Leukemia (1997) 11, 1318–1323
 1997 Stockton Press All rights reserved 0887-6924/97 $12.00
POEMS syndrome: report on six patients with unusual clinical signs, elevated levels
of cytokines, macrophage involvement and chromosomal aberrations of bone marrow
plasma cells
C Rose1, M Zandecki2, MC Copin3, P Gosset4, M Labalette5, PY Hatron6, MO Jauberteau7, B Devulder6, F Bauters1
and T Facon1
Service des Maladies du Sang; 2Laboratoire d’Hématologie A; 3Service d’Anatomie Pathologique C, CHU, Lille; 4Institut Pasteur Lille,
INSERM U416, Lille; 5Laboratoire d’Immunologie; 6Service de Médecine Interne A, CHU, Lille; and 7Laboratoire d’Immunologie, CHU,
Limoges, France
1
POEMS syndrome is a multisystemic disorder characterized by
the association of polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes and various other systemic
clinical signs. The pathophysiology of this syndrome remains
largely unknown. In order to gain insight into its pathophysiology, we studied the clinical characteristics and performed
serum analysis (auto-antibodies, cytokine levels) and phenotypic and cytogenetic studies of bone marrow plasma cells
(BMPC) in six patients with unequivocal POEMS syndrome.
Two unusual clinical signs were present in these patients: pulmonary hypertension (two patients) and diffuse cutaneous
necrosis (one patient). No auto-antibodies against peripheral
nerve (PN) antigens (SGPG and SGLPG glycolipids, GM1,
GD1a, GD1b and GT1b gangliosides) were found. Sequential
evaluations of serum cytokines (IL-1-beta, IL-6 and TNF-alpha)
showed a moderate to marked elevations of IL-6 and TNF-alpha
in all patients (up to six-fold for TNF-alpha and 16-fold for IL6). Using in situ hybridization of these cytokines mRNAs on
lymph node specimens of two patients who had an angiofollicular lymph node hyperplasia, a strong positivity was found with
the IL-1-beta antisense probe in lymph node macrophages. On
skin biopsy a high number of cells expressing TNF-alpha
mRNA was observed in the dermis. The biological features of
BMPC: phenotype (expression of CD19 and CD56 antigens),
kinetics (Ki-67 index), karyotype, DNA content and chromosomal in situ hybridization remained those of BMPC found in
monoclonal gammopathy of undetermined significance. We
conclude that POEMS syndrome is a hypercytokinemic syndrome in which BMPC are not of malignant type. Macrophages
are involved in this syndrome and their role has to be further
investigated as well as treatments which act through an anticytokine mechanism.
Keywords: POEMS syndrome; interleukin-6; TNF-alpha; macrophage; plasma cell
Introduction
POEMS syndrome is a variant of plasma cell dyscrasia with
polyneuropathy characterized by the association of polyneuropathy, organomegaly, endocrinopathy, M protein, and
skin changes.1 In addition to these five clinical features, a constellation of other clinical manifestations may be associated
with POEMS syndrome such as fever, peripheral edema,
ascites, pleural effusions, polycythemia or thrombocytosis. 2–5
The pathophysiology of this syndrome remains largely
unknown. Recently, an overproduction of proinflammatory
cytokines has been reported in POEMS syndrome.6–8 Furthermore, the question remains of the cellular origin of these cytokine overproductions. The role of plasma cell-derived products might be supported by the improvement occasionally
Correspondence: C Rose, Service des Maladies du Sang, CHU Lille
59037 Lille, France
Received 29 April 1996; accepted 3 March 1997
observed after surgery or local irradiation in patients with
POEMS syndrome and a solitary plasmocytoma.9,10 Nevertheless, the biological characteristics of bone marrow plasma
cells (BMPC) have not so far been studied and compared to
those of BMPC from other gammopathies. In this study, we
reviewed clinical aspects in six patients with POEMS syndrome. We also evaluated the levels and producing sites of
three cytokines, IL-1-beta, IL-6 and TNF-alpha and the presence of auto-antibodies directed against peripheral nerve
components. In addition, we studied phenotypic, kinetic and
genetic features of BMPC.
Patients and methods
Description of the population
Between 1988 and 1995, six patients with unequivocal
POEMS syndrome were referred to our department. Their
main clinical and biological characteristics are summarized in
Table 1. All patients had severe chronic demyelinating neuropathy and organomegaly. Endocrinopathy was also present in
all patients and included hypothyroidism (6/6), high serum
FSH (4/5), high serum LH (1/4), hyperprolactinemia (3/4), glucose intolerance (3/6), and hypotestosteronemia (4/5). Gynecomasty was found in 2/4 patients. Serum monoclonal protein
was detected in 4/6 patients (IgA lambda 3/6; IgG lambda 1/6).
Other classes of immunoglobulins had a normal level in these
patients. Serial and various electrophoresis (immunoelectrophoresis and immunofixation) were negative in patients
1 and 4 throughout the course of the disease. Median CRP
level was 12 mg/l (range 3–89). Skin changes were observed
in all patients and consisted of hyperpigmentation (5/6), skin
thickening (3/6), hypertrichosis (3/6), telangiectasis (4/6), and
finger clubbing (2/6). One patient had diffuse disease-related
cutaneous necrosis (patient 4). Bone lesions were solitary
sclerotic in one patient and multiple sclerotic in three patients.
Another patient had normal conventional bone X rays, but a
diffuse vertebral hypermagnetic resource imaging signal. Two
patients had angiofollicular lymph node hyperplasia resembling Castelman’s disease. Other clinical manifestations
reported in POEMS syndrome were present: edema (5/6),
papilledema (5/6), anasarca (4/6), proteinorachy greater than
500 mg/l (6/6), acrosyndrom (4/6), chronic diarrhea (3/6), and
cachexia (2/6), thrombocytosis (4/6), polycythemia (1/6).
Median platelet count was 395 × 109/l (range 215–689). The
white blood count was normal in all patients. Two patients
had pulmonary hypertension (PH) which was thought to be
related with POEMS syndrome. The diagnosis of PH was suggested by progressive dyspnea appearing during the course of
the disease and confirmed by high mean pulmonary artery
Unusual clinical signs in POEMS syndrome
C Rose et al
Table 1
1319
Main clinical and biological findings in the six patients with POEMS syndrome
Patient No.
1
2
Age (years)/Sex
Polyneuropathy
Hepatomegaly
Splenomegaly
Lymphadenopathy
Endocrinopathy
Skin change
Bone lesion
62/M
+
−
−
+
+
+
solitary sclerotic
32/M
+
+
+
+
+
+
no
Pulmonary hypertension
Angiofollicular hyperplasia
Thrombocytosis
Polycythemia
M component
−
+
+
−
never detected
−
not tested
+
−
IgG lambda
4g/l
−
−
−
−
IgA lambda
4g/l
+
+
+
−
never detected
4
ND
ND
ND
ND
ND
1
16
0
0.92
34
not demonstrated
15
37
10
0.90
26
trisomy 9
3
ND
ND
ND
ND
ND
Bone marrow plasmacytosis (%)
CD19 + PC (%)
CD56 + PC (%)
DNA index
% of aneuploid PC
Aneuploidy after FISH
3
4
33/F
44/M
+
+
+
+
+
+
−
+
+
+
+
+
multiple sclerotic multiple sclerotic
5
6
74/M
+
−
−
+
+
+
only MRI
hypersignal
65/F
+
+
+
+
+
+
multiple
sclerotic
−
not tested
+
−
IgA lambda
3g/l
+
not tested
−
+
IgA lambda
3g/l
3
4
72
ND
8
ND
1.33
0.94
42
61
trisomy 11 Not demonstrated
MRI, magnetic resonance imaging; ND, not done; PC, plasma cell; FISH fluorescence in situ hybridization.
pressure (mPAP): mPAP = 28 mmHg at rest in case 4 and
40 mmHg in case 6. Pulmonary hypertension was not associated with other secondary causes in these two patients. A complete description of these two patients and their hemodynamic
parameters is reported elsewhere.11
Serum study
Serum sampling:
Peripheral blood was taken in dry tubes
between 9 am and 12 am. The storage of the whole blood
was performed at room temperature. The serum was separated
within 30 min and was kept frozen at −80°C until analyzed.
Blood samples were obtained in the absence of fever, shock
and infection.
Detection of auto-antibodies directed against peripheral nerve
Screening of sera for an antiglycolipid reaccomponents:
tivity was performed with glycolipids purified from normal
human peripheral nervous system as previously described by
Jauberteau et al.12 This glycolipidic fraction contained gangliosides and the two antigens SGPG and SGLPG. Auto-antibodies to these sulfoglucuronyl glycolipids were characterized
by immunodetection on thin layer chromatography plates.13
Antibodies specific to gangliosides GM1, GD1a, GD1b, GT1b
(according to the nomenclature of Svennerholm14) and to the
sulfatide (cerebroside sulfate) were searched also by an
enzyme-linked immunosorbent assay as previously described
by Jauberteau et al15 and Brindel et al16 with purified glycolipids from Sigma (St Louis, MO, USA).
Plasma cell study
Serum cytokine levels:
Serum cytokine levels were evaluated prospectively in all six patients. Patients had one to 11
serial cytokine measurements, leading to 24 evaluations for
the six POEMS patients (19 samples only for TNF-alpha
measure). In comparison, serum cytokine levels were also
determined in other monoclonal gammopathies. Multiple
myeloma and Waldenström’s macroglobulinemia (MM + WM
group: five samples), polyneuropathy and plasma cell dyscrasia without criteria of POEMS syndrome (PPCD group:
three samples), and monoclonal gammopathies of undetermined significance (MGUS: four samples).
IL-1 beta, IL-6, and TNF-alpha assays:
Interleukin-1-beta
and interleukin-6 were measured using two sandwich type
enzyme immunoassays (Medgenix, Fleurus, Belgium and
Immunotech, Marseille, France). Interleukin-6 levels were
confirmed by a radio immunologic assay (IL-6 IRMA;
Medgenix). Tumor necrosis factor-alpha was measured using
the Medgenix kit. Cytokine levels were measured according
to the kit procedures.
The karyotype of BMPC was determined as previously
described.17 For interphase fluorescence in situ hybridization
(FISH) analysis, biotinylated centromeric probes directed
against chromosomes 3, 7, 8, 9 and 11 (D3Z1, D7Z1, D8Z2,
D9Z1, D11Z1; Oncor, Illkirch, France) were used.18 DNA
content of BMPC was measured using computerized imaged
analysis19 and the respective numbers of diploid and aneuploid BMPC were evaluated. Determination of the plasma cell
growth fraction used Ki-67 antibody,20 and expression of
CD19 and CD56 on BMPC were studied using immunocytochemistry.21
Immunohistochemistry and in situ hybridization for
cytokines
Two lymph nodes (patients 1 and 4), and one skin biopsy
(patient 4) were studied. Normal lymph node and skin were
used as negative controls. A benign follicular hyperplasia was
used as control for in situ hybridization. Six bone marrow
Unusual clinical signs in POEMS syndrome
C Rose et al
1320
Table 2
Serum cytokine levels in patients with POEMS syndrome and other monoclonal gammopathies
Cases
POEMS
1
2
3
4
5
6
PPCD
MM + WM
MGUS
No. of
samples
2
11
5
2
3
1
3
5
4
IL-1-beta
(n , 15 pg/ml)
median (range)
4
2
2.5
3
1
0.8
2
1
4
(1–7)
(0–13)
(0–10)
(1–5)
(0–2)
(1–4)
(0–1)
(0–13)
IL-6
(n , 8.5 pg/ml)
median (range)
91.5 (41–142)
10
(4–25)
17
(8–95)
25.5 (16–35)
16
(5–28)
18.5
4
(3–5)
12.5 (8–29)
9.5 (6–15)
TNF alpha
(n , 20 pg/ml)
median (range)
38
33
55
45.5
52.5
ND
21
20.5
22.5
(28–48)
(24–57)
(32–124)
(42–49)
(27–78)
(20–27)
(16–36)
(14–31)
PPCD, polyneuropathy and plasma cell dyscrasia; MM + WM, multiple myeloma + Waldenström’s macroglobulinemia; MGUS, monoclonal
gammopathy of undetermined significance.
Data presented in this Table are those of the Medgenix kit. Only 19 samples were available for TNF-alpha measure.
biopsies were immediately fixed in formalin and studied with
immunohistochemical methods only. Biopsy tissue was
immediately cut into two parts. Tissue was processed no more
than 30 min after surgical biopsy. One part was fixed in paraformaldehyde or formalin and paraffin-embedded for diagnostic evaluation. The other part was embedded in cryopreservative solution OCT (compound, Miles, Elkart, IN, USA),
snap-frozen in isopentane and stored at −80°C until use.
6 was found in all patients and in 13/24 serum samples. Serum
levels of TNF-alpha were elevated in all patients and all serum
samples (19 samples, elevation up to six-fold). All patients had
normal serum IL-1-beta levels using the Medgenix kit. One
patient (patient 4) had a very slight increase of IL-1-beta using
the Immunotech kit (15.5 pg/ml; normal value <5 pg/ml).
Immunohistochemistry:
We used the avidin-biotin technique as previously described.22 Monoclonal antibodies
employed included DBB42 (pan-B; Immunotech, Marseille,
France), L26 (anti-CD20; Dakopatts, Dako, Denmark), CD43
(Leu 22; Dakopatts), UCHL-1 (anti-CR45RO; Dakopatts),
CD68 (PG-M1; Dakopatts) and polyclonal IL-6 (Genzyme,
Cambridge, UK). On bone marrow specimens, antibodies
directed against kappa and lambda chains (Dakopatts) were
only performed. The following mouse monoclonal antibodies
were used to recognize B cells antigens: CD19 (Dakopatts),
CD20 (Dakopatts), CD22 (Leu 14; Dakopatts), T cell antigens:
CD3 (Dakopatts), CD4 (T4; Dakopatts), CD8 (T8; Dakopatts).
In situ hybridization for cytokines:
The cDNA for TNF and
for IL-1-beta (a generous gift of Dr P Vassali, Geneva,
Switzerland) were inserted into a p Bluescript vector, linearized with Pst1 or EcoR1 to produce antisense or sense probes before transcription. The IL-6 probe was generously purchased by Dr D Emilie (INSERM U131, Clamart, France).23 In
situ hybridization was performed as previously described.24
Non-specific mRNA signals never exceeded five grains/cell,
this observation leading to the definition of positivity threshold
for hybridization with the antisense probes. Positive mRNA
hybridization signals were only observed when slides were
hybridized with antisense probes.
Results
Serum studies
No patient had auto-antibodies directed against peripheral
nerve components. Serum cytokine levels are summarized in
Table 2. A moderate to marked (up to 16-fold) elevation of IL-
Figure 1
(a) Lymph node biopsy (patient No. 4): in situ hybridization with anti-IL-1 probe. Dark signals indicate the presence of IL-1
mRNAs in interfollicular macrophages. Inset: positivity of an interfollicular macrophage (clear cell with pale nuclei, original magnification
× 400). (b) Lymph node biopsy (patient No. 4): anti-CD68 monoclonal
antibody stains some interfollicular macrophages (original magnification × 100).
Unusual clinical signs in POEMS syndrome
C Rose et al
Plasma cell study
All patients had a bone marrow aspirate and a bone marrow
biopsy. Most results are reported in Table 1. Bone marrow
plasmacytosis was equal or less than 15% in all patients.
DNA index (DI) of BMPC was determined in four patients.
The DI ranged from 0.98 to 1.00 in normal controls and was
abnormal in the four tested POEMS patients (Table 1). All
patients had in fact two populations of BMPC, one diploid
and another one aneuploid, the latter ranging from 26 to 61%
of all BMPC. The karyotype (using conventional cytogenetics)
failed to show any anomaly in the three tested patients. Using
interphase FISH, patient 3 had 10% BMPC with trisomy 9 and
patient 5 had 17% BMPC with trisomy 11. The two other
patients tested were disomic with all tested probes.
The number of Ki-67-positive BMPC was less than 1% in
all patients. The CD19 and CD56 antigens, studied in three
patients, were expressed on 16–72% and 0–10% BMPC,
respectively (Table 1).
Immunohistochemistry and in situ hybridization for
cytokines
Lymph node biopsy of patients 1 and 4 demonstrated angiofollicular hyperplasia of the hyaline vacular type in patient 1
and of the mixed variety in patient 4. In patient 1, the interfollicular zones contained a polymorphic lymphoid infiltrate
with scattered plasma cells whereas numerous plasma cells
were present in patient 4 in the same zones. The germinal
centers were often atrophic. They contained a thickened vessel surrounded by concentric sheets of small lymphocytes.
Skin biopsy of patient 4 showed mild changes. The dermis
was infiltrated by a few inflammatory cells with scattered
small lymphocytes and mast cells around small vessels and
adnexia. Immunohistochemical studies showed a predominant population of B cells in the follicles and numerous T cells
and CD68-positive macrophages in the interfollicular spaces.
In both cases, a majority of interfollicular plasma cells were
lambda light-chain positive on paraffin-embedded sections. In
situ hybridization with sections of lymph nodes showed a
strong positive signal with IL-1-beta antisense probe in interfollicular spaces. These cells were medium-sized and mononuclear with an abundant clear cytoplasm. Localization in the
lymph node and morphologic characteristics of these cells
corresponded to those of macrophages. Immunohistochemistry with antibody anti-CD68 showed a strong positivity in the
same area (Figure 1a and b). In contrast, hybridization with
TNF-alpha and IL-6 antisense probes was negative on these
sections as well as in those from controls. In the cutaneous
biopsy from patient 4, who had diffuse cutaneous necrosis, a
high number of cells expressing TNF-alpha mRNA was
observed in the dermis whereas hybridization with IL-1-beta
and IL-6 antisense probes was negative.
Discussion
To our knowledge, diffuse cutaneous necrosis has never been
reported in patients with POEMS syndrome and pulmonary
hypertension (PH) has been reported in only one Japanese
case.25 There is some evidence that these two clinical signs
were related to cytokine overproduction, especially high levels of IL-6 and TNF-alpha. Patient 4, who had permanent high
levels of IL-6 and TNF-alpha (and a slight increase of IL-1-
beta using the Immunotech kit), had cutaneous necrosis and
pulmonary hypertension. Patient 6, the second patient with
pulmonary hypertension, also had an elevated level of IL-6 in
serum. In the cutaneous biopsy of patient 4, the role of TNFalpha in the necrosis was confirmed by the presence of a high
number of cells expressing TNF-alpha mRNA in the dermis.
Pathologically, PPH is associated with the proliferation of
smooth-muscle cells, fibroblasts, and endothelial cells in the
walls of small pulmonary arteries. The proliferative lesions are
associated with in situ microthrombosis.26,27 Interestingly, a
recent study demonstrated increased serum levels of IL-1-beta
and IL-6 in severe PPH and strongly suggested a role for these
cytokines in the pathogenesis of PPH.28 This progressive clinical course is in accordance with the slow progression of the
growth of smooth muscle cells, fibroblasts and endothelial
cells of the pulmonary arteries followed by microthrombotic
lesions. Overall, two out of six patients had in this series
proven PH and this incidence was possibly underevaluated.
We suggest that POEMS syndrome is an occasional cause of
secondary PH and that patients with POEMS syndrome
should be tested for PH, especially if they present with dyspnea.
No patient had auto-antibodies against peripheral nerve
components. Although the search for these auto-antibody
activities remains limited, this result does not support the role
of the M protein in the pathogenesis of polyneuropathy.
Another argument against the role of the M protein is that
some patients (patients 1 and 4 in this series) had neuropathy
without detectable M protein all over the course of the
disease.
Up to now, no study has been devoted to the BMPC in
POEMS syndrome, probably because of their low number and
the difficulty to biopsy osteosclerotic bone lesions. Over the
past few years, we have studied biological features of BMPC
in multiple myeloma and in MGUS, especially the Ki-67
kinetic index,17,19 immunophenotype,20 DNA content and
interphase FISH analysis.19 Our patients had a low BM plasmacytosis, a low proliferation rate and failed to exhibit karyotype anomaly using conventional cytogenetics. In the three
patients tested, CD19 was expressed by .10% BMPC in each
instance. In a previous study, we found that 77% of MGUS
patients had more than 10% CD19 positive plasma cells as
compared to only 12% of myeloma patients.20 All four
patients tested had an abnormal plasma cell DNA content,
restricted to a part of BMPC (26 to 61%), and this was confirmed by the exhibition of interphase FISH anomaly in some
BMPC. These findings were recently demonstrated as a quite
common anomaly in MGUS, exhibited by BMPC from more
than 50% of patients.19 Taking togther all these data, biological characteristics of BMPC from our patients with POEMS
syndrome are not far from what we observed in MGUS
patients. These data are in agreement with those from Miralles
et al,4 in which the outcome of 38 patients with plasma cell
dyscrasia and polyneuropathy (of whom 28 had >3 features
of POEMS syndrome) was multiple myeloma in only one case,
an incidence not far from that observed in MGUS.
Our study confirms the reports of Gherardi et al6–8 concerning the increase of IL-6 and TNF-alpha in the serum of patients
with POEMS syndrome. In contrast, we failed to demonstrate
elevated levels of IL-1-beta comparable to those achieved by
Gherardi et al. Normal levels of IL-1-beta in serum were also
found in a recent study from Japan.29 In our study, IL-1-beta
levels were measured by two different kits. We have no explanation for this discrepancy and a larger number of patients
should be studied to solve this problem. The most consistent
1321
Unusual clinical signs in POEMS syndrome
C Rose et al
1322
finding was an elevated level of TNF-alpha found in all
patients and all samples. In our opinion, the role of TNF-alpha
in the pathophysiology of polyneuropathy has to be strongly
considered. A high level of TNF-alpha in serum is in fact one
of the most frequent biological findings in these patients who
all suffer, by definition, from polyneuropathy. In addition,
high serum levels of TNF-alpha have been reported in patients
with Guillain–Barré syndrome and polyneuropathy associated
with monoclonal gammopathy.30 It has also been implicated
in auto-immune demyelination 31 and may alter the blood–
nerve barrier, leading to increased endoneural pressure and
damaging of nerve fibers.32 Finally, intraneural injections of
TNF-alpha can cause nerve destruction.32
The macrophage is the main producer of TNF-alpha and IL1-beta.33 Taking into account the high and prolonged production of TNF-alpha in POEMS syndrome, as well as the preliminary results we achieved with in situ hybridization using
the IL-1-beta probe, we can hypothesize that the macrophage
is involved in POEMS syndrome, at least for the abnormal production of these cytokines. The normal levels of interleukin2 and IFN-gamma also suggest that activation of macrophages
rather than T cells is concerned in POEMS syndrome.6
In conclusion, this study demonstrates that POEMS syndrome is an hypercytokinemic syndrome with elevated levels
of IL-6 and TNF-alpha in serum. It describes diffuse cutaneous
necrosis as a new and probably TNF-alpha-related clinical
sign. It also establishes pulmonary hypertension as a frequent
sign which was probably underevaluated in previous series
and is possibly IL-6-related. The biological characteristics of
bone marrow plasma cells were of non-malignant type. The
macrophage is involved in this syndrome. Further investigations will be necessary to fully appreciate its role, as well
as the impact of treatments which target the macrophage or
act through an anti-cytokine mechanism.
Acknowledgements
This work was supported by the Comités du Pas-de-Calais et
du Nord de la Ligue Nationale de Lutte contre le Cancer and
the CHRU, Lille. We thank Pierre Fenaux for critical review
of the manuscript and JL Faucompré, M Hammad and B
Hennache for expert technical assistance.
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