealing a critical role for EBV previously un-appreciated. This study points out the need to study both pathogens to understand the mechanism behind severe damage of the gastric mucosa, which could identified children with increased risk to present more serious lesions later in life.

Background and Aims: Epstein-Barr virus (EBV) is present in the malignant epithelial cells of 10% of all gastric adenocarcinomas; however, localization of the virus in normal gastrointestinal mucosa is largely unexplored. In the present study, we measured EBV DNA and localized viral gene products in gastritis specimens (n = 89), normal gastric and colonic mucosa (n = 14), Crohn's disease (n = 9), and ulcerative colitis (n = 11) tissues., Methods: A battery of sensitive and specific quantitative polymerase chain reactions targeted six disparate regions of the EBV genome: BamH1 W, EBNA1, LMP1, LMP2, BZLF1, and EBER1. EBV infection was localized by EBV-encoded RNA (EBER) in situ hybridization and by immunohistochemical stains for viral latent proteins LMP1 and LMP2 and for viral lytic proteins BMRF1 and BZLF1. B lymphocytes were identified using CD20 immunostains., Results: EBV DNA was essentially undetectable in normal gastric mucosa but was present in 46% of gastritis lesions, 44% of normal colonic mucosa, 55% of Crohn's disease, and 64% of ulcerative colitis samples. Levels of EBV DNA exceeded what would be expected based on the numbers of B lymphocytes in inflamed tissues, suggesting that EBV is preferentially localized to inflammatory gastrointestinal lesions. Histochemical staining revealed EBER expression in lymphoid cells of some PCR-positive lesions. The viral lytic viral proteins, BMRF1 and BZLF1, were expressed in lymphoid cells of two ulcerative colitis tissues, both of which had relatively high viral loads by quantitative PCR., Conclusion: EBV-infected lymphocytes are frequently present in inflamed gastric and colonic mucosa. Active viral replication in some lesions raises the possibility of virus-related perpetuation of gastrointestinal inflammation.

We report a case of gastritis cystica porfunda (GCP) associated with gastric carcinoma with lymphoid stroma (CLS). There was dysplastic change in the transitional area between GCP and CLS. Epstein-Barr virus (EBV) in situ hybridization (ISH) revealed positive reaction at the dysplastic area as well as at the CLS area. Immunohistochemical staining disclosed that dysplastic epithelium was similar to GCP in CK 20, MUC5AC, and E-cadherin expression, but similar to CLS in MUC6, CEA, p53, c-erb-B2, and EBV-ISH expression. Results of the EBV-ISH suggested that EBV infection may play a role in dysplastic change., (© 2012 The Authors. Pathology International © 2012 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.)

The results of investigation of 49 children suffering from chronic gastroduodenitis and atopic dermatitis are presented. All the child underwent serological blood analyses for Epsteine-Barr virus antibodies and fibrogastroduodenoscopy with antral and duodenal mucosal biopsy. Hystomorphological and immunohystochemical studies of mucosal biopsy specimens for Epsteine-Barr virus were carried out. The role of Epsteine-Barr virus in genesis of chronic gastroduodenitis is detected.

Infectious mononucleosis is a self-limiting clinical syndrome caused by primary Epstein-Barr virus (EBV) infection. EBV-associated gastritis, however, has rarely been documented. We report a case of a 17-year-old woman who presented with fever, sore throat, and epigastric pain. Upper endoscopy revealed diffuse granular mucosae and elevated lesions in the stomach. Histologically, the biopsied mucosa was infiltrated by numerous atypical lymphocytes. From clinical, histopathologic, immunohistochemical, and in situ hybridization analyses, we diagnosed EBV-associated gastritis. Her symptoms spontaneously resolved, and follow-up endoscopy revealed improvement and no atypical lymphocytes. To prevent misdiagnosis and unnecessary treatment, the possibility of EBV-associated gastritis should be considered.

To clarify the significance of p73 in Epstein-Barr virus (EBV)-associated gastric carcinoma (GC), the immunohistochemical expression and CpG-island methylation of p73 were evaluated in cancer tissues and adjacent nonneoplastic tissues of GC with and without EBV infection. Loss of p73 expression by immunohistochemistry was specific to EBV-associated GC (11/13) compared to EBV-negative GC (3/38), which was independent of abnormal p53 expression. With methylation-specific polymerase chain reaction (MSP), the aberrant methylation of p73 exon 1 was similarly specific to EBV-associated GC (12/13), and also rare in EBV-negative GC (2/38). Bisulfite sequencing for p73 exon 1 and its 5' region confirmed the MSP results, showing uniform and high-density methylation in EBV-associated GC. Comparative MSP analysis of p14, p16 and p73 methylation, using 20 cases each of formalin-fixed and paraffin-embedded tissues of early GC with and without EBV infection, confirmed 2 types of methylation: global methylation with increased rates (p14 and p16) and specific methylation of p73 in EBV-associated GC. In nonneoplastic mucosa, p14, p16 and p73 methylation occurred in both EBV-associated (8/33, 6/34 and 3/38, respectively) and EBV-negative GC (6/23, 4/35, and 1/35). p73 methylation was observed in the mucosa without H. pylori infection in all 4 samples. Loss of p73 expression through aberrant methylation of the p73 promoter occurs specifically in EBV-associated GC, together with the global methylation of p14 and p16. A specific type of gastritis, prone to a higher grade of atrophy and p73 methylation, may facilitate the development of EBV-associated GC.

Infectious mononucleosis is usually a self-limited clinical syndrome caused by primary Epstein-Barr virus infection. It is occasionally compounded by severe complications involving many different organ systems. Predominant gastrointestinal involvement is rarely documented. We present an unusual case of acute Epstein-Barr virus infection-associated gastritis with diffuse atypical lymphoid hyperplasia in gastric mucosa. The clinical, radiographic, histopathologic, immunohistochemical, and in situ hybridization features needed for accurate diagnosis and differentiation from gastric malignancies are discussed.

Purpose: We investigated the detectability of EBV DNA in the serum of gastric carcinoma patients in Hong Kong. Previous data have shown that approximately 10% of gastric carcinomas in Hong Kong are associated with EBV., Experimental Design: We recruited 51 patients with gastric carcinoma, 30 patients with gastritis, and 197 apparently healthy controls. For gastric carcinoma patients, blood samples were obtained before surgery. After surgery, the resected tumor samples from the cancer cases were subjected to in situ hybridization for small EBV-encoded RNA (EBER). Serum EBV DNA in all cases was measured by real-time quantitative PCR., Results: Serum EBV DNA was detectable in 5 of 5 (100%) EBER-positive gastric carcinoma cases (median concentration, 1063 copies/ml), in 13 of 14 (93%) EBER-negative gastric carcinoma cases with EBER-positive infiltrating lymphocytes (median concentration, 50 copies/ml), and in 0 of 32 (0%) EBER-negative cases. In the nontumor controls, serum EBV DNA was detectable in 7 of 30 (23%) gastritis cases (median concentration, 0 copies/ml) and in 7 of 197 (3.6%) apparently healthy individuals (median concentration, 0 copy/ml)., Conclusions: Our data indicate that serum EBV DNA reflects tumoral EBER status and opens up the possibility that circulating EBV DNA may be used as a tumor marker for the EBER-positive gastric carcinomas. The biological and clinical significance of the presence of low levels of circulating EBV DNA in the minority of gastritis patients and healthy individuals remains to be elucidated.