In Pediatric Mature B-Cell Non Hodgkin Lymphoma (NHL), Complex Karyotype or del(13q) Are Linked Prognostic Factors in Burkitt Lymphoma (BL) While 8q24/c-myc Rearrangement Is Associated with a Strong Adverse Effect in Diffuse Large B-Cell Lymphoma (DLBCL).

Abstract

Introduction: BL is the main childhood B-cell NHL, characterized by the 8q24 translocation [t(8q24)] leading to a c-myc deregulation. Additional chromosomal alterations have been described in BL as well as in DLBCL, but their prognostic value is not clearly evaluated, especially in children. We have already shown the prognostic value of complex karyotype in childhood B-cell NHL in general (Lugano 2005). We now study the role of c-myc rearrangement and of other chromosomal alterations in each sub entity, BL and DLBCL.Methods: Karyotypes from 237 children enrolled in the FAB/LMB96 study were centrally reviewed by each participating cooperative group and obtained an international morphological consensus diagnosis: BL 76.8%, BL-like (BLL) 7.6%, DLBCL 12.2%, unclassifiable 3.4%.Prognosis analyses (event free survival -EFS- and overall survival -OS-) were performed after adjustment on the national cooperative group, the therapeutic stratification group (C vs A & B), the morphological consensus classification (DLBCL vs BL & BLL), the LDH level (>2 vs <=2) & the CNS involvement.Results: The BL/BLL were usually diploid with a t(8q24) in 92% cases and associated with other chromosomal aberrations in 69%, mainly +1q, del(13q), +7q. The DLBCL were more heterogeneous and more complex than BL/BLL. t(8q24) incidence (34%) was higher than in adult DLBCL and the pattern of chromosomal alterations varied according to the presence of t(8q24) [diploidy, +1q, del(6q), +7q] or not [hyperdiploidy, der(11q) and +12q].Multivariate analysis identified two different associations of independent cytogenetic factors with worse prognosis on both OS and EFS. Model (A) for EFS: complex karyotype (more than 3 chromosomal alterations) [HR=3, p=0.0008] and t(8q24) [HR=5.1, p=0.04] or model (B) for EFS: del(13q) [HR=2.6, p=0.0008], +7q [HR=2.6, p=0.01] and t(8q24) [HR=5.7, p=0.03]. (+1q had no significant effect). In the BL entity (N=182), only the complexity [HR=2.5, p=0.02] persists in the model A and del(13q) [HR=4.2, p=0.002] in the model B. In the group of 29 DLBCL, the only significant variable (univariate analysis) is the t(8q24): the 3-yr EFS in DLBCL without t(8q24) is 100% while 50% in DLBCL with t(8q24) [p=0.0005].Conclusion: In BL/BLL, the strong effect of complex karyotype is partly explained by the role of del(13q) and to a lesser extent by +7q. The strong prognosis effect of t(8q24) in B-cell mature childhood NHL is mainly due to its role in DLBCL. This study emphasizes the impact of cytogenetics in both diagnostic characterization and prognostic stratification of childhood mature B-cell NHL.