Epstein–Barr virus-associated malignancies: epidemiologic patterns and etiologic implications
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)
- et al.
Virus particles in cultured lymphoblasts from Burkitt's lymphoma
Lancet
(1964) - et al.
The epidemiology of Hodgkin's disease
Bailliere's Clin. Haematol.
(1996) - et al.
Epstein–Barr virus antibody levels in children from the West Nile District of Uganda. Report of a field study
Lancet
(1972) - et al.
Expression of Epstein–Barr virus latent gene products in tumour cells of Hodgkin's disease
Lancet
(1991) - et al.
The structure of the termini of the Epstein–Barr virus as a marker of clonal cellular proliferation
Cell
(1986) - et al.
An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells
Cell
(1985) - et al.
Molecular epidemiology of Burkitt's lymphoma from South America: differences in breakpoint location and Epstein–Barr virus association from tumors in other world regions
Blood
(1992) - et al.
Epstein–Barr virus-associated gastric adenocarcinoma in Taiwan
Hum. Pathol.
(1995) - et al.
Epstein–Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation
Hum. Pathol.
(1996) - et al.
Epstein–Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation
Blood
(1988)
Posttransplant lymphoproliferative disorders in heart- lung transplant recipients: primary presentation in the allograft
Hum. Pathol.
Salivary gland cancer in Alaskan natives, 1966–1980
Hum. Pathol.
Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: demonstration of Epstein–Barr virus DNA by in situ nucleic acid hybridization
Hum. Pathol.
Expression of Epstein–Barr virus in carcinomas of major salivary glands: a strong association with lymphoepithelioma-like carcinoma
Hum. Pathol.
Unusual dural and skull-based mesenchymal neoplasms: a report of four cases
Hum. Pathol.
The association of Epstein–Barr virus with smooth-muscle tumors occurring after organ transplantation
New Engl. J. Med.
Cancers in children with HIV infection
Hematol. Oncol. Clin. North Am.
Epidemiological evidence suggesting an infective element in the aetiology
Immune regulation in Epstein–Barr virus-associated diseases
Microbiol. Rev.
Epstein–Barr virus
Association of Epstein–Barr virus with leiomyosarcomas in children with AIDS
New Engl. J. Med.
Etiology of nasopharyngeal carcinoma: a review
Epidemiol. Rev.
African Burkitt's lymphoma. History, biology, clinical features, and treatment
Am. J. Pediatr. Hematol. Oncol.
Viruses
Epstein–Barr virus and its replication
Epstein–Barr virus and its interaction with the host
Intervirology
Sero-epidemiology of the Epstein-Barr virus: preliminary analysis of an international study-a review
The spectrum of infections with Epstein–Barr virus: a hypothesis
J. Infect. Dis.
Seroepidemiologic study of Epstein–Barr virus infections in a rural community
J. Infect. Dis.
Epstein–Barr virus
Prospective studies of a group of Yale University freshmen. I. Occurrence of infectious mononucleosis
J. Infect. Dis.
Epidemiological evidence for causal relationship between Epstein–Barr virus and Burkitt's lymphoma from Ugandan prospective study
Nature
Elevated antibody titers to Epstein–Barr virus prior to the diagnosis of Epstein–Barr-virus-associated gastric adenocarcinoma
Int. J. Cancer
Detection of EBV gene expression in Reed–Sternberg cells of Hodgkin's disease
Int. J. Cancer
Prospective studies on nasopharyngeal carcinoma in Epstein–Barr virus IgA/VCA antibody-positive persons in Wuzhou City, China
Int. J. Cancer
Hodgkin's disease and Epstein–Barr virus. Altered antibody pattern before diagnosis
New Engl. J. Med.
Nasopharyngeal carcinoma: significance of changes in Epstein–Barr virus-related antibody patterns following therapy
Int. J. Cancer
Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells
Nature
Biochemical, genetic, and functional analyses of the phosphorylation sites on the Epstein–Barr virus-encoded oncogenic latent membrane protein LMP-1
J. Virol.
The truncated form of the Epstein–Barr virus latent-infection membrane protein expressed in virus replication does not transform rodent fibroblasts
J. Virol.
Hodgkin's disease
Epstein–Barr virus and malignant lymphomas
Nasopharyngeal cancer
Nasopharyngeal carcinoma
Epstein–Barr Virus DNA recombination and loss in sporadic Burkitt's lymphoma
J. Infect. Dis.
Cited by (246)
Long-term exposure to ambient air pollution and risk of leukemia and lymphoma in a pooled European cohort
2024, Environmental PollutionStructural and functional variation of human oral microbiome in health and disease
2023, Microbiome and the Eye: What's the Connection?Therapeutic potentials of CRISPR-Cas genome editing technology in human viral infections
2022, Biomedicine and PharmacotherapyThe intersection of virus infection and liver disease: A comprehensive review of pathogenesis, diagnosis, and treatment
2024, WIREs Mechanisms of Disease
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.