Current Hematologic Malignancy Reports

, Volume 7, Issue 3, pp 208–215 | Cite as

Lymphomatoid Granulomatosis and Other Epstein-Barr Virus Associated Lymphoproliferative Processes

  • Kieron Dunleavy
  • Mark Roschewski
  • Wyndham H. Wilson
Lymphomas (J Armitage and P McLaughlin, Section Editors)

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.

Keywords

Lymphomatoid granulomatosis LYG Epstein-Barr virus EBV Lymphoma LMP-1 EBNA-1 Lymphoproliferative disorders Cytotoxic T-lymphocyte Cellular therapy Interferon 

References

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

  1. 1.
    Epstein MA, Barr YM. Cultivation in vitro of human lymphoblasts from Burkitt's malignant lymphoma. Lancet. 1964;1(7327):252–3.PubMedCrossRefGoogle Scholar
  2. 2.
    Cohen JI. Epstein-Barr virus infection. N Engl J Med. 2000;343(7):481–92.PubMedCrossRefGoogle Scholar
  3. 3.
    Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008.Google Scholar
  4. 4.
    Young LS, Murray PG. Epstein-Barr virus and oncogenesis: from latent genes to tumours. Oncogene. 2003;22(33):5108–21.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 6.
    Roschewski M, Wilson WH. EBV-associated lymphomas in adults. Best Pract Res Clin Haematol. 2012;25(1):75–89.PubMedCrossRefGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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.Google Scholar
  9. 9.
    Jaffe ES, Wilson WH. Lymphomatoid granulomatosis: pathogenesis, pathology and clinical implications. Canc Surv. 1997;30:233–48.Google Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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. Google Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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. Google Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Aozasa K. Pyothorax-associated lymphoma. J Clin Exp Hematop. 2006;46(1):5–10.PubMedCrossRefGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 29.
    Thompson MP, Kurzrock R. Epstein-Barr virus and cancer. Clin Cancer Res. 2004;10(3):803–21.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 34.
    Jaccard A, Hermine O. Extranodal natural killer/T-cell lymphoma: advances in the management. Curr Opin Oncol. 2011;23(5):429–35.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 37.
    Dogan A, Attygalle AD, Kyriakou C. Angioimmunoblastic T-cell lymphoma. Br J Haematol. 2003;121(5):681–91.PubMedCrossRefGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 40.
    Dunleavy K, Wilson WH, Jaffe ES. Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications. Curr Opin Hematol. 2007;14(4):348–53.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.Google Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 48.
    DiNardo CD, Tsai DE. Treatment advances in posttransplant lymphoproliferative disease. Curr Opin Hematol. 2010;17(4):368–74.PubMedCrossRefGoogle Scholar
  49. 49.
    Ambinder RF. Epstein-Barr virus associated lymphoproliferations in the AIDS setting. Eur J Cancer. 2001;37(10):1209–16.PubMedCrossRefGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.PubMedCrossRefGoogle Scholar
  52. 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. 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.PubMedCrossRefGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedCrossRefGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar
  58. 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.PubMedCrossRefGoogle Scholar
  59. 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.PubMedCrossRefGoogle Scholar
  60. 60.
    Callan MF. Epstein-Barr virus, arthritis, and the development of lymphoma in arthritis patients. Curr Opin Rheumatol. 2004;16(4):399–405.PubMedCrossRefGoogle Scholar
  61. 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.PubMedCrossRefGoogle Scholar
  62. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (outside the USA) 2012

Authors and Affiliations

  • Kieron Dunleavy
    • 1
    • 2
  • Mark Roschewski
    • 1
  • Wyndham H. Wilson
    • 1
  1. 1.Metabolism Branch, Center for Cancer Research, National Cancer InstituteBethesdaUSA
  2. 2.Metabolism Branch, National Cancer InstituteBethesdaUSA

Personalised recommendations