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CORRESPONDENCE
Monocytosis and High Serum Macrophage Colony-Stimulating Factorin Waldenstriim's Macroglobulinemia
To the Mitor:
Waldenstrijm'smacroglobulinemia (WM) is a clonal lymphoid
disorder characterizedby the lymphoplasmacytic proliferationin the
bone marrow (BM) and the elevation of serum monoclonal IgM.'
Several cytokines were reported
to be involved inthe clonal proliferation of lymphoid neoplasm.For example,in patients with myeloma,
malignant plasma ceUs constitutively produce interleukin-6 (L-6)
and promote their autocrine proliferation.* Serum IL-lfl and L - 6
are elevated in the patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome,
suggesting a role of both cytokines in its pathogenesis? We report
a caseof macroglobulinemia with highserum concentration of macrophage colony-stimulating factor (M-CSF) and
L-6, which presented marked monocytosis and severe pulmonary hypertension.
A 56-year-old man was admitted to
our hospital because
of fatigue
and dyspnea on exertion. Physical examination showed mild hepatomegaly and holosystolic murmur at the left sternal margin. Serum
IgM was markedlyelevated to 7,120 mg/dL. shown to be monoclonal
IgM ( K ) by immunoelectrophoresis. The leukocyte count was 5.300/
pL with 34%of neutrophils, 25% lymphocytes, and 37% monocytes.
The hemoglobin was 7.9 g
/&
and the platelet count was 20.7
X
l@/&. He had no lytic bone lesions. BM examination showed the
proliferation of abnormallymphoplasmacytoid cells (up to 14%).
Chest radiograph disclosed enhanced pulmonary vascular shadow
and cardiomegaly. Echocardiography showed marked right ventricular enlargement and massive tricuspid regurgitation. The estimated
systolic pulmonary artery pressure was about60 mm Hg. Based on
these findings, he was diagnosed as having WM with monocytosis
and pulmonary hypertension. The observed monocytosis in this patient was transiently normalizedin response to chemotherapy (cyclophosphamideandprednisolone)andreturnedto
the pretreatment
level after 3weeks. Thus, we suspected its correlation to macroglobulinemia. To clarify the causeof monocytosis. we measured serum
M-CSFconcentration
by enzyme-linkedimmunosorbentassay
(ELBA). It was remarkably elevated to 2,319 U/& (mean 2 SD
serum level of M-CSF was
756 2 147 U/mL in 634 healthy individuals). Serum L - 6 was also elevated to 41.8 pg/& (normal: <4.0
pg/mL). Next we attempted to clarify which cell populations produced high level of M-CSF in
this patient. For this purpose, the
peripheralbloodmononuclear cells (PBMCs)fromthepatient as
well as a normal control were stained with anti-M-CSF antibody
in combination with anti-CD2O. The cells were then run on a laser
confocal scanning microscopy. It has been shown that the PBMCs
fromthepatientweredouble-stainedby
anti-CD20 andanti-MCSF (Fig lA), whereas those from a normal control were not (Fig
IB). These results strongly indicate that cD20+ B lymphocytes in
this patient produce M-CSF.
There are few reports describing serum cytokine concentrationin
patients with macroglobulinemia. Solary et a14 reported high serum
L-6 in 2 of 20 patients with macroglobulinemia. Gherardi et a13
also found one patient with high serum L-6, but no case with high
serum IL-lP, among five patients they studied. It
is reported that
serum M-CSF concentrationis elevated in some cases with lymphoplasmacytoid malignancy such as lymphoma, chronic lymphocytic
leukemia (CLL). and myeloma'; however, macroglobulinemia was
not included in this study. To our knowledge, this is the first report
of high serum M-CSF in patient with macroglobulinemia.
The major production sites of M-CSFare monocytes. fibroblasts,
endothelial cells,and placenta! However. Epstein-Barr virus (EBV)
Blood, Vol86, No 7 (October l),
1995: pp 2863-2864
'.
Fig 1. Analysis of "CSF production from peripheral B lymphcyter bylaser confocalscanning microscopy.Peripheral mononuclear
cells were separated by dendty-gradient centrifugation and
permeabilized with 0.05% digitonin forl 0 minuter. SurfaceCD20 and cytoplasmic "CSF werestainedbyphycoerythrin-labeled
antiGD20
antibody (redl together
with fluoreswin hthiocyanate-labaleda d "CSF antibody (gram). Cells were prepared on a slide glass and
scanned by laser confocal scanning microscopy IhleridianInstruments, Okemos, MI).Some of the cells from the patient were stained
by both antibodies, resultingin yellow color (A). In contrast, CD20*
cells from the normal individual were not stainedanti-M-CSF,
by
but
by anti-CD20, giving the red color (B).
2863
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2864
CORRESPONDENCE
transformed or mitogen-activated B lymphocytes are also reported
to express M-CSF mRNA by Northern blotting analy~is.~
These
results suggest that M-CSF mRNA is negatively regulated in resting
B lymphocytes, but could be induced by stimulation from the cell
interior or exterior. Thus, it is likely that M-CSF was produced by the
malignant and/or activated B lymphocytes in this patient. Although it
is difficult to determine which is the predominant population to
produce M-CSF, the malignant B cells could have a central role in
this setting either by producing M-CSF as an autocrine growth factor,
or producing some mitogenic substances that activate normal B lymphocytes.
The etiology of pulmonary hypertension is unclear because there
was no evidence of organic heart and pulmonary diseases. Vascular
intimal smooth muscle cells from the atherosclerotic lesions are
reported to proliferate in response to M-CSF, and these phenomena
contribute to the atherosclerotic process in the arterial wall.* Thus,
high serum M-CSF level may have some role in pulmonary hypertension through promoting arteriosclerosis of the pulmonary arteries.
Hideaki Nakajima
Shigehisa Mori
Tsutomu Takeuchi
Hiromi Sekine
Keiko Saito
Tohru Abe
The Second Department of Internal Medicine
Saitama Medical Center
Saitama Medical College
Saitama, Japan
Yasuo Ikeda
Division of Hematology
Keio University School of Medicine
Tokyo, Japan
REFERENCES
I . Dimopoulos MA, Alexanian R: Waldenstrom’s macroglobulinemia. Blood 83:1452, 1994
2. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K,
Asaoku H, Tang B, Tanabe 0, Tanaka H, Kuramoto A, Kishimoto
T: Autocrine generation and essential requirement of BSF-2nL-6
for human multiple myeloma. Nature 322:83, 1988
3. Gherardi RK, Belec N. Fromont G, Divine M, Malapert D,
Gaulard P, Degos JD: Elevated levels of interleukin-lp (IL-1p) and
IL-6 in serum and increased production of IL-lp mRNA in lymph
nodes in patients with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome. Blood
83:2587, 1994
4. Solary E, Guiguet M, Zeller V, Casasnovas RO, Caillot D,
Chavanet P, Guy H, Mack G: Radioimmunoassay for the measurement of serum L - 6 and its correlation with tumor cell mass parameters in multiple myeloma. Am J Hematol 39:163, 1992
5. Janowska-Wieczorek A, Belch AR, Jacobs A, Bowen D, Padua
R A , Paietta E, Stanley ER: Increased circulating colony-stimulating
factor-l in patients with preleukemia, leukemia, and lymphoid malignancies. Blood 77:1796, 1991
6. Pimentel E: Handbook of Growth Factors, v01 111: Hematopoietic Growth Factors and Cytokines. Boca Raton, FL, CRC, 1994, p
177
7. Reisbach G, Sindennann J, Kremer JP, Hultner L, Wolf H,
Dormer P: Macrophage colony-stimulating factor (CSF-I) is expressed by spontaneously outgrown EBV-B cell lines and activated
normal B lymphocytes. Blood 74:959, 1989
8. Inaba T, Yamada N, Gotoda T, Shimano H, Shimada M, MomomuraK,Kadowaki T, Motoyoshi K, Tsukada T, Morisaki N.
Saito Y, Yoshida S, Takaku F, Yazaki Y: Expression of M-CSF
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From www.bloodjournal.org by guest on December 29, 2014. For personal use only.
1995 86: 2863-2864
Monocytosis and high serum macrophage colony-stimulating factor in
Waldenstrom's macroglobulinemia [letter]
H Nakajima, S Mori, T Takeuchi, H Sekine, K Saito, T Abe and Y Ikeda
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