Prognostic Role of the Expression of Latent-Membrane Protein 1 of Epstein–Barr Virus in Classical Hodgkin Lymphoma

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.

The prognostic value of Epstein−Barr virus infection in Hodgkin lymphoma: A systematic review and meta-analysis

“…In the subgroup analysis by disease distribution on six continents, the African subgroup showed that EBV-positive patients had a borderline better OS (HR=0.408, 95% CI: 0.147-1.129; P =0.084). For age distribution, some articles ( 16 , 18 , 25 , 28 , 41 , 48 , 50 , 52 ) had sufficient age-stratified survival data, so we combined their HR by a random effects model (I 2 = 62.9%, P=0.003), which was 1.080 (95% CI: 0.657-1.776; P=0.762). In the subgroup of children and adolescents, the pooled HR showed that EBV positivity in HL was correlated with a favorable outcome for OS (HR=0.296, 95% CI: 0.085-1.034, P=0.056), while a significantly poorer OS was associated with EBV positivity in studies covering older adults (HR=1.905, 95% CI: 1.380–2.629; P<0.001).…”

“…Five studies ( 39 , 47 , 50 – 52 ) were included to analyze the impact of EBV infection on PFS. There was significant between-study heterogeneity (I 2 = 54.5%, P=0.066), and the pooled estimate by the random-effects model showed that no significant association was found between EBV positivity and PFS (HR=1.302, 95% CI: 0.881–1.926, P=0.186; Figure 4 ).…”

“…As with FFS, EFS and PFS were also unaffected by EBV infection status. The ending endpoint was PFS in a small number of articles ( 23 , 39 , 47 , 50 – 52 ), and we did not perform further subgroup analyses. A child-based study from India ( 48 ) showed that EBV-positive children have longer EFS than EBV-negative children, which contradicted our finding and may be explained by the high prevalence of EBV infection in Indian children and the greater chemotherapy and radiotherapy sensitivity of infected tumor cells ( 17 ).…”

Molecular Characterisation of Epstein–Barr Virus in Classical Hodgkin Lymphoma

“…The prognostic role of LMP1 expression in cHL was evaluated in several studies. The expression of LMP1 as a marker of EBV infection in HL is associated with the mixed-cellularity subtype of cHL and a high-risk international prognostic score [ 53 ]. According to Hu et al (2022), and their systematic review and meta-analysis of 42 qualified studies involving 9570 HL patients, there was an association between EBV positivity and significantly poorer overall survival, particularly in older patients [ 54 ].…”

Tumor Viruses and Their Associated Cancers: Remain on the Track with the Latest Advances

“…EBV, a gamma-herpesvirus (also known as human herpesvirus 4), is one of the bestexamined examples of a cancer-inducing virus [8]. In a study conducted on patients with classical Hodgkin lymphoma (cHL), the prognostic function of the expression of latent membrane protein 1 of EBV (EBV-LMP1) in cHL was notably unveiled by Santisteban-Espejo and colleagues [9]. The authors also indicated that the treatment protocol based on chemotherapy medications might affect the prognostic role of EBV in cHL.…”