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Apoptosis in EBV-associated childhood classical Hodgkin lymphoma.

In this issue Dinand et al (1) report the relationship of EBV and pro- and anti-apoptotic proteins, with clinical and histological factors, and patients' survival in a cohort of Indian childhood Hodgkin lymphoma (HL). Though there are several reports describing different markers which seem to be a prognostic factor for HL, as it is a malignancy characterized by clinical, histopathologic and epidemiologic heterogeneity, none described a universal marker, applicable to adult and paediatric populations of different socio-economic status and geographic regions, associated with better overall survival (OS) or failure free survival (FFS).

Harris et al (2) have described three different epidemiologic patterns according to the level of socioeconomic development. Here Dinand et al (1) report a histological distribution with mixed cellularity predominance and an early childhood peak (<10 yr) coincident with distribution found by our group (3,4) as well as by others in undeveloped countries and low socioeconomic groups (5). In paediatric HL, a male prevalence has been reported in different geographic regions, ranging from a slight male predominance in developed countries to 2-3:1 ratio in underdeveloped countries (5). However, in this report the authors describe an extremely low HL incidence among Indian girls (1), which is attributed to poor access to health care for females (6).

In a previous study (7) the authors have found the absence of CD15 as a bad predictor for poor overall survival (OS), unlike others who have failed to establish such prognostic value. It seems that CD15 expression is variable in the different series, which may perhaps be due to biological heterogeneity, making CD15 unsuitable as a universal marker.

Epstein-Barr virus (EBV) is associated with HL in a proportion of cases, where the virus is present in the tumour cell populations. The EBV-negative and EBV-positive forms of the disease are morphologically similar but appear to differ in terms of their precise underlying molecular changes and microenvironment. There are epidemiologic differences betweenEBV-positive and -negative HL that raise questions about the aetiologic contributions to EBV-defined HL of socio-economic and cultural exposures and of genetic predisposition. Even though the authors have not applied the gold standard EBERs in situ hybridization, they found by means of LMP1 labelling 91.6 per cent of EBV positivity on HL (1). This proportion is consistent with prior observations of EBV association in undeveloped countries where most of the EBV-positive cases were besides classified as mixed cellularity (8). However, in our paediatric based studies from Argentina and brazil, we found around 50 per cent EBV positivity resembling developed economies together with higher positivity in mixed cellularity subtype resembling developing ones (4). This discrepancy may reflect that our series may match an intermediate pattern corresponding to developing or transitional economies. Nevertheless, concerning the evaluation of EBV as a prognostic factor, in both situations EBV did not seem to worsen the overall survival or the failure free survival. This implies that EBV could not be used as a prognostic factor in paediatric population, as it was described for older adult HL (9).

Finally, the authors assess certain apoptosis-related proteins, since it has been described that germinal center B cells with unfavourable or crippling mutations are normally quickly eliminated by apoptosis. However, those cells that have an imbalance in pro-and anti-apoptotic proteins ratio could represent a transforming event rescuing pre-apoptotic GC B cells from apoptotic stimuli and finally could give rise to Hodgkin and Reed-Sternberg cells. They described bcl-2 and bak cytoplasmic expression in 83.3 and 92 per cent of the cases together with p53 nuclear expression 89.9 per cent of the cases. As they mentioned, the ratio of bcl-2 family members (bcl-2/bak) rather than any one protein may better determine a cellular response to apoptotic stimuli, but they failed to find a significant relation between this ratio and any survival difference between the categories when OS and FFS were assessed (1). P53 inactivation is an important cofactor in neoplastic transformation. The authors reported p53 expression was associated with poorer OS in univariate analysis but was not independent prognostic factor in multivariate analysis (1). According to other studies, our group has found in series of 54 paediatric HL a high proportion (81%) of p53 expression, and a much lower (44%) bcl-2 expression (10). Dinand et al (1) assessed bcl-2, bak and p53 on the context of OS and FFS, but they did not provide evidence of these being useful as predictive biomarkers of disease progression or therapeutic response. Our group also failed to find bcl-2 and p53 as predictor of event free survival in paediatric HL10. Therefore, loss of normal function of any of these oncogenes could be the first step leading to neoplastic transformation and proved to be involved in paediatric HL.

Finally, when the authors assessed the relationship between EBV expression and apoptotic proteins, they found that in Indian children with HL EBV was significantly associated with lower expression levels of the anti-apoptotic protein bak (1). Complete understanding of the pathogenesis of HL and EBV involvement in developing economies, particularly in paediatric population representing the first peak of the age distribution curve which is delayed to young adults in developed economies, points out the importance of creating a network that allows centers from developing countries devoted to study paediatric HL to co-operate with each other.

Maria Victoria Preciado * & Paola Chabay

Members, CONICET, Research Career Programme

Molecular Biology Laboratory

Pathology Division

Ricardo Gutierrez Children Hospital

Ciudad de Buenos Aires, Argentina

* For correspondence:


(1.) Dinand V, Malik A, Mohanty B, Chander B, Arya LS, Dawar R. Low apoptotic index & bak expression in EBV-associated childhood classical Hodgkin lymphoma. Indian J Med Res 2009; 130 : 526-32.

(2.) Harris N. The many faces of Hodgkin's disease around the world: what have we learned from its pathology? Ann Oncol 1998; 9 : S45-S56.

(3.) Preciado MV, De Matteo E, Diez B, Menarguez J, Grinstein S. Presence of Epstein Barr virus and strain type assignment in Argentine childhood Hodgkin's disease. Blood 1995; 86 : 3922-9.

(4.) Chabay P, Barros M, Hassan R, De Matteo E, Zalcberg I, Rey G, et al. Pediatric Hodgkin lymphoma in two South American series: a distinctive epidemiological pattern and lack of association of Epstein-Barr virus with clinical outcome. JPediatr Hematol Oncol 2008; 30 : 285-91.

(5.) Glaser S, Gulley M, Clarke C, Keegan T, Chang E, Shema S, et al. Racial/ethnic variation in EBV-positive classical Hodgkin lymphoma in California populations. Int J Cancer 2008; 123 : 1499-507.

(6.) Dinand V, Arya LS. Epidemiology of childhood Hodgkins disease: is it different in developing countries? Indian Pediatr 2006; 43 : 141-7.

(7.) Barros MH, Zalcberg IR, Hassan R. Prognostic impact of CD15 expression and proliferative index in the outcome of children with classical Hodgkin lymphoma. Pediatr Blood Cancer 2008; 50 : 428-9.

(8.) Kapatai G, Murray P. Contribution of the Epstein Barr virus to the molecular pathogenesis of Hodgkin lymphoma. J Clin Pathol 2007; 60 : 1342-9.

(9.) Keegan TH, Glaser SL, Clarke CA, Gulley ML, Craig FE, Digiuseppe JA, et al. Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a population-based study. J Clin Oncol 2005; 23 : 7604-13.

(10.) Chabay P, Pesce P, De Matteo E, Lombardi MG, Rey G, Preciado MV. No influence of bcl-2, p53 and p21waf1 protein expression on the outcome of pediatric Hodgkin's lymphomas. J Pediatr Hematol Oncol 2006; 28 : 552-8.
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Title Annotation:Commentary; Epstein-Barr virus
Author:Preciado, Maria Victoria; Chabay, Paola
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Nov 1, 2009
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