Assessment of the prognostic impact of the Epstein–Barr virus-encoded latent membrane protein-1 expression in Hodgkin’s disease

Abstract

SummaryWe have examined expression of the Epstein-Barr virus (EBV) latent membrane protein-1 (LMP1) in the malignant Hodgkin and Reed-Sternberg (HRS) cells of Hodgkin's disease (HD) and its impact on response to treatment and on survival. Paraffin tissue from 100 adult immunocompetent patients with HD were analysed using immunohistochemistry to identify LMP1 expression. According to the Rye classification, 8% of patients had lymphocyte predominance (LP) subtype, 48% had nodular sclerosis (NS) disease, 37% were of the mixed cellularity (MC) subtype and 7% were of the lymphocyte depletion (LD) subtype. During the five year follow-up period 27 patients died and 74 patients achieved a complete remission. Patients with LD subtype were older (P = 0.03), less frequently achieved complete remission (P = 0.01), had shorter disease-free survival (P = 0.01) and overall survival (P = 0.002) compared with the other subtypes of HD. LMP1 expression was found in the tumour cells of 26% of cases of HD. LMP1 expression was less common in NS disease than in the other subtypes (P = 0.05), whereas an association between MC subtype and LMP1 expression was not found (P = 0.22). Using the log-rank test there were no differences in overall survival or disease-free survival based on EBV status either when all patients were analysed or when LD and LP subtypes were excluded. However, the presence of EBV was associated with significantly longer disease-free survival in the subgroup of patients ≤ 30 years old (P = 0.02) and in those patients ≤ 34 years old (P = 0.05). In contrast, there was a trend for shorter disease-free survival for EBV-positive patients in the subgroup > 35 years old, but this difference was not statistically significant (P = 0.11). A similar trend was observed in patients > 50 years old. Analysis of the impact of LMP1 expression in patients who had different stage and B symptoms status showed that expression of EBV was associated with longer disease-free survival (P = 0.019) in early stage (1 + 2) patients without B symptoms. Significant differences in the other subgroups based on EBV status was not found. Factors adversely affecting the likelihood to achieve a complete remission were: absence of LMP1 expression (OR 6.4, 95% Cl 1.07-38.5, P = 0.04), age (OR 1.68, 95%Cl 1.15-2.5, P = 0.007) and subtype of HD (OR 3.32, 95%Cl 1.11-9.94, P = 0.03). Age and subtype of HD had an independent impact on overall survival (P = 0.01). We conclude that expression of LMP1 in HRS cells has a favourable impact on prognosis for HD patients, but that this effect may be restricted to young adult patients and those with early stage disease.

Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study

“…Glavina-Durdov et al 16 reported findings similar to those reported here in a 2-center study. This group found that HL tumor-cell EBV status had no impact on OS or disease-free survival (DFS) when their population was analyzed as a whole.…”

“…[1][2][3] The impact of the tumor-cell EBV status on the prognosis of patients with HL remains controversial. Most previous studies have not reported a significant association between EBV status and outcome, [4][5][6][7][8][9][10][11] while others have found that EBV-associated cases have either a more or less favorable prognosis [12][13][14][15][16][17][18] (Table 1). Some of the interstudy variation may be attributable to the different epidemiologic features of the disease in different geographic settings and some may be related to case selection.…”

Constitutive activation of STAT3 and STAT5 is present in the majority of nasopharyngeal carcinoma and correlates with better prognosis

“…LMP-1 can also upregulate expression of epidermal growth factor receptor (EGFR) (Miller et al, 1995), which may then modulate expression of specific STATs upon ligand stimulation (Petersen and Haldosen, 1998;Kloth et al, 2002;Leong et al, 2002). Interestingly, in line with our findings, despite the fact that LMP-1 of EBV is known for its transforming ability and promotes cellular proliferation in various studies (Baichwal and Sugden, 1988;Kaye et al, 1993), tumours with LMP-1 expression tend to have better prognosis in EBV-associated malignancies such as Hodgkin's disease (Montalban et al, 2000;Glavina-Durdov et al, 2001) and NPC (Hu et al, 1995). Regarding the intimate association between STATs and NPC, further clarification of the relation between STAT signalling and the gene expression pattern of EBV may shed light on the pathogenesis of this unique malignancy and might have future therapeutic applications.…”

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

“…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.…”