Epstein–Barr virus (EBV) was discovered 40 years ago from examining electron micrographs of cells cultured from Burkitt's lymphoma, a childhood tumour that is common in sub-Saharan Africa, where its unusual geographical distribution — which matches that of holoendemic malaria —indicated a viral aetiology. However, far from showing a restricted distribution, EBV — a γ-herpesvirus — was found to be widespread in all human populations and to persist in the vast majority of individuals as a lifelong, asymptomatic infection of the B-lymphocyte pool. Despite such ubiquity, the link between EBV and 'endemic' Burkitt's lymphoma proved consistent and became the first of an unexpectedly wide range of associations discovered between this virus and tumours.

Epstein–Barr virus: 40 years on

The Epstein–Barr virus (EBV) was discovered 36 years ago by electron microscopy of cells cultured from Burkitt's lymphoma tissue by Epstein, Achong, and Barr.1 Four years later, in 1968, EBV was shown to be the etiologic agent of heterophile-positive infectious mononucleosis.2 EBV DNA was detected in tissues from patients with nasopharyngeal carcinoma in 1970.3 In the 1980s, EBV was found to be associated with non-Hodgkin's lymphoma and oral hairy leukoplakia in patients with the acquired immunodeficiency syndrome (AIDS).4,5 Since then, EBV DNA has been found in tissues from other cancers, including T-cell lymphomas and Hodgkin's disease.6,7 EBV is . . .

https://www.nejm.org/doi/pdf/10.1056/NEJM200008173430707?listPDF=true

Epstein-Barr Virus Infection

Reactive oxygen species (ROS) are generated as by-products of normal cellular metabolic activities. Superoxide dismutase, glutathione peroxidase, and catalase are the enzymes involved in protecting cells from the damaging effects of ROS. ROS are produced in response to ultraviolet radiation, cigarette smoking, alcohol, nonsteroidal anti-inflammatory drugs, ischemia-reperfusion injury, chronic infections, and inflammatory disorders. Disruption of normal cellular homeostasis by redox signaling may result in cardiovascular, neurodegenerative diseases and cancer. ROS are produced within the gastrointestinal (GI) tract, but their roles in pathophysiology and disease pathogenesis have not been well studied. Despite the protective barrier provided by the mucosa, ingested materials and microbial pathogens can induce oxidative injury and GI inflammatory responses involving the epithelium and immune/inflammatory cells. The pathogenesis of various GI diseases including peptic ulcers, gastrointestinal cancers, and inflammatory bowel disease is in part due to oxidative stress. Unraveling the signaling events initiated at the cellular level by oxidative free radicals as well as the physiological responses to such stress is important to better understand disease pathogenesis and to develop new therapies to manage a variety of conditions for which current therapies are not always sufficient.

Oxidative Stress: An Essential Factor in the Pathogenesis of Gastrointestinal Mucosal Diseases

The incidence and mortality of gastric cancer have fallen dramatically in US and elsewhere over the past several decades. Nonetheless, gastric cancer remains a major public health issue as the fourth most common cancer and the second leading cause of cancer death worldwide. Demographic trends differ by tumor location and histology. While there has been a marked decline in distal, intestinal type gastric cancers, the incidence of proximal, diffuse type adenocarcinomas of the gastric cardia has been increasing, particularly in the Western countries. Incidence by tumor sub-site also varies widely based on geographic location, race, and socio-economic status. Distal gastric cancer predominates in developing countries, among blacks, and in lower socio-economic groups, whereas proximal tumors are more common in developed countries, among whites, and in higher socio-economic classes. Diverging trends in the incidence of gastric cancer by tumor location suggest that they may represent two diseases with different etiologies. The main risk factors for distal gastric cancer include Helicobacter pylori (H pylori) infection and dietary factors, whereas gastroesophageal reflux disease and obesity play important roles in the development of proximal stomach cancer. The purpose of this review is to examine the epidemiology and risk factors of gastric cancer, and to discuss strategies for primary prevention.

Epidemiology of gastric cancer

Epidemiology of gastric cancer.

In 1000 primary gastric carcinomas, 70 (7.0%) contained Epstein-Barr virus (EBV) genomic sequences detected by PCR and Southern blots. The positive tumors comprised 8 of 9 (89%) undifferentiated lymphoepithelioma-like carcinomas, 27 of 476 (5.7%) poorly differentiated adenocarcinomas, and 35 of 515 (6.8%) moderately to well-differentiated adenocarcinomas. In situ EBV-encoded small RNA 1 hybridization and hematoxylin/eosin staining in adjacent sections showed that the EBV was present in every carcinoma cell but was not significantly present in lymphoid stroma and in normal mucosa. Two-color immunofluorescence and hematoxylin/eosin staining in parallel sections revealed that every keratin-positive epithelial malignant cell expressed EBV-determined nuclear antigen 1 (EBNA1) but did not significantly express CD45+ infiltrating leukocytes. A single fused terminal fragment was detected in each of the EBNA1-expressing tumors, thereby suggesting that the EBV-carrying gastric carcinomas represent clonal proliferation of cells infected with EBV. The carcinoma cells had exclusively EBNA1 but not EBNA2, -3A, -3B, and -3C; leader protein; and latent membrane protein 1 because of methylation. The patients with EBV-carrying gastric carcinoma had elevated serum EBV-specific antibodies. The EBV-specific cellular immunity was not significantly reduced; however, the cytotoxic T-cell target antigens were not expressed. These findings strongly suggest a causal relation between a significant proportion of gastric carcinoma and EBV, and the virus-carrying carcinoma cells may evade immune surveillance.

https://www.pnas.org/content/pnas/91/19/9131.full.pdf

Gastric carcinoma : monoclonal epithelial malignant cells expressing epstein-barr virus latent infection protein

Epstein-Barr virus (EBV) involvement in gastric cancer is demonstrated by uniform presence of viral RNA in carcinoma cells as detected by EBV-encoded small RNA in situ hybridization, monoclonal proliferation of EBV-infected carcinoma cells, and elevated antibodies. Our review of selected early gastric cancers found that 46 of 49 EBV-positive lesions (94%) but only four of 97 EBV-negative lesions (4%) conformed to a unique morphology, in which carcinoma cells formed lace patterns of branching and/or anastomosing structures with lymphocytic infiltration in and around the carcinoma nests in the mucosa. We conclude that EBV-related gastric carcinoma has a distinct and characteristic morphology in the early stage of development, and this lace pattern is a biomarker of EBV involvement in early gastric cancer.

https://cebp.aacrjournals.org/content/cebp/3/7/607.full.pdf

A unique morphology of Epstein-Barr virus-related early gastric carcinoma.

We have examined the expression of specific mucin antigens in tissue sections from 92 cases of colorectal carcinoma, using sulfomucin-specific monoclonal antibody (MAb) 91.9H. The expression of sulfomucins was high in normal mucosae and much lower in primary colorectal carcinoma, in metastatic lesions in lymph nodes or in liver. The intracellular localization of sulfomucins was also different among these tissues. In normal mucosae, MAb 91.9H binding was seen in the supranuclear area, presumably Golgi complexes, the luminal surface, and secretory products. In primary colorectal carcinomas and in their metastatic lesions, MAb 91.9H was preferentially localized in the cell surface and substances attached to the luminal surface of glandular structures. Analysis of the lysates of normal and tumor tissues showed that very-high-molecular-weight components contained the antigenic epitopes. The intensity of MAb 91.9H binding was lower in tumors at advanced stages than in tumors at early stages. These high-molecular-weight components were apparently reactive with MAb FH6 specific for sialyl-Le X (s-Le X ) structures. Histological specimens with low levels of MAb 91.9H reactivity often exhibited relatively high levels of MAb FH6 reactivity. These two mucins may have reversed expression during carcinogenesis and carcinoma progression, and this change may be related to metastatic potential.

Expression of Sulfomucins in Normal Mucosae, Colorectal Adenocarcinomas, and Metastases

Malignant transformation in a benign eccrine spiradenoma is rare. Since it was first reported in 1972, 31 cases have been reported. Of these, six cases had sarcomatous components, mainly osteosarcomatous, and one had rhabdomyoblastic differentiation. A case is presented in which there were some small nodules of benign eccrine spiradenomas adjacent to a large nodule of malignant eccrine spiradenoma with leiomyosarcomatous components, determined by histologic and immunohistochemical studies.

Malignant eccrine spiradenoma with smooth muscle cell differentiation: Histological and immunohistochemical study

We described a case of splenic CD4 positive 7I8 Tcell lymphoma with bone marrow involvement, and leukemic change in the terminal stage. A 23-year-old male had high fever and hepatosplenomegaly with pancytopenia and histiocytic hemophagocytosis. In order to make an accurate diagnosis and to improve symptom, splenectomy was performed. Histological section of the spleen showed marked congestion and diffuse proliferation of atypical lymphocytes having oval nuclei with or without nuclear indentation in the red pulp, indicating diffuse, large cell lymphoma. Immunohistochemically, the atypical cells were positive for CD2, CD3, CD4, CD15 and CD25. The lymphoma cells were also positive for 8 TCSl and negative for TCR P FI. Despite the chemotherapy, his lymphoma did not improve and developed into leukemic change in the critical state. When his bone marrow was largely involved by blastic cells about 90%, phenotype examination by flow cytometry revealed CD3-positive and TCR 7 8 -1-positive, but CD 4negative. This case is thought to be an unusual splenic 718 Tcell lymphoma with onset of histiocytic hemophagocy tosis and CD4 expression in the initial stage. There are two forms of the T-cell receptor ; TCR a I P and TCR 718. The former is expressed on the majority of peripheral T-cells, whereas the latter is present on the minority, reported about 9% of the peripheral blood lymphocytes1^ These TCR 7/8 positive lymphocytes in the peripheral blood are small to medium-sized cells in normal donors. The spleen is

/pdf/splenic-gamma-delta-t-cell-lymphoma-report-of-a-case-pu7pzal4fk.pdf

Noriko Yamamoto

Papers

Gastric carcinoma : monoclonal epithelial malignant cells expressing epstein-barr virus latent infection protein

A unique morphology of Epstein-Barr virus-related early gastric carcinoma.

Expression of Sulfomucins in Normal Mucosae, Colorectal Adenocarcinomas, and Metastases

Malignant eccrine spiradenoma with smooth muscle cell differentiation: Histological and immunohistochemical study

Splenic gamma/delta T-cell Lymphoma Report of a Case