Abstract
The prognostic impact of the presence of Epstein–Barr virus (EBV) in classical Hodgkin lymphoma (cHL) is controversial. Previous studies reported heterogeneous results, rendering difficult the clinical validation of EBV as a prognostic biomarker in this lymphoma. The objective of this study was to evaluate the survival impact of the expression of EBV Latent-Membrane Protein 1 (EBV-LMP1) in tumoral Hodgkin–Reed–Sternberg (HRS) cells of primary diagnostic samples of cHL. Formalin-Fixed Paraffin-Embedded (FFPE) lymph node samples from 88 patients with cHL were analyzed. Patients were treated with the standard first-line chemotherapy (CT) with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) followed by radiotherapy. The Kaplan–Meier method and the Cox proportional hazards model were used for carrying out the survival analysis. In order to investigate whether the influence of EBV was age-dependent, analyses were performed both for patients of all ages and for age-stratified subgroups. In bivariate analysis, the expression of EBV was associated with older age (p = 0.011), mixed cellularity subtype cHL (p < 0.001) and high risk International Prognostic Score (IPS) (p = 0.023). Overall survival (OS) and progression-free survival (PFS) were associated with the presence of bulky disease (p = 0.009) and advanced disease at diagnosis (p = 0.016). EBV-positive cases did not present a significantly lower OS and PFS in comparison with EBV-negative cases, for all ages and when stratifying for age. When adjusted for covariates, absence of bulky disease at diagnosis (HR: 0.102, 95% CI: 0.02–0.48, p = 0.004) and limited disease stages (I–II) (HR: 0.074, 95% CI: 0.01–0.47, p = 0.006) were associated with a significant better OS. For PFS, limited-disease stages also retained prognostic impact in the multivariate Cox regression (HR: 0.145, 95% CI: 0.04–0.57, p = 0.006). These results are of importance as the early identification of prognostic biomarkers in cHL is critical for guiding and personalizing therapeutic decisions. The prognostic role of EBV in cHL could be modulated by the type of CT protocol employed and interact with the rest of presenting features.
Highlights
Classical Hodgkin lymphoma is a B-cell neoplasm characterized by scarce neoplastic Hodgkin’s Reed–Sternberg (HRS) cells surrounded by a heterogeneous tumoral microenvironment composed of B and T lymphocytes, eosinophils, macrophages, plasmatic cells, neutrophils and histiocytes [1]
Because Epstein–Barr virus (EBV) is clonal in HRS cells, this implicates its direct role in the oncogenic process [4]
Positivity for LMP1 was widespread (>50%) among HRS cells in the Classical Hodgkin lymphoma (cHL) samples defined as EBV-positive
Summary
Classical Hodgkin lymphoma (cHL) is a B-cell neoplasm characterized by scarce neoplastic Hodgkin’s Reed–Sternberg (HRS) cells surrounded by a heterogeneous tumoral microenvironment composed of B and T lymphocytes, eosinophils, macrophages, plasmatic cells, neutrophils and histiocytes [1]. The integration of the genome of the Epstein–Barr virus (EBV) in HRS cells has been demonstrated in a variable proportion of cases, ranging from 20% in industrialized countries to 90% in less developed countries [2]. Some studies have identified a shorter survival in EBV-positive cases, especially in older adults [6], but a protective influence [7–9] and a lack of survival impact [10,11] were reported. The heterogeneity of these results could be attributed to differences in sample sizes, follow-up times, methods to identify the presence of EBV, statistical analysis and clinical endpoints defined to evaluate prognostic relevance
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