Skip to main content

Advertisement

Log in

Epstein–Barr virus-associated primary central nervous system lymphomas in immunocompetent elderly patients: analysis for latent membrane protein-1 oncogene deletion and EBNA-2 strain typing

  • Clinical Study – Patient Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Epstein–Barr virus (EBV) has been implicated in the pathogenesis of primary central nervous system lymphomas (PCNLs) in immunocompetent hosts. To investigate the role of EBV in the pathogenesis of PCNLs in immunocompetent hosts, this study assessed six PCNL cases (elderly male immunocompetent patients; age ≥60 years) histologically and immunohistochemically, and an EBV genetic study was performed. Histologically, all cases were diagnosed as diffuse large B-cell lymphoma with extensive necrosis. In all six cases, PCNL cells showed immunohistochemical positivity for latent membrane protein 1 (LMP-1) and Epstein-Barr nuclear 2 (EBNA2). Lymphoma cells also showed positive signals for EBV-encoded small RNAs (EBERs) on in-situ hybridization. EBV subtyping-PCR analysis demonstrated that one case was EBNA 2B type and the other five cases were EBNA 2A type, and two cases were EBV wild-type and four cases showed 30-bp LMP-1 deletion by PCR analysis. It is therefore possible that LMP gene deletion or EBNA-2 strain type are important in the tumorigenesis of EBV-positive PCNLs. In addition, EBV-positive PCNLs in immunocompetent hosts may be related to immunological deterioration derived from the aging process.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ (2002) Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643–4648

    Article  PubMed  Google Scholar 

  2. Deckert M, Paulus W (2007) Malignant lymphomas. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds) Pathology and genetics of tumours of the nervous system. International Agency for Research on Cancer Press, Lyon, pp 188–192

    Google Scholar 

  3. Rouah E, Rogers BB, Wilson DR, Kirkpatrick JB, Buffone GJ (1990) Demonstration of Epstein-Barr virus in primary central nervous system lymphomas by the polymerase chain reaction and in situ hybridization. Hum Pathol 21:545–550

    Article  CAS  PubMed  Google Scholar 

  4. List AF, Greer JP, Cousar JP, Johnson DH, Greco FA, Volsky DJ, Purtilo DT (1990) Primary brain lymphomas in the immunocompetent host: relation to Epstein-Barr virus. Modern Pathol 3:609–612

    CAS  Google Scholar 

  5. Nakhleh RE, Manivel JC, Copenhaver CM, Sung JH, Strickler JG (1991) In situ hybridization for the detection of Epstein-Barr virus in central nervous system lymphomas. Cancer 67:444–448

    Article  CAS  PubMed  Google Scholar 

  6. O’Neill BP, Vernino S, Dogan A, Giannini C (2007) EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil. Neuro Oncol 9:364–369

    Article  PubMed  Google Scholar 

  7. Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO, Dogan A, Giannini C (2008) Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol 67:1103–1111

    Article  CAS  PubMed  Google Scholar 

  8. Zhang L, Zhang J, Lambert Q, Der CJ, Del Valle L, Miklossy J, Khalili K, Zhou Y, Pagano JS (2004) Interferon regulatory factor 7 is associated with Epstein-Barr virus-transformed central nervous system lymphoma and has oncogenic properties. J Virol 78:12987–12995

    Article  CAS  PubMed  Google Scholar 

  9. Hu L-F, Chen F, Zheng X, Ernberg I, Cao S-L, Christensson B, Klein G, Winberg G (1993) Clonability and tumorigenicity of human epithelial cells expressing the EBV encoded membrane protein LMP1. Oncogene 8:1575–1583

    CAS  PubMed  Google Scholar 

  10. Shibata D, Weiss LM, Hernandez AM, Nathwani BN, Bernstein L, Levine AM (1993) Epstein-Barr virus-associated non-Hodgkin’s lymphoma in patients infected with the human immunodeficiency virus. Blood 81:2102–2109

    CAS  PubMed  Google Scholar 

  11. Kingma DW, Weiss WB, Jaffe ES, Kumar S, Frekko K, Raffeld M (1996) Epstein-Barr virus latent membrane protein-1 oncogene deletion: correlation with malignancy in Epstein-Barr virus-associated lymphoproliferative disorders and malignant lymphomas. Blood 88:242–251

    CAS  PubMed  Google Scholar 

  12. Tabata Y, Hibi S, Teramura T, Kuriyama K, Yagi T, Todo S, Sawada T, Imashuku S (2000) Molecular analysis of latent membrane protein 1 in patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in Japan. Leuk Lymphoma 38:373–380

    CAS  Google Scholar 

  13. Yamato H, Ohshima K, Suzumiya J, Kikuchi M (2001) Evidence for local immunosuppression and demonstration of c-myc amplification in pyothorax-associated lymphoma. Histopathology 39:163–171

    Article  CAS  PubMed  Google Scholar 

  14. MacMahon EM, Glass JD, Hayward SD, Mann RB, Becker PS, Charache P, McArthur JC, Ambinder RF (1991) Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338:969–973

    Article  CAS  PubMed  Google Scholar 

  15. Guterman KS, Hair LS, Morgello S (1996) Epstein-Barr virus and AIDS-related primary central nervous system lymphoma. Viral detection by immunohistochemistry, RNA in situ hybridization, and polymerase chain reaction. Clin Neuropathol 15:79–86

    CAS  PubMed  Google Scholar 

  16. Ohshima K, Tutiya T, Yamaguchi T, Suzuki K, Suzumiya J, Kawasaki C, Haraoka S, Kikuchi M (2002) Infiltration of Th1 and Th2 lymphocytes around Hodgkin and Reed-Sternberg (H&R) cells in Hodgkin disease: relation with expression of CXC and CC chemokines on H&R cells. Int J Cancer 98:567–572

    Article  CAS  PubMed  Google Scholar 

  17. Ramasamy I, Brisco M, Morley A (1992) Improved PCR method for detecting monoclonal Immunoglobulin heavy chain rearrangement in B cell neoplasms. J Clin Pathol 45:770–775

    Article  CAS  PubMed  Google Scholar 

  18. Reed TJ, Reid A, Wallberg K, O’Leary TJ, Frizzera G (1993) Determination of B-cell clonality in paraffin-embedded lymph nodes using the polymerase chain reaction. Diag Mol Pathol 2:42–49

    CAS  Google Scholar 

  19. Ohshima K, Suzumiya J, Kanda M, Haraoka S, Kawasaki C, Shimazaki K, Kikuchi M (1999) Genotypic and phenotypic alternations in Epstein-Barr virus-associated lymphoma. Histopathology 35:539–550

    Article  CAS  PubMed  Google Scholar 

  20. Hudson GS, Bankier AT, Satchwell SC, Barrell BG (1985) The short unique region of the B95-8 Epstein-Barr virus genome. Virology 147:81–98

    Article  CAS  PubMed  Google Scholar 

  21. Nomura Y, Lavu EK, Muta K, Niino D, Takeshita M, Hirose S, Nakamura S, Yoshino T, Kikuchi M, Ohshima K (2008) Histological characteristics of 21 Papua New Guinean children with high-grade B-cell lymphoma, which is frequently associated with EBV infection. Pathol Int 58:695–700

    Article  PubMed  Google Scholar 

  22. Oyama T, Ichimura K, Suzuki R, Suzumiya J, Ohshima K, Yatabe Y, Yokoi T, Kojima M, Kamiya Y, Taji H, Kagami Y, Ogura M, Saito H, Morishima Y, Nakamura S (2003) Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathological study of 22 patients. Am J Surg Pathol 27:16–26

    Article  PubMed  Google Scholar 

  23. Oyama T, Yamamoto K, Asano N, Oshiro A, Suzuki R, Kagami Y, Morishima Y, Takeuchi K, Izumo T, Mori S, Ohshima K, Suzumiya J, Nakamura N, Abe M, Ichimura K, Sato Y, Yoshino T, Naoe T, Shimoyama Y, Kamiya Y, Kinoshita T, Nakamura S (2007) Age-related EBV-associated B-cell lymphoproliferative disorders constitute a distinct clinicopathologic group: a study of 96 patients. Clin Cancer Res 13:5124–5132

    Article  CAS  PubMed  Google Scholar 

  24. Takegawa S, Jin Z, Nakayama T, Oyama T, Hieshima K, Nagakubo D, Shirakawa A-K, Tsuzuki T, Nakamura S, Yoshie O (2008) Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder. Cancer Sci 99:296–302

    Article  CAS  PubMed  Google Scholar 

  25. Chan KH, Ng MH, Seto WH, Peiris JS (2001) Epstein-Barr virus (EBV) DNA in sera of patients with primary EBV infection. J Clin Microbiol 39:4152–4154

    Article  CAS  PubMed  Google Scholar 

  26. Takeuchi K, Tanaka-Taya K, Kazuyama Y, Ito YM, Hashimoto S, Fukayama M, Mori S (2006) Prevalence of Epstein-Barr virus in Japan: trends and future prediction. Pathol Int 56:112–116

    Article  PubMed  Google Scholar 

  27. Soussain C, Muldoon LL, Varallyay C, Jahnke K, DePaula L, Neuwelt EA (2007) Efficacy and MRI of rituximab and methotrexate treatment in a nude rat model of CNS lymphoma. Clin Cancer Res 13:2504–2511

    Article  CAS  PubMed  Google Scholar 

  28. Roychowdhury S, Peng R, Baiocchi RA, Bhatt D, Vourganti S, Grecula J, Gupta N, Eisenbeis CF, Nuovo GJ, Yang W, Schmalbrock P, Ferketich A, Moeschberger M, Porcu P, Barth RF, Caligiuri MA (2003) Experimental treatment of Epstein-Barr virus-associated primary central nervous system lymphoma. Cancer Res 63:965–971

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (2008–2010). We would like to thank Dr Daisuke Mori (Saga Prefectural Hospital) for providing valuable samples (case 1).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yasuo Sugita.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sugita, Y., Terasaki, M., Niino, D. et al. Epstein–Barr virus-associated primary central nervous system lymphomas in immunocompetent elderly patients: analysis for latent membrane protein-1 oncogene deletion and EBNA-2 strain typing. J Neurooncol 100, 271–279 (2010). https://doi.org/10.1007/s11060-010-0191-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-010-0191-z

Keywords

Navigation