Chronic B-cell lymphoproliferative disorders: How many diseases?

Chronic B-cell lymphoproliferative disorders (CLPD) are characterized by lymphocytosis due to circulating monoclonal B cells in patients without overt evidence of lymphoma. CLPD is often detected incidentally on the investigation of asymptomatic sustained lymphocytosis. Routine immunophenotype analysis by flow cytometry and interphase fluorescence in situ hybridization (FISH) analysis are usually but not invariably diagnostic. The majority of patients with CLPD have chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) and most non-CLL CLPD is due to the leukemic phase of lymphomas (including hairy cell leukemia) or prolymphocytic leukemia. However, in a small number of patients, no definitive diagnosis can be made (‘‘unclassified’’ CLPD). Although the application of modern analytical methods has clearly resulted in considerable progress in the classification and diagnosis of CLPD, a better definition of disease entities is still required to improve diagnostic accuracy and clinical care. The diagnosis of CLPD requires the identification of a light chain-restricted B-cell population, usually by flow cytometry using antibodies specific for light chain (k or l) and B-cell markers such as CD19. Further characterization of the monoclonal B cell provides additional diagnostic information. The CLL immunophenotype is defined by the World Health Organization using modified Royal Marsden Hospital (RMH) criteria [1] as co-expression of CD5 and CD23 in monoclonal B cells with dim expression of surface immunoglobulin (sIg) and CD79b (or CD22), and the absence of expression of FMC7 [2]. In patients with lymphocytosis and the characteristic immunophenotype of CLL, mantle cell lymphoma (MCL) should still be excluded by testing for the IgH/CCND1 translocation by interphase FISH or the expression of cyclin D1 [3]. CLPD due to the leukemic phase of MCL can usually be recognized by the characteristic immunophenotype (CD5þ/CD237/CD20 bright/sIg bright), although variations in this pattern have been well described [3]. The major diagnostic difficulties in CLPD occur in patients with CLPD who do not have CLL or MCL and are addressed in the article by Ugo et al. in this issue [4]. Ugo et al. reported a multicenter prospective study of 148 newly diagnosed patients with CLPD who did not fulfill the RMH criteria for the diagnosis of CLL. They showed that a sizable number of the patients with CD5þ CLPD had leukemic phase MCL. Among the non-MCL CD5þ CLPD patients, CD20 expression distinguished a group with CLPD similar to CLL (CD20 dim) from those who did not appear to have CLL (CD20 bright). Among the CD57 CLDP, the majority had leukemic phase mantle zone lymphoma. These results suggest that patients with CLPD could be divided into CLL (RMH 4 – 5 and CD5þ/CD20 dim), leukemic phase of well-defined lymphomas, and at least two additional groups that do not fit into the current classification system. The diagnosis of CLL can usually be made by clinical evaluation, lymphocyte morphology, flow cytometry, and molecular studies to distinguish CLL from MCL. The study by Ugo et al. reported a population of CD5þCD20 dim patients who did not meet the RMH criteria but were still considered by the authors to have CLL. The RMH criteria include both sIg and CD79b, which are known to be poorly expressed in most patients with CLL [5]. However, CD79b, also known as Igb, is a component of the B-cell receptor and expression levels correlate well with those of sIg. The inclusion of both sIg dim