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

AbstractTo 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.

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EBV-positive intravascular large B-cell lymphoma of the liver: a case report and literature review

10.21203/rs.3.rs-16787/v1 ◽

2020 ◽

Author(s):

Qingjiao Li ◽

Jinghe Li ◽

Keda Yang ◽

Ying Peng ◽

Yao Xiang ◽

...

Keyword(s):

In Situ Hybridization ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Barr Virus ◽

Large B Cell Lymphoma ◽

Epstein Barr ◽

Large B Cell

Abstract Background Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare subtype of diffuse large B-cell lymphoma that most commonly involves the central nervous system, skin, and bone marrow. To our knowledge, Epstein-Barr virus (EBV)-positive IVLBCL in the liver has never been reported in the literature. Case presentation We report a case of a 65-year-old Chinese man with complaint of fever for 18 days. No obvious abnormality was found by physical examination. Laboratory findings were notable for anemia, thrombocytopenia, and elevated level of serum lactate dehydrogenase. Imaging studies showed a slightly lower density lesion in the liver with high fluorodeoxyglucose uptake. Percutaneous liver biopsy revealed clustering of large atypical lymphocytes within the hepatic sinusoids. Immunohistochemically, these lymphoma cells were positive for CD20, PAX-5, MUM-1, BCL-6 and CD5, but negative for CD3 and CD10. Besides, Epstein-Barr virus-encoded RNA was detected in tumor cells by in situ hybridization. BCL-2 , BCL-6 and MYC genes were intact tested by fluorescence in situ hybridization analysis. The patient was diagnosed as IVLBCL and died after 1 month of hospitalization without receiving immunochemotherapy. Conclusions IVLBCL of the liver is a highly rare lymphoma with nonspecific manifestations and dismal prognosis. Full recognition of its clinicopathological features will help to better diagnose this disease.

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EBV-positive intravascular large B-cell lymphoma of the liver: a case report and literature review

10.21203/rs.3.rs-16787/v2 ◽

2020 ◽

Author(s):

Qingjiao Li ◽

Jinghe Li ◽

Keda Yang ◽

Ying Peng ◽

Yao Xiang ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Barr Virus ◽

Large B Cell Lymphoma ◽

Epstein Barr ◽

Large B Cell

Abstract Background Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare subtype of diffuse large B-cell lymphoma that most commonly involves the central nervous system, skin, and bone marrow. To our knowledge, Epstein-Barr virus (EBV)-positive IVLBCL in the liver has never been reported in the literature. Case presentation We report a case of a 65-year-old Chinese man with complaint of fever for 18 days. No obvious abnormality was found by physical examination. Laboratory findings were notable for anemia, thrombocytopenia, and elevated level of serum lactate dehydrogenase. Bone marrow on smear, biopsy, and flow cytometry revealed no lymphoma. Imaging studies showed a slightly lower density lesion in the liver with high fluorodeoxyglucose uptake and hepatosplenomegaly. Percutaneous liver biopsy revealed clustering of large atypical lymphocytes within the hepatic sinusoids. Immunohistochemically, these lymphoma cells were positive for CD20, PAX-5, MUM-1, BCL-6 and CD5, but negative for CD3 and CD10. Besides, Epstein-Barr virus-encoded RNA was detected in tumor cells by in situ hybridization. BCL-2 , BCL-6 and MYC genes were intact tested by fluorescence in situ hybridization analysis. The patient was diagnosed as IVLBCL and died after 1 month of hospitalization without receiving immunochemotherapy. Conclusions IVLBCL of the liver is a highly rare lymphoma with nonspecific manifestations and dismal prognosis. Full recognition of its clinicopathological features will help to better diagnose this disease.

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Epstein Barr Virus Micrornas Repress BCL6 Expression in Diffuse Large B Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.314.314 ◽

2009 ◽

Vol 114 (22) ◽

pp. 314-314 ◽

Cited By ~ 1

Author(s):

Daniel Martín-Pérez ◽

Pierfrancesco Vargiu ◽

Santiago Montes-Moreno ◽

David G Pisano ◽

Maria Socorro Rodriguez-Pinilla ◽

...

Keyword(s):

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

B Cell Differentiation ◽

Barr Virus ◽

Large B Cell Lymphoma ◽

Epstein Barr ◽

Bcl6 Expression

Abstract Abstract 314 Introduction: Epstein Barr Virus (EBV) is able to transform B-cells by disrupting the normal B-cell differentiation programme, leading to the development of different types of B-cell lymphoma. BCL6 is a key transcriptional repressor during normal B-cell differentiation that is required for germinal centre reaction and it has been shown to repress NF-kB in Diffuse Large B-Cell Lymphoma (DLBCL). In some B-cell lymphomas the expression of BCL6 and infection with EBV are mutual exclusive occurrences, although the causal mechanism of this phenomenon and its biological significance remain elusive. Patients and methods: A microRNA expression profile was investigated using Agilent's Human miRNA microarray kit. microRNA targets were predicted with the miRanda algorithm (http://www.microrna.org/). Immunohistochemical and in situ hybridization analyses were performed on 149 DLBCL samples to investigate the expression of BCL6 and EBV status, respectively. Luciferase assays were carried out by cloning the BCL6 3'-UTR into the pGL3-Control vector. Results: 22 viral microRNAs were found to be upregulated specifically in EBV-positive cases of DLBCL. By applying the miRanda algorithm, 10 of these 22 microRNAs were predicted potentially to target BCL6. To explore this possibility, immunohistochemical analysis and in situ hybridization were carried out on 149 cases of DLBCL. The results showed an almost perfect inverse correlation between BCL6 protein expression and EBV infection, even in the absence of LMP1 protein expression (p<0.001). Only one out of 34 EBV-positive cases expressed BCL6, although 87 out of 115 EBV-negative cases expressed BCL6. This phenomenon was confirmed in DLBCL cell lines. ebv-miR-BART3, ebv-miR-BART7, ebv-miR-BART9 and ebv-miR-BART17-5p were selected from the list of ten microRNAs for further functional validation, on the basis of the score calculated by miRanda. Thus, we transfected synthetic microRNAs and measured the luciferase activity in our reporter system. At least three of the assayed microRNAs were able to reduce the luciferase activity of the reporter. The effect of these microRNAs on the endogenous BCL6 protein was investigated in lymphoid BCL6-expressing cell lines by Western blot. The four microRNAs were able to downregulate the levels of endogenous BCL6. Conclusions: DLBCL cases infected by EBV express a restricted set of viral microRNAs. Several of these microRNAs can potentially target the BCL6 gene, highlighting the importance of BCL6 downregulation in the context of EBV infection. Functional studies demonstrate that at least three of these microRNAs are able to downregulate BCL6 expression. The reason why EBV downregulates BCL6 is still unknown, but we propose that it might be required for DLBCL cells to survive in the context of EBV-induced NF-κB pathway activation. Disclosures: No relevant conflicts of interest to declare.

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EBV-positive intravascular large B-cell lymphoma of the liver: a case report and literature review

10.21203/rs.3.rs-16787/v3 ◽

2020 ◽

Author(s):

Qingjiao Li ◽

Jinghe Li ◽

Keda Yang ◽

Ying Peng ◽

Yao Xiang ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Barr Virus ◽

Large B Cell Lymphoma ◽

Epstein Barr ◽

Large B Cell

Abstract Background Intravascular large B-cell lymphoma (IVLBCL) is an extremely rare subtype of diffuse large B-cell lymphoma that most commonly involves the central nervous system, skin, and bone marrow. To our knowledge, Epstein-Barr virus (EBV)-positive IVLBCL in the liver has never been reported in the literature. Case presentation We report a case of a 65-year-old Chinese man with complaint of fever for 18 days. No obvious abnormality was found by physical examination. Laboratory findings were notable for anemia, thrombocytopenia, and elevated level of serum lactate dehydrogenase. Bone marrow on smear, biopsy, and flow cytometry revealed no lymphoma. Imaging studies showed a slightly lower density lesion in the liver with high fluorodeoxyglucose uptake and hepatosplenomegaly. Percutaneous liver biopsy revealed clustering of large atypical lymphocytes within the hepatic sinusoids. Immunohistochemically, these lymphoma cells were positive for CD20, PAX-5, MUM-1, BCL-6 and CD5, but negative for CD3 and CD10. Besides, Epstein-Barr virus-encoded RNA was detected in tumor cells by in situ hybridization. BCL-2 , BCL-6 and MYC genes were intact tested by fluorescence in situ hybridization analysis. The patient was diagnosed as IVLBCL and died after 1 month of hospitalization without receiving immunochemotherapy. Conclusions IVLBCL of the liver is a highly rare lymphoma with nonspecific manifestations and dismal prognosis. Full recognition of its clinicopathological features will help to better diagnose this disease.

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