Scenario for FL pathogenesis. During early B-cell development, in rare instances, pro-B cells acquire a t(14;18) IGH-BCL2 translocation as a mistake of IGH recombination. This leads to constitutive expression of BCL2. t(14:18)-bearing B cells can develop further into mature naive B cells and may enter a GC reaction upon antigenic stimulation. In the GC, BCL2 is normally downregulated to promote apoptosis proneness of GC B cells. However, t(14;18)-carrying GC B cells have a survival advantage, and may clonally expand and become memory B cells. t(14;18)-positive B cells in the peripheral blood are mainly found among IgM memory B cells. Such cells may undergo repeated GC reactions and thereby acquire further genetic lesions. In some reactive lymph nodes, GCs dominated by monoclonal BCL2⁺ GC B cells can be found. These are called FLIS and the B-cell clones can be considered as premalignant as they often carry besides the t(14;18) further genetic lesions. From such structures, FLs can develop after additional gene mutations occurred. Furthermore, mutations promoting N-glycosylation of amino acids in the variable regions of the BCR have been detected in FLIS,^28,61  so that chronic antigenic stimulation as an additional pathogenetic factor occurring through BCR stimulation by lectins on stromal cells can occur already in FLIS (and perhaps even earlier, as the mutations causing N-glycosylation may well occur in early GC passages, when SHM is highly active). Nearly half of FL cases express IgG, so that at some stage during FL pathogenesis, a considerable fraction of cases have undergone class-switch recombination (CSR).