Japanese Journal of Clinical Oncology 30:362-365 (2000)
© 2000 Foundation for Promotion of Cancer Research
Chronic Neutrophilic Leukemia with Acute Myeloblastic Transformation
1Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu and 2First Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka, Japan,+
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ABSTRACT |
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We report a rare case of chronic neutrophilic leukemia (CNL) which terminated in acute myeloblastic transformation 3 years after the onset of the disease. The increased leukocytes were mainly neutrophils at various maturational stages until 1 month before transformation without dysplastic hematopoietic cells or other myeloproliferative disorders. Repeated analyses for the Philadelphia chromosome (Ph1), rearrangement of the BCR gene or chimeric BCR/ABL mRNA, major, minor and µ, were negative. Genomic analysis of granulocyte colony-stimulating factor (G-CSF) receptor did not reveal any abnormality. The clinical manifestations were characterized by hyperleukocyte syndrome with respiratory distress and ischemic legs with gangrene.
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INTRODUCTION |
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Chronic neutrophilic leukemia (CNL) is an extremely rare myeloproliferative disorder characterized by increased mature neutrophils, elevated neutrophil–alkaline phosphatase activity and absence of the Philadelphia chromosome (Ph1) (1). Several studies have examined the pathogenesis and clinical features of CNL, mainly in comparison with chronic myeloid leukemia (CML). However, the characteristics of CNL are not completely understood (2,3).
The French–American–British (FAB) Cooperative Leukemia Group proposed guidelines for distinguishing CML, atypical CML and chronic myelomonocytic leukemia (CMMoL) (2). However, cases with CNL were not included because of their distinct clinical features and rarity (2). CNL has been associated with other myeloproliferative disorders; such as cases evolving from myelodysplastic syndrome (MDS) including CMMoL (4,5), those associated with lymphoplasmacytic disease (6,7) and those with polycythemia vera (8). Patients with CNL rarely die during acute blastic transformation unlike those with CML (1).
The diversity of breakpoints of the breakpoint cluster region (BCR) gene resulting in various fusion transcripts of BCR/ABL genes and their products, as well as its relationship to the leukemia phenotype, was reviewed (3). In 30–50% of Ph1-patients, major (M)-BCR rearrangement can be detected by Southern blotting and reverse transcription polymerase chain reaction (RT-PCR) (3). A small proportion of Ph1+ CML patients are negative for the M-BCR rearrangement owing to a breakpoint outside M-BCR, at either e1a2 of the BCR/ABL genes, minor (m)-BCR or e19a2 (c3a2), µBCR, translated into a 230 kDa fusion protein (3). The latter cases were designated as Ph1+ neutrophilic myeloid leukemia (CML-N) (9,10).
Structural and functional analyses of the granulocyte colony-stimulating factor (G- CSF) receptor gene identified the intracytoplasmic proximal domain with neutrophil maturation potential (11,12). Mutations in the G-CSF receptor gene which encodes the C-terminal domain, resulting in truncation of the G-CSF receptor, were found in patients with acute myeloblastic leukemia (AML) preceded by severe congenital neutropenia (13) and in a patient with de novo AML (14).
We report a case of CNL in which increases in neutrophils of various maturational stages persisted for 3 years and myeloblastic transformation ultimately evolved just 1 month before death. In the present case, repeated examinations for Ph1 and BCR/ABL rearrangement (M, m and µ) were negative. Genomic analysis of the G-CSF receptor did not reveal any abnormality. Thus, our case of CNL was different from CML, atypical CML, CNL evolved from MDS or other myeloproliferative disorders and also differed from CML with known diverse rearrangement of the BCR/ABL genes, although the pathogenesis remains unclear.
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CASE REPORT |
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In May 1995, a 72-year-old male was referred to our clinic because of an increased leukocyte count. Physical examination revealed swelling of the axillar lymph nodes and hepatomegaly which was palpable 2 cm below the costal margin, but the spleen was not palpable. Hematological data on the first admission is shown in Table 1, column a. An increase in neutrophils of various maturational stages was observed in the peripheral blood and bone marrow (Fig. 1). Although the absolute count of monocytes in the peripheral blood elevated at more than 1 x 104/µl on admission, a bone marrow aspiration smear did not reveal any increase in myeloblasts or monocytes. Dysplastic cells were not observed. Neutrophil alkaline phosphatase score was 390 (count 249). Chromosome analysis revealed 46,XY. A test for rearrangement of the major BCR gene by Southern blot analysis using 5' and 3' BCR probes was negative. The primers used for RT-PCR of chimeric BCR/ABL mRNA (Table 2) and their locations (Fig. 2) are shown. These detect M, m and also µ-BCR/ABL mRNA, although the lower efficiency of PCR amplification may be conceivable for large size of µ-BCR product. Results for chimeric BCR/ABL mRNA, M, m and µ were negative. The patient was diagnosed as having CNL. The monocytosis was not observed thereafter during the clinical course.
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Initially, hydroxyurea 500 mg/day was administered and the leukocyte count was controlled at (50–100) x 103/µl. However, the level fluctuated and increased to 130 x 103/µl in December, 1996, when a small necrotic lesion was observed at the tip of the second toe of the right leg. The patient had no history of claudication or diabetes mellitus. The pulsations of the inguinal, popliteal and tibial arteries were audible by Doppler ultrasonography. Angiography was not performed because of the patient’s severe condition. Gangrene of the leg progressed and amputation of the right leg, leaving the upper one third, was performed in January 1997. For 1 month before and after surgery, the patient complained of dyspnea due to hypoxia, but chest X-ray did not reveal pneumonia. The patient was further treated with 1000–1500 mg/day of hydroxyurea and the neutrophil count stabilized at around 50–100 x 103/µl.
He was well until March, 1998, when he developed a cough, dyspnea and fever and was admitted. The toes of the left leg were cyanotic. A chest X-ray did not reveal pneumonia. Hematological data on the last admission are shown in Table 1, column b. Increased myeloblasts were observed as shown in Fig. 3, which were peroxidase positive and esterase positive for substrates of naphthol AS-D chloroacetate and 
-naphthyl butyrate. Chromosome analysis revealed 46,XY,add(5)(p15), i(8)(q10), –15, +mar1. Lysozyme levels were 116 µg/ml in serum (5.0–10.2) and 477 µg/ml in the urine (0). The patient refused intensive chemotherapy and he was treated with 1500 mg/day of hydroxyurea. The leukocyte count decreased markedly. However, blast cells did not decrease. Pneumonia developed and disseminated intravascular coagulation was aggravated. Angiography of the left external iliac, common femoral and popliteal arteries revealed arteriosclerotic changes. The patient died in April 1998. Macroscopic autopsy findings revealed hemorrhage of the lungs and pleura and swelling of the retroperitoneal lymph nodes. Microscopic findings revealed infiltration of leukemic blasts into the lungs, liver, spleen, lymph nodes, adrenal glands, pancreas and peritoneum. The lungs showed alveolar hemorrhage and infiltration of leukemic blasts into the alveolar septum. The aorta showed atherosclerotic changes.
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The G-CSF receptor gene was studied in the chronic phase and during the acute myeloblastic transformation. The details of the experimental conditions and results have been presented eleswhere (15). DNA extracted from the leukocytes was studied for mutations of the G-CSF receptor gene in the transmembrane domain and intracytoplasmic domain including the exons 14 and 17 (11,12), by single strand conformation polymorphism (SSCP) and direct sequencing. However, no band with different electrophoretic mobility or abnormal sequences was observed.
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DISCUSSION |
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Ph1– and BCR– cases, referred to as atypical CML, are characterized by the presence of granulocyte dysplasia, a low percentage of basophilia, monocytosis but not as severe as that in CMMoL and increased immature granulocytes and blasts (2). Martiat et al. also suggested that Ph1– and M-BCR– CML and CMMoL are only different aspects of the same disease and dysgranulopoiesis and monocytosis were quantitatively different (16). Zoumbos et al. reported cases of CNL with dysplastic hematopoietic cells, some of which later transformed acute myeloblastic leukemia, and proposed that these cases constituted a distinct variant of MDS, because they shared many characteristics with CMMoL except for prominent monocytosis (4).
Pane et al. (9) and Saglio et al. (10) reported that cases of Ph1+ and µBCR rearrangement were a milder benign form of myeloproliferative disease, since the total leukocyte count was lower, anemia was less severe, splenomegaly was less prominent and blastic transformation occurred much later, if at all. Their cases sometimes had thrombocytosis (3). They designated this new disease as Ph1+ neutrophilic chronic myeloid leukemia (CML-N). Hochhaus et al. described a patient with Ph1– CNL with a novel BCR/ABL fusion gene at e6a2 with a 185 kDa fusion protein (17). Their case had basophilia and low leukocyte alkaline phosphatase activity. Patients with CNL rarely die during acute myeloblastic transformation. A CNL patient reported by Shindo et al. died during blastic transformation. However, the bone marrow remained free of blastic infiltration while pleural and perispinal tissues were infiltrated with myeloblasts (18). Wada et al. described a patient with atypical CML with Ph1 and c3a2 BCR/ABL rearrangemant and a 230 kDa fusion protein who died during myeloblastic transformation 2 years after the disease onset. This case was later considered to be Ph1+ CML-N (19).
In the present case, an increase in meutrophils of various maturational stages persisted, without dysplastic hematopoietic cells, monocytosis, eosinophilia, basophilia or thrombocytosis and no associated hematological changes were observed for 3 years during the clinical course. Blast cells appeared only in the terminal stage, when anemia and thrombocytopenia occurred. Blast cells were morphologically myeloblasts and were not monocytoid. However, myelomonocytic features may have been expressed since blasts were positive for peroxidase and esterase and serum and urine lysozyme levels were high. Our case was different from CML, atypical CML, CNL with dysplastic hematopoietic cells including CMMoL and lymphoplasmocytic diseases and other myeloproliferative disorders, based on the clinical and morphological findings. The results also indicated that our case of CNL was molecularly different from CML or CNL with known aberrant BCR/ABL gene rearrangement, although the molecular pathogenesis remain unknown.
Our patient complained of respiratory distress due to dyspnea without evidence of pneumonia when leukocytosis became marked. The present case was also rare, since thrombotic complication of the leg arteries occurred and amputation of the right leg was performed due to gangrene formation, and the left leg was also cyanotic during the last admission. The ischemic effect may be augmented by arteriosclerotic changes. These 10 symptoms reflect the hyperleukocyte syndrome in hyperleukocytic leukemia (20–22).
Genomic analysis of the G-CSF receptor in the present patient by SSCP and direct sequencing revealed that a mutation of the G-CSF receptor gene was unlikely.
Thus, our case of CNL was different from similar diseases since the molecular studies that were positive in the latter diseases were negative here. Further study is necessary of the pathogenesis of CNL like the present case.
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FOOTNOTES |
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+ For reprints and all correspondence: Kenji Shinohara, Division of Hematology, Department of Medicine, Yamaguchi Prefecture Central Hospital, Hofu 747-8511, JapanAbbreviations: CNL, chronic neutrophilic leukemia; Ph1, Philadelphia chromosome; CML, chronic myeloid leukemia; CMMoL, chronic myelomonocytic leukemia; MDS, myelodysplastic syndrome; BCR, break point cluster region; RT-PCR, reverse transcription polyemerase chain reaction; G-CSF, granulocyte colony-stimulating factor; SSCP, single strand conformation polymorphism
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Received March 13, 2000; accepted May 17, 2000.
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