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[CD15.sup.+] Acute Lymphoblastic Leukemia and Subsequent Monoblastic Leukemia.

Persistence of t(4;11) Abnormality and B-Cell Gene Rearrangement

Lineage heterogeneity in acute leukemia associated with the translocation of chromosomes 4 and 11 (t[4;11]) has been described. Although originally considered characteristic of a subset of acute lymphoblastic leukemia (ALL), the t(4;11) abnormality has been detected in acute leukemias of mixed lineage and those of myelogenous origin.[1]

Morphologic and electron microscopic studies have suggested that leukemias associated with the t(4;11) abnormality consist of mixed lymphoid and monocytic cell populations.[2] In a study of 7 cases of childhood leukemia with the t(4;11) abnormality, flow cytometric immunophenotyping (FCI) revealed simultaneous expression of the lymphoid-associated antigen (CD19) and the myeloid-associated antigen (MY-l) on the blasts.[3] In addition, transformation of a lymphoblastoid to a monoblastoid morphologic structure has been described at relapse in rare cases.[4] However, these cases have lacked FCI and gene rearrangement studies to define the immunophenotype of and the presence of a B-cell gene rearrangement in the monoblastoid component.

We report a case of [CD15.sup.+] ALL with the t(4;11) abnormality that relapsed as a monoblastoid leukemia as evidenced by morphologic testing, enzyme cytochemistry (EC), and FCI. The original immunophenotype ([CD19.sup.+] ALL) was no longer present. However, cytogenetic analysis confirmed the persistence of the t(4;11) abnormality with additional abnormalities, and gene rearrangement analysis revealed a B-cell gene rearrangement.

REPORT OF A CASE

The patient was a 64-year-old woman who initially presented with a markedly increased white blood cell count of 136 000/[micro]L associated with anemia (hemoglobin, 8.8 g/dL) and thrombocytopenia (platelet count, 91 000/[micro]L). A bone marrow (BM) aspirate was performed and submitted for morphologic testing, FCI, and chromosomal analysis. A diagnosis of calla (CD10)-negative ALL of early pre-B-cell origin was rendered. The patient underwent induction and consolidation chemotherapy according to the Southwest Oncology Group protocol 9400: daunorubicin, vincristine, prednisone, L-asparaginase, cytoxan, arabinoside-C, 6-mercaptopurinol, and methotrexate. She developed severe hyperbilirubinemia secondary to the L-asparaginase. She went into remission with normal cytogenetic results. Subsequent to this remission, the patient developed a relapse of the ALL (3 months after original diagnosis) and underwent an allogeneic bone marrow transplantation (BMT). She developed numerous complications in the posttransplantation period, including severe mucositis, laryngeal edema, respiratory failure, renal failure, fungemia, and deep venous thrombosis of the upper extremities. Six weeks after BMT, she presented with anemia, thrombocytopenia, nausea and vomiting, and diarrhea. She was admitted to the hospital for possible acute graft-versus-host disease versus a chemotherapy-related complication. Peripheral blood samples were submitted for FCI and chromosomal analysis because of the presence of blasts. During hospitalization, the patient desaturated and developed adult respiratory distress syndrome, worsening anemia, and thrombocytopenia and became extremely hypotensive with subsequent expiration.

MATERIALS AND METHODS

Morphologic Testing and EC

The original diagnostic BM aspirate smears and subsequent peripheral blood smears were Wright stained and stained for the presence of the following: myeloperoxidase (MPO), Sudan Black B (SBB), chloroacetate esterase (CAE), [Alpha]-naphthyl acetate esterase (ANAE), and [Alpha]-naphthyl-butyrate esterase (ANBE).

Flow Cytometric Immunophenotyping

The original diagnostic BM aspirate and peripheral blood smears were analyzed on an Ortho Cytoronabsolute (Ortho Diagnostic Systems, Raritan, NJ) flow cytometer for various antigens using standard techniques and the following commercially available monoclonal antibodies: CD1, CD4, CD5, CD8, CD10, CD15, and HLA-DR (Ortho); CD2, CD13, CD14, CD19, CD24, CD33, CD34, CD56, CD64, CD117, and terminal deoxynucleotidyl transferase (TdT) (Coulter Clone, Coulter Immunology, Hialeah, Fla); CD3, CD7, and CD20 (Becton Dickinson, San Jose, Calif); CD45 (Caltag, Burlingame, Calif); and [Kappa] and [Lambda] light chains (Kallestad, Chaska, Minn). Dual staining was performed as follows: CD3/4, CD8/56, CD19/5, CD20/HLA-DR, CD45/10, CD13/14, [Kappa]/[Lambda], CD2/24, CD33/34, CD15/117, and TdT/CD45. The other antibodies were singly labeled. Regions analyzed included lymphocyte and monocyte regions that were gated on based on their forward and side light scatter properties.

Cytogenetic Analysis

The original diagnostic BM aspirate and subsequent peripheral blood smears were submitted to the Cytogenetics Laboratory at Cardinal Glennon Children's Hospital for chromosomal analysis.

DNA Molecular Analysis

The remainder of the subsequent peripheral blood smears submitted for FCI were subsequently submitted for polymerase chain reaction analysis for a rearrangement of the immunoglobulin heavy chain gene.

RESULTS

Morphologic Testing and EC

Cytomorphologic examination of the Wright-stained smear prepared from the original diagnostic BM aspirate revealed sheets of blasts, heterogenous in size, with variably condensed nuclear chromatin, variably prominent nucleoli, and variable amounts of bluish cytoplasm (Figure 1). Myeloid and erythroid maturation were markedly decreased; megakaryocytes were not identified. The blasts did not stain with MPO, SBB, CAE, ANAE, and ANBE.

[ILLUSTRATION OMITTED]

Cytomorphologic examination of the Wright-stained smear prepared from the subsequent peripheral blood samples revealed 34% blasts characterized by their pre dominantly large size with irregular nuclear membranes, immature chromatin pattern, and prominent nucleoli. There was a variable amount of bluish cytoplasm containing vacuoles (Figure 2). The blasts were variably positive for MPO, SBB, ANAE, and ANBE. They did not stain with CAE.

[ILLUSTRATION OMITTED]

Flow Cytometric Immunophenotyping

Flow cytometric analysis of the original diagnostic BM revealed 38% of cells within the lymphocyte region, 40% within the monocyte region, and 22% within the granulocyte region. Thus, there was expansion of both the lymphocyte and monocyte regions (Figure 3). Cells within the lymphocyte region were composed of only 15% T cells (CD4/CD8 ratio was 0.55), 4% B cells with polyclonal surface light chain expression, and approximately 85% of cells with an early pre-B-cell immunophenotype in that there was expression of CD19, HLA-DR, and aberrant expression of CD15 with much lesser expression of CD20 and surface light chains. There was no coexpression of additional early pre-B-cell antigens (CD10, CD24), myelomonocytic antigens (CD13, CD33), monocytic antigens (CD14, CD64), or stem cell antigens (CD117, CD34, TdT) by the early pre-B-cell population. Cells within the monocyte region were composed of approximately 97% of cells with the same immunophenotype. Thus, the total percentage of cells with an early pre-B-cell immunophenotype within the bone marrow by FCI was 71%. The flow cytometric data combined with the cytomorphologic test and EC stain results were diagnostic of involvement of the BM by calla-negative ALL of early pre-B-cell origin with aberrant CD15 expression.

Flow cytometric analysis of the subsequent peripheral blood smears revealed an increased white blood cell count (19 200/ [micro]L), with 7% of cells within the lymphocyte region, 59% within the monocyte region, and 34% within the granulocyte region. Thus, the monocyte region was expanded (Figure 4). Cells within the lymphocyte region were composed of 46% T cells (CD4/CD8 ratio was 0.53), 2% B cells, 53% of cells expressing the natural killer cell antigen CD56, and 6% expressing the monocyte marker CD64. Cells within the monocyte region were composed of 29% of cells expressing the monocyte-specific marker CD14 and 55% immature cells with an aberrant immunophenotype in that there was expression of CD15, CD33, CD56, and CD64 without associated expression of CD13 or CD14. In addition, there was no expression of CD19 or stem cell markers (CD117, CD34, TdT) by this immature cell population. The total percentage of these cells within the peripheral blood smears analyzed by FCI was 32%. The flow cytometric data combined with the cytomorphologic test and EC stain results were diagnostic of involvement of the peripheral blood by an acute leukemia with a monocytic immunophenotype.

Cytogenetic Analysis

Chromosomal analysis of 15 cells (2 cells karyotyped, GTL-banding [G-banding with trypsin and leischman stain]) from unstimulated bone marrow cultures of the original diagnostic BM showed the following pattern: 46,XX,t(4;11)(q21;q23)[13]/46,XX[2].

Chromosomal analysis of 10 cells (2 cells karyotyped, GTL-banding) from the subsequent peripheral blood samples showed the following pattern: 59,XXX, +2, +3, t(4; 11)(q21;q23), + der (4)t(4;11)(q21;q23) x 2, +5, +6, +7, +8, +13, +16, +19, +20[10].

DNA Molecular Analysis

DNA was isolated from the subsequent peripheral blood samples and analyzed by polymerase chain reaction to detect a population of cells with a monoclonal rearrangement of the immunoglobulin heavy chain gene. A monoclonal rearrangement was detected.

COMMENT

There is a subset of ALL of early pre-B-cell origin ([CD19.sup.+], [CD20.sup.-]) that characteristically lacks expression of CD10 and has aberrant expression of CD15; this subset is typically associated with t(4;11)(q21;q23) and has a poor prognosis in adults (median survival of only 7 months).[5]

Of interest, this t(4;11) abnormality has marked lineage heterogeneity, being present in ALL, acute myelogenous leukemias, and acute mixed lineage leukemias. It has been suggested that the acute leukemias associated with this abnormality arise from a multipotential progenitor cell. There is support in the literature for this concept. Strong et al[6] described a human acute leukemia cell line with t(4; 11) that exhibited B lineage and monocytic characteristics. The B-lineage component of these leukemias is supported by the characteristic finding of a heavy chain immunoglobulin gene rearrangement in these cases.[7] The monocytic component is supported by the aberrant expression of CD15, a myelomonocytic marker, and studies of ultrastructure and in vitro growth characteristics.[8-10]

As further support for a multipotential progenitor cell origin, this subset of ALL has relapsed as acute myelogenous leukemias, rarely described with a "monoblastoid" appearance (2 cases). The monocytic origin was defined in both cases by EC and ultrastructural studies; neither case had supportive FCI or B-cell gene rearrangement studies performed.

Our present case supports the concept that this leukemia arose from a multipotential progenitor cell. At original diagnosis, the ALL had the typical immunophenotype associated with t(4;11) (q21;q23). Although the morphologic test, EC stain, and FCI results clearly revealed 2 different immunophenotypes of the blast population at original diagnosis ([CD15.sup.+], [CD10.sup.-] early pre-B cell) and relapse ([CD19.sup.-] monoblast), the persistence of the t(4;11) abnormality and the presence of the immunoglobulin heavy chain gene rearrangement at relapse support the same cell of origin for both processes. This finding suggests that therapy directed at a multipotential progenitor cell may be beneficial in these patients.

We acknowledge Patty Jenkins and Linda Sheahan for secretarial assistance.

References

[1.] Childs CC, Hirsch-Ginsberg C, Culbert SJ, et al. Lineage heterogeneity in acute leukemia with the t(4;11) abnormality: implications for acute mixed lineage leukemia. Hematol Pathol. 1988;2:145-157.

[2.] Parkin JL, Arthur DC, Abramson CS, et al. Acute leukemia associated with the t(4;11) chromosome rearrangement: ultrastructural and immunologic characteristics. Blood. 1982;60:1321-1331.

[3.] Mirro J, Kitchingman G, Williams D, et al. Clinical and laboratory characteristics of acute leukemia with the 4;11 translocation. Blood. 1986;67:689-697.

[4.] Daniel M-T, Jonveaux PH, Berger R. Relapse as acute monocytic leukaemia of acute lymphoblastic leukaemia with t(4;11). Nouv Rev Fr Hematol. 1992;34: 347-348.

[5.] Bloomfield CD, Goldman Al, Alimena G, et al. Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia. Blood. 1986;67:415-420.

[6.] Strong RC, Korsmeyer SJ, Parkin JL, Arthur DC, Kersey JH. Human acute leukemia cell line with the t(4;11) chromosomal rearrangement exhibits B lineage and monocytic characteristics. Blood. 1985;65:21-31.

[7.] Crist WM, Cleary ML, Grossi CE, et al. Acute leukemias associated with the 4;11 chromosomal translocation have rearranged immunoglobulin heavy chain genes. Blood. 1985;66:33-38.

[8.] Parkin JL, Arthur DC, Abramson CS, et al. Acute leukemia associated with the t(4;11) chromosome rearrangement: ultrastructural and immunologic characteristics. Blood. 1982;60:1321-1331.

[9.] Nagasaka M, Maeda S, Maeda H, et al. Four cases of t(4;11) acute leukemia and its myelomonocytic nature in infants. Blood. 1983;61:1174-1181.

[10.] Stong J, Kersey JH. In vitro culture of leukemic cells in t(4;11) acute leukemia. Blood. 1985;66:439.

Accepted for publication March 22, 2001

From the Division of Hematopathology, Department of Pathology (Drs Dunphy, Gardner, and Evans), and Department of Internal Medicine (Dr Javadi), St Louis University Health Sciences Center, St Louis University School of Medicine, St Louis, Mo.

Reprints: Cherie H. Dunphy, MD, Department of Pathology and Laboratory Medicine, CB#7525, University of North Carolina, Chapel Hill, NC 27599-7525 (e-mail: cdunphy@unch.unc.edu).
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Author:Dunphy, Cherie H.; Gardner, Laura J.; Evans, H. Lance; Javadi, Nader
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Sep 1, 2001
Words:2041
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