Advances in Understanding the Pathogenesis of Epstein-Barr Virus-Associated Lymphoproliferative Disorders
Abstract
Epstein-Barr virus (EBV) was discovered 50 years ago from an African Burkitt lymphoma cell line. EBV-associated lymphoproliferative disorders (LPDs) are life-threatening diseases, especially in children. In this article, we review EBV-associated LPDs, especially in the area of primary immunodeficiency disease (PID). We searched PubMed for publications with key words including EBV infection, lymphoma, LPDs and PID, and selected the manuscripts written in English that we judged to be relevant to the topic of this review. On the basis of the data in the literature, we grouped the EBV-associated LPDs into four categories: nonmalignant disease, malignant disease, acquired immunodeficiency disease and PID. Each category has its own risk factor for LPD development. EBV-associated LPD is a complex disease, creating new challenges for diagnosis and treatment.
1. Cohen JI. Epstein–Barr virus infection. N Engl J Med 2000; 343(7):481-92.
2. Rezk SA, Weiss LM. Epstein-Barr virus-associated lymphoproliferative disorders. Hum Pathol 2007;38(9):1293-304.
3. Strowig T, Brilot F, Münz C. Noncytotoxic functions of NK cells: direct pathogen restriction and assistance to adaptive immunity. J Immunol 2008; 180(12):7785-91.
4. Sivachandran N, Wang X, Frappier L. Functions of the Epstein-Barr virus EBNA1 protein in viral reactivation and lytic infection. J Virol 2012; 86(11):6146-58.
5. Asano N, Yamamoto K, Tamaru J, Oyama T, Ishida F, Ohshima K, 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.
6. Hagler KT, Lynch JW. Paraneoplastic manifestations of lymphoma. Clin Lymphoma 2004; 5(1):29-36.
7. Williams H, Crawford DH. Epstein-Barr virus: the impact of scientific advances on clinical practice. Blood 2006;107(3):862-9.
8. Kutok JL, Wang F. Spectrum of Epstein-Barr virus- associated diseases. Annu Rev Pathol 2006; 1:375-404.
9. Kanegane H, Kanegane C, Yachie A, Miyawaki T, Tosato G. Infectious mononucleosis as a disease of early childhood in Japan caused by primary Epstein-Barr virus infection. Acta Paediatr Jpn 1997; 39(2):166-71.
10. Owen CE, Callen JP, Bahrami S. Cutaneous lymphoproliferative disorder complicating infectious mononucleosis in an immunosuppressed patient. Pediatr Dermatol 2011; 28(2):149-55.
11. He HL, Wang MC, Huang WT. Infectious mononucleosis mimicking malignant T-cell lymphoma in the nasopharynx: a case report and review of the literature. Int J Clin Exp Pathol 2013; 6(1):105-9.
12. Arai A, Yamaguchi T, Komatsu H, Imadome KI, Kurata M, Nagata K, et al. Infectious mononucleosis accompanied by clonal proliferation of EBV-infected cells and infection of CD8-positive cells. Int J Hematol 2014; 99(5):671-5.
13. Mbulaiteye SM, Pullarkat ST, Nathwani BN, Weiss LM, Rao N, Emmanuel B, et al. Epstein-Barr virus patterns in US Burkitt lymphoma tumors from the SEER residual tissue repository during 1979-2009. APMIS 2014;122(1):5-15.
14. Moormann AM, Snider CJ, Chelimo K. The company malaria keeps: how co-infection with Epstein-Barr virus leads to endemic Burkitt lymphoma. Curr Opin Infect Dis 2011; 24(5):435-41.
15. Carbone A, Gloghini A, Dotti G. EBV-associated lymphoproliferative disorders: classification and treatment. Oncologist 2008; 13(5):577-85.
16. Ambinder RF. Epstein-barr virus and hodgkin lymphoma.Hematology Am Soc Hematol Educ Program 2007:204-209.
17. Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84(5):1361-92.
18. Castillo JJ, Beltran BE, Miranda RN, Paydas S, Winer ES, Butera JN. Epstein-barr virus-positive diffuse large B-cell lymphoma of the elderly: what we know so far. Oncologist 2011; 16(1):87-96.
19. Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, 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.
20. Okano M, Kawa K, Kimura H, Yachie A, Wakiguchi H, Maeda A, et al. Proposed guidelines for diagnosing chronic active Epstein-Barr virus infection. Am J Hematol 2005; 80(1):64-9.
21. Kimura H. Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency? Rev Med Virol 2006; 16(4):251-61.
22. Takahashi E, Ohshima K, Kimura H, Hara K, Suzuki R, Kawa K, et al. Clinicopathological analysis of the age- related differences in patients with Epstein-Barr virus (EBV)-associated extranasal natural killer (NK)/T-cell lymphoma with reference to the relationship with aggressive NK cell leukaemia and chronic active EBV infection-associated lymphoproliferative disorders. Histopathology 2011; 59(4):660-71.
23. Kato S, Miyata T, Takata K, Shimada S, Ito Y, Tomita A, et al. Epstein-Barr virus-positive cytotoxic T-cell lymphoma followed by chronic active Epstein-Barr virus infection-associated T/NK-cell lymphoproliferative disorder: a case report. Hum Pathol 2013; 44(12):2849-52.
24. Vaccher E, Spina M, Tirelli U. Clinical aspects and management of Hodgkin’s disease and other tumours in HIV-infected individuals. Eur J Cancer 2001;37(10):1306-15.
25. Gucalp A, Noy A. Spectrum of HIV lymphoma 2009.Curr Opin Hematol 2010; 17(4):362-7.
26. Cingolani A, Gastaldi R. Fassone L, Pierconti F, Giancola ML, Martini M, et al. Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin’s lymphomas. J Clin Oncol 2000;18(19):3325-30.
27. Yanagisawa K, Tanuma J, Hagiwara S, Gatanaga H, Kikuchi Y, Oka S. Epstein-Barr viral load in cerebrospinal fluid as a diagnostic marker of central nervous system involvement of AIDS-related lymphoma. Intern Med 2013; 52(9):955-9.
28. Delecluse HJ, Anagnostopoulos I, Dallenbach F, Hummel M, Marafioti T, Schneider U, et al. Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection. Blood 1997; 89(4):1413-20.
29. Shiramizu B, Herndier BG, Mcgrath MS. Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus- associated lymphomas. Cancer Res 1994; 54(8):2069-72.
30. Lundell R, Elenitoba-Johnson KS, Lim MS. T-cell posttransplant lymphoproliferative disorder occurring in a pediatric solid-organ transplant patient. Am J Surg Pathol 2004; 28(7):967-73.
31. Opelz G, Döhler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4(2):222-30.
32. Jagadeesh D, Woda BA, Draper J, Evens AM. Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol 2012; 13(1):122-36.
33. McDonald RA, Smith JM, Ho M, Lindblad R, Ikle D, Grimm P, et al. Incidence of PTLD in pediatric renal transplant recipients receiving basiliximab, calcineurin inhibitor, sirolimus and steroids. Am J Transplant 2008;8(5):984-9.
34. Katzenstein AL, Carrington CB, Liebow AA.Lymphomatoid granulomatosis. A clinicopathologic study of 152 cases. Cancer 1979; 43(1):360-73.
35. 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.
36. Mariette X, Cazals-Hatem D, Warszawki J, Liote F, Balandraud N, Sibilia J, et al. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France. Blood 2002;99(11):3909-15.
37. Salloum E, Cooper DL, Howe G, Lacy J, Tallini G, Crouch J, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol 1996; 14(6):1943-9.
38. Nakanishi R, Ishida M, Hodohara K, Okuno H, Yoshii M, Horinouchi A, et al. Occurrence of Epstein-Barr virus- associated plasmacytic lymphoproliferative disorder after antithymocyte globulin therapy for aplastic anemia: a case report with review of the literature. Int J Clin Exp Pathol 2014; 7(4):1748-54.
39. Yang X, Miyawaki T, Kanegane H. Lymphoproliferative disorders in immunocompromised individuals and therapeutic antibodies for treatment. Immunotherapy 2013; 5(4):415-25.
40. Parvaneh N, Filipovich AH, Borkhardt A. Primary immunodeficiencies predisposed to Epstein-Barr virus- driven haematological diseases. Br J Haematol 2013;162(5):573-86.
41. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A.Development of cancer in patients with primary immunodeficiencies. Anticancer Res 2008; 28(2B):1263–9.
42. Canioni D, Jabado N, MacIntyre E, Patey N, Emile JF, Brousse N. Lymphoproliferative disorders in children with primary immunodeficiencies: immunological status may be more predictive of the outcome than other criteria. Histopathology 2001; 38(2):146-59.
43. Coles RE, Boyle TJ, DiMaio JM, Berend KR, Via DF, Lyerly HK. T cells or active Epstein-Barr virus infection in the development of lymphoproliferative disease in human B cell-injected severe combined immunodeficient mice. Ann Surg Oncol 1994; 1(15):405-10.
44. Touzot F, Dal-Cortivo L, Verkarre V, Lim A, Crucis- Armengaud A, Moshous D, et al. Massive expansion of maternal T cells in response to EBV infection in a patient with SCID-Xl. Blood 2012; 120(9):1957-9.
45. Cunningham-Rundles C, Lieberman P, Hellman G, Chaganti RS. Non-Hodgkin lymphoma in common variable immunodeficiency. Am J Hematol 1991;37(2):69-74.
46. Notarangelo LD, Miao CH, Ochs HD. Wiskott-Aldrich syndrome. Curr Opin Hematol 2008; 15(1):30-6.
47. Shcherbina A, Candotti F, Rosen FS, Remold-O’Donnell E. High incidence of lymphomas in a subgroup of Wiskott-Aldrich syndrome patients. Br J Haematol 2003;121(3):529-30.
48. Cotelingam JD, Witebsky FG, Hsu SM, Blaese RM, Jaffe ES. Malignant lymphoma in patients with the Wiskott-Aldrich syndrome. Cancer Invest 1985;3(6):515-22.
49. Sebire NJ, Haselden S, Malone M, Davies EG, Ramsay AD. Isolated EBV lymphoproliferative disease in a child with Wiskott-Aldrich syndrome manifesting as cutaneous lymphomatoid granulomatosis and responsive to anti-CD20 immunotherapy. J Clin Pathol 2003;56(7):555-7.
50. Yang X, Miyawaki T, Kanegane H. SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis. Pediatr Int 2012; 54(4):447-54.
51. Yang X, Wada T, Imadome K, Nishida N, Mukai T, Fujiwara M, et al. Characterization of Epstein-Barr virus (EBV)-infected cells in EBV-associated hemophagocytic lymphohistiocytosis in two patients with X-linked lymphoproliferative syndrome type 1 and type 2. Herpesviridae 2012; 3(1):1.
52. Schimmer AD, Dalili S, Batey RA, Riedl SJ. Targeting XIAP for the treatment of malignancy. Cell Death Differ 2006; 13(2):179-88.
53. Harrington DS, Weisenburger DD, Purtilo DT. Malignant lymphoma in the X-linked lymphoproliferative syndrome. Cancer 1987; 59(8):1419-29.
54. Brandau O, Schuster V, Weiss M, Hellebrand H, Fink FM, Kreczy A, et al. Epstein-Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). Hum Mol Genet 1999; 8(13):2407-13.
55. Stepensky P, Weintraub M, Yanir A, Revel-Vilk S, Krux F, Huck K, et al. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach.Haematologica 2011; 96(3):472-6.
56. Huck K, Feyen O, Niehues T, Rüschendorf F, Hübner N, Laws HJ, et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest 2009; 119(5):1350-8.
57. Mansouri D, Mahdaviani S a, Khalilzadeh S, Mohajerani SA, Hasanzad M, Sadr S, et al. IL-2-inducible T-cell kinase deficiency with pulmonary manifestations due to disseminated Epstein-Barr virus infection. Int Arch Allergy Immunol 2012; 158(4):418-22.
58. Salzer E, Daschkey S, Choo S, Gombert M, Santos- Valente E, Ginzel S, et al. Combined immunodeficiency with life-threatening EBV-associated lymphoproliferative disorder in patients lacking functional CD27. Haematologica 2013; 98(3):473-8.
59. van Montfrans JM, Hoepelman AI, Otto S, Van Gijn M, van de Corput L, de Weger RA, et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol 2012; 129(3):787-93.
60. Sharpe AH. Mechanisms of Costimulation. Immunol Rev 2009; 229(1):5-11.
61. Hendriks J, Gravestein LA, Tesselaar K, van Lier RA, Schumacher TN, Borst J. CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol 2000; 1(5):433-40.
62. Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schäffer AA, et al. The phenotype of human STK4 deficiency. Blood 2012; 119(15):3450-7.
63. Taylor LK, Wang HC, Erikson RL. Newly identified stress-responsive protein kinases, Krs-1 and Krs-2. Proc Natl Acad Sci U S A 1996; 93(19):10099-104.
64. Nehme NT, Pachlopnik Schmid J, Debeurme F, André- Schmutz I, Lim A, Nitschke P, et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 2012; 119(15):3458-68.
65. Moshous D, Martin E, Carpentier W, Lim A, Callebaut I, Canioni D, et al. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J Allergy Clin Immunol 2013;131(6):1594-603.
66. Mueller P, Massner J, Jayachandran R, Combaluzier B, Albrecht I, Gatfield J, et al. Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering. Nat Immunol 2008;9(4):424-31.
67. Shiow LR, Paris K, Akana MC, Cyster JG, Sorensen RU, Puck JM. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol 2009;131(1):24-30.
68. Li FY, Chaigne-Delalande B, Su H, Uzel G, Matthews H, Lenardo MJ. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 2014; 123(14):2148-52.
69. Li FY, Lenardo MJ, Chaigne-Delalande B. Loss of MAGT1 abrogates the Mg2+ flux required for T cell signaling and leads to a novel human primary immunodeficiency. Magnes Res 2011; 24(3):S109-14.
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| Issue | Vol 14, No 5 (2015) | |
| Section | Review Article(s) | |
| Keywords | ||
| Epstein-Barr virus Lymphoproliferative disorder Primary immunodeficiency disease | ||
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