Skip to main content

Advertisement

SpringerLink
Log in

Lymphomatoid Granulomatosis and Other Epstein-Barr Virus Associated Lymphoproliferative Processes

  • Lymphomas (J Armitage and P McLaughlin, Section Editors)
  • Published:
Current Hematologic Malignancy Reports Aims and scope Submit manuscript

Abstract

We now recognize that the Epstein-Barr virus (EBV), which is a member of the γ- herpesvirus family, plays a pivotal role in the development of several lymphomas and lymphoproliferative disorders that include B-cell, T-cell and NK-cell processes. While over recent years, EBV associated lymphomas that arise in patients with known defects in cellular immunity are relatively well characterized, these diseases are becoming increasingly recognized in patients without overt immunodeficiency. Improved understanding of the biology of these lymphomas including elucidating the role that EBV plays in their pathogenesis has paved the way for improved therapies targeted at critical signaling pathways as well as the development of novel cellular therapies. In this review, we focus on recent progress that has been made in the biology and treatment of the rare EBV-associated disorder lymphomatoid granulomatosis (LYG) and also discuss other EBV-associated processes that occur in both immunocompetent and immunocompromised hosts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Epstein MA, Barr YM. Cultivation in vitro of human lymphoblasts from Burkitt's malignant lymphoma. Lancet. 1964;1(7327):252–3.

    Article  PubMed  CAS  Google Scholar 

  2. Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481–92.

    Article  PubMed  CAS  Google Scholar 

  3. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008.

    Google Scholar 

  4. Young LS, Murray PG. Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene. 2003;22(33):5108–21.

    Article  PubMed  CAS  Google Scholar 

  5. • Saha A, Robertson ES. Epstein-Barr virus-associated B-cell lymphomas: pathogenesis and clinical outcomes. Clin Cancer Res. 2011;17(10):3056–63. This is a well written review that details the pathogenesis and clinical outcome of EBV-associated lymphoproliferative processes.

    Article  PubMed  CAS  Google Scholar 

  6. Roschewski M, Wilson WH. EBV-associated lymphomas in adults. Best Pract Res Clin Haematol. 2012;25(1):75–89.

    Article  PubMed  Google Scholar 

  7. Wilson WH, Kingma DW, Raffeld M, Wittes RE, Jaffe ES. Association of lymphomatoid granulomatosis with Epstein-Barr viral infection of B lymphocytes and response to interferon-alpha 2b. Blood. 1996;87(11):4531–7.

    PubMed  CAS  Google Scholar 

  8. Dunleavy K, Chattopadhyah P, Kawada J, et al. Immune characteristics associated with lymphomatoid granulomatosis and outcome following treatment with interferon-alpha. Blood (ASH Annual Meeting Abstracts). 2010;116:963.

  9. Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Canc Surv. 1997;30:233–48.

    CAS  Google Scholar 

  10. • Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology. 2005;23(1):265–73. This manuscript describes the appearances of lymphomatoid granulomatosis on neuroimaging from the largest series of these patients.

    Article  Google Scholar 

  11. Bird BH, Grant N, Dunleavy K, et al. Treatment and niology of Lymphomatoid Granulomatosis. JCO, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Suppl): 8029.

  12. Gulley ML, Raphael M, Lutz CT, Ross DW, Raab-Traub N. Epstein-Barr virus integration in human lymphomas and lymphoid cell lines. Cancer. 1992;70(1):185–91.

    Article  PubMed  CAS  Google Scholar 

  13. Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 2004;350(13):1328–37.

    Article  PubMed  CAS  Google Scholar 

  14. Shimizu N, Tanabe-Tochikura A, Kuroiwa Y, Takada K. Isolation of Epstein-Barr virus (EBV)-negative cell clones from the EBV-positive Burkitt's lymphoma (BL) line Akata: malignant phenotypes of BL cells are dependent on EBV. J Virol. 1994;68(9):6069–73.

    PubMed  CAS  Google Scholar 

  15. Komano J, Sugiura M, Takada K. Epstein-Barr virus contributes to the malignant phenotype and to apoptosis resistance in Burkitt's lymphoma cell line Akata. J Virol. 1998;72(11):9150–6.

    PubMed  CAS  Google Scholar 

  16. Kamranvar SA, Gruhne B, Szeles A, Masucci MG. Epstein-Barr virus promotes genomic instability in Burkitt's lymphoma. Oncogene. 2007;26(35):5115–23.

    Article  PubMed  CAS  Google Scholar 

  17. Kelly GL, Milner AE, Baldwin GS, Bell AI, Rickinson AB. Three restricted forms of Epstein-Barr virus latency counteracting apoptosis in c-myc-expressing Burkitt lymphoma cells. Proc Natl Acad Sci U S A. 2006;103(40):14935–40.

    Article  PubMed  CAS  Google Scholar 

  18. Dunleavy K, Pittaluga S, Wayne A, et al. MYC + Aggressive B-cell lymphomas: Novel therapy of untreated Burkitt lymphoma (BL) and MYC + Diffuse Large B-cell lymphoma (DLBCL) with DA-EPOCH-R. Ann Oncol. 2011;22: suppl 4. Abstract 071.

  19. Oyama T, Ichimura K, Suzuki R, et al. Senile EBV + B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol. 2003;27(1):16–26.

    Article  PubMed  Google Scholar 

  20. Shimoyama Y, Oyama T, Asano N, et al. Senile Epstein-Barr virus-associated B-cell lymphoproliferative disorders: a mini review. J Clin Exp Hematop. 2006;46(1):1–4.

    Article  PubMed  Google Scholar 

  21. Oyama T, Yamamoto K, Asano N, et al. Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res. 2007;13(17):5124–32.

    Article  PubMed  CAS  Google Scholar 

  22. Asano N, Yamamoto K, Tamaru J, et al. Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients. Blood. 2009;113(12):2629–36.

    Article  PubMed  CAS  Google Scholar 

  23. Aozasa K. Pyothorax-associated lymphoma. J Clin Exp Hematop. 2006;46(1):5–10.

    Article  PubMed  Google Scholar 

  24. Fukayama M, Ibuka T, Hayashi Y, Ooba T, Koike M, Mizutani S. Epstein-Barr virus in pyothorax-associated pleural lymphoma. Am J Pathol. 1993;143(4):1044–9.

    PubMed  CAS  Google Scholar 

  25. Nakatsuka S, Yao M, Hoshida Y, Yamamoto S, Iuchi K, Aozasa K. Pyothorax-associated lymphoma: a review of 106 cases. J Clin Oncol. 2002;20(20):4255–60.

    Article  PubMed  Google Scholar 

  26. Munoz N, Davidson RJ, Witthoff B, Ericsson JE, De-The G. Infectious mononucleosis and Hodgkin's disease. Int J Cancer. 1978;22(1):10–3.

    Article  PubMed  CAS  Google Scholar 

  27. Levine PH, Ablashi DV, Berard CW, Carbone PP, Waggoner DE, Malan L. Elevated antibody titers to Epstein-Barr virus in Hodgkin's disease. Cancer. 1971;27(2):416–21.

    Article  PubMed  CAS  Google Scholar 

  28. 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(8):502–6.

    Article  PubMed  CAS  Google Scholar 

  29. Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clin Cancer Res. 2004;10(3):803–21.

    Article  PubMed  CAS  Google Scholar 

  30. • Steidl C, Lee T, Shah SP, et al. Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. N Engl J Med. 2010;362(10):875–85. In this paper, the authors performed gene expression profiling on cases of Hodgkin lymphoma and identified that a signature of tumor-associated macrophages was associated with a poor outcome.

    Article  PubMed  CAS  Google Scholar 

  31. Hohaus S, Santangelo R, Giachelia M, et al. The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts for biological and clinical characteristics in Hodgkin lymphoma. Clin Cancer Res. 2011;17(9):2885–92.

    Article  PubMed  CAS  Google Scholar 

  32. Gualco G, Domeny-Duarte P, Chioato L, Barber G, Natkunam Y, Bacchi CE. Clinicopathologic and molecular features of 122 Brazilian cases of nodal and extranodal NK/T-cell lymphoma, nasal type, with EBV subtyping analysis. Am J Surg Pathol. 2011;35(8):1195–203.

    Article  PubMed  Google Scholar 

  33. Au WY, Weisenburger DD, Intragumtornchai T, et al. Clinical differences between nasal and extranasal natural killer/T-cell lymphoma: a study of 136 cases from the International Peripheral T-Cell Lymphoma Project. Blood. 2009;113(17):3931–7.

    Article  PubMed  CAS  Google Scholar 

  34. Jaccard A, Hermine O. Extranodal natural killer/T-cell lymphoma: advances in the management. Curr Opin Oncol. 2011;23(5):429–35.

    Article  PubMed  CAS  Google Scholar 

  35. Jaccard A, Gachard N, Marin B, et al. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2011;117(6):1834–9.

    Article  PubMed  CAS  Google Scholar 

  36. Anagnostopoulos I, Hummel M, Finn T, et al. Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. Blood. 1992;80(7):1804–12.

    PubMed  CAS  Google Scholar 

  37. Dogan A, Attygalle AD, Kyriakou C. Angioimmunoblastic T-cell lymphoma. Br J Haematol. 2003;121(5):681–91.

    Article  PubMed  Google Scholar 

  38. Alizadeh AA, Advani RH. Evaluation and management of angioimmunoblastic T-cell lymphoma: a review of current approaches and future strategies. Clin Adv Hematol Oncol. 2008;6(12):899–909.

    PubMed  Google Scholar 

  39. Zhou Y, Attygalle AD, Chuang SS, et al. Angioimmunoblastic T-cell lymphoma: histological progression associates with EBV and HHV6B viral load. Br J Haematol. 2007;138(1):44–53.

    Article  PubMed  CAS  Google Scholar 

  40. Dunleavy K, Wilson WH, Jaffe ES. Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications. Curr Opin Hematol. 2007;14(4):348–53.

    Article  PubMed  CAS  Google Scholar 

  41. Evens AM, Roy R, Sterrenberg D, Moll MZ, Chadburn A, Gordon LI. Post-transplantation lymphoproliferative disorders: diagnosis, prognosis, and current approaches to therapy. Curr Oncol Rep. 2010;12(6):383–94.

    Article  PubMed  Google Scholar 

  42. Paya CV, Fung JJ, Nalesnik MA, et al. Epstein-Barr virus-induced posttransplant lymphoproliferative disorders. ASTS/ASTP EBV-PTLD Task Force and The Mayo Clinic Organized International Consensus Development Meeting. Transplantation. 1999;68(10):1517–25.

    Article  PubMed  CAS  Google Scholar 

  43. Draoua HY, Tsao L, Mancini DM, Addonizio LJ, Bhagat G, Alobeid B. T-cell post-transplantation lymphoproliferative disorders after cardiac transplantation: a single institutional experience. Br J Haematol. 2004;127(4):429–32.

    Article  PubMed  CAS  Google Scholar 

  44. Nelson BP, Nalesnik MA, Bahler DW, Locker J, Fung JJ, Swerdlow SH. Epstein-Barr virus-negative post-transplant lymphoproliferative disorders: a distinct entity? Am J Surg Pathol. 2000;24(3):375–85.

    Article  PubMed  CAS  Google Scholar 

  45. Mautner J, Bornkamm GW. The role of virus-specific CD4+ T cells in the control of Epstein-Barr virus infection. Eur J Cell Biol. Mar 31 2011.

  46. Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113(20):4992–5001.

    Article  PubMed  CAS  Google Scholar 

  47. Peric Z, Cahu X, Chevallier P, et al. Features of Epstein-Barr Virus (EBV) reactivation after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation. Leukemia. 2011;25(6):932–8.

    Article  PubMed  CAS  Google Scholar 

  48. DiNardo CD, Tsai DE. Treatment advances in posttransplant lymphoproliferative disease. Curr Opin Hematol. 2010;17(4):368–74.

    Article  PubMed  CAS  Google Scholar 

  49. Ambinder RF. Epstein-Barr virus associated lymphoproliferations in the AIDS setting. Eur J Cancer. 2001;37(10):1209–16.

    Article  PubMed  CAS  Google Scholar 

  50. Camilleri-Broet S, Davi F, Feuillard J, et al. High expression of latent membrane protein 1 of Epstein-Barr virus and BCL-2 oncoprotein in acquired immunodeficiency syndrome-related primary brain lymphomas. Blood. 1995;86(2):432–5.

    PubMed  CAS  Google Scholar 

  51. Bayraktar S, Bayraktar UD, Ramos JC, Stefanovic A, Lossos IS. Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors. J Neurooncol. 2011;101(2):257–65.

    Article  PubMed  Google Scholar 

  52. Deckert M, Engert A, Bruck W, et al. Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. Leukemia. 2011;25(12):1797–807.

    Google Scholar 

  53. Fassone L, Bhatia K, Gutierrez M, et al. Molecular profile of Epstein-Barr virus infection in HHV-8-positive primary effusion lymphoma. Leukemia. 2000;14(2):271–7.

    Article  PubMed  CAS  Google Scholar 

  54. Nador RG, Cesarman E, Chadburn A, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's sarcoma-associated herpes virus. Blood. 1996;88(2):645–56.

    PubMed  CAS  Google Scholar 

  55. Colomo L, Loong F, Rives S, et al. Diffuse large B-cell lymphomas with plasmablastic differentiation represent a heterogeneous group of disease entities. Am J Surg Pathol. 2004;28(6):736–47.

    Article  PubMed  Google Scholar 

  56. Valera A, Balague O, Colomo L, et al. IG/MYC rearrangements are the main cytogenetic alteration in plasmablastic lymphomas. Am J Surg Pathol. 2010;34(11):1686–94.

    PubMed  Google Scholar 

  57. Baecklund E, Sundstrom C, Ekbom A, et al. Lymphoma subtypes in patients with rheumatoid arthritis: increased proportion of diffuse large B cell lymphoma. Arthritis Rheum. 2003;48(6):1543–50.

    Article  PubMed  Google Scholar 

  58. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56(9):2886–95.

    Article  PubMed  Google Scholar 

  59. Kamel OW, van de Rijn M, Weiss LM, et al. Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med. 1993;328(18):1317–21.

    Article  PubMed  CAS  Google Scholar 

  60. Callan MF. Epstein-Barr virus, arthritis, and the development of lymphoma in arthritis patients. Curr Opin Rheumatol. 2004;16(4):399–405.

    Article  PubMed  Google Scholar 

  61. • Heslop HE, Slobod KS, Pule MA, et al. Long-term outcome of EBV-specific T-cell infusions to prevent or treat EBV-related lymphoproliferative disease in transplant recipients. Blood. 2010;115(5):925–35. In this paper, the authors describe the long-term outcome of 114 patients who received EBV-specific cytotoxic T-lymphocytes to prevent or treat EBV positive lymphoproliferative disease arising after hematopoietic stem cell transplantation.

    Article  PubMed  CAS  Google Scholar 

  62. Bollard CM, Gottschalk S, Leen AM, et al. Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer. Blood. 2007;110(8):2838–45.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by the Intramural Research Program of the National Cancer Institute.

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Metabolism Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    Kieron Dunleavy, Mark Roschewski & Wyndham H. Wilson

  2. Metabolism Branch, National Cancer Institute, Building 10, Room 4N-115, 9000 Rockville Pike, Bethesda, MD, 20892, USA

    Kieron Dunleavy

Authors
  1. Kieron Dunleavy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark Roschewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wyndham H. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kieron Dunleavy.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dunleavy, K., Roschewski, M. & Wilson, W.H. Lymphomatoid Granulomatosis and Other Epstein-Barr Virus Associated Lymphoproliferative Processes. Curr Hematol Malig Rep 7, 208–215 (2012). https://doi.org/10.1007/s11899-012-0132-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11899-012-0132-3

Keywords

Search

Navigation