Immunophenotypic Differential Diagnosis of CLL

1.2.1. Background

As mentioned above, immunophenotyping has emerged as an essential tool in the diagnosis of CLL (4-6). A classic phenotype of typical CLL has been defined (see Subheading 1.2.2.). When demonstrated, this characteristic phenotype does not present diagnostic difficulties. The caveat lies in the fact that, absent this characteristic pattern, the overlap with other lymphoid proliferations may be quite substantial. Diagnostic dilemmas most often arise when the diagnostician is faced with a case of presumed CLL that does not fully demonstrate the requisite characteristic pattern, or in the setting of nontypical CLL lymphoid proliferations that express CD5. Although only two entities are defined by CD5 positivity (CLL and MCL), a number of mature B-cell neoplasms that may also demonstrate CD5 positivity. It should be noted, however, that a differential diagnosis of CLL based exclusively on immunophenotype is substantially broader than that of one that incorporates other parameters including clinical presentation, microscopy, cytogenetics, and molecular genetics. For example, entities that warrant consideration based solely on immunophenotypic profile can easily be eliminated with even cursory morphologic examination of the cells in question.

1.2.2. Immunophenotype of Classical Chronic Lymphocytic Leukemia

CLL, when it does demonstrate the classic pattern, is quite distinctive (2,7). Useful markers in the evaluation for CLL include CD5, CD10, CD11c, CD19, CD20, CD22, CD23, CD79b, FMC7, and surface immunoglobulin (sIg) expression. Diagnosis can be rendered based on the presence or absence of the expression of these markers in combination with the intensity of their expression. CLL demonstrates bright CD45 intensity, as do the most mature B-lymphocytic neoplasms. However, downregulation of CD45 with a spectrum of positivity, although still bright, is not an uncommon finding in CLL. CD19 expression is greater than CD20 expression in typical CLL. CD19 is bright and CD20 is classically dim or downregulated compared with CD19 and also compared with normal B-cells in the sample that may serve as internal controls. CD20 also shows more variability, i.e., broader distribution, compared with CD19 and normal internal B-cell controls. Typically CLL demonstrates dim sIg expression. CD23 is expressed in classical CLL and is perhaps the most useful single marker in distinguishing CLL from MCL (4). CLL is usually negative for CD79b (8,9) or, when present, expression is dim (10). FMC7 is also usually negative in CLL or dimly expressed (11,12). Lack of expression of these two latter markers is also very helpful in distinguishing CLL from MCL. Three markers are of paramount importance in making the diagnosis of typical CLL-CD5, CD10, and CD23. The sensitivity and specificity of a CD5+, CD10-, CD23+ chronic B-cell lymphoproliferative process for the diagnosis of CLL is extremely high. The combination of bright CD19, dim CD20, CD5, and CD23, and dim immunoglobulin expression in a monomorphopus small lymphocyte population is virtually pathognomonic for CLL.

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