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Author
S Vincent Rajkumar, MD
Section Editor
Robert A Kyle, MD
Deputy Editor
Rebecca F Connor, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process
is complete.
Literature review current through: May 2013. | This topic last updated: Mai 7, 2013.
The clinical features, diagnosis, and treatment of POEMS syndrome will be discussed
here. A discussion of Castleman's disease is presented separately. (See "Castleman's
disease".)
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal protein
Skin changes
Patients frequently have higher levels of interleukin-1 (IL-1), tumor necrosis factor
alpha (TNF-alpha), and interleukin-6 (IL-6) than patients with multiple myeloma [5]. It
has been postulated that manifestations of POEMS syndrome might be regarded as the
result of a marked activation of these cytokines associated with a weak or decreased
TGF-1 antagonistic reaction [5]. Serum IL-6 levels in six patients with active POEMS
syndrome were higher than those with stable POEMS; elevated levels of serum IL-6
increased before each exacerbation of clinical symptoms [8]. Elevated levels of IL-6
have also been reported in pericardial fluid in these patients [9].
Others have demonstrated that platelets [10] or plasma cells [11,12] were a major source
of vascular endothelial growth factor (VEGF), a potent inducer of increased vascular
permeability. In addition, elevated levels of VEGF were noted to decrease significantly
in patients with POEMS syndrome following successful therapy [7,13,14]. (See
"Overview of angiogenesis inhibitors", section on 'Vascular endothelial growth factor'.)
In a Mayo Clinic series of 99 patients with this syndrome, the median age was 51 years
(range: 30 to 83) and 63 percent were males.
Cerebrospinal fluid protein levels are increased in virtually all patients, with more than
half of patients having a cerebrospinal fluid protein level >100 mg/dL [16]. The total
cell count is typically normal.
Biopsy of the sural nerve usually shows both axonal degeneration and demyelination;
severe endoneurial edema may also be seen [1]. A loss of myelinated fibers and an
increased frequency of axonal degeneration in teased fibers have been reported [18],
along with high expression of VEGF in vasa nervorum and some non-myelin- forming
Schwann cells [7]. Endoneurial deposits of immunoglobulins of the same type as in the
serum have been reported in three of four patients with POEMS syndrome [19].
Papilledema was seen in 29 percent of patients with POEMS in the Mayo Clinic series
[1] and in 40 to 55 percent of patients in the two other major series [20,21].
Organomegaly Fifty percent of patients in the Mayo Clinic series had organomegaly
(hepatomegaly, splenomegaly, and/or lymphadenopathy) [1]. Each was present in about
one-fourth of the patients. These figures are lower than those seen in two other major
series, in which hepatomegaly, splenomegaly, and lymphadenopathy were present in 68
to 78, 35 to 52, and 52 to 61 percent, respectively [20,21]. When present, organomegaly
is mild, and massive enlargement of any of these organs is unusual. In the few liver
biopsies that were performed, only non-specific reactive changes were found, without
an infiltrative process.
Monoclonal plasma cell disorder All patients by definition must have evidence of a
monoclonal plasma cell proliferative disorder, either on serum and/or urine
immunofixation studies, or on immunostaining or flow cytometric studies done on the
bone marrow. (See 'Mayo Clinic criteria' below.)
Findings based on the Mayo Clinic series are listed below [1]:
The type of light chain seen in POEMS syndrome is almost always lambda [24].
The associated heavy chain was IgA, IgG, or IgM in 44, 40, and one patient
each, respectively.
Plasma VEGF levels appear to be at least as good as, if not better than, serum levels. In
a study of 105 patients (29 with POEMS, 9 with Castleman disease, 15 with monoclonal
plasma cell disorders, 52 with other disorders), a plasma VEGF level >200 pg/mL had a
sensitivity and specificity of 68 and 95 percent, respectively, in support of a diagnosis of
POEMS syndrome [27].
In this study, all patients who had treatment showed both clinical improvement as well
as a reduction in plasma levels of VEGF. However, there was no significant difference
in plasma VEGF levels on day 180 or last follow-up between those who did or did not
achieve complete clinical remission.
Renal disease In one study, 18 cases with acute and chronic renal failure associated
with POEMS syndrome were reported [33]. Prominent glomerular changes manifested
by mesangial proliferation and thickening of the capillary wall were seen. There was no
difference in IL-1, IL-6, or TNF-alpha levels in four cases of POEMS with renal
involvement when compared with those without this feature [34].
Another report examined 52 cases of POEMS syndrome with renal pathology described
in the literature [35]. Renal tissue was reviewed in 22 patients. Approximately one-half
of the patients had creatinine levels above 1.5 mg/dL; 10 percent required dialysis. The
major pathologic changes were glomerular and included glomerular enlargement,
cellular proliferation, mesangiolysis, and marked swelling of the endothelial mesangial
cells. Endarteritis-like lesions were found in the small renal arteries. In one reported
case, POEMS syndrome subsequently developed in a patient who presented with light
chain deposition disease producing nephrotic syndrome [36].
Cardiovascular disease Both arterial and venous thromboses have been described in
POEMS syndrome. Fifteen patients reported in the literature had gangrene, ischemia,
myocardial infarction, splenic infarcts, or strokes. Four patients have been reported with
POEMS syndrome who had an acute arterial thrombotic event [37]; all had elevated
cytokines. In a 31-year-old patient with POEMS, ischemic cardiomyopathy was
attributed to inflammation of the coronary arteries [38].
Forty-one thrombotic events occurred in 18 patients reported in the Mayo Clinic series
[1]. These most often consisted of cerebral infarction, myocardial infarction, or Budd-
Chiari syndrome. Three patients presented with heart failure and cardiomyopathy which
resolved following treatment of POEMS syndrome. Four other patients developed heart
failure, which occurred during an exacerbation of POEMS syndrome.
Pulmonary involvement In one small series, two of six patients with POEMS
syndrome had pulmonary hypertension [41]. Two additional patients with pulmonary
hypertension and POEMS syndrome have been described [42]. In a third series,
pulmonary hypertension developed in 5 of 20 patients with POEMS syndrome over a
10-year follow-up [6]; overproduction of interleukin-1beta, interleukin-6, tumor
necrosis factor-alpha, and vascular endothelial growth factor was found in all cases in
this latter series.
In the Mayo Clinic series of 137 patients with POEMS syndrome, pulmonary
manifestations were present in 28 percent, and included pulmonary hypertension,
restrictive lung disease, respiratory muscle weakness, and an isolated diminished
diffusing capacity [43]. Significant radiographic findings such as pleural effusion,
elevated diaphragm, and increased cardiac silhouette were seen in 28 percent of
patients. Respiratory muscle weakness and cough were associated with a poor
prognosis. (See 'Clinical course' below.)
Anemia (hemoglobin concentration <11 g/dL) is present in <5 percent of patients, while
a hemoglobin >16 g/dL (eg, polycythemia) is seen in approximately 15 percent. Blood
volume studies, erythropoietin levels, and reticulocyte counts have not been routinely
obtained for evaluating elevated hemoglobin levels.
The total white blood cell count and platelet count are elevated (ie, >10,500 and
>450,000/microL, respectively) in approximately 20 and 50 percent of our patients,
respectively.
Bone marrow examination shows monotypic plasma cells (usually lambda) in about
two-thirds of patients, typically in a background of increased polytypic plasma cells
[44]. In about half of the patients, lymphoid aggregates surrounded by a rim of plasma
cells can be seen. Megakaryocyte hyperplasia and clusters are also frequent. The
constellation of lambda-restricted monoclonal gammopathy, plasma cell rimming
around lymphoid aggregates, and megakaryocyte hyperplasia may be highly suggestive
of this diagnosis [44].
Lymph node biopsies are most often read as showing either Castleman's disease or
reactive changes. Criteria for the diagnosis of multiple myeloma are not met in any
patient (eg, multiple bone fractures, progressive bone marrow failure, or
hypercalcemia). No patients in our series died of typical multiple myeloma. (See
"Clinical features, laboratory manifestations, and diagnosis of multiple myeloma",
section on 'Diagnosis'.)
Other signs and symptoms Other findings commonly seen in POEMS syndrome
include [1]:
Fatigue 31 percent
Papilledema 29 percent
Clubbing 5 percent
DIAGNOSIS In the three major series of patients with POEMS syndrome, all
presented with polyneuropathy and 75 to 100 percent had initial evidence for a
monoclonal plasma cell disorder [1,20,21]. The immunoglobulin light chain type in
POEMS syndrome is almost always lambda. The other three key features defining this
syndrome (organomegaly, endocrinopathy, skin changes) were variably met (table 1).
Mayo Clinic criteria In a series of 99 patients at the Mayo Clinic, only 29 had all five
of the originally described features of this syndrome [1]. On the basis of these
observations, the current Mayo Clinic criteria for POEMS syndrome are based on five
major (two of them mandatory) and six minor criteria (table 2). The diagnosis of
POEMS syndrome requires the presence of at least three major criteria (polyneuropathy,
monoclonal plasma cell disorder plus any one of the following three: osteosclerotic
myeloma, Castlemans disease, or elevated serum or plasma VEGF levels at least three
to four times the upper limit of normal), along with the presence of at least one of the
six minor criteria (excluding diabetes mellitus or hypothyroidism) [45]. Atypical
cases (eg, without polyneuropathy or without a monoclonal paraprotein) have been
described [46-48].
The absence of either osteosclerotic myeloma or Castleman's disease should make the
diagnosis of POEMS syndrome suspect. Not every patient who meets the above criteria
will have POEMS syndrome; the abnormal features should have a temporal relationship
to each other and no other attributable cause. Elevations in plasma or serum levels of
vascular endothelial growth factor, thrombocytosis, and polycythemia are common
features of the syndrome and are helpful when the diagnosis is difficult. (See 'Vascular
endothelial growth factor (VEGF) levels' above.)
A metastatic bone survey must be done in a search for osteosclerotic lesions. These
lesions can be subtle and easily confused with benign bony sclerosis, fibrous dysplasia,
or a vertebral hemangioma. Osteolytic lesions may have a sclerotic rim, which is a
helpful diagnostic finding.
In rare instances, multiple myeloma may be associated with the presence of diffuse
osteosclerotic bone disease in areas of active hematopoiesis, different from the focal
sclerotic lesions seen in POEMS. Such patients have the typical clinical and laboratory
features of multiple myeloma and do not have the other characteristics of POEMS
syndrome [53].
The natural history is one of progressive peripheral neuropathy until the patient is
bedridden. Death usually occurs from inanition or a terminal bronchopneumonia. The
most commonly identified causes of death in our series were cardiorespiratory failure
and infection. None of our patients died of classic myeloma with progressive bone
marrow failure, pathologic fractures, or hypercalcemia. Those patients who died of renal
failure had coexistent ascites and a capillary leak-like syndrome. Light chain deposition
was not observed.
Overall median survival was 13.7 years in the Mayo Clinic series [1], while those with
clubbing or extravascular volume overload had median survivals of 2.6 and 6.6 years,
respectively. Survival was not related to the number of minor criteria present at the time
of diagnosis. Patients who received radiation therapy with a good response to treatment
had superior survival. (See 'Radiation therapy' below.)
Fifty-nine patients with POEMS syndrome have undergone autologous HCT using
peripheral blood stem cells at the Mayo Clinic [58]. Clinical improvement was nearly
universal in these patients with five-year overall and progression-free survivals of 94
and 75 percent, respectively. Other reports of autologous HCT in POEMS have also
described clinical improvement, with often dramatic neurologic improvement [14,66-
68]. These studies illustrate that for transplant eligible patients, autologous HCT is one
of the most important treatment advances in the treatment of POEMS syndrome.
POEMS syndrome is characterized by the presence of the following elements (table 1).
Polyneuropathy
Organomegaly
Endocrinopathy
Monoclonal protein
Skin changes
This condition should be suspected in a patient with polyneuropathy and evidence for a
monoclonal plasma cell disorder (table 1). (See 'Clinical features' above.)
The diagnosis of POEMS syndrome requires the presence of at least three major
criteria (ie, polyneuropathy plus monoclonal plasma cell disorder plus any one
of the following three: osteosclerotic bone lesion(s), Castlemans disease, or
elevated serum or plasma VEGF levels), along with the presence of at least one
of the six minor criteria (table 2). The absence of either osteosclerotic myeloma
or Castleman's disease should make the diagnosis of POEMS syndrome suspect.
(See 'Diagnosis' above.)
There is no standard treatment for this disorder and there have been no
randomized controlled clinical trials of treatment for POEMS syndrome.
However, approximately 75 percent of treated patients have had some response
to therapy.
The best chemotherapeutic responses to date have been seen following treatment with
melphalan and dexamethasone, although the role of novel agents used effectively in
multiple myeloma (eg, lenalidomide, bortezomib) has not been well studied. (See
'Chemotherapy' above.)
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GRAPHICS
Clinical features of POEMS syndrome
Mayo series (n Soubrier, et al. (n Nakanishi, et al. (n =
Criterion
= 99) = 25) 102)
Polyneuropathy 100 100 100
Organomegaly 50 NA NA
Hepatomegaly 24 68 78
Splenomegaly 22 52 35
Lymphadenopathy 26 52 61
Endocrinopathy 67 NA NA
Diabetes mellitus 3 36 25
Monoclonal plasma cell
100 100 75
disorder
Skin changes 68 NA NA
Hyperpigmentation 46 48 93
Hypertrichosis 26 24 74
This table indicates the percent of patients from three major series of patients with
POEMS who satisfied each of the original five components of this syndrome.
NA: data not available.
Data from: Dispenzieri, A, et al. Blood 2003; 101:2496.
Criteria for the diagnosis of POEMS syndrome
Mandatory major criteria (both required)
Polyneuropathy
Monoclonal plasma cell proliferative disorder (almost always lambda)
Other major criteria (one required)
Sclerotic bone lesions
Castleman's disease
Elevated levels of vascular endothelial growth factor (VEGF)*
Minor criteria (one required)
Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy)
Extravascular volume overload (edema, pleural effusion, or ascites)
Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora,
acrocyanosis, flushing, white nails)
Papilledema
Thrombocytosis/polycythemia
The diagnosis of POEMS syndrome is confirmed when both of the mandatory major
criteria, one of the three other major criteria, and one of the six minor criteria are
present.
* The source data do not define an optimal cut off value for considering elevated VEGF
level as a major criterion. We suggest that VEGF measured in the serum or plasma
should be at least three- to fourfold higher than the normal reference range for the
laboratory that is doing the testing to be considered a major criterion. In order to
consider endocrinopathy as a minor criterion, an endocrine disorder other than diabetes
or hypothyroidism is required since these two disorders are common in the general
population.
Original figure modified for this publication. Dispenzieri A. POEMS syndrome. Blood
Rev 2007; 21:285. Illustration used with the permission of Elsevier Inc. All rights
reserved.