Epstein–Barr virus is rarely associated with diffuse large B cell lymphoma in Taiwan and carries a trend for a shorter median survival time

Chang, Sheng‐Tsung; Lu, Yi‐Hsuan; Lu, Chin-Li; Weng, Shih‐Feng; Lin, Shu-Hui; Kuo, Szu-Yin; Chuang, Yu-Ting; Takeuchi, Kengo; Ohshima, Koichi; Chuang, Shih‐Sung

doi:10.1136/jclinpath-2013-201905

Cited by 24 publications

(24 citation statements)

References 23 publications

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“…Several retrospective studies have reported adverse impacts of EBER‐positivity on outcomes for DLBCL patients . However, when we interpret the data from these previous studies, caution should be exercised in that most of such studies included patients in the era before the advent of rituximab.…”

Section: Discussionmentioning

confidence: 99%

“…‘EBV‐positive DLBCL of the elderly’ is defined as an EBV‐positive clonal B‐cell lymphoid proliferation occurring in patients over the age of 50 years without any known immunodeficiency or prior lymphoma . Most previous studies , if not all , have shown that this subtype is associated with poor prognosis.…”

Section: Introductionmentioning

confidence: 94%

“…However, this method is a semi‐quantitative analysis, and reported results are observer‐dependent. Moreover, there are no established criteria regarding the percentage of EBER‐positive cells for the definition of EBV‐positivity: some studies employed 10% as a threshold , and others 20% , 30% or 50% . These conditions could plausibly hamper the accurate determination of whether and to what extent EBV is involved.…”

Section: Introductionmentioning

confidence: 99%

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The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B‐cell lymphoma patients

Okamoto

Yanada

Inaguma

et al. 2015

Hematological Oncology

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Epstein-Barr virus (EBV)-encoded small RNA in situ hybridization (EBER-ISH) is a widely accepted method to evaluate EBV involvement in diffuse large B-cell lymphoma (DLBCL), although little is known regarding associations between EBV DNA load and the EBER status and whether EBV DNA load data provide additional clinical information. In this study, we quantified EBV DNA load in diagnostic specimens from DLBCL patients diagnosed at our hospital to evaluate clinical implications of EBV DNA load in diagnostic specimens as contrasted with EBER-ISH. Among 140 DLBCL patients without underlying immunodeficiency, 51 were evaluable for both EBER and EBV DNA load, 83 for EBER only and one for EBV DNA load only. The median EBV DNA load was 708 copies/μg. Although EBV DNA load was significantly higher for EBER-positive patients than for EBER-negative patients (p < 0.001), EBV DNA was detected in up to 72% of EBERnegative patients. Progression-free survival and overall survival were significantly worse for patients with EBV DNA load above 700 copies/μg than for those with EBV DNA load below 700 copies/μg (p = 0.009 and p = 0.003); they were also significantly worse for EBER-positive patients than for EBER-negative patients (p < 0.001 and p = 0.001). Even among EBER-negative patients, higher EBV DNA load conferred worse progression-free survival and overall survival (p = 0.041 and p = 0.013). These findings indicate that EBV DNA load in diagnostic specimens is not a simple surrogate for the EBER status and may be a potential biomarker associated with EBV involvement and prognosis in DLBCL.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B‐cell lymphoma patients

Okamoto

Yanada

Inaguma

et al. 2015

Hematological Oncology

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“…Though first reported in 2003 [ 2 , 3 ] and identified as a subtype of DLBCL in 2008, this disease is not universally recognized and remains controversial for both clinicians and pathologists. This malignancy has a low incidence rate, reportedly ranging from 3.5% to 9% of all cases of DLBCL among the elderly [ 4 , 5 , 6 , 7 ]. Because there is no clearly superior treatment for this disease, some lymphoma specialists do not feel the need to distinguish this subtype from “normal” senile DLBCL.…”

Section: Introductionmentioning

confidence: 99%

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

Song

Huang

Li³

et al. 2015

PLoS ONE

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BackgroundEpstein-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.MethodsIn 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.ResultsA 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).ConclusionEBV-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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“…Epstein-Barr virus (EBV)-positive (+) diffuse large B-cell lymphoma (DLBCL) accounts for 4–11% of all cases of DLBCL [1–3]. EBV+ DLBCL exhibits relatively few genetic alterations compared with EBV- DLBCL [4].…”

Section: Introductionmentioning

confidence: 99%

LMP1+SLAMF1high cells are associated with drug resistance in Epstein-Barr virus-positive Farage cells

Yoon

2017

Oncotarget

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How Epstein-Barr virus (EBV) affects the clinical outcome of EBV-positive diffuse large B-cell lymphoma (DLBCL) remains largely unknown. The viral oncogene LMP1 is at the crux of tumorigenesis and cell survival. Therefore, we examined the association between LMP1high cells drug resistance. We first assessed SLAMF1 as a surrogate marker for LMP1high cells. LMP1 and its target gene CCL22 were highly expressed in SLAMF1high Farage cells. These cells survived longer following treatment with a combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Genes associated with interferon-alpha, allograft rejection, NF-κB and STAT3 were also overexpressed in the surviving Farage cells. Specifically, CHOP treatment increased IL10, LMP1 and pSTAT3 expression levels in a dose-dependent fashion. Addition of exogenous IL4 greatly increased the levels of LMP1 and pSTAT3, which rendered the Farage cells more resistant to CHOP by up-regulating the anti-apoptotic genes BCL-XL and MCL1. The Farage cells were sensitive to Velcade and STAT3, 5, and 6 inhibitors. Inhibition of NF-κB and STAT3, in combination with CHOP, decreased LMP1 levels and effectively induced cell death in the Farage cells. We suggest that LMP1high cells are responsible for the poor drug response of EBV+ DLBCL and that perturbation of the NF-κB and STAT signaling pathways increases toxicity in these cells.

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Epstein–Barr virus is rarely associated with diffuse large B cell lymphoma in Taiwan and carries a trend for a shorter median survival time

Abstract: EBV-positive DLBCL of the elderly is relatively rare in Taiwan, with an incidence intermediate between Japan/Korea and the West. Further studies are warranted to clarify the association of EBV and the clinicopathological features and the prognostic significance in patients with DLBCL.

Cited by 24 publications

References 23 publications

The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B‐cell lymphoma patients

The prognostic significance of EBV DNA load and EBER status in diagnostic specimens from diffuse large B‐cell lymphoma patients

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

LMP1+SLAMF1high cells are associated with drug resistance in Epstein-Barr virus-positive Farage cells

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