Acute Leukemias of Ambiguous Lineage

  • Min ShiEmail author
  • Kaaren K. Reichard
Part of the Atlas of Anatomic Pathology book series (AAP)


Acute leukemias of ambiguous lineage are defined by the World Health Organization (WHO) classification as leukemias that either lack a specific lineage association or show features of concurrent multiple lineage associations [1, 2]. Ambiguous-lineage leukemias are more rare and more diagnostically challenging than conventional acute myeloid leukemias and lymphoblastic leukemias [1–11]. Given that the cytologic features of these leukemias are generally nonspecific, the diagnosis rests upon extensive immunophenotypic analysis. Multiparametric flow cytometric immunophenotyping is the preferred method for immunophenotyping, but in some cases, immunohistochemistry may be performed and may facilitate the recognition of two distinct blast populations in tissue sections. In addition to standard immunophenotypic studies, further evaluation should include cytogenetic studies to identify cases with t(9;22)(q34.1;q11.2); BCR-ABL1 or t(v;11q23.3); KMT2A rearranged. Table 13.1 highlights the diagnostic subcategories of acute leukemias of ambiguous lineage, Table 13.2 lists the diagnostic criteria for lineage determination, and Table 13.3 compares lineage-specific and lineage-associated markers in acute leukemia. This chapter provides pathologic examples of various ambiguous-lineage leukemias and illustrates the key diagnostic challenges, considerations, and caveats in establishing these rare diagnoses (Figs. 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 13.10, 13.11, 13.12, 13.13, 13.14, 13.15, 13.16, and 13.17).


Acute leukemia of ambiguous lineage Acute undifferentiated leukemia Mixed phenotype acute leukemia, T/myeloid, NOS Mixed phenotype acute leukemia, B/myeloid, NOS Mixed phenotype acute leukemia with t(9;22)(q34.1;q11.2) BCR-ABL1 Mixed phenotype acute leukemia with t(v;11q23.3) KMT2A rearranged Flow cytometric immunophenotyping 


  1. 1.
    Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405. CrossRefPubMedGoogle Scholar
  2. 2.
    Borowitz MJ, Béné MC, Harris NL, Porwit A, Matutes E, et al. Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. p. 150–5.Google Scholar
  3. 3.
    Béné MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9:1783–6.PubMedGoogle Scholar
  4. 4.
    Porwit A, Béné MC. Acute leukemias of ambiguous origin. Am J Clin Pathol. 2015;144:361–76. Scholar
  5. 5.
    Heesch S, Neumann M, Schwartz S, Bartram I, Schlee C, Burmeister T, et al. Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization. Ann Hematol. 2013;92:747–58. CrossRefPubMedGoogle Scholar
  6. 6.
    van den Ancker W, Westers TM, de Leeuw DC, van der Veeken YF, Loonen A, van Beckhoven E, et al. A threshold of 10% for myeloperoxidase by flow cytometry is valid to classify acute leukemia of ambiguous and myeloid origin. Cytometry B Clin Cytom. 2013;84:114–8. CrossRefPubMedGoogle Scholar
  7. 7.
    Steensma DP. Oddballs: acute leukemias of mixed phenotype and ambiguous origin. Hematol Oncol Clin North Am. 2011;25:1235–53. CrossRefPubMedGoogle Scholar
  8. 8.
    Yang W, Tran P, Khan Z, Rezk S, O’Brien S. MLL-rearranged mixed phenotype acute leukemia masquerading as B-cell ALL. Leuk Lymphoma. 2017;58:1498–501. CrossRefPubMedGoogle Scholar
  9. 9.
    Wolach O, Stone RM. How I treat mixed-phenotype acute leukemia. Blood. 2015;125:2477–85. CrossRefPubMedGoogle Scholar
  10. 10.
    Weinberg OK, Seetharam M, Ren L, Alizadeh A, Arber DA. Mixed phenotype acute leukemia: a study of 61 cases using World Health Organization and European group for the immunological classification of Leukaemias criteria. Am J Clin Pathol. 2014;142:803–8. CrossRefPubMedGoogle Scholar
  11. 11.
    Borowitz MJ. Mixed phenotype acute leukemia. Cytometry B Clin Cytom. 2014;86:152–3. CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of Laboratory Medicine and Pathology, Division of HematopathologyMayo ClinicRochesterUSA

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