Epstein-Barr Virus in Patients with Classical Hodgkin’s Lymphoma

VE Gurtsevitch, EA Demina, NB Senyuta, IV Botezatu, KV Smirnova, TE Dushen’kina, DM Maksimovich, UV Paramonova, IS Monin, AV Lichtenshtein

NN Blokhin National Medical Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

For correspondence: Prof. Vladimir Eduardovich Gurtsevitch, MD, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: 8(499)324-25-64; e-mail: gurtsevitch-vlad-88@yandex.ru

For citation: Gurtsevitch VE, Demina EA, Senyuta NB, et al. Epstein-Barr Virus in Patients with Classical Hodgkin’s Lymphoma. Clinical oncohematology. 2018;11(2):160–6.

DOI: 10.21320/2500-2139-2018-11-2-160-166


ABSTRACT

Background. A close relationship between Epstein-Barr virus (EBV) and classical Hodgkin’s lymphoma (cHL) has been established in approximately 1/3 patients. EBV-positive lymphomas are characterized by increased level of EBV specific antibodies emerging long before tumor symptoms, аs well as a high plasma EBV DNA concentration. These viral markers normally correlate with clinical manifestations and the outcome of treatment performed. In patients with EBV-negative lymphomas, however, there has been no attempt to assess the clinical significance of either humoral response to EBV or EBV DNA concentration in plasma.

Aim. To evaluate diagnostic and prognostic significance of EBV markers in patients with EBV-negative lymphomas.

Methods. The clinical trial included 13 cHL-patients admitted at the Department of chemotherapy of hemoblastoses of NN Blokhin National Medical Cancer Research Center. The male to female ratio was 1:1.3, the median age was 26.4 years. Leukocyte and lymphocyte counts were evaluated in all the patients before, during, and after treatment as well as throughout the follow-up period. The same indicators were analysed in the control group which contained 40 healthy persons (with the median age of 41.1 years, male to female ratio 1.5:1). The study was based on serologic test for EBV antibodies and quantitative analysis of the viral DNA copy number in plasma.

Results. The obtained data show a low immunie response to EBV and its diminishment after several polychemotherapy treatment cycles, correlating with decreased leukocyte and lymphocyte levels. As opposed to levels of virus-specific antibodies which do not reflect the efficacy of anticancer therapy, plasma EBV DNA concentration in 2 patients decreased to 0 after remission had been achieved.

Conclusion. Although the number of observations is limited, one could suggest that viral load values in plasma of patients with EBV-negative lymphomas can prove to be a useful marker of anticancer therapeutic effect. Additional studies of these markers are required.

Keywords: Epstein-Barr virus (EBV), classical Hodgkin’s lymphoma, EBV DNA, EBV-negative classical Hodgkin’s lymphoma, level of virus-specific antibodies.

Received: November 13, 2017

Accepted: February 8, 2018

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REFERENCES

  1. 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(5):1117–21.
  2. 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(11):689–95. doi: 10.1056/nejm198903163201103.
  3. Anagnostopoulos I, Herbst H, Niedobitek G, et al. 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(2):810–6.
  4. Tanyildiz HG, Yildiz I, Bassullu N, et al. The Role of Epstein-Barr Virus LMP-1 Immunohistochemical Staining in Childhood Hodgkin Lymphoma. Iran J Pediatr. 2015;25(6):e2359. doi: 10.5812/ijp.2359.
  5. Iwakiri D, Takada K. Role of EBERs in the pathogenesis of EBV infection. Adv Cancer Res. 2010;107:119–36. doi: 10.1016/s0065-230x(10)07004-1.
  6. 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(4):375–82. doi: 10.1002/(sici)1097-0215(19970207)70:4<375::aid-ijc1>3.3.co;2-l.
  7. Jarrett AF, Armstrong AA, Alexander E. Epidemiology of EBV and Hodgkin’s lymphoma. Ann Oncol. 1996;7(Suppl 4):s5–s10. doi: 10.1093/annonc/7.suppl_4.s5.
  8. Ambinder RF. Gammaherpesviruses and “Hit-and-Run” oncogenesis. Am J Pathol. 2000;156(1):1–3. doi: 10.1016/s0002-9440(10)64697-4.
  9. Meij P, Vervoort MB, Bloemena E, et al. Antibody responses to Epstein-Barr virus-encoded latent membrane protein-1 (LMP1) and expression of LMP1 in juvenile Hodgkin’s disease. J Med Virol. 2002;68(3):370–7. doi: 10.1002/jmv.10213.
  10. Chang ET, Zheng T, Lennette ET, et al. Heterogeneity of risk factors and antibody profiles in Epstein-Barr virus genome-positive and -negative Hodgkin lymphoma. J Infect Dis. 2004;189(12):2271–81. doi: 10.1086/420886.
  11. Gallagher A, Perry J, Freeland J, et al. Hodgkin lymphoma and Epstein-Barr virus (EBV): no evidence to support hit-and-run mechanism in cases classified as non-EBV-associated. Int J Cancer. 2003;104(5):624–30. doi: 10.1002/ijc.10979.
  12. Staratschek-Jox A, Kotkowski S, Belge G, et al. Detection of Epstein-Barr virus in Hodgkin-Reed-Sternberg cells: no evidence for the persistence of integrated viral fragments in Latent membrane protein-1 (LMP-1)-negative classical Hodgkin’s disease. Am J Pathol. 2000;156(1):209–16. doi: 10.1016/s0002-9440(10)64721-9.
  13. zur Hausen H, de Villiers EM. Virus target cell conditioning model to explain some epidemiologic characteristics of childhood leukemias and lymphomas. Int J Cancer. 2005;115(1):1–5. doi: 10.1002/ijc.20905.
  14. Jelcic I, Hotz-Wagenblatt A, Hunziker A, et al. Isolation of multiple TT virus genotypes from spleen biopsy tissue from a Hodgkin’s disease patient: genome reorganization and diversity in the hypervariable region. J Virol. 2004;78(14):7498–507. doi: 10.1128/jvi.78.14.7498-7507.2004.
  15. Feng H, Shuda M, Chang Y, et al. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008;319(5866):1096–100. doi: 10.1126/science.1152586.
  16. Volter C, Hausen H, Alber D, et al. Screening human tumor samples with a broad-spectrum polymerase chain reaction method for the detection of polyomaviruses. Virology. 1997;237(2):389–96. doi: 10.1006/viro.1997.8772.
  17. Lo YM, Leung SF, Chan LY, et al. Kinetics of plasma Epstein-Barr virus DNA during radiation therapy for nasopharyngeal carcinoma. Cancer Res. 2000;60(9):2351–5.
  18. Wang WY, Twu CW, Chen HH, et al. Plasma EBV DNA clearance rate as a novel prognostic marker for metastatic/recurrent nasopharyngeal carcinoma. Clin Cancer Res. 2010;16(3):1016–24. doi: 10.1158/1078-0432.ccr-09-2796.
  19. Au WY. Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. Blood. 2004;104(1):243–9. doi: 10.1182/blood-2003-12-4197.
  20. 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. doi: 10.1158/1078-0432.ccr-10-3327.
  21. Kasamon YL, Jacene HA, Gocke CD, et al. Phase 2 study of rituximab-ABVD in classical Hodgkin lymphoma. Blood. 2012;119(18):4129–32. doi: 10.1182/blood-2012-01-402792.
  22. 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(18):3547–53. doi: 10.1182/blood-2012-09-454694.
  23. Dinand V, Sachdeva A, Datta S, et al. Plasma Epstein Barr Virus (EBV) DNA as a Biomarker for EBV associated Hodgkin lymphoma. Indian Pediatr. 2015;52(8):681–5. doi: 10.1007/s13312-015-0696-9.
  24. Stein H, Delsol G, Pileri SA, et al. Classical Hodgkin lymphoma, introduction. In: Swerdlow SH, Campo E, Harris NL, et al. (eds) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edition. Lyon: IARC Press; 2008.
  25. Lo YM, Chan LY, Chan AT, et al. Quantitative and temporal correlation between circulating cell-free Epstein-Barr virus DNA and tumor recurrence in nasopharyngeal carcinoma. Cancer Res. 1999;59(21):5452–5.
  26. Botezatu IV, Kondratova VN, Shelepov VP, et al. DNA melting analysis: application of the “open tube” format for detection of mutant KRAS. Anal Biochem. 2011;419(2):302–8. doi: 10.1016/j.ab.2011.08.015.
  27. Srinivas SK, Sample JT, Sixbey JW. Spontaneous loss of viral episomes accompanying Epstein-Barr virus reactivation in a Burkitt’s lymphoma cell line. J Infect Dis. 1998;177(6):1705–9. doi: 10.1086/517427.
  28. Razzouk BI, Srinivas S, Sample CE, et al. Epstein-Barr Virus DNA recombination and loss in sporadic Burkitt’s lymphoma. J Infect Dis. 1996;173(3):529–35. doi: 10.1093/infdis/173.3.529.