Morphological and Immunophenotypic Features of Chronic Lymphocytic Leukemia

Abstract

In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.

Divergence in CD19-Mediated Signaling Unfolds Intraclonal Diversity in Chronic Lymphocytic Leukemia, Which Correlates with Disease Progression

“…Owing to the prime importance of the BCR in the physiology of malignant B cells, the expression of some of its components and associated molecules serves as prognostic factors (e.g., ZAP70) (8) or as therapeutic targets (e.g., CD20, Syk, Btk) in CLL and other lymphoproliferative disorders (LPD) (9,10). Growing evidence supports the concept that intraclonal CLL cell diversity plays a role in the disease biology and eventual clinical outcome (11)(12)(13). Intraclonal heterogeneity is acquired through spontaneous genetic alterations or driven by microenvironmental stimuli (14,15).…”

The clinical significance of large cells in bone marrow in patients with chronic lymphocytic leukemia

“…Bone marrow aspirates often reveal the presence of small, CLL-like cells and variable proportions of large cells (greatest dimension Ͼ 2 times that of red blood cells) and cells in between. 1 The immunophenotype of these large cells is no different from that of small, typical CLL cells. RS indicates progression of disease; some patients may have similar progression without transformation to overt RS, but abnormal cell morphology and increases in the number of prolymphocytes and large cells are noted frequently.…”

“…1 Multiple prognostic factors have been considered in helping provide clinical guidelines for the management and treatment of CLL. These include clinical stage, lymphocyte doubling time, bone marrow histology, cell morphology, molecular genetics, mutation status of the immunoglobulin (Ig) gene, and serum levels of lactate dehydrogenase (LDH), ␤ 2 -microglobulin (␤ 2 -M), CD38, and cytokines.…”

“…These include clinical stage, lymphocyte doubling time, bone marrow histology, cell morphology, molecular genetics, mutation status of the immunoglobulin (Ig) gene, and serum levels of lactate dehydrogenase (LDH), ␤ 2 -microglobulin (␤ 2 -M), CD38, and cytokines. [1][2][3][4][5][6][7][8][9][10][11][12] However, to our knowledge, no known factors predict the development of Richter syndrome (RS) in these patients. Atypical lymphocyte morphology is noted frequently in the peripheral blood and bone marrow when a patient's cells transform from CLL to RS, even when the bone marrow is not diagnostic for RS.…”

Report on the second Latin American consensus conference for flow cytometric immunophenotyping of hematological malignancies

“…The feasibility to ship DNA samples to distant places, without significant deterioration of its analytical quality, makes molecular analysis of gene rearrangements the more suitable approach. The consensual decision algorithm is shown in Table 4 (9)(10)(11)(12)(13)(14).…”