B-cell lymphomas arise from B lymphocytes. B-cell development can be conveniently divided into 2 phases:(1) an antigen-independent phase and (2) an antigen-dependent phase. The antigen-independent phase takes place almost exclusively in the bone marrow. During this time, B-cell precursors undergo a rearrangement of the V, D, and J gene segments and, under the influence of a myriad of enzymes, including terminal deoxynucleotidyl transferase (TdT) as well as exonucleases, the initial antibody repertoire is developed. Most acute B-cell leukemias involve cells in this phase of development. Obviously, tumors can be staged by the various cell surface phenotypes of the developing B cell. In addition, the B-cell receptor chains (heavy and light) can be assessed. In the most immature cells, no rearrangements have taken place, whereas in the later phase of this antigen-independent stage of development (before exit from the marrow), there has been complete VDJ rearrangement. Because the cells have not been exposed to antigen or to T cells in germinal centers, when the heavy and light chain genes are sequenced they display no somatic mutation (see Fig 1). Naive B cells leave the bone marrow and enter the peripheral blood as IgM+/IgD+ cells. Phenotypic analysis of mature human B cells has lagged considerably behind T cells. CD4 and CD8 ratios were in widespread use in a variety of clinical settings more than 2 decades ago. The mature human B lymphocyte has been particularly resistant to analysis, although its characterization with monoclonal antibodies to CD5, CD19, CD23, CD38, and CD77 is more and more common. Additionally, the characterization of Ig receptor isotype (IgM, G, D, A, and E) is in widespread clinical use. Nonetheless, there are few clinically relevant issues that require such characterizations. Recent progress has been made in understanding the normal germinal center reaction, and from those studies, certain phenotypes of mature B cells seemed likely to be of clinical relevance. It is in the germinal center that the second or antigen-dependent stage of B-cell development takes place. Years ago now, we proposed (in collaboration with Virginia Pascual, Jacques Banchereau, and Yong Jun Liu) that IgD and

CD38, in conjunction with CD23, CD77, and IgM, could be used to classify human mature B lymphocytes into 7 subsets. 1-3 The most important conclusion of that work was that most IgD+ CD38J normal tonsillar B cells were naive or virgin B cells. When we studied the VH gene sequences in these cells, they were unmutated. These and other studies demonstrated that these cells were located in the follicular mantle. On the other hand, the IgDJ, CD38+ subset was extensively mutated (see Fig 2). Other studies showed that these cells were germinal center B cells (centroblasts and centrocytes). Finally, double negatives (IgDJ, CD38J) represented the memory subpopulation. It was only logical that malignant counterparts for these normal cells existed.