Nature and importance of follicular lymphoma precursors.

It is now widely recognized that cancer development is a protracted process requiring the stepwise acquisition of multiple oncogenic events. In humans, this process can take decades, if not a lifetime, blurring the notion of 'healthy' individuals. Follicular lymphoma exemplifies this multistep pathway of oncogenesis. In recent years, variants of follicular lymphoma have been recognized that appear to represent clonal B-cell expansions at an early stage of follicular lymphoma lymphomagenesis. These include follicular lymphoma in situ, duodenal follicular lymphoma, partial involvement by follicular lymphoma, and in the blood circulating follicular lymphoma-like B cells. Recent genetic studies have identified similarities and differences between the early lesions and overt follicular lymphoma, providing important information for understanding their biological evolution. The data indicate that there is already genomic instability at these early stages, even in instances with a low risk for clinical progression. The overexpression of BCL2 in t(14;18)-positive B cells puts them at risk for subsequent genetic aberrations when they re-enter the germinal center and are exposed to the influences of activation-induced cytidine deaminase and somatic hypermutations. The emerging data provide a rationale for clinical management and, in the future, may identify genetic risk factors that warrant early therapeutic intervention.