Acute Leukemias of Ambiguous Lineage

Definition

Cases of ALAL mostly fall into two broad categories. The first are composed of blasts that have a rudimentary or hematopoietic “stem cell” phenotype, characterized by the failure to express lineage-defining features of differentiation. These acute leukemias with primitive phenotypes are commonly referred to as acute undifferentiated leukemias (AULs). Other cases of ALAL demonstrate a multiplicity of antigens that are associated with two or, rarely, three different lineages and are now referred to as mixed-phenotype acute leukemias (MPALs).

Terminology referring to MPAL has been confusing, and terms such as mixed-lineage or dual-lineage leukemia , hybrid leukemia , biphenotypic leukemia , and bilineal leukemia have all been used. MPALs vary widely in their phenotypical properties with two classic forms of MPAL. The first form has a single dominant population of blasts that express antigens in combinations that preclude definitive lineage assignment; historically these were referred to as biphenotypic leukemias . The second form is recognized as having more than one population of blasts, each of which exhibits an unequivocal, lineage-specific pattern of differentiation. This latter group has traditionally been referred to as bilineal leukemia to convey the presence of two disparate populations of blasts. In fact, these extremes are more the exception that the rule; most cases of MPAL present with overlapping features of both biphenotypic and bilineal leukemia, making an arbitrary distinction between them difficult; thus, acute leukemias with biphenotypic or bilineal features are now combined into a single category of MPAL. The classification of ALAL in the recently published 2016 WHO classification is shown in Box 43-1 .

Epidemiology and Etiology

Collectively, ALAL account for less than 3% of all acute leukemias. They occur in patients of all ages, although those with the t(9;22) are more common in adults than in children, whereas those with KMT2A(MLL) rearrangements occur most commonly in infancy. The cause of ALAL is largely unknown but, as with most leukemias, environmental toxins and radiation exposure are putative causes.

Clinical Features

As in other types of leukemia, the clinical symptoms in ALAL are usually a manifestation of bone marrow failure and include fatigue, infections, and bleeding disorders related to anemia, neutropenia, and thrombocytopenia, respectively. The white blood cell count is often high, and reported cases have a varying proportion of circulating blasts. There have also been case reports of T/myeloid MPAL that show involvement of both the bone marrow and lymph nodes.

Acute Undifferentiated Leukemia

The diagnosis of ALAL without differentiation, or AUL, has become increasingly rare. Early studies that distinguished AUL from myeloid and lymphoid leukemias suggested an incidence of 4% to 5% of all acute leukemias, whereas more recent reports estimate a relative incidence of less than 1%. This change in the reported frequency of AUL largely reflects both the adoption of more stringent classification criteria coupled with the use of increasingly complex immunophenotypic analysis, making it possible to recognize leukemias showing unusual patterns of early differentiation toward lineages such as basophils or dendritic cells.

AUL is characterized by a prominent and uniform population of blasts that lack morphologic features associated with a specific pattern of differentiation. The blasts are small to medium-sized and generally have round or oval nuclei, conspicuous nucleoli, and scant cytoplasm. Invariably, they lack myeloid-specific Auer rods or coarse cytoplasmic granulation, and only rarely do they demonstrate abnormal nuclear shapes. Moreover, by definition, less (usually much less) than 3% of the blasts show a positive cytochemical reaction with myeloperoxidase (MPO) or Sudan black B (SBB) by light microscopy, and none of the blasts react with stains for nonspecific esterases, periodic acid–Schiff, and acid phosphatase. Immunophenotypic criteria are non-specific but often include expression of the stem cell marker CD34; variable expression of other hematopoietic precursor antigens such as CD38, HLA-DR, and even CD7; and lack of expression of the following lymphoid- and myeloid-restricted markers: CD79a, cytoplasmic CD22, CD19, cytoplasmic or surface CD3ε, and MPO ( Fig. 43-1 ). These leukemias may express a single myeloid- or lymphoid-associated marker (e.g., CD13, CD33, CD15, CD64, CD2, CD5, CD10), but not in combination with a second marker associated with the same lineage. Terminal deoxynucleotidyl transferase (TdT) may even be expressed. Problems often arise when antigens are expressed at very low intensity; however, in general, dim expression of only a single even more specific marker, such as CD19, should not, by itself, exclude a diagnosis of AUL.

A frequent diagnostic challenge is distinguishing AUL from minimally differentiated acute myeloid leukemia, although the clinical distinction between these two subtypes may be insignificant because both respond poorly to conventional chemotherapy. In this context, CD117 (c-kit) expression is useful in identifying the myeloid lineage. Expression of CD117 along with CD13 and/or CD33 indicates commitment to the myeloid lineage and should exclude a diagnosis of AUL. However, CD117 is also found in a subset of precursor T-lymphoblastic leukemia, so by itself CD117 expression cannot be considered myeloid-specific.

Little is known about the biologic significance of undifferentiated leukemia. Although specific cytogenetic changes have not been associated with AUL, the majority of these leukemias are characterized by a heterogeneous mixture of clonal chromosomal abnormalities, and some demonstrate a complex karyotype. Of note, cases of AUL with a complex karyotype may have cytogenetic findings that are consistent with AML with myelodysplasia-related changes, and this diagnosis should take precedence over a diagnosis of AUL. One study that investigated gene-expression profiles in AUL found that they tend to show a relative overexpression of several genes associated with poor prognosis in leukemias, including BAALC, ERG, and MN1. Moreover, a subset of AUL has also been shown to demonstrate clonal but non-specific rearrangements of the immunoglobulin heavy-chain gene. AUL is usually treated with a myeloid leukemia type of therapeutic regimen, and although one short series reported a poor prognosis with short median survival, others have shown a high rate of continuous remission after myeloablation.