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      Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma in the Elderly: A Matched Case-Control Analysis

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          Abstract

          Background

          Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) in the elderly has rarely been reported. This study aimed to explore the clinical characteristics and prognosis of this entity.

          Methods

          In situ hybridization (ISH) analysis of Epstein-Barr virus (EBV) and immunohistochemistry was performed in 230 tumor specimens from consecutive de novo DLBCL patients over 50 years old. A matched-case control analysis (1:3) was utilized to compare EBV-positive and EBV-negative DLBCL in the elderly.

          Results

          A total of 16 patients (7.0%) were diagnosed with EBV-positive DLBCL. Of these 16 cases, the median age was 62 years, with a male to female ratio of 11:5. Elderly EBV-positive DLBCL patients had a higher incidence of non-germinal center B-cell (non-GCB) subtypes (87.5%) and high Ki67 (75%) and CD30 expression (93.8%). For EBV-positive patients undergoing initial chemotherapy, 7 of 16 (43.8%) had complete remission, 2 (12.5%) had partial remission, 2 (12.5%) had stable disease, and 5 (31.3%) had progressive disease. The median overall survival was 9 months for the EBV-positive patients. A matched-case control analysis suggested that EBV-positive patients had inferior survival outcomes compared with EBV-negative patients (3-year progression-free survival [PFS]: 25% vs. 76.7%, respectively; 3-year overall survival [OS]: 25% vs. 77.4%, respectively; P<0.001).

          Conclusion

          EBV-positive DLBCL of the elderly is associated with an inferior clinical course and inferior survival outcomes. The role of EBV in this disease and the optimal management of this subgroup warrants further investigation.

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          Most cited references27

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          Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte.

          Bertrand Coiffier, Catherine Thieblemont, Eric Van Den Neste … (2010)
          We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.
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            MYC status in concert with BCL2 and BCL6 expression predicts outcome in diffuse large B-cell lymphoma.

            Heike Horn, Marita Ziepert, Claudia Becher … (2013)
            MYC rearrangements occur in 5% to 10% of diffuse large B-cell lymphomas (DLBCL) and confer an increased risk to cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and rituximab (R)-CHOP treated patients. We investigated the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression in a prospective randomized trial. Paraffin-embedded tumor samples from 442 de novo DLBCL treated within the RICOVER study of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) were investigated using immunohistochemistry and fluorescence in situ hybridization (FISH) to detect protein expression and breaks of MYC, BCL2, and BCL6. Rearrangements of MYC, BCL2, and BCL6 were detected in 8.8%, 13.5%, and 28.7%, respectively. Protein overexpression of MYC (>40%) was encountered in 31.8% of tumors; 79.6% and 82.8% of tumors expressed BCL2 and BCL6, respectively. MYC translocations, MYChigh, BCL2high, and BCL6low protein expressions were associated with inferior survival. In multivariate Cox regression modeling, protein expression patterns of MYC, BCL2 and BCL6, and MYC rearrangements were predictive of outcome and provided prognostic information independent of the International Prognostic Index (IPI) for overall survival and event-free survival. A combined immunohistochemical or FISH/immunohistochemical score predicts outcome in DLBCL patients independent of the IPI and identifies a subset of 15% of patients with dismal prognosis in the high-risk IPI group following treatment with R-CHOP. Registered at http://www.cancer.gov/clinicaltrials: RICOVER trial of the DSHNHL is NCT 00052936.
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              Double hit lymphoma: the MD Anderson Cancer Center clinical experience.

              Yasuhiro Oki, Mansoor Noorani, Pei Lin … (2014)
              We report our experience with 129 cases of double hit lymphoma (DHL), defined as B-cell lymphoma with translocations and/or extra signals involving MYC plus BCL2 and/or BCL6. All cases were reviewed for histopathological classification. Median age was 62 years (range, 18-85), 84% of patients had advanced-stage disease, and 87% had an International Prognostic Index score ≥2. Fourteen patients (11%) had a history of low-grade follicular lymphoma. MYC translocation was present in 81%, and extra signals of MYC in 25% of patients. IGH-BCL2 translocation was present in 84% and extra signals of BCL2 in 12% of patients. Two-year event-free survival (EFS) rates in all patients and patients who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R-HyperCVAD/MA (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with cytarabine plus methotrexate) were 33%, 25%, 67% and 32%, respectively. In patients achieving complete response with initial therapy (n = 71), 2-year EFS rates in patients who did (n = 23) or did not (n = 48) receive frontline stem cell transplantation were 68% and 53%, respectively (P = 0·155). The cumulative incidence of central nervous system involvement was 13% at 3 years. Multivariate analysis identified performance status ≥2 and bone marrow involvement as independent adverse prognostic factors for EFS and OS. Further research is needed to identify predictive and/or targetable biological markers and novel therapeutic approaches for DHL patients. © 2014 John Wiley & Sons Ltd.
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                Author and article information

                Contributors
                Gulfaraz Khan: 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): 29 July 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 7
                Electronic Location Identifier: e0133973
                Affiliations
                [1 ]Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China
                [2 ]Tumor Hospital of Hunan Province, Changsha, Hunan, China
                United Arab Emirates University, UNITED ARAB EMIRATES
                Author notes

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

                Conceived and designed the experiments: ZML WQJ. Performed the experiments: CGS JJH YJL. Analyzed the data: CGS JJH YJL. Contributed reagents/materials/analysis tools: XY YW XWB WQJ HQH TYL ZML. Wrote the paper: CGS JJH ZML.

                Article
                Publisher ID: PONE-D-15-01921
                DOI: 10.1371/journal.pone.0133973
                PMC ID: 4519250
                PubMed ID: 26222726
                SO-VID: e6967c80-9cb9-4411-81df-7830d31ce923
                Copyright statement: Copyright @ 2015
                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 : 16 January 2015
                Date accepted : 4 July 2015
                Page count
                Figures: 2, Tables: 4, Pages: 11
                Funding
                This work was supported by the National Natural Science Foundation of China (project number: 81472759, 81301903), Guangdong Natural Science Foundation (project number: S2013010016331), Science and Technology Planning Project of Guangdong Province, China (project number: 2014J4100163), Science and Technology Planning Project of Guangzhou, China (project number: 2013B021800142), Fundamental Research Funds for the Central Universities (project number: 10ykpy36), and Research Award Funds for Outstanding Young Researchers in Sun Yat-Sen Cancer Center.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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