Latent Epstein-Barr Virus Infection of Tumor Cells in Classical Hodgkin's Lymphoma Predicts Adverse Outcome in Older Adult Patients

Diepstra, Arjan; Imhoff, Gustaaf W. van; Schaapveld, Michael; Karim‐Kos, Henrike E.; Berg, Anke van den; Vellenga, Edo; Poppema, Sibrand

doi:10.1200/jco.2008.20.5138

Cited by 85 publications

(58 citation statements)

References 40 publications

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“…Therefore, LMP1 may have reciprocal effects on the expressing cells, that is, even though LMP1-expressing cells show a malignant phenotype, an extrinsic immune system can eradicate these cells in vivo. In Hodgkin lymphoma, the presence of LMP1 seems to influence its clinical behavior in concert with the patient's age and histology (37,38). In addition, LMP1- Days after diagnosis 0 1,000 2,000 3,000 4,000 5,000 Days after diagnosis 0 1,000 2,000 3,000 4,000 5,000…”

Section: Discussionmentioning

confidence: 99%

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

Kanemitsu

Isobe

Masuda

et al. 2012

Clinical Cancer Research

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Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is closely associated with Epstein-Barr virus (EBV). To elucidate its pathogenetic role, we examined the expression profiles of EBV-encoded proteins, especially focusing on latent membrane protein 1 (LMP1).Experimental Design: Immunohistochemistry was carried out using clinical samples from ENKL cases, which were diagnosed between 1996 and 2010 at our institution. We statistically assessed the correlation between LMP1 positivity and the clinicopathologic data and further examined phosphorylation status of NF-kB RelA and Akt in ENKL cell lines.Results: Most of the 30 examined cases showed pleomorphic morphology, natural killer cell immunophenotype, and a localized disease. Immunohistochemistry detected EBERs, but not EBNA2, in all cases. LMP1 and LMP2A were positive in 22 (73.3%) and 12 cases (40.0%), respectively. LMP1-positive cases tended to show a localized disease (P ¼ 0.060, the Fisher exact test). Nuclear localization of phosphorylated RelA and detection of phosphorylated Akt were predominantly observed in LMP1-positive cases (P ¼ 0.002 and P < 0.001, respectively, the Fisher exact test). RNA silencing experiments of LMP1 in Hank1 cells suggested a positive correlation between LMP1 expression and phosphorylation of RelA and Akt. With a median follow-up period of 26.7 months (range, 0.2-142.3 months), the 2.5-year overall survival rates for LMP1-positive and -negative cases were estimated at 78.3% and 12.5%, respectively (P ¼ 0.001, log-rank test).Conclusions: LMP1 expression shows correlations with phosphorylation of RelA and Akt and possibly has a favorable impact on clinical outcome in ENKL.

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Section: Discussionmentioning

confidence: 99%

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

Kanemitsu

Isobe

Masuda

et al. 2012

Clinical Cancer Research

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“…14 The impact of EBV infection on outcome remains controversial, but appears to be dependent on age. Accordingly, many studies support an association between EBV positivity and adverse outcome in older adult patients, [15][16][17] while in younger and, specifically in pediatric patients, EBV positivity has been linked to better outcome. 15,18,19 It will be of interest in subsequent studies to assess the interaction between EBV infection and tumorassociated macrophages as outcome predictors in cHL.…”

Section: The Phenotype Of Tumor-associated Macrophages and Correlatiomentioning

confidence: 99%

Macrophages predict treatment outcome in Hodgkin's lymphoma

Steidl¹,

Farinha²,

Gascoyne³

2011

Haematologica

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“…The role of EBV status of HRS cells as an unfavorable prognostic marker is controversial (31)(32)(33)(34)(35) and probably limited to older adult patients. The association of EBV status with older age, a higher proportion of tumor-infiltrating CD68þ cells in EBER-positive HL, and higher levels of circulating EBV-DNA in older patients may all point to a different biology and disease activity in EBV-associated HL of the elderly, as factors contributing to unfavorable prognosis.…”

Section: Cd68mentioning

confidence: 99%

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

Hohaus

Santangelo

Giachelia

et al. 2011

Clinical Cancer Research

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Purpose: The Epstein-Barr virus (EBV) is present in the malignant Hodgkin/Reed-Sternberg (HRS) cells of 20% to 40% cases of Hodgkin lymphoma (HL) in Western countries. We were interested in the detection and quantification of cell-free plasma EBV-DNA as an indicator of biological and clinical characteristics in EBV-associated HL.Experimental Design: EBV was detected in peripheral blood compartments (whole blood, plasma, and mononuclear cells) at diagnosis by real-time PCR for the EBNA (EB nuclear antigen) region (n ¼ 93) and in HRS cells by in situ hybridization for EBV-encoded small RNAs (EBER; n ¼ 63). These data were correlated to histological and clinical characteristics, EBV serology, circulating cell-free DNA, and interleukin (IL)-6 levels.Results: Detection of EBV-DNA in plasma had a high specificity (90%), but a relatively low sensitivity (65%) to predict for EBV association. The viral load was higher in patients with advanced stage disease, older age in the presence of B-symptoms, and international prognostic score more than 2. The presence of EBV in HRS cells and higher plasma EBV-DNA copy numbers correlated to an increased frequency of tumor-infiltrating CD68þ macrophages in lymph node biopsies. Plasma EBV-DNA load correlated to circulating cell-free DNA and IL-6 levels, and inversely correlated to lymphocyte counts and EBNA1 antibody titers.Conclusion: Although the presence of EBV-DNA in peripheral blood cannot be regarded as a surrogate marker for EBER, the plasma EBV-DNA load at HL diagnosis is an indicator of disease activity and biological characteristics associated with negative prognosis. Moreover, the inverse correlation to EBNA1 antibody titers and lymphocyte counts may indicate a reduction in immunosurveillance, favoring the expansion of EBV-HRS cells in HL. Clin Cancer Res; 17(9); 2885-92. Ó2011 AACR.

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Latent Epstein-Barr Virus Infection of Tumor Cells in Classical Hodgkin's Lymphoma Predicts Adverse Outcome in Older Adult Patients

Abstract: This study indicates that treatment failure in older adult patients with cHL is associated with positive tumor cell EBV status.

Cited by 85 publications

References 40 publications

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

Expression of Epstein-Barr Virus–Encoded Proteins in Extranodal NK/T-cell Lymphoma, Nasal Type (ENKL): Differences in Biologic and Clinical Behaviors of LMP1-Positive and -Negative ENKL

Macrophages predict treatment outcome in Hodgkin's lymphoma

The Viral Load of Epstein–Barr Virus (EBV) DNA in Peripheral Blood Predicts for Biological and Clinical Characteristics in Hodgkin Lymphoma

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