Pathology of Acute Leukemias of Ambiguous Lineage

Updated: Mar 24, 2017
  • Author: Enrique Ballesteros, MD; Chief Editor: Christine G Roth, MD  more...
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Overview

Overview

Acute leukemias in general have a distinct lineage, either lymphoid (ie, acute lymphoblastic leukemia [ALL]) or myeloid (ie, acute myeloid leukemia [AML]). However, in a small subset of patients who present with acute leukemia, a specific lineage cannot be assigned. These cases are characterized as acute leukemias of ambiguous lineage (ALAL).

ALALs include immature hematopoietic neoplasms that show no distinct evidence of specific lineage differentiation (ie, acute undifferentiated leukemia [AUL]) as well as leukemias that express markers of more than one lineage (ie, mixed phenotype acute leukemia [MPAL]). The MPAL further includes two subtypes: (1) those in which there is more than one malignant (blast) population, each of which represents a different lineage (formerly known as bilineal leukemia); and (2) those in which the malignant (blast) clone coexpresses lineage-specific markers (formerly known as biphenotypic acute leukemias).

In the 2016 revision of the World Health Organization (WHO) Classification, the category of acute leukemias of ambiguous lineage includes the following [1] :

  • AULs
  • MPAL with t(9;22)(q34.1;q11.2); BCR-ABL1 rearranged
  • MPAL with t(v;11q23.3); KMT2A ( MLL) rearranged
  • MPAL, B/myeloid, not otherwise specified (NOS)
  • MPAL, T/myeloid, NOS

Various scoring systems have been used previously; however, the 2016 WHO criteria for lineage assessment in MPAL are presented in Table 1. [1, 2, 3]  It is important to recognize that these recommendations only apply to MPAL; these criteria do not apply to straightfoward cases of AML or ALL in which MPAL is not a diagnostic consideration. The 2016 WHO update also emphasizes that for bilineal MPAL, it is more important that each individual blast population would meet the criteria for B, T, or myeloid leukemia, than that the specific markers below be present. [1]   

Table 1. MPAL Lineage Assessment Criteria [1] (Open Table in a new window)

B-Lymphoid T-Lymphoid Myeloid
Strong CD19 with at least 1 of the following



strongly expressed:



  • CD79a
  • Cytoplasmic CD22
  • CD10
Strong cytoplasmic CD3 MPO (flow cytometry, immunohistochemistry, or cytochemistry)
or



 



Weak CD19 with at least 2 of the following



strongly expressed:



  • CD79a
  • Cytoplasmic CD22
  • CD10
or



 



Surface CD3



or



 



Monocytic differentiation



(at least 2:



  • NSE [cytochemistry]
  • CD11c
  • CD14
  • CD64
  • lysozyme)
MPAL = mixed phenotype acute leukemia; MPO = myeloperoxidase; NSE = nonspecific esterase.

 

Of note, ALALs exclude distinct cases of AML that may express lymphoid-associated markers or ALL that may express myeloid-associated markers. For example, low-intensity myeloperoxidase (MPO) expression has been noted in otherwise typical cases of B-cell ALL (B-ALL), and the 2016 WHO guidelines caution against making a diagnosis of B/myeloid MPAL in the absence of other evidence of myeloid differentiation. [1]  It is also important that flow cytometry antibodies against the CD3 epsilon chain be used, as immunohistochemical antibodies may detect the zeta chain of CD3, which lack specificity. [2]  Cases of acute leukemia that may be classified in another category based on genetic or clincial features are also excluded (eg, AML with translocation t(8;21) and expression of multiple B cell markers).

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Epidemiology

Acute undifferentiated leukemia (AUL) is extremely rare, and little is known about the frequency of this disease.

Mixed phenotype acute leukemia (MPAL) with t(9;22)(q34;q11.2) (or BCR-ABL1 rearrangement) is also rare, accounting for less than 1% of acute leukemias. It is the most common form of MPAL that is associated with a recurrent cytogenetic abnormality. This diagnosis should not be made in patients with known chronic myeloid/myelogenous leukemia (CML) who progress to the blast phase with features of MPAL. Although this condition does occur in children, it is more common in adults.

MPAL with t(v;11q23) (or KMT2A (MLL) rearrangement) is more common in children and infants than older individuals. The MPALs (B/myeloid and T/myeloid types) include those that are biphenotypic or of mixed lineage. They account for less than 1% of acute leukemias. 

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Clinical and Morphologic Features

There are no unique clinical features associated with the various types of acute leukemias of ambiguous lineage (ALALs). Generally, patients with ALAL have a poor prognosis. Factors that increase the mortality risk in the geriatric population include age older than 80 years and not receiving chemotherapy. [4]

The blasts of acute undifferentiated leukemia (AUL) clearly have no morphologic features of myeloid or lymphoid differentiation (see the image below).

Blasts of acute undifferentiated leukemia. Blasts of acute undifferentiated leukemia.

 

The MPALs with t(9;22) q34;q11.2) (or BCR-ABL1 rearrangement) and the MPALs with t(v;11q23) (or KMT2A (MLL) rearrangement) commonly have a dimorphic blast population. One such population resembles lymphoblasts, and the other resembles myeloblasts or monoblasts (see the following image).

Blasts of mixed phenotype acute leukemia with t(4; Blasts of mixed phenotype acute leukemia with t(4;11q23).

 

As mentioned above, the MPALs (B/myeloid and T/myeloid) are biphenotypic or of mixed lineage. As such, in most cases, either the blasts have no distinguishing morphologic features (ie, undifferentiated blasts), or the blast populations are dimorphic, with features of lymphoblasts and myeloblasts.

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Immunophenotypic Features

The diagnosis of acute leukemia of ambiguous lineage (ALAL) is based on immunophenotyping—primarily, flow cytometric immunophenotyping, although immunohistochemistry and/or cytochemistry may also play important roles in characterization (see Table 1 under the Overview section). [1, 5, 6]  

Acute undifferentiated leukemias (AULs) typically express no more than one surface membrane antigen of any given lineage. By definition, they lack T-cell–specific, myeloid-specific, and B-lineage–specific markers, as well as other lineage-specific markers (eg, those for plasmacytoid dendritic cells, erythroid precursors, and megakaryocytes). AULs are negative for MPO and the esterases by enzyme cytochemistry. The blasts often express CD34, CD38, TdT and/or HLA-DR—all nonlineage-specific markers of immaturity or activation.

The mixed phenotype acute leukemias (MPALs) with t(9;22)(q34;q11.2) (or BCR-ABL1 rearrangement) are most often composed of myeloblasts and lymphoblasts that type as precursor B cells, although some have myeloblasts and precursor T-cell lymphoblasts, and others even have three components (ie, myeloblasts, precursor B-cell lymphoblasts, and precursor T-cell lymphoblasts). The MPALs with t(v;11q23) (or KMT2A (MLL) rearrangement) are most often composed of lymphoblasts with the following immunophenotypes: CD19+, CD15+, CD20-, CD10-, and HLA-DR+, as well as a myeloblast component with monocytic differentiation (ie, monoblasts). In rare cases, a more mature immunophenotype with surface light chain expression may be seen; in these cases, there is no evidence of a c-myc rearrangement. [7, 8] The MPALs (B/myeloid and T/myeloid) may be biphenotypic or of mixed lineage.  

 

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Molecular/Genetic Features

There are too few cases of acute undifferentiated leukemia (AUL) to determine whether there is an associated consistent genetic abnormality.

As described with regard to mixed phenotype acute leukemia (MPAL) with t(9;22)(q34;q11.2) (or BCR-ABL1 rearrangement) and MPAL with t(v;11q23) (or KMT2A (MLL) rearrangement), these leukemias are defined by the consistent presence of their respective genetic abnormalities. Of note, it appears that patients with MPAL with t(9;22) may respond favorably to treatment with tyrosine kinase inhibitors (TKI). [9]

The most common partner gene in the KMT2A (MLL) rearrangement is AF4 on chromosome 4, band q21. [10, 11] Translocations t(9;11) and t(11;19) are also encountered. MPALs (B/myeloid and T/myeloid) commonly have clonal cytogenetic abnormalities, none of which are specifically identified. In the B/myeloid type, abnormalities encountered in more than one single case include the following: del(6p), 12p11.2 abnormalities, del(5q), structural abnormalities of 7, and numeric abnormalities, including near tetraploidy. [10, 11]

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