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

Abstract

We 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.