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  Mixed phenotype acute leukemia—case presentation

 

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April 2012
Feature Story

The following is one of the cases, No. 35, from the new book, Flow Cytometry in Evaluation of Hematopoietic Neo-plasms.

Clinical history

A 64-year-old man presents to his primary care physician with fatigue and a “pale appearance” for the past 2 weeks. Screening labs include a CBC that shows a hematocrit of 19% and a WBC of 25,000 cells per microliter with 85% unclassified cells. A sample of peripheral blood is submitted to the flow cytometry laboratory.

Diagnosis

Mixed phenotype acute leukemia, T/myeloid, not otherwise specified.

Discussion

Mixed phenotype acute leukemia (MPAL)1-3 is a rare subset of acute leukemia, accounting for less than 5%4-8 of newly diagnosed cases, that includes both biphenotypic acute leukemia, in which markers of more than one lineage are expressed on a single blast population, and bilineal acute leukemia, in which two distinct blast populations of different lineages are present. Although the presence of multiple lineages may be suggested by morphology, flow cytometry plays a critical role in lineage assignment, allowing one to establish this diagnosis.

A diagnosis of MPAL can be established in one of three ways.1-3 First is if two distinct blast populations are present, one of which would meet immunophenotypic criteria for acute myeloid leukemia (myeloid or monocytic) and the other representing an abnormal lymphoid blast population (bilineal acute leukemia). Second is if there is a single population of blasts meeting criteria for B lymphoblastic leukemia (B-ALL) or T lymphoblastic leukemia (T-ALL) with expression of MPO. And third is if there is a single population of blasts meeting criteria for B-ALL or T-ALL with evidence of monocytic differentiation. Of note, expression of markers, including CD13, CD33, and CD117, is not sufficient for assignment of myeloid lineage according to World Health Organization (WHO) criteria (Table 1). Myeloid lineage is established by expression of MPO or demonstration of monocytic lineage by expression of at least two monocytic antigens (CD11c, CD14, CD64, lysozyme and/or diffuse NSE expression by cytochemistry). T-cell lineage is established by expression of CD3 (surface or cytoplasmic). B-cell lineage requires either expression of strong CD19 with strong expression of one additional B-cell marker, or weak CD19 with two additional B-cell markers (additional B-cell markers may include CD79a, cytoplasmic CD22, and CD10). No clear cutoff is specified in the WHO classification to determine when to consider a blast positive for a lineage-specific marker. Although the European Group for Immunological Classification of Acute Leukemia (EGIL) previously recommended a cutoff of 20% for most markers and 10% for markers including MPO and CD3, given their high specificity,2,9,10 this was not adopted in the latest WHO revision, and ambiguity remains in the application of these criteria in some cases. If a blast population is noted that lacks all lineage-specific antigens, it may be considered an undifferentiated acute leukemia.

On the basis of antigen expression, MPAL is then subclassified as B/myeloid, not otherwise specified (NOS), or T/myeloid, NOS. Of these categories, B/myeloid is more common in the majority of reported series,5-8,11 with rare exceptions in pediatric populations.12 The most common cytogenetic changes seen in MPAL are t(9;22) and MLL rearrangements.2,7,11 MPAL harboring one of these structural genetic abnormalities are classified separately in the 2008 WHO classification.1 MPAL with t(9;22) most commonly has a myeloid and B lymphoid component and should be distinguished from blast crisis of chronic myelogenous leukemia (CML) on clinical grounds. MPAL with an MLL rearrangement occurs most commonly in children and has a myeloid (typically monoblastic) component often associated with a B lymphoid blast component that expresses CD15 without CD10 (similar to B-ALL with an MLL rearrangement). Both recurrent cytogenetic changes are associated with a poor prognosis.

Of note, progenitor cells in some chronic myeloid stem-cell neoplasms and blasts in some subtypes of acute myeloid leukemia (AML) characteristically show expression of non–lineage-specific antigens. Cases that would be better classified under a different WHO recognized subtype should be classified as such, rather than as MPAL. For instance, AML with t(8;21) frequently shows expression of B-cell antigens but should not be considered MPAL. Similarly, blast crisis of CML and therapy-related myeloid stem-cell neoplasms should not be classified as MPAL.

B/T MPAL is rarely described; however, care should be taken not to overdiagnose this entity, as CD79a and CD10 are frequently reported in T-ALL. Rare cases of trilineage MPAL have been reported as well.5,7

Careful immunophenotypic evaluation is critical in establishing a diagnosis of MPAL, with accurate diagnosis being important because some studies show a poorer prognosis in adults for this group of acute leukemias as compared to ALL or AML2,5 and poorer prognosis for children with MPAL as compared to ALL.12,13 Furthermore, the therapeutic approach is generally driven by the lineages represented at diagnosis. Either or both of the lineages present at diagnosis may be seen at relapse.

Take-home points

  • Flow cytometry is critical in establishing a diagnosis of mixed phenotype acute leukemia and distinguishing this entity from other acute leukemias.
  • In cases classified as MPAL, it is important to look for cytogenetic abnormalities including t(9;22) and translocations involving 11q23.
  • Cases falling into a different WHO category, such as AML with a t(8;21) translocation or blast crisis of CML, should not be classified as MPAL.

References

1. Swerdlow SH, Campo E, Harris NL, et al, eds. World Health Organization Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: WHO Press; 2008.

2. Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia. Nov 2010;24(11):1844-1851.

3. Bene MC. Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica. Jul 2009;94(7):891–893.

4. Thalhammer-Scherrer R, Mitterbauer G, Simonitsch I, et al. The immunophenotype of 325 adult acute leukemias: relationship to morphologic and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination. Am J Clin Pathol. Mar 2002;117(3):380–389.

5. Xu XQ, Wang JM, Lu SQ, et al. Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population. Haematologica. Jul 2009;94(7):919–927.

6. Al-Seraihy AS, Owaidah TM, Ayas M, et al. Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica. Dec 2009;94(12):1682–1690.

7. 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. Apr 2006;20(4):620–626.

8. Gerr H, Zimmermann M, Schrappe M, et al. Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol. Apr 2010;149(1):84–92.

9. Bene MC, Bernier M, Casasnovas RO, et al. The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL). Blood. Jul 15 1998;92(2):596–599.

10. Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. Oct 1995;9(10):1783–1786.

11. Matutes E, Morilla R, Farahat N, et al. Definition of acute biphenotypic leukemia. Haematologica. Jan-Feb 1997;82(1):64–66.

12. Rubnitz JE, Onciu M, Pounds S, et al. Acute mixed lineage leukemia in children: the experience of St Jude Children’s Research Hospital. Blood. May 21 2009;113(21):5083–5089.

13. Mejstrikova E, Volejnikova J, Fronkova E, et al. Prognosis of children with mixed phenotype acute leukemia treated on the basis of consistent immunophenotypic criteria. Haematologica. Jun 2010;95(6): 928–935.