Biphenotypic leukemia. The widespread application of flow cytometric immunophenotyping to leukemia has led to the recognition of many cases that do not fit uniformly into standard myeloid or lymphoid lineages. Initially, most of these were termed biphenotypic or mixed lineage leukemias. In some series, the incidence approached 50%. In a review of 746 cases of acute leukemia,47 7% fulfilled strict criteria for biphenotypic leukemia. In another study, cases of AML with isolated expression of TdT, B-cell, or T-cell antigens did not correlate with Ig or TCR gene rearrangements. In contrast, expression of two or more lymphoid antigens did correlate with Ig or TCR rearrangements.138 True bilineage phenotype is most consistently encountered in patients with t(9; 22) or rearrangements of the MLL gene at (11q23).28,138-140 An interesting group of patients mentioned above with t(8; 13) have lymphoblastic lymphoma and myeloid hyperplasia or AML. We strongly support the use of strict, uniform diagnostic criteria. Many cases of apparent biphenotypic acute leukemia represent aberrant patterns associated with specific genetic alterations, as described in this review. The most common problems leading to overdiagnosis of biphenotypic leukemia are failure to exclude nonleukemia cells from the analysis, overinterpretation of weak nonspecific binding, and failure to recognize the lack of lineage specificity of several antibodies. Recent advances in understanding the biologic function of the molecules carrying individual CD epitopes has elucidated their lack of lineage fidelity.141 For example, CD10 and CD13 are membrane-associated enzymes with common structural and regulatory features.141 The most important lineage-specific antigens are cytoplasmic CD22, CD3, and MPO for B, T, and myeloid lines, respectively.