Model for Identifying the Etiology of Acute Lymphoblastic Leukemia in Children

Abstract

The incidence of ALL varies throughout the world; however, there is a greater frequency of the disease in those countries with a higher socio-economic level [1], with the exception that a higher frequency of ALL has been reported for some Hispanic cities [2]—cities that gener‐ ally are considered to have a lower standard of living. The highest incidence of ALL has been reported for Costa Rica and for Mexico City [3]. It is accepted that ALL is the result of the interaction, which occurs at a specific moment of life, between environmental factors and susceptibility to the disease [4]. The theories con‐ cerning the origin of this illness have been focussed fundamentally on the B-cell precursors of ALL [1]. The most important of these theories was proposed by Greaves and Kinlen; sev‐ eral more recent variations, such as the adrenal theory and infective lymphoid recovery hy‐ pothesis have attempted to include these theories [5-8]. The theory of Greaves and that of Kinlen have been discussed in one of the chapters in this book. One of the limitations of the theory of Greaves is that it has not been possible to dem‐ onstrate it empirically. In his theory, Greaves argues that some cases of the pre-B ALL ob‐ served in the peak age of 2 to 5 years could be associated with an aberrant immune response displayed by an immature immune system. The early exposition to common infectious agents are required for the proper maturation of the immune system, lack of these exposi‐ tions results in aberrant responses when children are finally in contact with the agent When follow-up studies were carried out in order to evaluate whether children who suffered infec‐ tions during the first months of life had a greater risk of leukemia, it was not possible to demonstrate any such correlation. When kindergarten registries were used as information source, it was also not possible to demonstrate that there was an association with B-cell pre‐ cursors of ALL, or in a specific manner in which ALL appears between two and five years of age [9,10]. In addition, data are emerging from epidemiological databases that the idea of early infection being a protective factor for ALL originated due to a bias (non-differential misclassification) [11] and that, in reality, no such association exists. At any rate, determina‐ tion of whether a child suffered from different infections during the first year of life is ex‐ tremely difficult; for this reason, the empirical reference will need to be improved in order to lend greater support to this hypothesis. Nevertheless, the principal importance of the hypothesis of Greaves cannot be questioned, because it does not exclude what epidemiological methods have been able to demonstrate concerning late infection [12]. These data are conclusive in showing that, in the majority of cases, ALL originates during intrauterine life [13] and that proliferation of the B cells, in fact, the time in which the highest peak of proliferation occurs, is during the first year of life [12]. All these findings permit the deduction that ALL requires a first "hit" in the intrauterine stage and another hit during a later stage of life and that some infections may play a very important role in the causality of B-cell precursors of ALL.