Submitting Author: Cantu, Carlos Luis, MD
Institution: University of Arizona
Additional authors:Arthur R. Brothman, PhD, Catherine M. Spier, MD
Session: Acute leukemias of ambiguous lineage

A 31-year-old female with a prior medical history significant only for a complicated intra-uterine device removal with subsequent oopherectomy presents with generalized aches and pains clinically attributed to prior surgical procedure. Physical examination upon admission shows cervical lymphadenopathy and scattered petechial hemorrhages of the lower extremities and anterior chest. Radiologic examination shows prominent mediastinal lymphadenopathy with small bilateral pleural effusions. Laboratory examination showed a marked leukocytosis, 83,000/uL with 31% circulating blasts, and a markedly decreased platelet count (20,000/uL). The patient is admitted for further evaluation.

A bone marrow biopsy is performed of the left iliac crest following admission. The submitted bone marrow core is decalcified and subsequently submitted in 5% neutral buffered formalin along with the clot tissue section.

The peripheral white blood cell count is 83,000/uL with 30% blasts. The blasts show convoluted nuclei with lightly condensed to immature chromatin. No Auer rods are identified.

Evaluation of the bone marrow aspirate shows trilineage hematopoiesis to be markedly reduced. In addition, dysplasia of the rarely identified granulocyte and erythroid precursors is identified. Enumerated blasts account for 77% of total cells evaluated with a small subset, 5% of total, noted to be monocytic precursors. Auer rods are not identified in any of the evaluated cells. An iron stain of the aspirate shows absent storage iron.

Evaluation of the bone marrow biopsy and clot tissue sections shows the marrow to be 95% cellular and predominately composed of a neoplastic blast population exhibiting vesicular nuclei with delicate nuclear folding. Trilineage hematopoiesis is virtually absent with only rare erythroid or myeloid precursors identified. Megakaryocytes are not readily identified.

No immunohistochemistry is performed.

Flow cytometry performed on the bone marrow aspirate shows 82% of cells to have an aberrant immunoprofile significant for expression of CD2, CD4, CD13, CD33, dim CD34, CD56, CD64, and myeloperoxidase (MPO).

Cytogenetic studies show an abnormal stem line in 40% of examined cells to have a pericentric inversion of chromosome 21 as the sole abnormality. A composite sideline is identified and shows the inv(21) in addition to additional material of unknown origin on the short arms of chromosomes 6 and 16, an isochromosome 8q, a derivative chromosome 11 which appeared to be from a translocation between 11p and 11q, resulting in a duplication of 11q, , a loss of the short arm of chromosome 12, a loss of chromosome 17, and an 18q deletion. All cytogenetic findings are supported by the FISH results.

Karyotype:

46,XX,inv(21)(p13q22.1)[8]/45-46,sl,add(6)(p22),i(8)(q10)[2],der(11)t(11;11)(p15;q13),del(12)(p11.2)[2],add(16)(p13.1),-17[3],add(17)(p13)[3],del(17)(p13)[4],del(18)(q21.1)[2][cp10]/46XX[2]

Fluorescence in situ hybridization (FISH) studies show normal PML/RARA, a gain of MLL (11q23), a gain of RUNX1 (21q22), a gain of MYC (8q24), a gain of ABL1 and ASS1 (9q34), and a loss of TP53 (17p13.1).

A unique feature of this case is the morphologic and phenotypic similarity to acute promyelocytic leukemia. The blasts of this case exhibit delicate nuclear folding, at times prominently, with scant to moderate amounts of lightly granular cytoplasm. In addition, expression of CD2, CD13, CD33, MPO and CD64 without expression of HLA-DR by flow cytometry make acute promyelocytic leukemia (APL), microgranular variant, a diagnostic consideration. However, faint expression of CD34 without expression of CD117, and strong expression of CD56 is uncharacteristic for APL. More importantly, no t(15;17) was detected by either conventional cytogenetics or FISH studies.

Previous work performed by Scott et al. (Blood, 1994. 84(1): p. 244-55) proposed a new diagnostic entity they termed myeloid/natural killer cell acute leukemia hypothesized to originate from a common progenitor to the myeloid and NK cell lineages after reviewing a series of morphologically and immunophenotypically similar leukemias. All of the cases examined showed the bone marrow to contain a high percentage of blasts with several showing markedly invaginated nuclear membranes and scant to moderate amounts of cytoplasm containing azurophilic granules. In addition, extramedullary disease to include hepatosplenomegaly and lymphadenopathy was identified in a subset of patients. Immunophenotypically, these leukemias expressed CD13, CD33, variable CD34, no HLA-DR, and strong CD56. Cytogenetic studies showed several of these cases to have non-recurrent abnormalities of the chromosomes similar to those seen with the presented case.

Myeloid/Natural Killer Cell Acute Leukemia

Acute myeloid leukemia with myelodysplasia related changes (complex karyotype)

Case 261