American Journal of Hematology 77:167–170 (2004)
Case of Chronic-Phase Chronic Myelogenous Leukemia With an Abdominal Hematopoietic Tumor of Leukemic Clone Origin Miho Sakakura,1 Kohshi Ohishi,1* Kenichi Nomura,2 Naoyuki Katayama,1 Kazuhiro Nishii,1 Masahiro Masuya,3 Kazunori Nakase,1 and Hiroshi Shiku1 2
1 Second Department of Internal Medicine, Mie University School of Medicine, Mie, Japan Department of Medicine, Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan 3 Blood Transfusion Service, Mie University Hospital, Mie, Japan
We report a 59-year-old man with chronic myelogenous leukemia (CML) in chronic phase who presented with a large abdominal tumor. Biopsy revealed proliferation of granulocytic-, erythroid-, and megakaryocytic-lineage cells in a retroperitoneal lymph node. The BCR/ABL fusion gene was detected on a paraffin-embedded tissue section of the lymph node by double-color fluorescence in situ hybridization, indicating an extramedullary hematopoietic tumor of CML origin. This patient has achieved a complete cytogenetic response for 19 months with imatinib mesylate (STI571; Gleevec), in association with the regression of the tumor. However, the development of an extramedullary tumor in chronic-phase CML generally indicates a poor prognosis, because it commonly consists of blast proliferation and is followed by blast crisis in the marrow within a few months. This case, therefore, points to the importance of histological examination of extramedullary tumors in CML for evaluation of disease status and for therapeutic decisions. Am. J. Hematol. 77:167–170, 2004. ª 2004 Wiley-Liss, Inc. Key words: chronic myelogenous leukemia; extramedullary hematopoiesis; hematopoietic tumor; chronic phase; imatinib mesylate
INTRODUCTION
Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem-cell disorder with chromosomal translocation between chromosome 9 and 22, resulting in a shortened chromosome 22, referred to as the Philadelphia chromosome. This translocation leads to the formation of a BCR/ABL fusion gene and generates a chimeric fusion protein p210BCR/ABL, with constitutively activated tyrosine kinase, which plays an important role in the development of CML [1–3]. The clinical course of CML is characterized by three sequential phases; chronic phase, accelerated phase, and blast crisis. The initial chronic phase usually persists for three to five years, and is followed by an increase in blasts in marrow or peripheral blood, often associated with the clonal cytogenetic evolution that characterizes accelerated phase and blast crisis [1–3]. Blast crisis, which morphologically resembles acute leukemia, is the end stage of CML and carries a poor prognosis ª 2004 Wiley-Liss, Inc.
[4,5]. Blast proliferation often occurs in extramedullary sites simultaneously with or a few months prior to blast crisis in the marrow [6–8]. Until recently, interferon a was the first-line therapy for CML in chronic phase, while HLA-identical hematopoietic stem-cell transplantation has been performed wherever possible [9]. However, therapeutic strategies for patients with CML have dramatically changed with the emergence of a selective BCR/ABL tyrosine kinase inhibitor, imatinib mesylate (STI571; *Correspondence to: Kohshi Ohishi, M.D., Second Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. E-mail:
[email protected] Received for publication 18 December 2003; Accepted 20 April 2004 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ajh.20165
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Case Report: Sakakura et al.
Gleevec) [9,10]. Currently, imatinib mesylate is used as a standard therapy for CML because of its superiority to interferon a with or without cytarabine therapy [11,12]. Nevertheless, the response rate and response period to imatinib mesylate diminishes in accordance with disease progression, and the estimated median overall survival for patients with CML in blast crisis, including those with extramedullary blast proliferation, is still 6–7 months [13,14]. Here we report a rare case of a patient with chronicphase CML, who presented with a large retroperitoneal lymph node mass due to extramedullary hematopoiesis of the CML clone, and who has achieved a complete cytogenetic response and regression of the tumor for 19 months with imatinib mesylate.
CASE REPORT
A 59-year-old man, who had been healthy until last year, presented with abdominal fullness and a decrease in appetite in July 2002. Physiological examination revealed an abdominal mass in the lower abdomen. A subsequent laboratory evaluation in August 2002 showed 270 109/L white blood cells, comprising of 3.0% blasts, 2.0% promyelocytes, 24.5% myelocytes, 8.0% metamyelocytes, 40% band cells, 11.5% segmented cells, 1.5% lymphocytes, 5.0% eosinophils, and 1.5% basophils; 10.5 g/dL hemoglobin; 308 109/L platelets; and 1,361 U/L LDH. Bone marrow was hypercellular, with increased myeloid components at all stages of maturation. Cytogenetic analysis revealed a 46, XY, t(9;22;12) (q34;q11;q13) karyotype in all of 20 metaphase cells. A major BCR/ABL fusion gene was detected with a reverse transcriptase-polymerase chain reaction analysis. Fluorescence in situ hybridization (FISH) analysis of bone marrow indicated that 98.9% of interphase nuclei were positive for the BCR/ABL fusion gene. These data suggested CML, with an additional karyotypic abnormality. Abdominal ultrasonography showed a large 87 70 mm mass, several lymph node swellings with a diameter of about 20 mm in the para-aortic region, and mild splenomegaly. A large soft-tissue mass, several lymph node swellings in the retroperitoneal region, and mild hepatosplenomegaly were observed by computed tomography scan (Fig. 1). A lymph node biopsy revealed extensive proliferation of granulocytic cells in various stages of differentiation together with erythroid cells and megakaryocytes (Fig. 2). The BCR/ABL fusion gene was detected in these granulocytic, erythroid, and megakaryocytic cells by double-color FISH on a paraffin-embedded tissue section (Fig. 3) [15,16]. Thus the tumor was
Fig. 1. Computed tomography scan showed the presence of a large retroperitoneal soft-tissue mass, as indicated by the red arrow.
Fig. 2. Biopsy of the tumor showed the proliferation of granulocytes in various stages of differentiation with a few erythroid cells and megakaryocytes (hematoxylin and eosin stain, original magnification 200·). [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com.]
diagnosed as an extramedullary hematopoietic tumor of CML clone origin. In August 2002, treatment was started with imatinib mesylate at 600 mg per day. The patient responded well to imatinib mesylate therapy and showed a major hematological response after 1 month. Four months after the start of therapy, the BCR/ABL fusion gene in peripheral blood became undetectable by FISH analysis, and the tumor size had decreased to 57 39 mm. A complete cytogenetic response in the marrow was confirmed after 5 months. The patient has maintained a complete cytogenetic response for 19 months with imatinib mesylate
Case Report: Hematopoietic Tumor in Chronic-Phase CML
Fig. 3. Detection of BCR/ABL fusion genes by dual-color fluorescence in situ hybridization on a paraffin-embedded tissue section. BCR/ABL fusion genes are indicated by colocalized signals (yellow arrows) of BCR genes (green signals) and ABL genes (red signals); counterstaining with 4,6-diamino-2-phenyl-indole. [Color figure can be viewed in the online issue, which is available at www.interscience. wiley.com.]
therapy, while the tumor has shown no change in size and appearance since 4 months after the therapy.
DISCUSSION
Here we reported a patient with CML in chronic phase who presented with an abdominal tumor. The proliferation of myeloid-, erythroid-, and megakaryocytic-lineage cells with the BCR/ABL fusion gene in the tumor indicated that the tumor developed due to extramedullary hematopoiesis of the CML clone. Extramedullary hematopoiesis is the proliferation of all three lineages of cells, including myeloid, erythroid, and megakaryocytic cells, in extramedullary sites [17,18]. The enlargement of the spleen and liver, often seen in the early stage of CML, is attributed to extramedullary hematopoiesis [17]. Meanwhile, extramedullary hematopoiesis occasionally develops in the late stage of CML, in association with myelofibrosis, in various lesions such as liver, spleen, breast, lymph nodes, and skin [17,18]. However, it is uncommon for extramedullary hematopoiesis to generate a large hematopoietic tumor in the early stage of CML. In fact, this is, to our knowledge, the first case showing the development of an extramedullary hematopoietic tumor of CML clone origin in the early stage of CML. A case was reported of chronic-phase CML accompanied by a hematopoietic tumor in the skin, but the tumor was negative for the BCR/ABL fusion
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gene by FISH analysis, indicative of normal hematopoietic cell origin [19]. Since the development of extramedullary hematopoiesis in CML does not usually affect the prognosis of patients [17], this patient was treated with imatinib mesylate and a complete cytogenetic response, associated with the persistent regression of the tumor, has been achieved for 19 months. However, in general, extramedullary tumors in patients with CML in chronic phase indicate a poor prognosis because they commonly consist of extramedullary blast proliferation. Extramedullary blast proliferation often develops simultaneously or a few months prior to a blast crisis in the marrow, and 50–88% of extramedullary blast proliferation occurs while the marrow is still in the chronic phase [6–8]. It has been reported that the median time from extramedullary blast proliferation to blast crisis in the marrow is 4 months, and the median survival from the development of extramedullary blast proliferation is 5 months [6,7]. Importantly, since the prognosis of patients with extramedullary blast proliferation has not been markedly improved by imatinib mesylate, intensive therapy is required to cure these patients [13,14]. Thus, the diagnosis of extramedullary tumors is critical in CML, particularly in chronic phase, because the prognosis and therapeutic strategy will differ significantly, depending on the diagnosis. Taken together, this case demonstrates the importance of a histological examination of extramedullary tumors in CML, especially in chronic phase, for the evaluation of disease progression and therapeutic decisions.
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