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      Clinical characteristics and prognostic significance of EBER positivity in diffuse large B-cell lymphoma: A meta-analysis

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          Abstract

          Recent studies show that Epstein-Barr virus (EBV) positivity might be related to adverse prognosis in patients with diffuse large B-cell lymphoma (DLBCL), but the results are still inconclusive. We conducted this meta-analysis to define the clinical value of EBV infection in DLBCL. All potential articles in PubMed, Web of Science, Medline, and Embase were retrieved. Using the random-effects or fixed-effect model, pooled hazard ratios (HRs) or relative risk (RR) with 95% confidence intervals (CIs) were used to calculate the correlation between EBER and prognosis and clinical features in DLBCL. A total of 13 qualified studies with 4111 patients were identified in our meta-analysis based on the inclusion and exclusion criteria. The overall estimates revealed that EBV-encoded small RNAs (EBER) positivity was significantly correlated with worse overall survival (HR = 2.43, 95% CI: 1.73–3.36) and progression-free survival (HR = 3.60, 95% CI: 2.07–6.26). In addition, EBER positivity was associated with age older than 60 years (RR = 1.51, 95% CI: 1.02–2.24), male sex (RR = 1.34, 95% CI: 1.05–1.71), more advanced stage (RR = 2.25, 95% CI: 1.72–2.96), high international prognostic index (RR = 2.20, 95% CI: 1.71–2.82), more than one extranodal involvement (RR = 1.69, 95% CI: 1.27–2.26), presence of B symptom (RR = 1.75, 95% CI: 1.30–2.35), non-germinal center B-cell subtype (RR = 1.35, 95% CI: 1.03–1.78), and elevated lactate dehydrogenase levels (RR = 1.30, 95% CI: 0.98–1.72). EBER positivity was correlated with worse outcomes, worse clinical course, and adverse clinicopathologic features among patients with DLBCL.

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          The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP.

          Laurie Sehn, Brian Berry, Mukesh Chhanabhai … (2007)
          Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, with patients exhibiting a wide range of outcomes. The addition of rituximab to CHOP chemotherapy (R-CHOP)has led to a marked improvement in survival and has called into question the significance of previously recognized prognostic markers. Since randomized controlled trials of R-CHOP in DLBCL have included select subgroups of patients, the utility of the International Prognostic Index (IPI) has not been reassessed. We performed a retrospective analysis of patients with DLBCL treated with R-CHOP in the province of British Columbia to assess the value of the IPI in the era of immunochemotherapy. The IPI remains predictive, but it identifies only 2 risk groups. Redistribution of the IPI factors into a revised IPI (R-IPI) provides a more clinically useful prediction of outcome. The R-IPI identifies 3 distinct prognostic groups with a very good (4-year progression-free survival [PFS] 94%, overall survival [OS] 94%), good (4-year PFS 80%, OS 79%), and poor (4-year PFS 53%, OS 55%) outcome, respectively (P < .001). The IPI (or R-IPI) no longer identifies a risk group with less than a 50% chance of survival. In the era of R-CHOP treatment, the R-IPI is a clinically useful prognostic index that may help guide treatment planning and interpretation of clinical trials.
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            A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project.

            W.C. Chan, F. Cavalli, P Jacobs … (1997)
            The recognition of several new types of non-Hodgkin's lymphoma (NHL) in recent years has led to proposals for changing lymphoma classifications, including a new proposal put forth by the International Lymphoma Study Group (ILSG). However, the clinical significance of the new entities and the practical utility of this new proposal have not been studied. Therefore, we performed a clinical evaluation of the ILSG classification. A cohort of 1,403 cases of NHL was organized at nine study sites around the world and consisted of consecutive patients seen between 1988 and 1990 who were previously untreated. A detailed protocol for histologic and clinical analysis was followed at each site, and immunologic characterization as to T- or B-cell phenotype was required. Five expert hematopathologists visited the sites and each classified each case using the ILSG classification. A consensus diagnosis was also reached in each case, and each expert rereviewed a 20% random sample of the cases. Clinical correlations and survival analyses were then performed. A diagnosis of NHL was confirmed in 1,378 (98.2%) of the cases. The most common lymphoma types were diffuse large B-cell lymphoma (31%) and follicular lymphoma (22%), whereas the new entities comprised 21% of the cases. Diagnostic accuracy was at least 85% for most of the major lymphoma types, and reproducibility of the diagnosis was 85%. Immunophenotyping improved the diagnostic accuracy by 10% to 45% for a number of the major types. The clinical features of the new entities were distinctive. Both the histologic types and the patient characteristics as defined by the International Prognostic Index predicted for patient survival. In conclusion we found that the ILSG classification can be readily applied and identifies clinically distinctive types of NHL. However, for clinical application, prognostic factors as defined by the International Prognostic Index must be combined with the histologic diagnosis for appropriate clinical decisions.
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              Epstein-Barr virus: exploiting the immune system.

              D A Thorley-Lawson (2001)
              In vitro, Epstein-Barr virus (EBV) will infect any resting B cell, driving it out of the resting state to become an activated proliferating lymphoblast. Paradoxically, EBV persists in vivo in a quiescent state in resting memory B cells that circulate in the peripheral blood. How does the virus get there, and with such specificity for the memory compartment? An explanation comes from the idea that two genes encoded by the virus--LMP1 and LMP2A--allow EBV to exploit the normal pathways of B-cell differentiation so that the EBV-infected B blast can become a resting memory cell.
              Article 0 comments Cited 214 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Xiaojuan Gao: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: Writing – original draftRole: Writing – review & editing
                Jia Li: Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Yaqi Wang: Role: ConceptualizationRole: MethodologyRole: Writing – review & editing
                Shuai Liu: Role: SupervisionRole: Validation
                Baohong Yue:
                ORCID: http://orcid.org/0000-0001-6911-0177
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: Validation
                Riccardo Dolcetti: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 19 June 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 6
                Electronic Location Identifier: e0199398
                Affiliations
                [1 ] Department of Laboratory Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, P. R. China
                [2 ] Faculty of Laboratory Medicine, Zhengzhou University, Zhengzhou, P. R. China
                [3 ] Key Laboratory Medicine of Henan Province, Faculty of Laboratory Medicine of Zhengzhou University, Zhengzhou, P. R. China
                [4 ] Open Laboratory, Henan Province Key Subject of Clinical Medicine, Zhengzhou, P. R. China
                Fondazione IRCCS Istituto Nazionale dei Tumori, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-6911-0177
                Article
                Publisher ID: PONE-D-18-09906
                DOI: 10.1371/journal.pone.0199398
                PMC ID: 6007832
                PubMed ID: 29920566
                SO-VID: 76d343f3-4f8b-4ef7-99dc-6eddc858c44f
                Copyright © © 2018 Gao et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 4 April 2018
                Date accepted : 6 June 2018
                Page count
                Figures: 5, Tables: 1, Pages: 13
                Funding
                The authors received no specific funding for this work.
                Categories
                Subject: Research Article
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: DNA viruses
                Subject: Herpesviruses
                Subject: Epstein-Barr virus
                Subject: Biology and life sciences
                Subject: Microbiology
                Subject: Medical microbiology
                Subject: Microbial pathogens
                Subject: Viral pathogens
                Subject: Herpesviruses
                Subject: Epstein-Barr virus
                Subject: Medicine and health sciences
                Subject: Pathology and laboratory medicine
                Subject: Pathogens
                Subject: Microbial pathogens
                Subject: Viral pathogens
                Subject: Herpesviruses
                Subject: Epstein-Barr virus
                Subject: Biology and life sciences
                Subject: Organisms
                Subject: Viruses
                Subject: Viral pathogens
                Subject: Herpesviruses
                Subject: Epstein-Barr virus
                Subject: Medicine and Health Sciences
                Subject: Diagnostic Medicine
                Subject: Prognosis
                Subject: Medicine and health sciences
                Subject: Oncology
                Subject: Cancers and neoplasms
                Subject: Hematologic cancers and related disorders
                Subject: Lymphomas
                Subject: Diffuse large B-cell lymphoma
                Subject: Medicine and health sciences
                Subject: Hematology
                Subject: Hematologic cancers and related disorders
                Subject: Lymphomas
                Subject: Diffuse large B-cell lymphoma
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: People and Places
                Subject: Geographical Locations
                Subject: Asia
                Subject: Japan
                Subject: People and Places
                Subject: Geographical Locations
                Subject: Asia
                Subject: Korea
                Subject: Biology and Life Sciences
                Subject: Molecular Biology
                Subject: Molecular Biology Techniques
                Subject: Molecular Probe Techniques
                Subject: Probe Hybridization
                Subject: In Situ Hybridization
                Subject: Research and Analysis Methods
                Subject: Molecular Biology Techniques
                Subject: Molecular Probe Techniques
                Subject: Probe Hybridization
                Subject: In Situ Hybridization
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                Data Availability All relevant data are within the paper and its Supporting Information files.

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