A new morphologic classification system for acute promyelocytic leukemia distinguishes cases with underlying PLZF/RARA gene rearrangements

Acute promyelocytic leukemia (APL) is typified by the t(15;17) translocatio n, which leads to the formation of the PML/ RARA fusion gene and predicts a beneficial response to retinoids. However, approximately 10% of all APL ca ses lack the classic t(15;17). This group includes (1) cases with cryptic P ML/RARA gene rearrangements and t(5;17) that leads to the NPM/RARA fusion g ene, which are retinoid-responsive, and (2) cases with t(11; 17)(q23;q21) t hat are associated with the PLZF/RARA fusion gene, which are retinoid-resis tant. A key issue is how to rapidly distinguish subtypes of APL that demand distinct treatment approaches. To address this issue, a European workshop was held in Monza, Italy, during June 1997, and a morphologic, immunophenot ypic, cytogenetic, and molecular review was undertaken in 60 cases of APL l acking t(15;17). This process led to the development of a novel morphologic classification system that takes into account the major nuclear and cytopl asmic features of APL. There were no major differences observed in morpholo gy or immunophenotype between cases with the classic t(15;17) and those wit h the cryptic PML/ RARA gene rearrangements. Auer rods were absent in the t (5;17) case expressing NPM/RARA. Interestingly, this classification system distinguished 9 cases with t(11;17)(q23;q21) and, in addition, successfully identified 2 cases tacking t(11;17), which were subsequently shown to have underlying PLZF/RARA fusions. The PLZF/RARA cases were characterized by a predominance of blasts with regular nuclei, an increased number of Pelger-l ike cells, and by expression of CD56 in 4 of 6 cases tested. Use of this cl assification system, combined with an analysis for CD56 expression, should allow early recognition of APL cases requiring tailored molecular investiga tions. (Blood. 2000;96:1287-1296) (C) 2000 by The American Society of Hemat ology.