Proposed model for follicular lymphogenesis and diffuse large B cell lymphoma (DLBCL) transformation.

The t(14;18) is a rare event occurring in naïve B cells and likely at a time when the RAG complex is active (primary VDJ recombination). These cells are relatively immortalized resulting from overexpression of the Bcl-2 protein and likely seed lymph nodes and reside within follicles. Without significant clonal evolution and independence, these follicular lympoma (FL) cells may require a microenvironment complete with follicular dendritic cells and reactive T cells. Repeated cycles of proliferation occur (despite the expression of Bcl-2), but at a low rate as is characteristic of follicular lymphoma (FL). With cell divisions the clone expands and secondary cytogenetic alterations occur. If critical cytogenetic events occur early in the evolution of this process, the cells may lose the need for a germinal center (GC) microenvironment and patients may present as de novo DLBCL. Alternatively, patients present with FL characterized by a diverse spectrum of cytogenetic alterations, the majority of which are copy number alterations (chromosomal gains and losses). The presence of FDCs and T cells within the follicle recapitulates the normal secondary follicle, but their presence in FL may be as immune response cells or alternatively, reflect the clonal evolution of the malignant B cells.

Abbreviations: FDC, follicular dendritic cell; GC, germinal center; MZ, mantle zone