Follicular lymphoma: A model of lymphoid tumor progression in man

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Abstract
Human follicular lymphoma can be viewed as a malignancy in evolution. Since this disease is composed of a clonal population of B lymphocytes all expressing a given immunoglobulin light chain and heavy chain, it seems possible that the initial transforming event, the t(14; 18) chromosomal translocation, occurs in a cell already committed to the expression of a particular VH and VL gene. A panel of antibodies has been assembled which define a set of idiotypes expressed repeatedly by B-cell lymphomas. Nonetheless, VH gene usage in follicular lymphoma tumors appears to reflect the normal B-cell repertoire. Growth of follicular lymphoma appears to be partially under normal regulatory control. The expanding malignant B-cell clone grows in follicles with particular apposition to follicular dendritic cells and heavy infiltration with CD4+ T cells. Interaction with T cells can induce the proliferation of follicular lymphoma cells. This tumor eventually evolves into a diffuse large-cell lymphoma which is highly aggressive and lethal. It is now clear that the malignant progression occurs from a single cell within the expanding follicular lymphoma clone. A panel of monoclonal antibodies to cell surface molecules has been generated that inhibit proliferation of diffuse lymphoma cell lines, and some of the target molecules have been partially characterized. Therapeutic application of anti-idiotype monoclonal antibodies has shown a high degree of tumor responsiveness, but ultimately escape of idiotype-negative variant cells occurs. These variants arise as a result of extensive somatic point mutation in the VH and VL genes of follicular lymphoma. Active immunization can result in an immune response by patients directed against the idiotype expressed on their own B-cell tumors. It is anticipated that such immune responses will be polyclonal and better able to deal with the problem of tumor heterogeneity.