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Pathology of Acute Leukemias of Ambiguous Lineage

  • Author: Cherie H Dunphy, MD; Chief Editor: Cherie H Dunphy, MD  more...
 
Updated: Jun 05, 2013
 

Overview

Acute leukemias of ambiguous lineage include undifferentiated acute leukemias (see the image below) and acute leukemias of mixed phenotype. The acute leukemias of mixed phenotype includes 2 subtypes: (1) those in which there is more than 1 malignant population, each of which has a distinct immunophenotype and represents a different lineage (ie, mixed lineage acute leukemias); and (2) those in which the malignant clone coexpresses lineage-specific markers (ie, biphenotypic acute leukemias).

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

The definition of a biphenotypic acute leukemia is currently based on the scoring system presented in Table, below. According to this scoring system, a diagnosis of acute leukemia of mixed phenotype is established when the score from 2 separate lineages is each greater than 2.[1]

Table. Scoring System for the Definition of Acute Leukemias of Ambiguous Lineage (Open Table in a new window)

Score B-lymphoid T-lymphoid Myeloid
2 cCD79a* cCD3 or sCD3 MPO
  cIgM Anti-TCR  
  cCD22    
       
1 CD19 CD2 CD117
  CD20 CD5 CD13
  CD10* CD8 CD33
    CD10 CD65
       
0.5 TdT TdT CD14
  CD24 CD7 CD15
    CD1a CD64
c = cytoplasmic; s = surface.



* CD79a and CD10 may also be expressed in some cases of precursor T-cell lymphoblastic leukemia/lymphoma. The World Health Organization (WHO) classification system recommends that in assigning B-lineage to a case of precursor T-cell lymphoblastic leukemia, CD79 and CD10 not be considered as evidence of B-cell differentiation.



Acute leukemias of ambiguous lineage include the following:

  • Acute undifferentiated acute leukemia
  • Mixed phenotype acute leukemia with t(9;22)(q34;q112.); BCR-ABL1
  • Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged
  • Mixed phenotype acute leukemia, B/myeloid, NOS
  • Mixed phenotype acute leukemia, T/myeloid, NOS
  • Mixed phenotype acute leukemia, NOS rare types
  • Other acute leukemias of ambiguous lineage

A diagnosis of acute leukemia of ambiguous lineage requires that the blasts demonstrate no clear evidence of differentiation along a single lineage. This group includes those acute leukemias in which there is no associated expression of lineage-specific antigens, as well as those in which there is expression of antigens associated with more than one lineage (ie, mixed phenotype acute leukemias). These different subtypes are further discussed in the next section.

See also the following:

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Epidemiology

Acute undifferentiated leukemia is extremely rare, and little is known about the frequency of this disease. Mixed phenotype acute leukemia with t(9;22)(q34;q11.2) (or BCR-ABL1 rearrangement) is also rare, accounting for less than 1% of acute leukemias. Although this condition does occur in children, it is more common in adults. It is the most common form of mixed phenotype acute leukemia that is associated with a recurrent cytogenetic abnormality.

However, mixed phenotype acute leukemia with t(v;11q23) (or MLL rearrangement) is more common in children and infants. The mixed phenotype acute leukemias (B/myeloid and T/myeloid types) include those that are biphenotypic or of mixed lineage. They account for less than 1% of acute leukemias. Although both the B/myeloid and T/myeloid types may be seen in adults and children, the T/myeloid type occurs more frequently in children.

The other types of acute leukemias of ambiguous lineage (eg, mixed phenotype acute leukemia, not otherwise specified [NOS]–rare types) are extremely rare. Not much is known about their frequency.

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Clinical and Morphologic Features

Mixed phenotype acute leukemia with t(v;11q23) (or MLL rearrangement) is commonly associated with particularly high white blood cell counts. There are no unique clinical features associated with other types of acute leukemias of ambiguous lineage. Generally, patients with acute leukemias of ambiguous lineage have a poor prognosis.

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

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

The mixed phenotype acute leukemias with t(9;22) q34;q11.2) (or BCR-ABL1 rearrangement) and the mixed phenotype acute leukemias with t(v;11q23) (or MLL rearrangement) commonly have a dimorphic blast population. One such population resembles lymphoblasts and myeloblasts; the other resembles lymphoblasts and 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 mixed phenotype acute leukemias (B/myeloid and T/myeloid) are biphenotypic or of mixed lineage. As such, in most cases, either the blasts have no distinguishing morphologic features and resemble lymphoblasts, or the blast populations are dimorphic, with lymphoblasts and myeloblasts.

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Immunophenotypic Features

The diagnosis of acute leukemia of ambiguous lineage is based on immunophenotyping—primarily, flow cytometric immunophenotyping. Acute undifferentiated leukemia typically expresses 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 (ie, CD3, myeloperoxidase-MPO, cCD22, cCD79a, and strong CD19), as well as other lineage-specific markers (eg, those for erythroid precursors, megakaryocytes, and plasmacytoid dendritic cells). They are negative for MPO and the esterases by enzyme cytochemistry. The blasts often express HLA-Dr, CD34, CD38, and TdT—all nonlineage-specific markers of immaturity or activation.

The mixed phenotype acute leukemias 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 some even have 3 components (ie, myeloblasts, precursor B-cell lymphoblasts, and precursor T-cell lymphoblasts). The mixed phenotype acute leukemias with t(v;11q23) (or MLL rearrangement) are most often composed of blasts with the following immunophenotype: CD19+, CD15+, CD20-, CD10-, and HLA-DR+. The lymphoblasts in this leukemia generally test negative for all other myeloid antigens, as well as CD24. In rare cases, they demonstrate a mature immunophenotype (ie, λ sIg+, CD19+, CD10-, TdT-, and CD34-); in these cases, there is no evidence of a c-myc rearrangement.[2, 3] The mixed phenotype acute leukemias (B/myeloid and T/myeloid) may be biphenotypic or of mixed lineage.

The biphenotypic cases must meet the criteria for precursor B-cell and myeloid blasts or precursor T-cell and myeloid blasts, as outlined in Table 1 in the Overview section. The mixed phenotype acute leukemias of the not-otherwise-specified (NOS)–rare types include those that demonstrate evidence of both precursor B-cell and precursor T-cell lineages (biphenotypic or mixed lineages).

Some acute leukemias do not meet the criteria for acute undifferentiated leukemia or for any of the types of mixed phenotype acute leukemias discussed above. This group is designated "other acute leukemias of ambiguous lineage." These leukemias often express lineage-associated (but not lineage-specific) markers for different lineages (ie, CD5 and CD7 with CD33 and CD13, but there is no expression of CD3 or MPO).

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Molecular/Genetic Features

There are too few cases of acute undifferentiated leukemia to determine whether there is an associated consistent genetic abnormality. As described with regard to mixed phenotype acute leukemia with t(9;22)(q34;q11.2) (or BCR-ABL1 rearrangement) and mixed phenotype acute leukemia with t(v;11q23) (or MLL rearrangement), these leukemias are defined by the consistent presence of these respective genetic abnormalities.

The most common partner gene in the MLL rearrangement is AF4 on chromosome 4, band q21.[4, 5] Translocations t(9;11) and t(11;19) are also encountered. Mixed phenotype acute leukemias (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.[4, 5]

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Contributor Information and Disclosures
Author

Cherie H Dunphy, MD FCAP, FASCP, Professor of Pathology and Laboratory Medicine, Diector of Hematopathology and Hematopathology Fellowship, Associate Director, Core, Flow Cytometry, and Special Procedures Laboratories, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine

Cherie H Dunphy, MD is a member of the following medical societies: American Society for Clinical Pathology, College of American Pathologists, International Academy of Pathology, North Carolina Medical Society, Children's Oncology Group

Disclosure: Nothing to disclose.

Chief Editor

Cherie H Dunphy, MD FCAP, FASCP, Professor of Pathology and Laboratory Medicine, Diector of Hematopathology and Hematopathology Fellowship, Associate Director, Core, Flow Cytometry, and Special Procedures Laboratories, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine

Cherie H Dunphy, MD is a member of the following medical societies: American Society for Clinical Pathology, College of American Pathologists, International Academy of Pathology, North Carolina Medical Society, Children's Oncology Group

Disclosure: Nothing to disclose.

Additional Contributors

Yuri Fedoriw, MD Assistant Professor, Associate Director of Hematopathology, Director of Analytical Hematology, Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine

Yuri Fedoriw, MD is a member of the following medical societies: American Society for Clinical Pathology

Disclosure: Nothing to disclose.

References
  1. The value of c-kit in the diagnosis of biphenotypic acute leukemia. EGIL (European Group for the Immunological Classification of Leukaemias). Leukemia. 1998 Dec. 12(12):2038. [Medline].

  2. Tsao L, Draoua HY, Osunkwo I, Nandula SV, Murty VV, Mansukhani M, et al. Mature B-cell acute lymphoblastic leukemia with t(9;11) translocation: a distinct subset of B-cell acute lymphoblastic leukemia. Mod Pathol. 2004 Jul. 17(7):832-9. [Medline].

  3. Frater JL, Batanian JR, O'Connor DM, Grosso LE. Lymphoblastic leukemia with mature B-cell phenotype in infancy. J Pediatr Hematol Oncol. 2004 Oct. 26(10):672-7. [Medline].

  4. Carbonell F, Swansbury J, Min T, Matutes E, Farahat N, Buccheri V, et al. Cytogenetic findings in acute biphenotypic leukaemia. Leukemia. 1996 Aug. 10(8):1283-7. [Medline].

  5. Owaidah TM, Al Beihany A, Iqbal MA, Elkum N, Roberts GT. Cytogenetics, molecular and ultrastructural characteristics of biphenotypic acute leukemia identified by the EGIL scoring system. Leukemia. 2006 Apr. 20(4):620-6. [Medline].

 
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Blasts of acute undifferentiated leukemia.
Blasts of mixed phenotype acute leukemia with t(4;11q23).
Blasts of acute myeloid leukemia, type M0.
Table. Scoring System for the Definition of Acute Leukemias of Ambiguous Lineage
Score B-lymphoid T-lymphoid Myeloid
2 cCD79a* cCD3 or sCD3 MPO
  cIgM Anti-TCR  
  cCD22    
       
1 CD19 CD2 CD117
  CD20 CD5 CD13
  CD10* CD8 CD33
    CD10 CD65
       
0.5 TdT TdT CD14
  CD24 CD7 CD15
    CD1a CD64
c = cytoplasmic; s = surface.



* CD79a and CD10 may also be expressed in some cases of precursor T-cell lymphoblastic leukemia/lymphoma. The World Health Organization (WHO) classification system recommends that in assigning B-lineage to a case of precursor T-cell lymphoblastic leukemia, CD79 and CD10 not be considered as evidence of B-cell differentiation.



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