Immunophenotyping Versus Morphology

There is a strong tendency to divide diseases into subtypes that share clinical, biological, and hopefully, prognostic features that can predict success if a uniform treatment approach is taken. In the acute leukemias, the first comprehensive classification scheme was based on the site of origin, that is, myeloblastic leukemia was considered to be that which arises from the bone marrow whereas the lymphoblastic leukemias were considered to originate in lymphoid tissue.7

Relatively precise criteria for the differentiation of acute lymphoid from acute myeloid leukemia (AML) were brought forward by a consortium of French, American, and British (FAB) investigators, who relied on morphological and cyto-chemical cell characteristics.8 That leukemias comprise a group of diseases much more diverse than represented in the FAB classification scheme is suggested by its insignificant influence on prognosis in both ALL and AML, with the exception of FAB-M3. The clinical importance of the APL subtype FAB-M3 and its hypogranular variant M3v as a morphologic diagnosis is related to two facts: 1. that this diagnosis requires immediate intervention owing to the existing coagulopathy; and 2. that there exists a phenotype-specific therapy, namely, all-trans retinoic acid (ATRA). However, even in the case of FAB-M3, immunophenotypic, cytogenetic, and molecular tests are essential to recognize APL-like phenotypes that lack sensitivity to ATRA.9 The subclasses FAB-M6 and M7, the acute erythroid and megakaryocytic leukemias, respectively, usually cannot be identified with certainty without immunologic cell marker studies. The FAB-M0 subtype, the AML type that remains unclassified by standard cytological examination,10 represents a phenotypically and genotypically very heterogeneous group, which awaits further subclassification based on immunopheno-typic and/or genetic findings.

Irrespective of FAB subtype, multilineage dysmyelopoiesis presents a highly unfavorable parameter in AML,11 enough to warrant its own subclass (AML with multilineage dysplasia).6 The morphologic subclassification of ALL into L1, L2, and L3 was recently found to be no longer relevant.6

Diagnoses based on morphology cannot be easily interchanged with immunophenotypic findings, since with the exception of FAB-M3, morphologic subclasses do not relate to specific immunophenotypes. Neither morphology nor cytochemistry can predict the expression of antigens different from those expected to be present on cells of a particular cell lineage, that is, the expression of myeloid antigens by leukemic cells with characteristics of a lymphoid FAB subtype and vice versa. There are rare examples of antigens correlating with particular morphologic features. For instance, in APL, CD34 and CD2 expression is uncommon but when present corresponds to M3v morphology.12-14 Low expression of CD65s (defined as 20 percent or less of positive blast cells) in otherwise unequivocal AML shows significant association with immature morphologic FAB classes M0 and M1.15


Specific associations between particular antigen expression patterns and cytogenetic—molecular abnormalities have been established. In increasing instances immunophenotypic findings can be used as surrogate markers for genetic aberrations.2,3 This is important given the prognostic significance of many of the known cytogenetic abnormalities and their molecular equivalents. In cases in which cytogenetic analysis cannot be performed, is unsuccessful (for example, when a bone marrow aspirate could not be obtained), or yields a normal result, particular immunophenotypic findings may predict the presence of certain genetic abnormalities. This may prompt targeted molecular testing or may even be used as diagnostic evidence if molecular testing is unavailable.

For example, in a patient with differentiated AML, immuno-logic analysis may demonstrate combined expression of CD19 (a B cell-associated antigen) and CD56 (an NK cell marker) on otherwise typical myeloblasts. This antigen pattern is unequivocally associated with the chromosomal (8;21) translocation.16 In particular, the combination CD19-CD34 accurately predicts t(8;21) AML.17 Furthermore, blasts containing t(8;21) show low expression of the integrin CD11a,2 a finding otherwise reserved for APL cells among the myeloid leukemias.18 Another example is the expression of the interleukin-2 receptor a chain, CD25, by leukemic lymphoblasts containing the Philadelphia chromosome and its molecular equivalent, the BCR/ABL fusion transcript.19 It is not uncommon in ALL to find BCR/ABL tran scripts in patients with an apparently normal karyotype. In view of the strong negative prognostic impact of BCR/ABL transcripts in ALL, including the CD25 antibody in the biologic characterization of ALL can yield a quick and cost-effective indicator of this clinically important genetic abnormality. Borowitz et al.20 and De Zen et al21 have suggested that the surface antigen phenotype, in particular the low expression of CD20, in childhood B-precursor ALL can predict the TEL/AML1 rearrangement. The cryptic (12;21)(p13;q22) translocation that results in the TEL-AML1 fusion gene is found in approximately 25 percent of childhood ALL and carries a favorable prognosis. Incidence, outcome, and immuno-phenotypic data in adult ALL are too limited to permit similar conclusions.

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