Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Acute Undifferentiated Leukemia and Mixed-Phenotype Acute Leukemias
■
Introduction
Acute leukemias of ambiguous lineage may be divided into acute undifferentiated leukemia (AUL) and mixed-phenotype acute leukemias (MPALs). AULs are leukemias with very primitive phenotypes that lack definitive lineage-specific antigens. MPAL encompasses rare blastic hematopoietic cell neoplasms that express a mixture of myeloid and lymphoid (B- or T-lineage) antigens. Alternative names for these leukemias include hybrid acute leukemias, acute leukemias of indeterminate lineage, and biphenotypic or bilineal acute leukemia. The 2008 World Health Organization (WHO) classification defines several categories of MPALs based on the presence of recurrent cytogenetic lesions or in their absence, on the lineage of the leukemic blasts, defined as B-myeloid, T-myeloid, B-T, or B-T-myeloid. Any of these leukemias can develop as biphenotypic or bilineal (bilineage) acute leukemias. In the biphenotypic leukemias, blasts may be morphologically homogeneous or heterogeneous, but they uniformly express myeloid and lymphoid antigens. In the bilineal acute leukemias, two morphologically and immunophenotypically distinct blast populations (lymphoid and myeloid) can be discerned. The latter category also incorporates acute leukemias that switch lineage during chemotherapy. Some MPALs have both a bilineal and a biphenotypic population; for example, B-lineage clone, myeloid-lineage clone, and a third population that expresess both sets of antigens. The WHO 2016 update will maintain WHO 2008 criteria for MPAL with additional clarifications. In cases of two distinct blast populations (bilineal), each population can be evaluated by the usual leukemia criteria and do not need to fulfill MPAL lineage criteria ( Table 16.1 ). Also, dim MPO staining should be interpreted with caution, especially if no other myeloid-associated antigens are detected.
TABLE 16.1
Criteria Required by the Most Recent World Health Organization Classification for Assigning More Than One Lineage to a Leukemic Process
| Myeloid lineage |
| Myeloperoxidase expression a or Monocytic antigen expression (at least two of the following: nonspecific esterase, CD11c, CD14, CD64, lysozyme) |
| T lineage |
| Cytoplasmic CD3 b or surface CD3 |
| B lineage |
| Strong expression of CD19 and strong expression of at least one of the following: CD79a, cytoplasmic CD22, CD10 Weak expression of CD19 and strong expression of at least two of the following CD79a, cytoplasmic CD22, CD10 |
a Myeloperoxidase may be detected by cytochemical or immunologic methods. Cytochemically positive myeloperoxidase should be present in at least 3% of the morphologically identified leukemic blasts. Immunophenotypically positive myeloperoxidase should be seen on a blast population that shows other immunophenotypic aberrancies (in order to exclude residual benign myeloblasts).
b Cytoplasmic CD3 expression should be detected by flow cytometry with antibodies to the CD3ε chain (immunohistochemistry using polyclonal anti-CD3 antibodies may detect CD3 zeta chain, which is not specific for T-lineage).
■
Acute Undifferentiated Leukemias
Clinical Features
Acute undifferentiated leukemias are diagnosed with decreasing frequency due to more stringent criteria; they likely represent less than 1% of acute leukemias. Patients present with signs and symptoms of bone marrow failure, as with other acute leukemias. These include easy bruising, infection, and fatigue due to cytopenias such as thrombocytopenia, leukopenia, and anemia. Leukocytosis with blasts is also commonly seen.
Pathologic Features
Microscopic Features
Blasts, the dominant cell population in bone marrow, are usually intermediate in size with round nuclei and fine chromatin containing visible nucleoli. Blasts may also be smaller, resembling morphologically lymphoblasts. Cytoplasm is scant without azurophilic granules or Auer rods. By definition they are negative for Sudan black B (SBB) and myeloperoxidase (MPO) by cytochemistry. Trephine biopsy generally shows replacement of the marrow cellularity by sheets of blasts with little to no residual hematopoietic elements.
Ancillary Studies
Immunophenotypic Findings
Flow cytometry shows only immature, primitive hematopoietic cells without expression of antigens that define a lineage such as CD19 for B lymphoblasts, cytoplasmic CD3 for T lymphoblasts, myeloperoxidase for myeloblasts, or other myeloid-associated markers with myeloblasts/monoblasts. The last is not precisely defined, leading to contradictory specifications in the 2008 WHO classification. AUL is defined to permit a single myeloid-associated marker, but a single myeloid marker such as CD33 is sufficient to define AML with minimal differentiation (AML-M0). The distinction between AUL and AML-M0 can be difficult and somewhat arbitrary, but a recent hematopathology workshop on MPAL agreed that AML-M0 is the diagnosis based solely on CD33 expression provided the absence of any B- or T-cell markers.
Molecular and Cytogenetic Findings
Little is known about the genetic findings in AUL. No specific genetic abnormalities have been associated with these leukemias. Clonal karyotypic abnormalities appear to be detected in most cases, but changes are not specific.
Differential Diagnosis
The main differential diagnosis is with minimally differentiated acute myeloid leukemia. Both lack SBB and MPO. However, minimally differentiated acute myeloid leukemia will express a combination of myeloid-associated markers such as CD13, CD33. Acute erythroid or megakaryoblastic leukemias may appear as AUL on initial work-up until blasts are studied for erythroid markers (glycophorin, hemoglobin A) or megakaryoblastic markers such as CD41 and CD61.
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here
