Acute leukemias of ambiguous lineage are a heterogenous group of diseases that include acute undifferentiated leukemias and mixed-phenotype acute leukemias (MPALs). These leukemias pose a challenge for pathologists and clinicians alike in diagnosis, treatment, and further management. Recent genetic characterization has provided insights into their underlying biology and classification, and has offered potential for targeted therapies. This article addresses diagnosis of MPALs with examples of the most common pitfalls, recent comprehensive molecular studies, and advancement in treatment and follow-up modalities.
Mixed-phenotype acute leukemias is a heterogenous group of leukemias that are difficult to diagnose, treat, and follow minimal residual disease.
It is a diagnosis of exclusion after leukemias with specific diagnostic categories are excluded.
The genetic abnormalities to look for include rearrangements involving KMT2A , BCR-ABL1 , ZNF384 , FGFR1 , PICALM , BCR-ABL1 –like, and WT1 mutations.
Although the line of treatment is controversial, most clinicians prefer to start treatment with a lymphoblastic regimen rather than an acute myeloblastic leukemia regimen.
Acute leukemia of ambiguous lineage (ALAL) either shows no commitment to either the myeloid B-lymphoid or T-lymphoid lineages (acute undifferentiated leukemia [AUL]) or simultaneously shows commitment to more than 1 lineage (mixed-phenotype acute leukemia [MPAL]). These conditions have been difficult to diagnose and treat and have historically been referred to by different terminologies, including bilineage acute leukemia (presence of 2 morphologically and immunophenotypically separate blasts) and biphenotypic acute leukemias (single blast population expressing mixed phenotypic markers). To create a standardize approach, different classification systems have been proposed over the years. The European Group for the Immunological Characterization of Leukemias (EGIL) algorithm was developed in 1995 to 1998 and was based on a point system with a requirement of more than 2 points in 2 separate lineages for a diagnosis of MPAL. In 2008, the World Health Organization (WHO) classification system grouped bilineal and biphenotypic acute leukemias into a unified heading of MPAL and further provided more stringent criteria using fewer but more lineage-specific antibodies. The most recently updated 2017 WHO classification recommends the use of a total of 10 antibodies for such a diagnosis. , Two genetically defined subgroups are recognized within the MPAL group: t(9;22)/BRC-ABL MPAL and KMT2A (MLL) rearranged MPAL. These 2 subgroups make up a total of 19% to 28% of all MPAL cases, leaving most MPALs defined as B-myeloid, T-myeloid, and not otherwise specified subsets, which includes exceedingly rare T/B MPAL. This article discusses the various antigens suggested and the issues surrounding their use. Because of the rarity of pediatric MPAL, studies limited to children and adolescent cohorts are sparse. B-lymphoblastic leukemia (B-ALL) is the most common pediatric malignancy and expression of myeloperoxidase (MPO) by otherwise typical patients with B-ALL has been well documented, and caution is now advised in avoiding a diagnosis of MPAL in these patients.