Journal List > Korean J Hematol > v.42(2) > 1032716

Korean J Hematol. 2007 Jun;42(2):151-156. English.
Published online June 30, 2007.  https://doi.org/10.5045/kjh.2007.42.2.151
Copyright © 2007 Korean Society of Hematology; Korean Society of Blood and Marrow Transplantation; Korean Society of Pediatric Hematology-Oncology; Korean Society on Thrombosis and Hemostasis
A Case of Chronic Neutrophilic Leukemia with Multiple Myeloma and an Increased Function of Her Neutrophils
Sollip Kim, M.D., Chan-Jeong Park, M.D., Kyoo Hyung Lee, M.D.,1 Seongsoo Jang, M.D., Hyun Sook Chi, M.D. and Eul-Ju Seo, M.D.
Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
1Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Correspondence to: Chan-Jeoung Park, M.D. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1, Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea. Tel: +82-2-3010-4508, Fax: +82-02-478-0884, Email: cjpark@amc.seoul.kr
Received February 05, 2007; Revised April 24, 2007; Accepted May 02, 2007.

Abstract

We describe here a 64-year-old woman who simultaneously presented with chronic neutrophilic leukemia (CNL) and multiple myeloma (MM). The patient presented with mature neutrophilic leukocytosis, hepatosplenomegaly, the absence of Philadelphia chromosome and the BCR-ABL fusion gene, along with IgG kappa type monoclonal gammopathy in her serum and urine. The bone marrow aspirates showed hypercellularity with marked granulocytic hyperplasia and an increase in immature plasma cells. The neutrophil function tests showed increased phagocytosis, chemotaxis and respiratory burst activity, but there was normal microbial killing activity. The patient was treated with dexamethasone and pamidronate for MM and with hydroxyurea for CNL, and she was discharged from the hospital in an improved condition.

Keywords: Chronic neutrophilic leukemia; Multiple myeloma; Neutrophil function test

INTRODUCTION

Chronic neutrophilic leukemia (CNL) is a rare myeloproliferative syndrome of elderly patients. Its diagnostic criteria include peripheral blood leukocytosis due to an increase in the number of mature neutrophils; hypercellularity on bone marrow biopsy; hepatosplenomegaly; no identifiable cause of physiologic neutrophilia; the absence of a Philadelphia chromosome or the BCR/ABL fusion gene; and no evidence of another myeloproliferative disease, a myelodysplastic syndrome or a myelodysplastic/myeloproliferative disorder.1) CNL is occasionally associated with multiple myeloma (MM). Neutrophil functions in CNL cases have been reported to vary, and they may be important in maintaining the function of the patient's immune system and in understanding the pathophysiology of CNL associated with MM. In this report, we describe a patient presenting with simultaneous IgG kappa type MM and CNL with increased neutrophil functions.

CASE REPORT

A 64-year-old woman was admitted to our hospital with an 8 month history of cough, sputum and aggravated dyspnea on exertion. She was transferred to our hospital for evaluation of marked neutrophilia. She had been on medication for hypertension for 5 years, and had taken thyroxine for hypothyroidism. Vital signs were blood pressure 162/82mmHg, temperature 35.9℃, pulse rate 81/min and respiration rate 24/min. She appeared chronically ill. Physical examination revealed hepatosplenomegaly, the liver extending 2FB and the spleen 5FB below the costal margins. Pitting edema was present on both legs.

One month earlier, hemoglobin was 8.9g/dL, platelet count was 105,000/µL and leukocyte count was 59,770/µL. On admission, hemoglobin 9.1g/dL, platelet count was 73,000/µL and leukocyte count was 93,000/µL, with the latter consisting of 93% segmented neutrophils, 2% lymphocytes, 4% monocytes, and 1% eosinophils. The neutrophils were of mature appearance with toxic changes and the rouleaux formation was observed. A bone marrow (BM) aspirate from the iliac crest was hypercellular, with marked granulocytic hyperplasia and predominant mature neutrophilic expansion, along with 12.2% plasmablasts and 30.6% plasma cells. The ratio of myeloid to erythroid cells was 25.9:1. A BM biopsy revealed packed marrow with marked mature granulocytic hyperplasia. Plasmablasts and plasma cells were present in the intertrabecular space (Fig. 1).


Fig. 1
Peripheral blood and bone marrow findings in the patient showing coexistence of chronic neutrophilic leukemia and multiple myeloma. (A) Neutrophilia, toxic changes of neutrophils and rouleaux formation of red cells in peripheral blood (Wright stain, ×400). (B) Markedly increased granulocytic series and frequent plasmablasts and plasma cells in bone marrow aspirate (Wright stain, ×400). (C) Hypercellular marrow with granulocytic hyperplasia and increased plasmablasts and plasma cells (H&E stain, ×400).
Click for larger image

Serum protein concentration was 9.6g/dL and albumin concentration was 2.3g/dL. Serum M-protein was 4.0g/dL. Serum and urine immunofixation electrophoresis showed IgG kappa monoclonality (Fig. 2). A skeletal x-ray showed no lytic lesions. Cytogenetic analysis of the BM aspirate showed normal karyotype with no evidence of Philadelphia chromosome by the G banding technique. Molecular genetic analysis by reverse transcriptase-polymerase chain reaction failed to reveal fusion of the chimeric bcr-abl messenger RNA. From these results, the patient was diagnosed as having CNL associated with MM.


Fig. 2
Immunofixation electrophoresis shows IgG kappa type monoclonal gammopathy in serum (A) and IgG kappa and free kappa type Bence-Jones proteinuria in urine (B). SPE, serum protein electrophoresis; UPE, concentrated urine electrophoresis.
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Neutrophil function tests2, 3) showed increased chemotaxis, as measured by the modified Boyden chamber method; and phagocytosis, as determined by flow cytometry after incubation of neutrophils with FITC-conjugated Candida albicans. In addition, respiratory burst activity was increased, as shown by flow cytometry using the DCF-DA method; and respiratory burst activity in the absence of stimulation (spontaneous respiratory burst activity) was markedly increased, whereas microbial killing activity was normal, as shown by flow cytometry of propidium iodide stained neutrophils that had been incubated with Candida albicans (Table 1).


Table 1
Neutrophil function in the patient with coexisting chronic neutrophilic leukemia and multiple myeloma
Click for larger image

The patient was treated with dexamethasone and pamidronate for MM and with hydroxyurea for CNL. She was discharged from the hospital with clinical improvement and has been followed up until now.

DISCUSSION

The clinical and laboratory findings of this patient satisfied the criteria required for the diagnosis of CNL. The diagnosis of MM was based on IgG kappa monoclonal hypergammaglobulinemia and increased plasmablasts and plasma cells in BM aspirates.

Although light and electron microscopy studies of neutrophils from a CNL patient do not reveal any differences from normal mature neutrophils, functional characterization shows marked differences. For example, neutrophils from a CNL patient are less viable.4) In this case, phagocytosis, chemotaxis and respiratory burst activity (superoxide production) were increased, especially in the absence of stimulation (spontaneous respiratory burst activity), whereas microbial killing activity was similar to that of normal control neutrophils. Normal or elevated phagocytosis and respiratory burst activity5-8) and decreased bactericidal activity of neutrophils4, 6, 7) have been reported in patients with CNL. Differences in neutrophil function may be due to differences in the pathophysiology of each patient or to technical differences in the assessment of neutrophil function.5)

To our knowledge, 22 patients, including ours, have been reported to have CNL associated with monoclonal gammopathy.9-12) The clonality types were IgG-lambda in 9 patients, IgA-lambda in 5 patients, IgG-kappa in 3 patients, IgA-kappa in 2 patient, kappa light chain in 2 patients and lambda light chain in 1 patient. 1 patient showed biclonal gammopathy.9-12) As previously reported by Ito et al.11), disproportionate association with lambda light chain rather than kappa chain was documented (κ:λ=7:15).9-12) In 16 cases, including the present case, CNL and monoclonal gammopathy presented simultaneously. However, in 5 cases, CNL was seen to occur before the appearance of monoclonal gammopathy. There were 2 cases in which CNL was preceded by monoclonal gammopathy.9-12) Although CNL is generally regarded as a myeloproliferative disorder and has shown evidence of clonality,13) myeloma-associated CNL can be caused by reactive myeloid proliferation.14) In this situation, the myeloid expansion might represent a leukemoid response induced by the plasma cell population.14) Plausible mechanisms could include enhanced release of stimulatory factors, for example, G-CSF or interleukin-3, and decreased production of putative inhibitory mediators which normally function to suppress granulocyte production.14) Recently, Kohmura et al.15) demonstrated that CD138 positive plasma cells purified from bone marrow of MM associated with neutrophilia expressed G-CSF mRNA. By immunohistochemical stain, Kusaba et al.16) demonstrated that G-CSF-producing myeloma with clinical manifestations mimicking chronic neutrophilic leukemia. In their case, atypical plasma cells were positive for anti G-CSF antibody.16) Therefore, it is possible that the production of G-CSF by plasma cells is involved in the development of chronic neutrophilic leukemia. If clonal neoplastic neutrophils proliferate, they may show decreased neutrophil functions. In contrast, the granulocytic expansion in CNL associated with MM may represent a polyclonal reactive response to the plasma cell clone rather than a co-existent myeloproliferative disorder.14) Elevated levels of IL-6 in patients with MM may stimulate granulopoiesis, resulting in expanding granulocytosis as in CNL17), which could explain our case, where marked neutrophilia, along with toxic changes and increased neutrophil functions, especially the markedly increased spontaneous respiratory burst activity of neutrophils.

We report a case of MM associated with a CNL and increased neutrophil function with review of the literatures. We agree that the so-called "CNL" is a syndrome of heterogeneous disorders, some of which are apparently clonal myeloid proliferation and others which may be leukemoid reactions.11) Especially in cases associated with monoclonal gammopathy, the evidence of clonality of neutrophils by molecular method and an evidence of no role of growth factors might be demonstrated to rule out a polyclonal reactive response to the plasma cell clone.

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