Transfusion and NHL risk: a meta-answer?

The rapid increase followed by a leveling off in the incidence of non-Hodgkin lymphoma (NHL) in the United States and Europe in the last half of the 20th century4,5 has largely remained unexplained, a situation that has fascinated and frustrated a generation of lymphoma researchers. This state of affairs is likely due in part to a multifactorial etiology and the heterogeneous nature of this malignancy with its many subtypes. A flurry of epidemiologic work starting in the 1990s has provided many new leads, including the observation that blood transfusions might be associated with an increased risk of developing NHL.6,7 Several biologic mechanisms provided a plausible explanation for the association,8 although bias, confounding by indication or some other factor, and chance all remain viable alternative explanations. Although the number of transfusions and the amount of blood transfused increased dramatically after World War II until the early 1980s,9 concerns of transmitting infectious agents led to a decline in allogeneic transfusion, which has only recently rebounded.3 What is the current evidence for an association of transfusion history and NHL risk? In their article, Castillo and colleagues report the first meta-analysis of the observational data on this topic, using a comprehensive search strategy to identify relevant studies and a state-ofthe-art meta-analysis approach.10 Their main finding, based on 9 case-control and 5 cohort studies, was that blood transfusions were associated with a 20% increase in the risk of NHL. These results were similar for men and women and for transfusions given before or after 1992. The latter finding is of particular interest because there have been major changes in transfusion practice over the last 30 years that have dramatically decreased the risk of pathogen transmission.11 Thus, any mechanism explaining a transfusion and NHL association will need to account for the impact of extensive screening, changes in the use of blood components, the advent of leukodepletion, and other changes in transfusion practices over this timeframe, as well as the leveling off of NHL incidence (see figure). There were 2 important sources of heterogeneity specifically identified in the metaanalysis that warrant discussion. The first was by study design, such that cohort studies observed an association of transfusion and NHL risk (meta–relative risk [meta-RR] of 1.34) while case-control studies did not (meta-RR of 1.05). Castillo et al offered several potential explanations for this discrepancy, including small sample size, failure to take into account confounding variables, and recall bias in casecontrol studies. However, small sample size is not likely to explain the discrepancy (there were more total cases contributed from casecontrol compared with cohort studies in the meta-analysis), and there has been little evidence from individual studies for strong confounding factors beyond confounding by indication, which could not be directly addressed in the meta-analysis. Recall bias could play a role, although one would predict that this would inflate (not attenuate) any association based on the presumption that cases would be more likely to ruminate and better report on prior transfusions relative to controls. Other explanations include selection bias due to low Rate of NHL and transfusion since 1973. Blue line indicates the age-adjusted incidence of NHL in the United States, 1973-2007.2 Red line indicates the estimated rate of allogeneic transfusion in the United States, 1980-2006.3