The impact of Epstein-Barr virus status on clinical outcome in diffuse large B-cell lymphoma.

To define prognostic impact of Epstein-Barr virus (EBV) infection in diffuse large B-cell lymphoma (DLBCL), we investigated EBV status in patients with DLBCL. In all, 380 slides from paraffin-embedded tissue were available for analysis by EBV-encoded RNA-1 (EBER) in situ hybridization, and 34 cases (9.0%) were identified as EBER-positive. EBER positivity was significantly associated with age greater than 60 years (P = .005), more advanced stage (P < .001), more than one extranodal involvement (P = .009), higher International Prognostic Index (IPI) risk group (P = .015), presence of B symptom (P = .004), and poorer outcome to initial treatment (P = .006). The EBER(+) patients with DLBCL demonstrated substantially poorer overall survival (EBER(+) vs EBER(-) 35.8 months [95% confidence interval (CI), 0-114.1 months] vs not reached, P = .026) and progression-free survival (EBER(+) vs EBER(-) 12.8 months [95% CI, 0-31.8 months] vs 35.8 months [95% CI, 0-114.1 months], respectively (P = .018). In nongerminal center B-cell-like subtype, EBER in situ hybridization positivity retained its statistical significance at the multivariate level (P = .045). Nongerminal center B-cell-like patients with DLBCL with EBER positivity showed substantially poorer overall survival with 2.9-fold (95% CI, 1.1-8.1) risk for death. Taken together, DLBCL patients with EBER in situ hybridization+ pursued more rapidly deteriorating clinical course with poorer treatment response, survival, and progression-free survival.

[1]  P. Gaulard,et al.  Prognostic significance of Epstein-Barr virus in nodal peripheral T-cell lymphoma, unspecified: A Groupe d'Etude des Lymphomes de l'Adulte (GELA) study. , 2006, Blood.

[2]  H. Koo,et al.  The effect of Epstein–Barr virus status on clinical outcome in Hodgkin’s lymphoma , 2006, Annals of Hematology.

[3]  Y. Kagami,et al.  Senile Epstein-Barr virus-associated B-cell lymphoproliferative disorders: a mini review. , 2006, Journal of clinical and experimental hematopathology : JCEH.

[4]  T. Yoshino,et al.  Epstein–Barr virus involvement is a predictive factor for the resistance to chemoradiotherapy of gastric diffuse large B‐cell lymphoma , 2006, Cancer science.

[5]  J. Butel,et al.  Simian virus 40 tumor antigen expression and immunophenotypic profile of AIDS-related non-Hodgkin's lymphoma. , 2005, Virology.

[6]  M. Gulley,et al.  Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a population-based study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  G. M. Taylor,et al.  Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. , 2005, Blood.

[8]  K. Grønbæk,et al.  Microarray‐based classification of diffuse large B‐cell lymphoma , 2005, European journal of haematology.

[9]  H. Heslop.  Biology and treatment of Epstein-Barr virus-associated non-Hodgkin lymphomas. , 2005, Hematology. American Society of Hematology. Education Program.

[10]  W. Au,et al.  Quantification of circulating Epstein-Barr virus (EBV) DNA in the diagnosis and monitoring of natural killer cell and EBV-positive lymphomas in immunocompetent patients. , 2004, Blood.

[11]  L. Staudt,et al.  Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. , 2004, Blood.

[12]  L. Young,et al.  Epstein-Barr Virus Latent Membrane Protein 1 (LMP1) Activates the Phosphatidylinositol 3-Kinase/Akt Pathway to Promote Cell Survival and Induce Actin Filament Remodeling* , 2003, The Journal of Biological Chemistry.

[13]  K. Ohshima,et al.  Senile EBV+ B-Cell Lymphoproliferative Disorders: A Clinicopathologic Study of 22 Patients , 2003, The American journal of surgical pathology.

[14]  L. Hutt-Fletcher,et al.  Alternate replication in B cells and epithelial cells switches tropism of Epstein–Barr virus , 2002, Nature Medicine.

[15]  Y. Kwong,et al.  Natural killer cell malignancies: clinicopathologic and molecular features. , 2002, Histology and histopathology.

[16]  D. Weisenburger,et al.  Epstein-Barr Virus Genome in Non-Hodgkin ’ s Lymphomas Occurring in Immunocompetent Patients : Highest Prevalence in Nonlymphoblastic T-cell Lymphoma and Correlation With a Poor Prognosis , 2002 .

[17]  Meland,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[18]  D. Thorley-Lawson,et al.  Epstein-Barr virus: exploiting the immune system , 2001, Nature Reviews Immunology.

[19]  N. Nakamura,et al.  The Characteristics of Epstein‐Barr Virus (EBV)‐positive Diffuse Large B‐Cell Lymphoma: Comparison between EBV+ and EBV‐ Cases in Japanese Population , 2000, Japanese journal of cancer research : Gann.

[20]  J. Armitage,et al.  Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  W. Hammerschmidt,et al.  Epstein–Barr virus‐mediated B‐cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor , 1998, The EMBO journal.

[22]  N. Cooper,et al.  Activation of a ras-MAPK-dependent pathway by Epstein-Barr virus latent membrane protein 1 is essential for cellular transformation. , 1998, Virology.

[23]  B. Nathwani,et al.  A clinical evaluation of the International Lymphoma Study Group Classification of non-Hodgkin's lymphoma: a report of the Non-Hodgkin's Lymphoma Classification Project , 1997 .

[24]  James Olen Armitage,et al.  A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. , 1997, Blood.

[25]  D. Weisenburger,et al.  Epstein-Barr virus genome in non-Hodgkin's lymphomas occurring in immunocompetent patients: highest prevalence in nonlymphoblastic T-cell lymphoma and correlation with a poor prognosis. Danish Lymphoma Study Group, LYFO. , 1996, Blood.

[26]  M. Rowe,et al.  The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. , 1995, Oncogene.

[27]  A. López-Guillermo,et al.  Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. , 1994, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  E. Kieff,et al.  Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[30]  M. Tiemann,et al.  [Heterogeneous Epstein-Barr virus infection patterns in peripheral T cell lymphoma of the angioimmunoblastic lymphadenopathy type]. , 1992, Verhandlungen der Deutschen Gesellschaft fur Pathologie.

[31]  M. Tiemann,et al.  Heterogeneous Epstein-Barr virus infection patterns in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type. , 1992, Blood.

[32]  E. Kieff,et al.  Induction of bcl-2 expression by epstein-barr virus latent membrane protein 1 protects infected B cells from programmed cell death , 1991, Cell.

[33]  S. Hamilton-Dutoit,et al.  Expression of Epstein-Barr virus latent gene products in tumour cells of Hodgkin's disease , 1991, The Lancet.

[34]  G. Nemerow,et al.  Identification of gp350 as the viral glycoprotein mediating attachment of Epstein-Barr virus (EBV) to the EBV/C3d receptor of B cells: sequence homology of gp350 and C3 complement fragment C3d , 1987, Journal of virology.

[35]  L. Dintenfass,et al.  MYOCARDIAL DAMAGE DUE TO FAULTY HEAT EXCHANGE , 1976, The Lancet.

[36]  N. Andén,et al.  Baclofen and lithium in Huntington's chorea. , 1973, Lancet.

[37]  P. Gerber,et al.  Selective transformation of B lymphocytes by E.B. virus. , 1973, Lancet.

[38]  J. H. Pope,et al.  Transformation of foetal human leukocytes in vitro by filtrates of a human leukaemic cell line containing herpes‐like virus , 1968 .