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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 12 (June 15), 1999:
pp. 4144-4148
Serum Hyaluronan in Patients With Multiple Myeloma: Correlation With
Survival and Ig Concentration
By
Inger Marie S. Dahl,
Ingemar Turesson,
Erik Holmberg, and
Karin Lilja for the Nordic Myeloma Study Group
From the Section of Hematology, University Hospital, Tromsø, Norway;
the Department of Medicine, University Hospital, Malmö, Sweden;
the Oncological Centre, Sahlgrenska University Hospital, Gothenburg,
Sweden; and the Department of Medical and Physiological Chemistry,
Biomedical Centre, University of Uppsala, Uppsala, Sweden.
 |
ABSTRACT |
Serum from 386 myeloma patients were analyzed for serum hyaluronan
(HYA) at diagnosis. Median age was 68 years (range, 32 to 87 years).
The distribution of Ig classes was typical (58% IgG, 21% IgA, 1%
IgD, and 20% light chain disease). The patients comprised 58% in
stage III, 33% in stage II, and 9% in stage I. The majority (82%)
had HYA values within an intermediate range (10 to 120 µg/L), 13%
had high values (>120 µg/L), and 5% had abnormally low values (0 to 9 µg/L). For the first time, a patient group with abnormally low
HYA serum values is reported. An inverse correlation between survival
and HYA serum level was found (P = .015). When tested
separately, patients with abnormally low or high HYA values had
significantly shorter median survival (21.1 and 19.7 months,
respectively) than those with an intermediate HYA concentration (32.6 months; P = .005). Patients with abnormally low or high HYA
levels had more advanced disease as judged by staging and biochemical
markers. Interestingly, there was an inverse correlation between the
HYA value and the M-component concentration in serum. Fifty percent of
patients with abnormally low HYA values had IgA myelomas. In
conclusion, the serum concentration of HYA may be of prognostic value
in selected cases of multiple myeloma. Further studies will be
performed to elucidate possible explanations for our findings,
especially those related to the HYA cell surface binding proteins.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
HYALURONAN (HYA) IS A high molecular
weight polysaccharide that is mainly located extracellularly in all
tissues. The concentration varies with the localization and state of
the tissue investigated. The highest quantities are found in loose
connective tissues such as the umbilical cord (4,100 mg/kg) and the
synovial fluid (1,400 to 3,600 mg/L). High concentrations are also
found in the vitreous body (140 to 340 mg/kg) and dermis (200 mg/kg). The biosynthesis of this large, linear chain molecule occurs in the
plasma membrane of cells, which are regulated by different factors such
as inflammatory mediators, hormones, and growth factors (for review see
Fraser et al1). HYA production increases in proliferating
cells, especially during mitosis. For several decades, it has been
known that mesenchymal cells form a hyaluronidase-sensitive pericellular layer.2 Discoveries of specific cell surface
receptors that can attach HYA to cells make it probable that HYA is an
important regulator of cellular activities.3 Various
HYA-receptors have been identified on different cell types, such as
CD44 present on lymphocytes,4 and more recently described
on myeloma cells (for review, see Cook et al5).
Expression of the HYA-binding CD44-receptor and its specific splice
variants have also been reported in many other malignancies and, in
various ways, have been linked to their metastatic
behavior.6-14
Since a method for detecting nanogram amounts of HYA was
developed15,16 that uses the ability of this molecule to
bind to proteoglycans, HYA has been detected in body fluids, such as lymph, serum, urine, and pleural fluid. Rough calculations indicate that one-third of all HYA in tissues (15 g in an average adult) is
catabolized every day. The major part is catabolized by local uptake in
cells and in lymph nodes. The remaining, regarded as normal spill-over,
is carried to the blood by lymph in an amount of 20 to 40 mg/d and is
rapidly taken up mainly by the liver endothelial cells viz. specific
receptors. The half-life of circulating HYA in healthy adults is 2.5 to
5.5 minutes (see Fraser et al1 and references therein).
The serum HYA value is the steady-state level arising from supply and
removal. Normal healthy middle-aged persons have been found to have
serum HYA levels in the order of 10 to 100 µg/L, with an
age-dependent continued increase from the level at 16 years of 29 ± 17 µg/L (mean ± standard deviation [SD]) to 177 ± 133 µg/L
in elderly healthy persons over 75 years of age.17 In the
age group of 61 to 70 years, ie, close to the mean age of the patients
in the present study, the level was 112 ± 88 µg/L. Very high serum
levels of HYA have been found in patients with liver disease (>700
µg/L), and high concentrations are correlated with histopathological
diagnosis of cirrhosis. This is because of an impaired clearance from
blood, manifested as a longer half-life in serum, a lower splanchnic
extraction, and a lower maximal clearance capacity of the liver
endothelial cells (see Laurent et al18 and references
therein). High HYA levels are also seen in joint disease such as
rheumatoid arthritis (mean values up to 297 µg/L), because of a large
increase in total HYA in the joint fluid that is driven out by lymph
into the circulation by physical activity. Serum HYA is found to
correlate to the total joint involvement.19,20 In septic
patients, high serum HYA is correlated with a bad
prognosis.21 Probably, HYA synthesis is enhanced by tumor
necrosis factor- (TNF-), and increased capillary permeability may
lead to a wash-out of HYA from the interstitium. Patients with certain
tumors are also found to have high values of HYA, first described in
children with nephroblastoma (see Laurent et al18 and
references therein). Extreme values have been reported in patients with
progressive malignant mesothelioma (median value, 250 µg/L; range, 41 to 37, 880 µg/L).22 In these cases, the increased amount
of HYA is probably produced locally due to stimulation by various
growth factors.23 No medical condition with serum HYA
levels less than 10 µg/L has been reported so far.
Multiple myeloma (MM) is a B-cell malignancy of unknown etiology with
expansion of clonal malignant plasma cells. Clinically, this can result
in the presence of monoclonal Igs in serum and/or urine, pancytopenia,
renal dysfunction, hypercalcemia, and/or bone destruction. The purpose
of this study was to examine serum HYA in a large, unselected group of
patients with newly diagnosed MM and see if HYA could serve as a
disease marker in this condition. Information about HYA is of special
interest as myeloma cells express receptors for this
polysaccharide.5
| |
MATERIALS AND METHODS |
Patients
A total of 583 patients were entered in the Nordic Myeloma Study Group
(NMSG) randomized trial from June 1990 to November 1992. Patients with
newly diagnosed MM were randomized to receive Melphalan-Prednisone or
Melphalan-Prednisone-Interferon 2b. The diagnostic and eligibility
criteria and results of treatment were described by Hjorth et
al.24 Our study group consisted of 386 unselected patients from whom serum samples were drawn before randomization and start of therapy. The median age of the patients in
the study group was 68.0 years (range, 32 to 87 years; mean age,
66.7 ± 9.0 SD). There were 228 males and 158 females. The distribution of myeloma characteristics were typical, with M-component type IgG in 58.3%, IgA in 21.2%, and IgD in 3 patients (0.8%). One
patient (0.3%) had a nonsecreting myeloma. Seventy-six patients (19.7%) had light chain disease. According to the clinical staging system by Durie and Salmon,25 8.5% of the patients were in
stage I, 33.2% in stage II, and 58.3% in stage III. Additional
parameters measured were the percentage of plasma cells in bone marrow,
hemoglobin, calcium, creatinine, serum albumin, and serum
 2-microglobulin. After completion of the study, all sera
were analyzed for interleukin-6 (IL-6), IL-6 receptor (IL-6sR), and
C-reactive protein (CRP).
Methods
Serum analyses.
The serum samples were analyzed by a radiometric assay16
based on the use of specific HYA binding proteins isolated from bovine
cartilage. The HYA in the serum sample reacts with
125I-labeled HYA binding proteins in solution. The unbound
label is then quantitated by incubating with HYA covalently bound to Sepharose particles of small size and low density. Separation is
performed by centrifugation, followed by decanting, and the radioactivity bound to the particles is counted in a gamma counter. The
radioactivity is inversely related to the HYA concentration in the
serum sample.
Because the majority of the samples with abnormally low HYA levels
appeared to have high levels of Ig, the sera were stepwise diluted up
to 10 times with normal serum to ensure that the very low HYA
concentrations were not due to an assay artifact.
Statistical analyses.
The survival time was measured from the date of randomization to death
or last follow-up. To estimate the association to survival, the HYA
serum values were transformed to rank order and analyzed univariately
by the Cox proportional hazard model. The survival curves for different
groups of HYA serum values were constructed by the Kaplan-Meier method
and compared by the log-rank test. The nonparametric Mann-Whitney-U
test was used to compare patient characteristics between patients with
abnormally low (<10 µg/L), intermediate (10 to 120 µg/L), and
high (>120 µg/L) HYA serum levels. P values less than .05 were considered statistically significant. The analyses were performed
on a Macintosh computer with the use of the statistical program
StatView 4.5 (Abacus Concepts, Inc; Berkeley, CA). The NMSG study found
no survival differences between the two arms of treatment; thus, it was
possible to pool data from both treatment arms in the evaluation of
prognostic significance for the parameters studied.
| |
RESULTS |
The median HYA value was 47 µg/L (range, 0 to 19,650 µg/L). The HYA
values of 315 (82%) myeloma patients were within the intermediate range, whereas 51 (13%) had elevated values and 20 (5%) had
abnormally low values.
HYA serum levels were not associated with survival when used as
absolute values. However, after transformation to rank order, a
significant inverse correlation to survival was found in a univariate analysis (P = .015). HYA was not a significant independent
prognostic factor when tested in a multivariate analysis. HYA serum
levels transformed to rank order were correlated to M-component
concentration (r =  .245), age (r = .215), serum
creatinine (r = .201), and serum
2-microglobulin (r = .146).
A more complex pattern was seen when the patients were grouped
according to high, intermediate, or abnormally low HYA serum levels.
Patients with either abnormally low or high serum HYA levels had
significantly shorter survival (median survival, 21.1 and 19.7 months,
respectively) than patients with serum HYA levels within the
intermediate range (32.6 months; Fig 1).
Table 1 displays the association between
stages of disease, according to Durie and Salmon,25 and HYA
levels. There were relatively more patients with advanced disease in
the groups with abnormal low or high serum HYA levels. The Ig class of
the M-component was also unevenly distributed, with a higher proportion
of IgA myeloma cases in the group with abnormally low HYA levels and
more Bence Jones myeloma cases among patients with high HYA levels.
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| Fig 1.
Kaplan-Meier survival curves for 386 myeloma patients
separated by low (0 to 9 µg/L, n = 20), intermediate (10 to 120 µg/L, n = 315), and high (>120 µg/L, n = 51) HYA value.
The survival difference between the abnormally low or high and the
intermediate HYA level group were significant (P = .005).
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Patients in the group with abnormally low HYA levels had a
higher percentage of bone marrow plasma cells, higher
M-component concentration, and lower levels of hemoglobin and
albumin when compared with patients with HYA levels in the intermediate
range (Table 2). Patients in the group with
high HYA levels had significantly lower hemoglobin levels and higher
2-microglobulin levels when compared with patients with
HYA levels in the intermediate range. There was an inverse correlation
between serum HYA level and M-component concentration most pronounced
in the IgG myeloma (Fig 2). Serum levels of
Ca, creatinine, IL-6, IL-6sR, and CRP did not differ significantly
between the three HYA level groups. The age distribution was also
similar (mean ± SD of 63.1 ± 12.7, 66.7 ± 8.7, and
67.7 ± 9.3 years in the abnormally low, intermediate, and high HYA level groups, respectively).
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| Fig 2.
Box plots of IgG (n = 224; upper panel) and IgA
(n = 82; lower panel) concentrations in myeloma patients separated
by low (0 to 9 µg/L; left), intermediate (10 to 120 µg/L; middle),
and high (>120 µg/L; right) HYA serum values (number of patients in
each group is given in Table 1). The horizontal lines in the plots
represent the 10th, 25th, 50th, 75th, and 90th percentile,
respectively. The differences between the abnormally low and
intermediate HYA value groups were significant (P = .016
[IgG] and P = .009 [IgA], respectively).
|
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| |
DISCUSSION |
Because our patient group has a median age of 68.0 years with a very
wide range (32 to 87 years), it is not possible to give a normal HYA
level range that includes all the patients. We find it therefore more
correct to describe levels ranging from 10 to 120 µg/L as
intermediate values. The main finding in this study is that, in a large
well-defined population of myeloma patients, the HYA concentration in
serum before start of treatment was within the intermediate range in
the majority of patients. Only 13% of the patients had values above
120 µg/L, ie, a limit above which earlier studies have shown
increased morbidity in middle aged patients.18,19 This is
in accordance with our own observation in a small group of myeloma
patients,26 but in contrast to the findings of Abildgaard
et al,27 who found increased levels in serum of all 15 myeloma patients investigated. This emphasizes the importance of
investigating large groups of patients when testing HYA as a suitable
tumor marker.
An interesting observation in the present study is that a small group
(n = 20 [5%]) of patients showed abnormally low serum HYA levels,
which were previously not reported for any patient group. Experiments
were performed to ensure that this was not due to an assay artifact,
because Ig theoretically could interfere with the binding protein in
the HYA assay.
When testing patients showing abnormally low, intermediate, and high
serum HYA levels for clinical and laboratory parameters, it appeared
that a majority with abnormally low or high HYA values were patients
with advanced disease, as judged by staging (Table 1) or by measuring
parameters such as hemoglobin, serum albumin, and Bence Jones protein
(Table 2). It is emphasized that the patient age and CRP status were
similar in the different HYA groups, because it is known that HYA
levels increase with age17 and with
infection.21 A connection between low HYA levels and
disease activity has, to our knowledge, not been reported earlier. In addition, there turned out to be a strong inverse correlation between
the levels of Ig and HYA in serum, in particular IgG. In correspondence
with this finding, the patient group with abnormally low HYA had the
highest number of abnormal plasma cells in the bone marrow. This
negative correlation between Ig and HYA persisted when patients with
IgG and IgA myeloma were investigated separately (Fig 2).
Interestingly, we also found an increased number (50%) of IgA myeloma
in the low HYA level group (Table 1).
Even if the majority of patients had HYA levels within the intermediate
range, an inverse correlation between increasing serum HYA levels and
survival was found. This is in accordance with several studies on
patients with various diseases, malignant as well as
nonmalignant.18,19,28 The finding of a connection between
elevated serum HYA levels and 2-microglobulin, an
accepted prognostic marker in MM, supports the significance of the
finding of an inverse correlation between increasing serum HYA and
survival. However, the association of HYA levels to survival is more
complex, because it was observed that patients with abnormally low
levels also have a poor prognosis (Fig 1). It may be argued that the finding of a bad prognosis in patients with abnormal levels is to be
expected, because abnormal serum levels of any biologically important
component of blood may be correlated to bad outcome by different
mechanisms. However, we have no indication to believe that it is the
abnormal HYA value that induces a shorter survival. We suggest that the
abnormal HYA serum level is mirroring serious pathological mechanisms
within the malignant myeloma clones.
It is known that the survival of cancer cells depends on their ability
to adhere to the tissue matrix, to proliferate, to migrate, to invade
the tissue, and to form metastases. It has also been proposed that HYA
is involved in all these steps. The presence of HYA binding adhesion
molecules, especially CD44 and receptor for hyaluronic acid-mediated
motility (RHAMM), is under intensive investigation at present. The
binding of HYA to these cell receptors is claimed to be of great
importance for cell-cell and cell-matrix interaction and thereby for
cell migration and metastatic expansion of malignant
cells.3,12,14,29 Concerning MM, it is known that neoplastic
myeloma cells differ from normal plasma cells and other B-cell
malignancies by an almost exclusive homing to the bone marrow
microenvironment. Cook et al5 claim that cellular adhesion
molecules such as the HYA-binding CD44 receptor are involved in this
homing and that some of these adhesion molecules potentiate
proliferation rather than Ig production. This mechanism could be one
among several possible reasons for this inverse association between
serum values of Ig and HYA in our patients. One explanation for the
abnormally low HYA values in the circulation in some myeloma patients
is the occurrence of an excess of unoccupied HYA binding receptors on
myeloma cells in the bone marrow that can bind circulating HYA produced
in other tissues. This may result in an even shorter half-life of
circulating HYA than otherwise found in normal subjects.1
Furthermore, the occurrence of adhesion molecules has been more
frequently found in the bone marrow of patients with active multiple
myeloma compared with patients with inactive disease.30
Recently Masellis-Smith et al31,32 have shown the
importance of subsets of B cells or leukemic plasma cells in blood for
the HYA-dependent spread of malignant myeloma cells in patients with MM.
Concerning patient survival and CD44 expression, an important
observation was made by Kaufmann et al,33 who demonstrated an association between the expression of CD44 variant exon epitopes in
primary breast cancer and length of survival. The presence of these
CD44 epitopes absent in nonmalignant tissue controls was correlated
with poor overall survival. Furthermore, patients with CD44 splice
variant positive ovarian carcinomas had a significantly shorter
disease-free survival than patients with CD44 splice variant negative
tumors.34
To our knowledge, no work has been performed to elucidate the
correlation between HYA serum level and expression of HYA binding cell
receptors in vivo. However, by testing melanoma cell lines, those with
high metastatic potential did show an increased migration rate on an
HYA-rich matrix in addition to a significant increased number of the
HYA binding CD44 epitopes.35 Production of HYA as well as
the CD44 receptor was increased in those cell lines, indicating an
autocrine mechanism that could eventually result in an elevated serum
level of HYA. In line with these speculations, high HYA serum levels in
some of the current myeloma patients may indicate an increased HYA
production by the myeloma cells and increased growth of the cells in
the marrow, resulting in spill-over of HYA to the circulation. High HYA
serum level could alternatively originate from other adjacent cells
under influence of growth factors, as in mesothelioma cell
lines.23 Why abnormally low HYA levels are inversely
associated to survival could be explained correspondingly. The low HYA
levels in these patients may be due to absence of autocrine mechanisms
for HYA production combined with a strong binding of circulating HYA to
internalizing HYA receptors on the myeloma cells. This adds to the
receptor-mediated clearance of circulating HYA by the liver endothelial
cells, as previously discussed.
In conclusion, the measurement of serum HYA levels alone in myeloma
patients is unlikely to give significant prognostic information, because the majority of our patients had values within an intermediate range. However, our findings may have impact regarding myeloma pathophysiology. At present, we are investigating, in addition to HYA
serum level, HYA binding adhesion molecules on myeloma cells from
patients with various forms of MM. By combining these different
parameters, we hope to find new ways to characterize this complex
disease and to elucidate its biological aspects.
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FOOTNOTES |
Submitted September 17, 1998; accepted February 17, 1999.
Supported by the Norwegian Cancer Society, Oslo, Norway.
Members of the directory board of the Nordic Myeloma Study Group in
alphabetical order: I.M.S. Dahl, P. Gimsing, E. Hippe, M. Hjorth, E. Holmberg, J. Lamvik, E. Löfvenberg, S. Magnusson, J.L. Nielsen,
I. Palva, S. Rödjer, I. Talstad, I. Turesson, J. Westin, and F. Wisløff.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Inger Marie S. Dahl, Section of Hematology,
University Hospital, 9038 Tromsø, Norway.
| |
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35.
Goebeler M, Kaufmann D, Bröcker EB, Klein CE:
Migration of highly aggressive melanoma cells on hyaluronic acid is associated with functional changes, increased turnover and shedding of CD44 receptors.
J Cell Sci
109:1957, 1996[Abstract]
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