Atypical CLL

1.3.1. Immunophenotype

Atypical CLL (aCLL) is an ill-defined term applied to cases that mimic CLL but do not have the classical morphological or immunophenotypic features. Uniformly accepted criteria for aCLL do not exist. Historically the term aCLL has been used primarily for lymphocytosis with morphologically atypical cells (lymphoplasmacytoid features, irregular/clefted nuclei) (13). Numerous studies have attempted to correlate the morphological definition of aCLL with immunophenotype (7,14,15), but these studies have failed to identify an immunophenotypic pattern that is pathognomonic for aCLL. Some authors have defined aCLL by the presence of any deviation from the typical phenotype or morphology of CLL in a setting that is otherwise consistent with CLL (16). Others include CD5 negativity in the definition in a morphological and phenotypic picture that is otherwise characteristic of CLL (17), whereas other authors prefer to separate CD5-lymphoproliferative disorders from aCLL, using the term CD5- CLL (18). Some have argued that the entity of aCLL by definition should be CD5+, CD19+, CD23+, monotypic sIg+ and make the distinction solely based on the morphological criteria outlined by the French-American-British (FAB) Group (19). No clear link with CD38 expression has been demonstrated (19).

More recent reports have stressed the importance of specifically evaluating the density of various surface antigens by quantitative flow cytometry, vs. just the percentage of positive cells, in distinguishing between classical (cCLL) and aCLL (4). Accordingly, an increased intensity, or increased numbers of molecules, of CD20 and CD22 compared with cCLL, as well as increased percentages of CD79b and FMC7, with compared with cCLL cells, are used to define aCLL immunophenotypically. D'Arena et al. (20) found no differences in CD23, CD79b, CD11c, and CD5 in terms of number of molecules/per cell between cCLL and aCLL. It is obvious that further studies are necessary to establish a clear definition of aCLL and to determine whether it is a unique clinical and/or pathological entity.

1.3.2. Molecular Genetics/Cytogenetics

The distinction between cCLL and aCLL can be aided by molecular/cytogenetic evaluation. aCLL, largely classified on the basis of morphological definition, is associated with an increased incidence of trisomy 12 and poorer survival than typical CLL (21,22). As such, the presence of trisomy 12 is a useful adjunct in separating aCLL from cCLL. Molecular and cytogenetic data are also important in the differential diagnosis between aCLL and MCL (23,24).

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