58 year old man with acute myeloid blast phase of chronic

By Patrick Morales,2015-01-15 00:04
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58 year old man with acute myeloid blast phase of chronic



    1Katalin Kelemen1.Oregon Health Science University, Pathology, Portland, Oregon, United States

    Clinical history: A 58 year old man with history of chronic myelogenous leukemia for 16 months in complete hematologic remission on 400mg/day imatinib mesylate, presented with fatigue and progressive pancytopenia. He also had a history of renal cell carcinoma treated with nephrectomy 2 years before and left lung lobectomy for stage IB poorly differentiated squamous cell carcinoma 3 years before. A bone marrow biopsy was performed.3, 3. Hb 7.8 g/dL, WBC 500/mm Plt 28 000/mm Other lab. parameters: MCV:110.1 fL.

    Biopsy fixation: Fixed in 10% buffered formalin prior to embedding.

    Microscopy: The 1.2 cm core biopsy contains cortical bone and hypocellular bone marrow with less then

    10% cellularity over two third of the biopsy. In the hypocellular area the cellularity is composed of few myeloid and erythroid elements at various stages of maturation and rare small megakaryocytes. One third of the biospy shows a diffuse dense infiltrate ( cellularity of 100%) of large pale cells with high nuclear/cytoplasmic ratios, dispersed chromatin, visible to prominent nucleoli and high number of associated mitotic figures. The pale cells are focally arranged in nests and are surrounded by halos. The peripheral blood smear shows

    pancytopenia. Red blood cells are decreased in number and are macrocytic. White blood cells are markedly decreased and are represented by rare scattered small lymphocytes only. Mature granulocytes are absent. There are no ciculating blasts. Platelets are also decreased in numbers. The bone marrow aspirate smears

    are hypocellular and show only a few small bone marrow stromal fragments. Scattered hematopoietic cells are present and include myeloid and erythroid elements at various stages of maturation and occasional blasts. Megakaryocytes are not identified. The nature of the bone marrow aspirate smear does not allow for a bone marrow aspirate differential.

    Immunohistochemical studies are performed on the bone marrow core biopsy to evaluate the pale cell infiltrate using antibodies to CD34, CD117, Cytokeratin cocktail (CKCKT), Prostate specific antigen (PSA), and TTF-1. The pale cells are positive for CD34 and CD117 and negative for CKCKT, PSA and TTF-1.Flow cytometric analysis performed on the bone marrow aspirate shows mixed leukocyte lineages with a predominance of lymphocytes, very few monocytes and granulocytes, consitent with hemodilution. An increased myeloid blast population id identified comprising 8-9% of total cellular events and showing the following immunophenotype: CD7, CD13, dim CD33, CD34, CD117, HLA-DR and MPO positive. Lymphocytes are composed of 88% T cells and a few polyclonal B cells. T cells are present in a CD4/CD8 ratio of 1:1, and show no T-cell antigen aberrancies. The following antibodies were used: CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b, CD13, CD14, CD15, CD16, CD19, CD20, CD33, CD34, CD45, CD56, CD64, CD71, CD117, CD123, sKappa, sLambda, HLA-DR, cCD3, Tdt, cCD22, cCD79a, MPO

    Cytogenetics: Bone marrow aspirate: Conventional karyotype analysis of 20 metaphases reveals an abnormal complex karyotype (see below) including 12 metaphases without t(9;22) but with monosomy 7, and 8 metaphases with hyperdiploidy including four copies of derivative 22 of the Philadelphia rearrangement. Karyotype:45,XY,-7[12]/70~81<4n>,X,-X,-Y,-Y,-3,-3,-4,-4,+8,-9,-9,-10,-10,-11,-11,-12,-12,-13,-13,-14,-14,-16,-17,-17,+21,+22,+22,,der(22)t(9;22)(q34;q11.2)x4[cp8].

    FISH was performed using Abbott probes for chromosome 5, chromosome 7, chromosome 8, chromosome 20, ETO/AML1 t(8;21), PML/RARA t(15;17), Inv(16) CBFB, BCR/ABL/ASS, and MLL (11q23). 200 interphease cells were scored for each probe set. The FISH results are are consistent with the extra chromosomes as follows: EGR-1: extra chromosome 5. D7S522/CEP7: 45.5% of cells show monosomy 7; 54% of cells with show extra chromsome 7 signal. D20S108/20ptel: 92.5% of cells has extra chromosome 20 signal. ETO/AML1, PML/RAR, Inv(16)CBFB and MLL are negative. BCR/ABL: 182 of 200 cells are negative; 4of 200 cells has abnormal 1 green/1red/2 yellow fusion signals; the reaining cells show 1 green signal with 3 (6 cells, and 7(2 cells) fusion signals. Abnormal with extra fusion signals.

    Proposed diagnosis

    Acute myeloid blast phase of chronic myelogenous leukemia

    Interesting feature(s) of the submitted case

    This case has two interesting features, one from the morphologic, another one from the cytogenetic point of view. From the morphologic point of view, this is an example of acute myeloid blast phase of chronic

    myelogenous leukemia where the accumulation of blasts occupy focal but significant area of the bone marrow core biopsy, without blasts in peripheral blood and a significantly lower percentage of blasts detected in bone marrow aspirate (8% by flow cytometry).

    From the cytogenetic point of view, the cytogenetic findings reflect clonal evolution of the chronic myelogenous leukemia including the evolution of a Philadelphia-negative clone with monosomy 7. Clonal cytogenetic abnormalities in Philadelphia negative metaphases have been observed during imatinib tretment of patients with chronic myelogenous leukemia ( Bumm et al, 2003; Lin et al, 2006 ). Monosomy 7 in particular, as an anomaly in Philadelphia negative clonal hematopoiesis in chronic myelogenous lekemia, is associated with MDS/AML with poor risk (Kovitz et al, 2006) as it is well illustrated with the bad outcome of our patient, who died 6 weeks after diagnosis of acute myeloid leukemia.

    The case also emphasizes the importance of cytogenetic follow-up of imatinib-treated patients in complete hematologic remission of chronic myelogenous leukemia.


    1.Bumm, T, Muller, C, Al-Ali, H-K, Krohn, K, Shepherd, P, Schmidt, E, Leiblein,S, Franke, C, Hennig, E, Friedrich, T, Krahl, R, Niederwieser, D, and Deininger, M. W. N. Emergence of clonal cytogenetic abnormalities in Ph- cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood, 2003; 101:1941-1949.

    2. Lin, Y, Bruyere, H, Horsman, D.E, Pantzar, T, Barnett, M.J, Hogge, D.E, Nevill, T.J, Nantel, S.H, Sutherland, H.J, Toze, C.L, Shepherd, J.D, Lavoie, J.C, Song, K.W, Smith, C.A, and Forrest, D.L. Philadelphia-negative clonal hematopoiesis following imatinib therapy in patients with chronic myeloid leukemia: a report of nine cases and analysis of predictive factors. Cancer Genetics and Cytogenetics, 2006; 170: 1, 16-23.

    3.Kovitz, C, Kantarjian, H, Garcia-Manero, G, Abruzzo, L.V,, Cortes, J. Myelodysplastic syndromes and acute myeloid leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia. Blood, 2006; 108: 28-11-2813.

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