gms | German Medical Science

Introduction: In many cancers that occur in both children and adults there is clinical discussion where to set the border between paediatric and adult trials and treatment strategy. For example, diffuse large B-cell lymphoma (DLBCL) constitutes about 30% of adult lymphomas and 10% of lymphomas diagnosed before the age of 18 years. The clinical outcome of DLBCL is in children much better than in adults. Several lines of evidence suggest that biological features might contribute to this age associated difference in prognosis.

Methods: A cohort of 364 mature aggressive B-cell lymphomas of the Deutsche Krebshilfe Network “Molecular Mechanisms in Malignant Lymphoma” representing predominately DLBCL were characterized by morphologic panel review, immunohistochemistry, interphase fluorescence in situ hybridization (FISH), array-CGH, gene expression profiling (GEP) and EZH2 Tyr 641 mutation analysis. Naïve analysis may be misled by the distorting effect of the distribution of age at diagnosis. We used logistic regression to model the conditional probability of displaying a molecular feature given age at diagnosis and propose an appropriate visualisation.

Results: LRA revealed a statistically significant association of ABC subtype by GEP, BCL2 protein expression, absence of IRF4 translocations, gains in 1q21, 18q21, 7p22 and 7q21 as well as changes in 3q27, including gains and translocations affecting the BCL6 locus, with increasing age. The LRA analyses reveal a significant continuous increase of the probability of several molecular features of DLBCL with patient age rather than a strict border between age groups. Remarkably, the genetic features increasing in likelihood with age in the LRA included changes associated with both, ABC (changes 3q27/BCL6, +18q21) and GCB-type DLBCL (+1q21, +7p22, +7q21), indicating an increase in genetic complexity with age somewhat independent of the molecular lymphoma subtype. Poisson regression showed the number of chromosomal aberrations to significantly increase with age. Moreover genomic complexity, a variable proposed in many studies to be associated with unfavourable outcome, loses prognostic power if age is taken into account.

Discussion: The analysis of the present cohort, which represents the largest study of DLBCL analyzed by comprehensive molecular profiling so far, challenges current pathogenetic and clinical concepts in DLBCL: On the one hand, the biologic rationale for the use and level of age borders for the stratification into clinical trials as well as the application of some age-associated biomarkers is questioned. On the other hand, our data indicate a continuous increase in genomic complexity with age suggesting an “age evolution model” of DLBCL lymphomagenesis.