Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

The role of Epstein-Barr virus in Hodgkin lymphoma

Richard F Ambinder, MD, PhD
Section Editor
Arnold S Freedman, MD
Deputy Editor
Alan G Rosmarin, MD


Hodgkin lymphoma (HL), formerly called Hodgkin's disease, is a neoplasm that arises from germinal center or post-germinal center B cells. HL has a unique cellular composition, containing a minority of neoplastic cells (Reed-Sternberg cells and their variants) in an inflammatory background. It is separated from the other B cell lymphomas based on its unique clinicopathologic features. (See "Epidemiology, pathologic features, and diagnosis of classical Hodgkin lymphoma".)

Epstein-Barr virus (EBV) is a ubiquitous herpesvirus, which is spread mainly through saliva between susceptible persons and asymptomatic EBV shedders. The majority of primary EBV infections throughout the world are subclinical. Antibodies to EBV have been demonstrated in all population groups with a worldwide distribution; approximately 90 to 95 percent of adults are EBV-seropositive. (See "Virology of Epstein-Barr virus".)

The pathobiology of HL remains poorly understood. The role of EBV infection in the development of HL will be reviewed here. Further details on the pathogenesis of HL are discussed separately. (See "The Reed-Sternberg cell and the pathogenesis of Hodgkin lymphoma".)


Early epidemiologic data suggested that HL develops among persons with a delayed exposure to a ubiquitous infectious agent, EBV. The following sections will review data suggesting an association between EBV and HL. Mechanisms thought to be involved in the development of EBV-negative HL are presented separately. (See "The Reed-Sternberg cell and the pathogenesis of Hodgkin lymphoma".)

Association with infectious mononucleosis and EBV — Initial epidemiologic studies that demonstrated an increased risk of HL in patients with a history of infectious mononucleosis were further substantiated by case control studies showing that patients with HL had elevated antibody titers against EBV antigens, which preceded the disease [1-3]. Subsequent studies showed that EBV could be detected in the tumor cells of a subset of patients with HL [4-8]. Finally, in a population-based cohort study of young adults with infectious mononucleosis in Denmark and Sweden, the risk of developing EBV-negative HL after infectious mononucleosis was not increased (relative risk 1.5, 95% CI 0.9-2.5), whereas the risk of developing EBV-positive HL was increased (relative risk 4.0, 95% CI 3.4-4.5), with a median incubation time from mononucleosis to EBV-positive HL of 4.1 years (95% CI 1.8-8.3 years) [9]. In this population, the absolute risk of developing HL after infectious mononucleosis was approximately 1 in 1000.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Oct 2017. | This topic last updated: Jun 15, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Mueller N, Evans A, Harris NL, et al. Hodgkin's disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med 1989; 320:689.
  2. Lehtinen T, Lumio J, Dillner J, et al. Increased risk of malignant lymphoma indicated by elevated Epstein-Barr virus antibodies--a prospective study. Cancer Causes Control 1993; 4:187.
  3. Alexander FE, Jarrett RF, Lawrence D, et al. Risk factors for Hodgkin's disease by Epstein-Barr virus (EBV) status: prior infection by EBV and other agents. Br J Cancer 2000; 82:1117.
  4. Staal SP, Ambinder R, Beschorner WE, et al. A survey of Epstein-Barr virus DNA in lymphoid tissue. Frequent detection in Hodgkin's disease. Am J Clin Pathol 1989; 91:1.
  5. Wu TC, Mann RB, Charache P, et al. Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin's disease. Int J Cancer 1990; 46:801.
  6. Ambinder RF, Browning PJ, Lorenzana I, et al. Epstein-Barr virus and childhood Hodgkin's disease in Honduras and the United States. Blood 1993; 81:462.
  7. Chang KL, Albújar PF, Chen YY, et al. High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of Hodgkin's disease occurring in Peru. Blood 1993; 81:496.
  8. Weiss LM, Movahed LA, Warnke RA, Sklar J. Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin's disease. N Engl J Med 1989; 320:502.
  9. Hjalgrim H, Askling J, Rostgaard K, et al. Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 2003; 349:1324.
  10. Goedert JJ, Coté TR, Virgo P, et al. Spectrum of AIDS-associated malignant disorders. Lancet 1998; 351:1833.
  11. Garnier JL, Lebranchu Y, Dantal J, et al. Hodgkin's disease after transplantation. Transplantation 1996; 61:71.
  12. Tinguely M, Vonlanthen R, Müller E, et al. Hodgkin's disease-like lymphoproliferative disorders in patients with different underlying immunodeficiency states. Mod Pathol 1998; 11:307.
  13. Glaser SL, Clarke CA, Gulley ML, et al. Population-based patterns of human immunodeficiency virus-related Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998. Cancer 2003; 98:300.
  14. Siebert JD, Ambinder RF, Napoli VM, et al. Human immunodeficiency virus-associated Hodgkin's disease contains latent, not replicative, Epstein-Barr virus. Hum Pathol 1995; 26:1191.
  15. Carbone A, Gloghini A, Larocca LM, et al. Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. Blood 1999; 93:2319.
  16. Levine AM. HIV-associated Hodgkin's disease. Biologic and clinical aspects. Hematol Oncol Clin North Am 1996; 10:1135.
  17. Herndier BG, Sanchez HC, Chang KL, et al. High prevalence of Epstein-Barr virus in the Reed-Sternberg cells of HIV-associated Hodgkin's disease. Am J Pathol 1993; 142:1073.
  18. Audouin J, Diebold J, Pallesen G. Frequent expression of Epstein-Barr virus latent membrane protein-1 in tumour cells of Hodgkin's disease in HIV-positive patients. J Pathol 1992; 167:381.
  19. Pelstring RJ, Zellmer RB, Sulak LE, et al. Hodgkin's disease in association with human immunodeficiency virus infection. Pathologic and immunologic features. Cancer 1991; 67:1865.
  20. Shiels MS, Koritzinsky EH, Clarke CA, et al. Prevalence of HIV Infection among U.S. Hodgkin lymphoma cases. Cancer Epidemiol Biomarkers Prev 2014; 23:274.
  21. Diepstra A, Niens M, Vellenga E, et al. Association with HLA class I in Epstein-Barr-virus-positive and with HLA class III in Epstein-Barr-virus-negative Hodgkin's lymphoma. Lancet 2005; 365:2216.
  22. Hjalgrim H, Rostgaard K, Johnson PC, et al. HLA-A alleles and infectious mononucleosis suggest a critical role for cytotoxic T-cell response in EBV-related Hodgkin lymphoma. Proc Natl Acad Sci U S A 2010; 107:6400.
  23. Kennedy AE, Singh SK, Dorak MT. Re: genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups. J Natl Cancer Inst 2012; 104:884.
  24. Urayama KY, Jarrett RF, Hjalgrim H, et al. Genome-wide association study of classical Hodgkin lymphoma and Epstein-Barr virus status-defined subgroups. J Natl Cancer Inst 2012; 104:240.
  25. Huang X, Kushekhar K, Nolte I, et al. HLA associations in classical Hodgkin lymphoma: EBV status matters. PLoS One 2012; 7:e39986.
  26. Kanakry JA, Li H, Gellert LL, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood 2013; 121:3547.
  27. Welch J, Schwartz CL, Higman M, et al. Epstein-Barr virus DNA in serum as an early prognostic marker in children and adolescents with Hodgkin lymphoma. Blood Advances 2017; 1:681.
  28. Glaser SL, Keegan TH, Clarke CA, et al. Exposure to childhood infections and risk of Epstein-Barr virus--defined Hodgkin's lymphoma in women. Int J Cancer 2005; 115:599.
  29. Weiss LM, Strickler JG, Warnke RA, et al. Epstein-Barr viral DNA in tissues of Hodgkin's disease. Am J Pathol 1987; 129:86.
  30. Hu E, Hufford S, Lukes R, et al. Third-World Hodgkin's disease at Los Angeles County-University of Southern California Medical Center. J Clin Oncol 1988; 6:1285.
  31. Pallesen G, Hamilton-Dutoit SJ, Rowe M, Young LS. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet 1991; 337:320.
  32. Gulley ML, Eagan PA, Quintanilla-Martinez L, et al. Epstein-Barr virus DNA is abundant and monoclonal in the Reed-Sternberg cells of Hodgkin's disease: association with mixed cellularity subtype and Hispanic American ethnicity. Blood 1994; 83:1595.
  33. Carbone A, Gloghini A, Zanette I, et al. Co-expression of Epstein-Barr virus latent membrane protein and vimentin in "aggressive" histological subtypes of Hodgkin's disease. Virchows Arch A Pathol Anat Histopathol 1993; 422:39.
  34. Murray PG, Young LS, Rowe M, Crocker J. Immunohistochemical demonstration of the Epstein-Barr virus-encoded latent membrane protein in paraffin sections of Hodgkin's disease. J Pathol 1992; 166:1.
  35. Weiss LM, Chen YY, Liu XF, Shibata D. Epstein-Barr virus and Hodgkin's disease. A correlative in situ hybridization and polymerase chain reaction study. Am J Pathol 1991; 139:1259.
  36. Uccini S, Monardo F, Stoppacciaro A, et al. High frequency of Epstein-Barr virus genome detection in Hodgkin's disease of HIV-positive patients. Int J Cancer 1990; 46:581.
  37. Anagnostopoulos I, Herbst H, Niedobitek G, Stein H. Demonstration of monoclonal EBV genomes in Hodgkin's disease and Ki-1-positive anaplastic large cell lymphoma by combined Southern blot and in situ hybridization. Blood 1989; 74:810.
  38. Gledhill S, Gallagher A, Jones DB, et al. Viral involvement in Hodgkin's disease: detection of clonal type A Epstein-Barr virus genomes in tumour samples. Br J Cancer 1991; 64:227.
  39. Herbst H, Steinbrecher E, Niedobitek G, et al. Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease. Blood 1992; 80:484.
  40. Deacon EM, Pallesen G, Niedobitek G, et al. Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med 1993; 177:339.
  41. Grässer FA, Murray PG, Kremmer E, et al. Monoclonal antibodies directed against the Epstein-Barr virus-encoded nuclear antigen 1 (EBNA1): immunohistologic detection of EBNA1 in the malignant cells of Hodgkin's disease. Blood 1994; 84:3792.
  42. Niedobitek G, Kremmer E, Herbst H, et al. Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis. Blood 1997; 90:1664.
  43. Young LS, Deacon EM, Rowe M, et al. Epstein-Barr virus latent genes in tumour cells of Hodgkin's disease. Lancet 1991; 337:1617.
  44. Murray PG, Constandinou CM, Crocker J, et al. Analysis of major histocompatibility complex class I, TAP expression, and LMP2 epitope sequence in Epstein-Barr virus-positive Hodgkin's disease. Blood 1998; 92:2477.
  45. Glaser SL, Lin RJ, Stewart SL, et al. Epstein-Barr virus-associated Hodgkin's disease: epidemiologic characteristics in international data. Int J Cancer 1997; 70:375.
  46. Gahn TA, Schildkraut CL. The Epstein-Barr virus origin of plasmid replication, oriP, contains both the initiation and termination sites of DNA replication. Cell 1989; 58:527.
  47. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 2004; 350:1328.
  48. Kilger E, Kieser A, Baumann M, Hammerschmidt W. Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J 1998; 17:1700.
  49. MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12:117.
  50. Jarrett RF, MacKenzie J. Epstein-Barr virus and other candidate viruses in the pathogenesis of Hodgkin's disease. Semin Hematol 1999; 36:260.
  51. Kulwichit W, Edwards RH, Davenport EM, et al. Expression of the Epstein-Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice. Proc Natl Acad Sci U S A 1998; 95:11963.
  52. Sylla BS, Hung SC, Davidson DM, et al. Epstein-Barr virus-transforming protein latent infection membrane protein 1 activates transcription factor NF-kappaB through a pathway that includes the NF-kappaB-inducing kinase and the IkappaB kinases IKKalpha and IKKbeta. Proc Natl Acad Sci U S A 1998; 95:10106.
  53. Cader FZ, Vockerodt M, Bose S, et al. The EBV oncogene LMP1 protects lymphoma cells from cell death through the collagen-mediated activation of DDR1. Blood 2013; 122:4237.
  54. Mancao C, Hammerschmidt W. Epstein-Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 2007; 110:3715.
  55. Merchant M, Caldwell RG, Longnecker R. The LMP2A ITAM is essential for providing B cells with development and survival signals in vivo. J Virol 2000; 74:9115.
  56. Bräuninger A, Schmitz R, Bechtel D, et al. Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 2006; 118:1853.
  57. Bechtel D, Kurth J, Unkel C, Küppers R. Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 2005; 106:4345.
  58. Chaganti S, Bell AI, Pastor NB, et al. Epstein-Barr virus infection in vitro can rescue germinal center B cells with inactivated immunoglobulin genes. Blood 2005; 106:4249.