Low apoptotic index & bak expression in EBV-associated childhood classical Hodgkin lymphoma

Association of Epstein-Barr virus (EBV) with Hodgkin lymphoma (HL) is particularly high in low-income countries, and resistance to apoptosis might play a role in pathogenesis and survival. Data from previous studies are not consistent, and none is available in children. Thus this study was undertaken on Indian children with classical Hodgkin lymphoma to assess the significance of bcl-2, bak and p53 expression, and apoptotic index in relation with EBV status and treatment outcome with chemotherapy alone.

Children (age<15 yr) with classical HL (n=143) were included in the study. Bcl-2, bak, p53, Ki67 and latent membrane protein-1 (LMP1) were detected by immunohistochemistry in pre-treatment lymph node biopsies. Apoptotic index was assessed by TdT-dUTP nick-end labelling (TUNEL).

Bcl-2, bak, p53 were expressed above positivity threshold in 83.3, 94.0 and 7.1 per cent of the cases respectively. More than 10 per cent of apoptotic tumour cells were seen in 60.4 per cent of the cases. 131 (91.6%) cases were EBV associated. EBV-positive cases had a significantly lower mean bak expression (p=0.001) and a lower apoptotic index, without higher proliferation index. Advanced stage showed a borderline association with bcl-2 expression in >25 per cent of tumour cells and p53 negative tumours. In univariate analysis, p53 positive cases, which were significantly associated with B symptoms, had a poorer overall survival (P=0.03) while low proliferation index was associated with poorer failure-free survival. Neither EBV status nor any of the apoptotic parameters studied showed independent association with survival.

EBV detection in children with classical Hodgkin lymphoma was associated with significant lower bak expression and with lower spontaneous apoptosis of H-RS cells suggesting that EBV-LMP1 might downregulate bak pro-apoptotic protein. this needs to be substantiated further.