Classification of Pediatric Myeloid Malignancies
Less than 5% of cases of acute leukemia in children are of ambiguous lineage, expressing features of both myeloid and lymphoid lineage.[18,19,20] These cases are distinct from ALL with myeloid coexpression in that the predominant lineage cannot be determined by immunophenotypic and histochemical studies. The definition of leukemia of ambiguous lineage varies among studies, although most investigators now use criteria established by the European Group for the Immunological Characterization of Leukemias (EGIL) or the more stringent WHO criteria.[21,22,23] In the WHO classification, the presence of MPO is required to establish myeloid lineage. This is not the case for the EGIL classification. Leukemias of mixed phenotype comprise two groups of patients: (1) bilineal leukemias in which there are two distinct population of cells, usually one lymphoid and one myeloid, and (2) biphenotypic leukemias where individual blast cells display features of both lymphoid and myeloid lineage. Biphenotypic cases represent the majority of mixed phenotype leukemias. B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have a lower rate of complete remission and a significantly worse event-free survival compared with patients with B-precursor ALL. Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen,[19,20,24] although the optimal treatment for patients remains unclear.
Cytogenetic Evaluation and Molecular Abnormalities
Chromosomal analyses of leukemia should be performed on children with AML because chromosomal abnormalities are important diagnostic and prognostic markers.[25,26,27,28,29,30] Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t[8;21] with M2, t[15;17] with M3, inv with M4 Eo, 11q23 abnormalities with M4 and M5, t[1;22] with M7). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.
Molecular probes and newer cytogenetic techniques (e.g., fluorescence in situ hybridization [FISH]) can detect cryptic abnormalities that were not evident by standard cytogenetic banding studies. This is clinically important when optimal therapy differs, as in APL. Use of these techniques can identify cases of APL when the diagnosis is suspected but the t(15;17) is not identified by routine cytogenetic evaluation. The presence of the Philadelphia (Ph) chromosome in patients with AML most likely represents chronic myelogenous leukemia (CML) that has transformed to AML rather than de novo AML. Molecular methods are also being used to identify recurring gene mutations in adults and children with AML, and as described below, some of these recurring mutations appear to have prognostic significance.