Epstein–Barr virus-associated malignancies: epidemiologic patterns and etiologic implications

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Abstract

Epstein–Barr virus (EBV), a ubiquitous B-lymphotrophic herpesvirus, has been found in the tumor cells of a heterogeneous group of malignancies (Burkitt's lymphoma, lymphomas associated with immunosuppression, other non-Hodgkin’s lymphomas, Hodgkin's disease, nasopharyngeal carcinoma, gastric adenocarcinoma, lymphoepithelioma-like carcinomas, and immunodeficiency-related leiomyosarcoma). As the epidemiologic characteristics of these cancers have not been considered together, this review seeks to relate their incidence patterns and risk factors to EBV biology and virus-host interaction in an attempt to help elucidate factors involved in EBV-related carcinogenesis. We include a brief review of EBV virology and primary infection to provide a biologic context for considering the epidemiology, summarize the most salient epidemiologic features of each malignancy, synthesize epidemiologic data by risk factor to uncover commonalities and informative contrasts across the diseases, and propose hypotheses regarding etiologic mechanisms, based on the possible effect of the risk factors at various stages in the viral life cycle.

Introduction

In 1958, Denis Burkitt described in African children a unique lymphoma whose high incidence in low-lying, tropical regions of Uganda and absence from nearby higher elevations, as well as similarity to tropical diseases with known arthropod vectors, led researchers to suspect an infectious etiology [1]. In 1964 Epstein, Achong and Barr discovered a previously undescribed herpes virus in cultured cell lines of this tumor [2]. Subsequent studies demonstrated that the virus, named Epstein–Barr virus (EBV) and designated human herpesvirus 4, is a potent lymphotrophic agent capable of transforming B-cells in vitro into a state of continuous proliferation called ‘immortalization’ [3]. This behavior and the consistent viral presence in African Burkitt’s lymphoma implicated EBV as the first candidate human tumor virus [4].

In recent years, serologic and molecular assays have provided evidence that EBV is associated with several malignancies. Besides Burkitt’s lymphoma, EBV is now suspected to be a pathogenic agent in other non-Hodgkin's lymphomas (e.g. AIDS-associated, post-transplant, and nasal T/natural killer cell) and Hodgkin's disease; in nasopharyngeal carcinoma, lymphoepithelioma-like carcinoma, and gastric adenocarcinoma; and in leiomyosarcomas associated with immunosuppression [4], [5]. Although these diseases are rare in most populations, their incidence is elevated in certain groups: nasopharyngeal carcinoma is an important source of cancer morbidity in southern Chinese, Burkitt’s lymphoma is a common cancer of children in equatorial Africa and Papua New Guinea, and Hodgkin's disease is one of the most frequent malignancies affecting young adults [6], [7], [8]. Thus, clearer understanding of the pathogenesis of this heterogeneous group of cancers has considerable public health importance. Examination of the epidemiologic characteristics of these diseases offers the opportunity to identify common population-level features that may provide clues to viral oncogenesis. Therefore, we have undertaken a review of the epidemiology of EBV-linked cancers to identify consistencies as well as unique characteristics across the incidence patterns and risk factors for these diseases and to relate these population patterns to EBV biology and virus-host interaction in an attempt to elucidate EBV carcinogenesis. Toward this end, we first briefly review EBV virology and primary infection to provide a biologic context for considering the epidemiology, then summarize the most salient epidemiologic features of each malignancy, presenting supporting data in tables and figures. We next synthesize these epidemiologic data by risk factor to uncover commonalities and informative contrasts across diseases, and finally we put forth hypotheses regarding etiologic mechanisms, based on the possible effect of these risk factors at various stages in the viral life cycle.

Section snippets

Basics of EBV biology

EBV consists of an icosahedral capsid and a double-stranded DNA core that encodes approximately 100 genes [3], [9]. Infection with EBV, like that with other herpes viruses, involves both a lytic and a latent phase. Oropharyngeal epithelial cells were once thought to be the site of primary infection, but it is now believed that EBV initially targets B-cells located in pharyngeal tissues (e.g. tonsillar parenchyma) [10]. While the ability of this virus to infect oropharyngeal epithelial cells is

Epidemiology of primary infection with EBV

EBV is transmitted through saliva, although blood transfusion and bone marrow and organ transplantation also have been implicated [12]. Seroepidemiologic studies indicate that >90% of adults worldwide are infected with EBV [13]. However, there is substantial variation in the age at primary infection, likely due to socio-demographic factors controlling exposure to the virus [14]. In the poor hygienic and dense living conditions of many developing countries, primary infection occurs early in life

Laboratory methods and evidence associating EBV with malignancy

Serologic documentation of EBV infection has proved valuable for establishing and characterizing the association between EBV and disease. Antibodies to specific EBV antigens reveal not only the presence but also the characteristics of infection: for example, titers to early antigen (EA) indicate viral replication and titers to nuclear antigen indicate immune control of latent EBV infection [9]. The detection of elevated titers, particularly months to years prior to the diagnosis of cancer,

Methods

Because the malignancies linked with EBV are heterogeneous, they can be classified along various axes. Here, we group EBV-related cancers by cell lineage, into lymphomas, carcinomas, and sarcomas. As several of these diseases have been the subject of recent detailed reviews [10], [31], [32], [33], [34], our approach here is to briefly summarize for each the extent of association with EBV and the essentials of epidemiology, including incidence patterns and the more established risk factors. Data

Epidemiologic commonalities and contrasts

Beyond the common monoclonal appearance of EBV within their tumor cells, the malignancies linked to this virus differ substantially (Table 3). They vary in the cell-type and anatomic site affected, in the extent of EBV association, in the degree of preexisting immunocompromise, and in overall incidence, geographic distribution, age- and race-specific occurrence, and epidemiologic risk factors. Yet, within this heterogeneity, a picture of the complex, multifactorial nature of EBV-related

Implications of epidemiologic patterns to etiology

The relationship between EBV and the human host is an evolutionarily well established, life-long process. Because this interaction is medically benign in the vast majority of persons, the development of malignancy is likely to require an unusual confluence of circumstances that leads to a persistent and/or substantial disruption of the normal balance between maintenance of the virus and its elimination by the immune system. Despite the heterogeneity of cancers associated with EBV, common

Conclusion

Considering the epidemiologic commonalities across all EBV-associated cancers together with what is known about the interaction between EBV and the human host has allowed us to speculate broadly about EBV-related carcinogenesis, proposing several pathways along which malignancy may arise. As EBV-associated cancers are uncommon, this process must require particular combinations of both exposure opportunities (e.g. cultural practices, environmental pathogens, genetic susceptibility) and temporal

Reviewers

Dr Richard Burt, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., P.O. Box 19024, Seattle, WA 98109-1024, USA.

Dr Ian Magrath, National Cancer Institute, Pediatric Oncology Branch, Lymphoma Biology Section, 10 Centre Drive, MSC 1928,Building 10, Room 13N240, Bethesda, MA 20892, USA.

Acknowledgements

We thank Dr Angela W. Prehn, Dr Christina A. Clarke, Dr Richard F. Ambinder, Liza Lou and Edward M. Forster for their contributions to this project. Some of the cancer incidence data used in this article were collected by the Northern California Cancer Center under contract N01-CN-65107 with the National Cancer Institute, National Institutes of Health, and with support of the California Cancer Registry, a project of the Cancer Surveillance Section, California Department of Health Services,

Joe Hsu, M.P.H., received his degree in epidemiology from the Boston University School of Public Health. He is currently a medical student at Tufts University.

References (202)

  • S.A. Yousem et al.

    Posttransplant lymphoproliferative disorders in heart- lung transplant recipients: primary presentation in the allograft

    Hum. Pathol.

    (1989)
  • S. Krishnamurthy et al.

    Salivary gland cancer in Alaskan natives, 1966–1980

    Hum. Pathol.

    (1987)
  • S.J. Hamilton-Dutoit et al.

    Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: demonstration of Epstein–Barr virus DNA by in situ nucleic acid hybridization

    Hum. Pathol.

    (1991)
  • C.C. Tsai et al.

    Expression of Epstein–Barr virus in carcinomas of major salivary glands: a strong association with lymphoepithelioma-like carcinoma

    Hum. Pathol.

    (1996)
  • B.K. Kleinschmidt-DeMasters et al.

    Unusual dural and skull-based mesenchymal neoplasms: a report of four cases

    Hum. Pathol.

    (1998)
  • E.S. Lee et al.

    The association of Epstein–Barr virus with smooth-muscle tumors occurring after organ transplantation

    New Engl. J. Med.

    (1995)
  • K.L. McClain et al.

    Cancers in children with HIV infection

    Hematol. Oncol. Clin. North Am.

    (1996)
  • A. Haddow

    Epidemiological evidence suggesting an infective element in the aetiology

  • R. Khanna et al.

    Immune regulation in Epstein–Barr virus-associated diseases

    Microbiol. Rev.

    (1995)
  • A.B. Rickinson et al.

    Epstein–Barr virus

  • K.L. McClain et al.

    Association of Epstein–Barr virus with leiomyosarcomas in children with AIDS

    New Engl. J. Med.

    (1995)
  • A. Hildesheim et al.

    Etiology of nasopharyngeal carcinoma: a review

    Epidemiol. Rev.

    (1993)
  • I.T. Magrath

    African Burkitt's lymphoma. History, biology, clinical features, and treatment

    Am. J. Pediatr. Hematol. Oncol.

    (1991)
  • N.E. Mueller et al.

    Viruses

  • IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Epstein–Barr Virus and Kaposi's Sarcoma...
  • E. Kieff

    Epstein–Barr virus and its replication

  • H. Wolf et al.

    Epstein–Barr virus and its interaction with the host

    Intervirology

    (1993)
  • G. de-Thé et al.

    Sero-epidemiology of the Epstein-Barr virus: preliminary analysis of an international study-a review

  • A.S. Evans

    The spectrum of infections with Epstein–Barr virus: a hypothesis

    J. Infect. Dis.

    (1971)
  • C.V. Sumaya et al.

    Seroepidemiologic study of Epstein–Barr virus infections in a rural community

    J. Infect. Dis.

    (1975)
  • J. Niederman et al.

    Epstein–Barr virus

  • R.N. Sawyer et al.

    Prospective studies of a group of Yale University freshmen. I. Occurrence of infectious mononucleosis

    J. Infect. Dis.

    (1971)
  • G. de-Thé et al.

    Epidemiological evidence for causal relationship between Epstein–Barr virus and Burkitt's lymphoma from Ugandan prospective study

    Nature

    (1978)
  • P.H. Levine et al.

    Elevated antibody titers to Epstein–Barr virus prior to the diagnosis of Epstein–Barr-virus-associated gastric adenocarcinoma

    Int. J. Cancer

    (1995)
  • T.C. Wu et al.

    Detection of EBV gene expression in Reed–Sternberg cells of Hodgkin's disease

    Int. J. Cancer

    (1990)
  • Y. Zeng et al.

    Prospective studies on nasopharyngeal carcinoma in Epstein–Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China

    Int. J. Cancer

    (1985)
  • N. Mueller et al.

    Hodgkin's disease and Epstein–Barr virus. Altered antibody pattern before diagnosis

    New Engl. J. Med.

    (1989)
  • W. Henle et al.

    Nasopharyngeal carcinoma: significance of changes in Epstein–Barr virus-related antibody patterns following therapy

    Int. J. Cancer

    (1977)
  • J.L. Yates et al.

    Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells

    Nature

    (1985)
  • R.K. Moorthy et al.

    Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein–Barr virus-encoded oncogenic latent membrane protein LMP-1

    J. Virol.

    (1993)
  • D. Wang et al.

    The truncated form of the Epstein–Barr virus latent-infection membrane protein expressed in virus replication does not transform rodent fibroblasts

    J. Virol.

    (1988)
  • N. Mueller

    Hodgkin's disease

  • A.S. Evans et al.

    Epstein–Barr virus and malignant lymphomas

  • M. Yu et al.

    Nasopharyngeal cancer

  • G. de-Thé

    Nasopharyngeal carcinoma

  • B.I. Razzouk et al.

    Epstein–Barr Virus DNA recombination and loss in sporadic Burkitt's lymphoma

    J. Infect. Dis.

    (1996)
  • Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer Incidence in Five Continents. IARC Scientific Publications...
  • Ries LAG, Kosary CL, Hankey BF. SEER Cancer Statistics Review, 1973–1994. NIH Publication No. 97-2789. Bethesda, MD:...
  • C.I. Perkins et al.
  • Centers for Disease Control and Prevention. AIDS Public Information Data Set. Atlanta: Centers for Disease Control and...
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    Joe Hsu, M.P.H., received his degree in epidemiology from the Boston University School of Public Health. He is currently a medical student at Tufts University.

    Sally Glaser, Ph.D., trained in epidemiology at the University of California, Berkeley, is a cancer epidemiologist and Director for Registry Research at the Northern California Cancer Center.

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