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. 2001 May;84(9):1227–1234. doi: 10.1054/bjoc.2001.1774

Assessment of the prognostic impact of the Epstein–Barr virus-encoded latent membrane protein-1 expression in Hodgkin's disease

M Glavina-Durdov 1, J Jakic-Razumovic 3, V Capkun 2, P Murray 4
PMCID: PMC2363896  PMID: 11336475

Abstract

We have examined expression of the Epstein–Barr virus (EBV) latent membrane protein-1 (LMP1) in the malignant Hodgkin and Reed–Sternberg (HRS) cells of Hodgkin's disease (HD) and its impact on response to treatment and on survival. Paraffin tissue from 100 adult immunocompetent patients with HD were analysed using immunohistochemistry to identify LMP1 expression. According to the Rye classification, 8% of patients had lymphocyte predominance (LP) subtype, 48% had nodular sclerosis (NS) disease, 37% were of the mixed cellularity (MC) subtype and 7% were of the lymphocyte depletion (LD) subtype. During the five year follow-up period 27 patients died and 74 patients achieved a complete remission. Patients with LD subtype were older (P = 0.03), less frequently achieved complete remission (P = 0.01), had shorter disease-free survival (P = 0.01) and overall survival (P = 0.002) compared with the other subtypes of HD. LMP1 expression was found in the tumour cells of 26% of cases of HD. LMP1 expression was less common in NS disease than in the other subtypes (P = 0.05), whereas an association between MC subtype and LMP1 expression was not found (P = 0.22). Using the log-rank test there were no differences in overall survival or disease-free survival based on EBV status either when all patients were analysed or when LD and LP subtypes were excluded. However, the presence of EBV was associated with significantly longer disease-free survival in the subgroup of patients ≤ 30 years old (P = 0.02) and in those patients ≤ 34 years old (P = 0.05). In contrast, there was a trend for shorter disease-free survival for EBV-positive patients in the subgroup > 35 years old, but this difference was not statistically significant (P = 0.11). A similar trend was observed in patients > 50 years old. Analysis of the impact of LMP1 expression in patients who had different stage and B symptoms status showed that expression of EBV was associated with longer disease-free survival (P = 0.019) in early stage (1 + 2) patients without B symptoms. Significant differences in the other subgroups based on EBV status was not found. Factors adversely affecting the likelihood to achieve a complete remission were: absence of LMP1 expression (OR 6.4, 95% Cl 1.07–38.5, P = 0.04), age (OR 1.68, 95%Cl 1.15–2.5, P = 0.007) and subtype of HD (OR 3.32, 95%Cl 1.11–9.94, P = 0.03). Age and subtype of HD had an independent impact on overall survival (P = 0.01). We conclude that expression of LMP1 in HRS cells has a favourable impact on prognosis for HD patients, but that this effect may be restricted to young adult patients and those with early stage disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Selected References

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  1. Axdorph U., Porwit-MacDonald A., Sjöberg J., Grimfors G., Ekman M., Wang W., Biberfeld P., Björkholm M. Epstein-Barr virus expression in Hodgkin's disease in relation to patient characteristics, serum factors and blood lymphocyte function. Br J Cancer. 1999 Dec;81(7):1182–1187. doi: 10.1038/sj.bjc.6690827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Claviez A., Tiemann M., Peters J., Kreipe H., Schneppenheim R., Parwaresch R. The impact of EBV, proliferation rate, and Bcl-2 expression in Hodgkin's disease in childhood. Ann Hematol. 1994 Feb;68(2):61–66. doi: 10.1007/BF01715132. [DOI] [PubMed] [Google Scholar]
  3. Coates P. J., Mak W. P., Slavin G., d'Ardenne A. J. Detection of single copies of Epstein-Barr virus in paraffin wax sections by non-radioactive in situ hybridisation. J Clin Pathol. 1991 Jun;44(6):487–491. doi: 10.1136/jcp.44.6.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cossman J., Messineo C., Bagg A. Reed-Sternberg cell: survival in a hostile sea. Lab Invest. 1998 Mar;78(3):229–235. [PubMed] [Google Scholar]
  5. Dukers D. F., Jaspars L. H., Vos W., Oudejans J. J., Hayes D., Cillessen S., Middeldorp J. M., Meijer C. J. Quantitative immunohistochemical analysis of cytokine profiles in Epstein-Barr virus-positive and -negative cases of Hodgkin's disease. J Pathol. 2000 Feb;190(2):143–149. doi: 10.1002/(SICI)1096-9896(200002)190:2<143::AID-PATH519>3.0.CO;2-5. [DOI] [PubMed] [Google Scholar]
  6. Enblad G., Sandvej K., Lennette E., Sundström C., Klein G., Glimelius B., Pallesen G. Lack of correlation between EBV serology and presence of EBV in the Hodgkin and Reed-Sternberg cells of patients with Hodgkin's disease. Int J Cancer. 1997 Jul 29;72(3):394–397. doi: 10.1002/(sici)1097-0215(19970729)72:3<394::aid-ijc3>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  7. Engel M., Essop M. F., Close P., Hartley P., Pallesen G., Sinclair-Smith C. Improved prognosis of Epstein-Barr virus associated childhood Hodgkin's lymphoma: study of 47 South African cases. J Clin Pathol. 2000 Mar;53(3):182–186. doi: 10.1136/jcp.53.3.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Fellbaum C., Hansmann M. L., Niedermeyer H., Kraus I., Alavaikko M. J., Blanco G., Aine R., Busch R., Pütz B., Fischer R. Influence of Epstein-Barr virus genomes on patient survival in Hodgkin's disease. Am J Clin Pathol. 1992 Sep;98(3):319–323. doi: 10.1093/ajcp/98.3.319. [DOI] [PubMed] [Google Scholar]
  9. Frisan T., Sjöberg J., Dolcetti R., Boiocchi M., De Re V., Carbone A., Brautbar C., Battat S., Biberfeld P., Eckman M. Local suppression of Epstein-Barr virus (EBV)-specific cytotoxicity in biopsies of EBV-positive Hodgkin's disease. Blood. 1995 Aug 15;86(4):1493–1501. [PubMed] [Google Scholar]
  10. Glaser S. L., Lin R. J., Stewart S. L., Ambinder R. F., Jarrett R. F., Brousset P., Pallesen G., Gulley M. L., Khan G., O'Grady J. Epstein-Barr virus-associated Hodgkin's disease: epidemiologic characteristics in international data. Int J Cancer. 1997 Feb 7;70(4):375–382. doi: 10.1002/(sici)1097-0215(19970207)70:4<375::aid-ijc1>3.0.co;2-t. [DOI] [PubMed] [Google Scholar]
  11. Glickman J. N., Howe J. G., Steitz J. A. Structural analyses of EBER1 and EBER2 ribonucleoprotein particles present in Epstein-Barr virus-infected cells. J Virol. 1988 Mar;62(3):902–911. doi: 10.1128/jvi.62.3.902-911.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gruss H. J., Pinto A., Duyster J., Poppema S., Herrmann F. Hodgkin's disease: a tumor with disturbed immunological pathways. Immunol Today. 1997 Apr;18(4):156–163. doi: 10.1016/s0167-5699(97)84661-0. [DOI] [PubMed] [Google Scholar]
  13. Gutensohn N., Cole P. Epidemiology of Hodgkin's disease. Semin Oncol. 1980 Jun;7(2):92–102. [PubMed] [Google Scholar]
  14. Henderson S., Rowe M., Gregory C., Croom-Carter D., Wang F., Longnecker R., Kieff E., Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991 Jun 28;65(7):1107–1115. doi: 10.1016/0092-8674(91)90007-l. [DOI] [PubMed] [Google Scholar]
  15. Herbst H., Foss H. D., Samol J., Araujo I., Klotzbach H., Krause H., Agathanggelou A., Niedobitek G., Stein H. Frequent expression of interleukin-10 by Epstein-Barr virus-harboring tumor cells of Hodgkin's disease. Blood. 1996 Apr 1;87(7):2918–2929. [PubMed] [Google Scholar]
  16. Herbst H., Steinbrecher E., Niedobitek G., Young L. S., Brooks L., Müller-Lantzsch N., Stein H. Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease. Blood. 1992 Jul 15;80(2):484–491. [PubMed] [Google Scholar]
  17. Hummel M., Anagnostopoulos I., Dallenbach F., Korbjuhn P., Dimmler C., Stein H. EBV infection patterns in Hodgkin's disease and normal lymphoid tissue: expression and cellular localization of EBV gene products. Br J Haematol. 1992 Dec;82(4):689–694. doi: 10.1111/j.1365-2141.1992.tb06945.x. [DOI] [PubMed] [Google Scholar]
  18. Hummel M., Ziemann K., Lammert H., Pileri S., Sabattini E., Stein H. Hodgkin's disease with monoclonal and polyclonal populations of Reed-Sternberg cells. N Engl J Med. 1995 Oct 5;333(14):901–906. doi: 10.1056/NEJM199510053331403. [DOI] [PubMed] [Google Scholar]
  19. Jiwa N. M., Oudejans J. J., Bai M. C., Van den Brule A. J., Horstman A., Vos W., Van der Valk P., Kluin P. M., Walboomers J. M., Meijer C. J. Expression of bcl-2 protein and transcription of the Epstein-Barr virus bcl-2 homologue BHRF-1 in Hodgkin's disease: implications for different pathogenic mechanisms. Histopathology. 1995 Jun;26(6):547–553. doi: 10.1111/j.1365-2559.1995.tb00273.x. [DOI] [PubMed] [Google Scholar]
  20. Kanzler H., Küppers R., Hansmann M. L., Rajewsky K. Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med. 1996 Oct 1;184(4):1495–1505. doi: 10.1084/jem.184.4.1495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kaufman D., Longo D. L. Hodgkin's disease. Crit Rev Oncol Hematol. 1992 Sep;13(2):135–187. doi: 10.1016/1040-8428(92)90021-h. [DOI] [PubMed] [Google Scholar]
  22. Khanna R., Burrows S. R., Nicholls J., Poulsen L. M. Identification of cytotoxic T cell epitopes within Epstein-Barr virus (EBV) oncogene latent membrane protein 1 (LMP1): evidence for HLA A2 supertype-restricted immune recognition of EBV-infected cells by LMP1-specific cytotoxic T lymphocytes. Eur J Immunol. 1998 Feb;28(2):451–458. doi: 10.1002/(SICI)1521-4141(199802)28:02<451::AID-IMMU451>3.0.CO;2-U. [DOI] [PubMed] [Google Scholar]
  23. Kordek R., Jesionek-Kupnicka D., Biernat W., Woźniak L. Expression of the latent membrane protein of Epstein-Barr virus in Hodgkin's disease. Age and subtype distribution in Polish patients. Acta Haematol Pol. 1996;27(1):15–20. [PubMed] [Google Scholar]
  24. Lee S. P., Constandinou C. M., Thomas W. A., Croom-Carter D., Blake N. W., Murray P. G., Crocker J., Rickinson A. B. Antigen presenting phenotype of Hodgkin Reed-Sternberg cells: analysis of the HLA class I processing pathway and the effects of interleukin-10 on epstein-barr virus-specific cytotoxic T-cell recognition. Blood. 1998 Aug 1;92(3):1020–1030. [PubMed] [Google Scholar]
  25. Levine P. H., Ablashi D. V., Berard C. W., Carbone P. P., Waggoner D. E., Malan L. Elevated antibody titers to Epstein-Barr virus in Hodgkin's disease. Cancer. 1971 Feb;27(2):416–421. doi: 10.1002/1097-0142(197102)27:2<416::aid-cncr2820270227>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  26. MacMahon B. Epidemiology of Hodgkin's disease. Cancer Res. 1966 Jun;26(6):1189–1201. [PubMed] [Google Scholar]
  27. Macák J., Habanec B., Fabián P. Detection of Epstein-Barr virus in Hodgkin's lymphoma (patients in the Czech Republic). Neoplasma. 2000;47(3):156–161. [PubMed] [Google Scholar]
  28. Morente M. M., Piris M. A., Abraira V., Acevedo A., Aguilera B., Bellas C., Fraga M., Garcia-Del-Moral R., Gomez-Marcos F., Menarguez J. Adverse clinical outcome in Hodgkin's disease is associated with loss of retinoblastoma protein expression, high Ki67 proliferation index, and absence of Epstein-Barr virus-latent membrane protein 1 expression. Blood. 1997 Sep 15;90(6):2429–2436. [PubMed] [Google Scholar]
  29. Mueller N., Evans A., Harris N. L., Comstock G. W., Jellum E., Magnus K., Orentreich N., Polk B. F., Vogelman J. Hodgkin's disease and Epstein-Barr virus. Altered antibody pattern before diagnosis. N Engl J Med. 1989 Mar 16;320(11):689–695. doi: 10.1056/NEJM198903163201103. [DOI] [PubMed] [Google Scholar]
  30. Murray P. G., Billingham L. J., Hassan H. T., Flavell J. R., Nelson P. N., Scott K., Reynolds G., Constandinou C. M., Kerr D. J., Devey E. C. Effect of Epstein-Barr virus infection on response to chemotherapy and survival in Hodgkin's disease. Blood. 1999 Jul 15;94(2):442–447. [PubMed] [Google Scholar]
  31. Murray P. G., Constandinou C. M., Crocker J., Young L. S., Ambinder R. F. Analysis of major histocompatibility complex class I, TAP expression, and LMP2 epitope sequence in Epstein-Barr virus-positive Hodgkin's disease. Blood. 1998 Oct 1;92(7):2477–2483. [PubMed] [Google Scholar]
  32. Murray P. G., Young L. S., 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 Jan;166(1):1–5. doi: 10.1002/path.1711660102. [DOI] [PubMed] [Google Scholar]
  33. Nakagomi H., Dolcetti R., Bejarano M. T., Pisa P., Kiessling R., Masucci M. G. The Epstein-Barr virus latent membrane protein-1 (LMP1) induces interleukin-10 production in Burkitt lymphoma lines. Int J Cancer. 1994 Apr 15;57(2):240–244. doi: 10.1002/ijc.2910570218. [DOI] [PubMed] [Google Scholar]
  34. Naresh K. N., Johnson J., Srinivas V., Soman C. S., Saikia T., Advani S. H., Badwe R. A., Dinshaw K. A., Muckaden M., Magrath I. Epstein-Barr virus association in classical Hodgkin's disease provides survival advantage to patients and correlates with higher expression of proliferation markers in Reed-Sternberg cells. Ann Oncol. 2000 Jan;11(1):91–96. doi: 10.1023/a:1008337100424. [DOI] [PubMed] [Google Scholar]
  35. Niedobitek G., Kremmer E., Herbst H., Whitehead L., Dawson C. W., Niedobitek E., von Ostau C., Rooney N., Grässer F. A., Young L. S. Immunohistochemical detection of the Epstein-Barr virus-encoded latent membrane protein 2A in Hodgkin's disease and infectious mononucleosis. Blood. 1997 Aug 15;90(4):1664–1672. [PubMed] [Google Scholar]
  36. Oudejans J. J., Jiwa N. M., Kummer J. A., Horstman A., Vos W., Baak J. P., Kluin P. M., van der Valk P., Walboomers J. M., Meijer C. J. Analysis of major histocompatibility complex class I expression on Reed-Sternberg cells in relation to the cytotoxic T-cell response in Epstein-Barr virus-positive and -negative Hodgkin's disease. Blood. 1996 May 1;87(9):3844–3851. [PubMed] [Google Scholar]
  37. Oudejans J. J., Jiwa N. M., Meijer C. J. Epstein-Barr virus in Hodgkin's disease: more than just an innocent bystander. J Pathol. 1997 Apr;181(4):353–356. doi: 10.1002/(SICI)1096-9896(199704)181:4<353::AID-PATH782>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  38. Pallesen G., Hamilton-Dutoit S. J., Rowe M., Young L. S. Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease. Lancet. 1991 Feb 9;337(8737):320–322. doi: 10.1016/0140-6736(91)90943-j. [DOI] [PubMed] [Google Scholar]
  39. Roskrow M. A., Suzuki N., Gan Y. j., Sixbey J. W., Ng C. Y., Kimbrough S., Hudson M., Brenner M. K., Heslop H. E., Rooney C. M. Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes for the treatment of patients with EBV-positive relapsed Hodgkin's disease. Blood. 1998 Apr 15;91(8):2925–2934. [PubMed] [Google Scholar]
  40. Shibata D., Hansmann M. L., Weiss L. M., Nathwani B. N. Epstein-Barr virus infections and Hodgkin's disease: a study of fixed tissues using the polymerase chain reaction. Hum Pathol. 1991 Dec;22(12):1262–1267. doi: 10.1016/0046-8177(91)90109-3. [DOI] [PubMed] [Google Scholar]
  41. Sing A. P., Ambinder R. F., Hong D. J., Jensen M., Batten W., Petersdorf E., Greenberg P. D. Isolation of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes that lyse Reed-Sternberg cells: implications for immune-mediated therapy of EBV+ Hodgkin's disease. Blood. 1997 Mar 15;89(6):1978–1986. [PubMed] [Google Scholar]
  42. Vestlev P. M., Pallesen G., Sandvej K., Hamilton-Dutoit S. J., Bendtzen S. M. Prognosis of Hodgkin's disease is not influenced by Epstein-Barr virus latent membrane protein. Int J Cancer. 1992 Feb 20;50(4):670–671. doi: 10.1002/ijc.2910500432. [DOI] [PubMed] [Google Scholar]
  43. Wang D., Liebowitz D., Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. doi: 10.1016/0092-8674(85)90256-9. [DOI] [PubMed] [Google Scholar]
  44. Wang S., Rowe M., Lundgren E. Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Cancer Res. 1996 Oct 15;56(20):4610–4613. [PubMed] [Google Scholar]
  45. Weiss L. M., Strickler J. G., Warnke R. A., Purtilo D. T., Sklar J. Epstein-Barr viral DNA in tissues of Hodgkin's disease. Am J Pathol. 1987 Oct;129(1):86–91. [PMC free article] [PubMed] [Google Scholar]
  46. Wu T. C., Mann R. B., Charache P., Hayward S. D., Staal S., Lambe B. C., Ambinder R. F. Detection of EBV gene expression in Reed-Sternberg cells of Hodgkin's disease. Int J Cancer. 1990 Nov 15;46(5):801–804. doi: 10.1002/ijc.2910460509. [DOI] [PubMed] [Google Scholar]

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