Received: 13 April 2019 Accepted: 17 April 2019
DOI: 10.1002/ajh.25495
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL
MALIGNANCIES
POEMS Syndrome: 2019 Update on diagnosis,
risk-stratification, and management
Angela Dispenzieri
Division of Hematology and Division of
Clinical Chemistry, Mayo Clinic, Rochester,
Minnesota
Correspondence
Angela Dispenzieri, Department of Medicine
and Laboratory Medicine, Mayo Clinic,
Rochester, MN.
Email: dispenzieri.angela@mayo.edu
Funding information
Andrew & Lillian A. Posey Foundation; Predolin
Foundation the JABBS Foundation; Robert
A. Kyle Hematologic Malignancies Fund
812 © 2019 Wiley Periodicals, Inc.
Abstract
Disease Overview: Polyneuropathy, organomegaly, endocrinopathy, M-protein, skin
changes (POEMS) syndrome is a paraneoplastic syndrome due to an underlying plasma
cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy, clonal
plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth
factor, and the presence of Castleman disease. Minor features include organomegaly,
endocrinopathy, characteristic skin changes, papilledema, extravascular volume over-
load, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare
and can be mistaken for other neurologic disorders, most commonly chronic inflamma-
tory demyelinating polyradiculoneuropathy. POEMS syndrome should be distinguished
from the Castleman disease variant of POEMS syndrome, which has no clonal PCD and
typically little to no peripheral neuropathy but has several of the minor diagnostic
criteria for POEMS syndrome.
Diagnosis: The diagnosis of POEMS syndrome is made with three of the major
criteria, two of which must include polyradiculoneuropathy and clonal PCD, and at
least one of the minor criteria.
Risk Stratification: Because the pathogenesis of the syndrome is not well under-
stood, risk stratification is limited to clinical phenotype rather than specific molecular
markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary
hypertension, and reduced eGFR.
Risk-Adapted Therapy: For those patients with a dominant sclerotic plasmacytoma,
first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated
bone marrow involvement and for those who have progression of their disease 3 to
6 months after completing radiation therapy should receive systemic therapy. Cortico-
steroids are temporizing, but alkylators are the mainstay of treatment, either in the
form of low dose conventional therapy or high dose with stem cell transplantation.
Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib
also have activity, but their benefit needs to be weighed against their risk of exacerbat-
ing the peripheral neuropathy. Prompt recognition and institution of both supportive
care measures and therapy directed against the plasma cell result in the best
outcomes.
wileyonlinelibrary.com/journal/ajh Am J Hematol. 2019;94:812–827.
DISPENZIERI 813

1 | D I S E A S E OV E R V I E W with POEMS revealed 20 mutations in 7 recurrently mutated genes:

KLHL6, LTB, EHD1, EML4, HEPHL2, HIPK2, and PCDH10.40
POEMS syndrome is a rare paraneoplastic syndrome due to an under-
lying plasma cell disorder (PCD). The acronym, which was coined by
2 | DIAGNOSIS
Bardwick in 1980,1 refers to several, but not all, of the features of the
syndrome: polyradiculoneuropathy, organomegaly, endocrinopathy,
The diagnosis is made based on a composite of clinical and laboratory
monoclonal PCD, and skin changes. There are three important points
features (Table 1), and the diagnosis will be missed if it is not consid-
that relate to this memorable acronym: (a) not all of the features
ered. Most notably, the constellation of neuropathy and any of the fol-
within the acronym are required to make the diagnosis; (b) there are
lowing should elicit an in-depth search for POEMS syndrome:
other important features not included in the POEMS acronym, includ-
monoclonal protein (especially lambda light chain); thrombocytosis;
ing papilledema, extravascular volume overload, sclerotic bone lesions,
anasarca; or papilledema. Any patient who carries a diagnosis of
thrombocytosis/erythrocytosis (PEST), elevated vascular endothelial
chronic inflammatory demyelinating polyneuropathy (CIDP) that is not
growth factor (VEGF) levels, a predisposition toward thrombosis, and
responding to standard CIDP therapy should be considered as a possi-
abnormal pulmonary function tests; and (c) there is a Castleman dis-
ease variant of POEMS syndrome may is associated with a clonal ble POEMS syndrome patient, and additional testing should be done

PCD. Other names of the POEMS syndrome that are less frequently to rule in or rule out the diagnosis of POEMS syndrome. The

used are osteosclerotic myeloma, Takatsuki syndrome or Crow-

Fukase syndrome.2,3 The disease was initially thought to be more TABLE 1 Criteria for the diagnosis of POEMS syndromea
common in patients of Japanese descent given the largest initial Mandatory major 1. Polyneuropathy (typically demyelinating)
reports from Japan.2,3 However, over the years, large series have also criteria 2. Monoclonal plasma cell-proliferative
been reported from France, the United States, China, and India.4-8 A disorder (almost always λ)
national survey conducted in Japan in 2003 showed a prevalence of Other major criteria 3. Castleman diseasea
9 (one required)
approximately 0.3 per 100 000. 4. Sclerotic bone lesions
The pathogenesis of the syndrome is not well understood. Distinc- 5. Vascular endothelial growth factor
tive presenting characteristics of the syndrome that differentiate elevation
POEMS syndrome from standard multiple myeloma (MM) include the Minor criteria 6. Organomegaly (splenomegaly,
following: (a) dominant symptoms are typically neuropathy, endocrine hepatomegaly, or lymphadenopathy)

dysfunction, and volume overload; (b) dominant symptoms have little 7. Extravascular volume overload (edema,
pleural effusion, or ascites)
to nothing to do with bone pain, extremes of bone marrow infiltration
by plasma cells, or renal failure; (c) VEGF levels are high; (d) sclerotic 8. Endocrinopathy (adrenal, thyroid,b
pituitary, gonadal, parathyroid, pancreaticb)
bone lesions are present in the majority of cases; (e) overall survival is
9. Skin changes (hyperpigmentation,
typically superior; and (f) lambda clones predominate.10
hypertrichosis, glomeruloid hemangiomata,
To date, VEGF is the cytokine that correlates best with disease plethora, acrocyanosis, flushing, white
activity,11-20 although it may not be the driving force of the disease nails)
based on the mixed results seen with anti-VEGF therapy.21-28 VEGF is 10. Papilledema
known to target endothelial cells, induce a rapid and reversible 11. Thrombocytosis/polycythemiac
increase in vascular permeability, and be important in angiogenesis. It Other symptoms Clubbing, weight loss, hyperhidrosis,
is expressed by osteoblasts, in bone tissue, macrophages, tumor and signs pulmonary hypertension/restrictive lung
cells29 (including plasma cells),30,31 and megakaryocytes/platelets.32 disease, thrombotic diatheses, diarrhea,
low vitamin B12 values
Wang and colleagues have demonstrated the bone marrow plasma
cells of patients with POEMS syndrome had higher levels of VEGF Abbreviation: POEMS, polyneuropathy, organomegaly, endocrinopathy,
M-protein, skin changes.
mRNA expression than did their CD138 negative cells.33 A remarkable
The diagnosis of POEMS syndrome is confirmed when both of the
observation was that both polyclonal plasma cells and clonal plasma mandatory major criteria, one of the three other major criteria, and one of
cells had equally high levels of intracellular VEGF though monoclonal the six minor criteria are present.
a
PCs had higher levels of intracellular IL-6 expression. Both IL-1β and There is a Castleman disease variant of POEMS syndrome that occurs
without evidence of a clonal plasma cell disorder that is not accounted for
IL-6 have been shown to stimulate VEGF production.29 IL-12 has also
in this table. This entity should be considered separately.
been shown to correlate with disease activity.34 Little is known about b
Because of the high prevalence of diabetes mellitus and thyroid
the plasma cells in POEMS syndrome except that more than 95% of abnormalities, this diagnosis alone is not sufficient to meet this minor
the time they are lambda light chain restricted with restricted immu- criterion.
c
Approximately 50% of patients will have bone marrow changes that
noglobulin light chain variable gene usage.35-37 Translocations and
distinguish it from a typical MGUS or myeloma bone marrow.41 Anemia
deletion of chromosome 13 have been described.38,39 Whole exome and/or thrombocytopenia are distinctively unusual in this syndrome unless
sequencing, targeted sequencing, and RNA sequencing of 11 patients Castleman disease is present.
814 DISPENZIERI

requirements set forth in Table 1 are designed to retain both sensitiv-
ity and specificity, potentially erring on the side of specificity. Making
the diagnosis can be a challenge, but a good history and physical
examination followed by appropriate testing—most notably radio-
graphic assessment of bones,42-44 measurement of VEGF,13,17,20,45,46
and careful analysis of a bone marrow biopsy41—can differentiate this
syndrome from other conditions like CIDP, monoclonal gammopathy
of undetermined significance (MGUS) neuropathy, and immunoglobu-
lin light chain amyloid neuropathy. A high platelet count is seen in
54% of POEMS patients as compared to 1.5% of patients with CIDP.47
Helpful cut-offs for plasma and serum VEGF levels to diagnosis
POEMS syndrome are 200 pg/mL (specificity 95%; sensitivity 68%)20
and 1920 pg/mL (specificity 98%; sensitivity 73%),48 respectively.
Wang and colleagues have identified N-terminal propeptide of type I
collagen as a novel marker for the diagnosis of patients with
POEMS.48 They found the best cut-off of N-terminal propeptide of
type I collagen to diagnosis POEMS syndrome is 70 ng/mL with a
specificity of 91.5% and a sensitivity of 80%. As will be discussed,
there is a Castleman's variant of POEMS syndrome that does not have
a clonal plasma cell-proliferative disorder underlying, but have many
of the other paraneoplastic features.49
Distinguishing POEMS syndrome from a MGUS, smoldering MM
(SMM), MM, or solitary plasmacytoma is important as the treatment,
supportive care, and the expected treatment-related toxicities are
quite different. If a patient with POEMS syndrome is incorrectly
deemed to have a MGUS or SMM, then no treatment directed at the
clone will be recommended, existing symptoms will worsen, and the
patient will accumulate additional elements of the paraneoplastic syn-
drome. If the patient is diagnosed with MM or plasmacytoma, and
standard therapies for these disorders are administered, the likelihood
is high that there will be increased treatment-related morbidity and
inadequate supportive care. Therefore, a patient with POEMS syn-
drome should be thoroughly evaluated to define a baseline that can
be used for future assessments (Table 2).
A thorough review of systems and physical examination are
required. Estimated frequencies of findings are shown in Table 3. The
variability between series is most likely a function retrospective
reporting—that is, if a physician does not order a test or chart a

TABLE 2 Recommended minimum testing

Every Every
Test Baseline 3-6 months 1-2 years
History and review of systems
Detailed neurologic history (numbness, pain, weakness, balance, orthostasis) X X
History regarding menstrual and sexual function X X
Skin pigment, thickening and texture, body hair quantity and texture, color of distal extremities, X X
and development of cherry angiomata
Physical exam
Neurologic exam X X
Fundoscopy X X
Organomegaly, lymphadenopathy, extravascular volume overload X X
Skin (see above) X X
Blood
Complete blood count (hemoglobin, platelet) X X
Serum protein electrophoresis, quantitative immunoglobulin and immunofixation X X
Vascular endothelial growth factor X X
Testosterone, estradiol, fasting glucose, glycosylated hemoglobin, thyroid stimulating hormone, X Xa X
prolactin
Follicle stimulating hormone, luteinizing hormone, adrenocorticotropin hormone, cortrosyn Xa Xa
stimulation test, serum cortisol, parathyroid hormone
Other studies
24 hour urine total protein, electrophoresis, and immunofixation X X
Bone marrow aspirate and biopsy (test for kappa/lambda by IHC) X Xa
Electrophysiologic study (nerve conduction studies) X Xa
Sural nerve biopsy Xa
Echocardiography to assess right ventricular systolic and pulmonary artery pressures X Xb
Pulmonary function tests including DLCO X Xb
a
Skeletal CT and/or PET/CT for bone lesions, organomegaly, effusions X X

Abbreviations: DLCO, diffusion capacity of carbon monoxide; IHC, immunohistochemistry.

a
As clinically indicated.
b
Only if affected.
DISPENZIERI 815

T A B L E 3 Summary of frequencies of POEMS syndrome findings may be a dominant feature in about 10% to 15% of patients, though
based on large retrospective series2,3,5,7,50,51 in one report as many as 76% of patients had hyperesthesia.9,53
Characteristic % Affectedb Papilledema is present in at least one-third of patients (Figure 1A). Of
the 33 patients at our institution referred for a formal ophthalmologic
Polyneuropathy 100
examination during a 10-year period, 67% had ocular signs and symp-
Organomegaly 45-85
toms, the most common of which was papilledema in 52% of those
Hepatomegaly 24-78
examined.54 The most common ocular symptoms reported were
Splenomegaly 22-70
blurred vision in 15, diplopia in 5, and ocular pain in 3. In a series of
Lymphadenopathy 26-74
41 patients from China, there was a positive correlation between
Castleman disease 11-25 serum VEGF levels and the binocular mean retinal nerve fiber layer
Endocrinopathy 67-84 thickness.55 In another series of 94 patients, papilledema, which was
Gonadal axis abnormality 55-89 found in approximately 50% of patients, was an adverse prognostic
Adrenal axis abnormality 16-33 feature for overall survival.56
Increased prolactin value 5-20 A whole skin examination should be performed looking for hyper-
Gynecomastia or galactorrhea 12-18 pigmentation, a recent out-cropping of hemangioma, hypertrichosis,
Diabetes mellitus 3-36 dependent rubor and acrocyanosis, white nails (Figure 1B), sclero-

Hypothyroidism 9-67 dermoid changes, facial atrophy, flushing, or clubbing.2,4-8,57,58 Rarely

calciphylaxis is seen.59,60 Respiratory complaints are usually limited
Monoclonal plasma cell dyscrasiaa 100
given patients' neurologic status impairing their ability to induce car-
M-protein on serum protein electrophoresis 24-54
diovascular challenges. In a series of 137 POEMS syndrome patients
Skin changes 68-89
seen at our institution between 1975 and 2003, at presentation the
Hyperpigmentation 46-93
frequency with which patients reported dyspnea, chest pain, cough,
Acrocyanosis and plethora 19
and orthopnea, were 20%, 10%, 8%, and 7%, respectively.61
Hemangioma/telangiectasia 9-35 Patients are at increased risk for arterial and/or venous thrombo-
Hypertrichosis 26-74 ses during their course, with nearly 20% of patients experiencing one
Thickening 5-43 of these complications.10,62 Ten percent of patients present with a
Papilledema 29-64 cerebrovascular event, most commonly embolic or vessel dis-
Extravascular volume overload 29-87 section and stenosis.63 The median time between peripheral neuropa-
Peripheral edema 24-89 thy symptom onset and the cerebrovascular event was 23 months
Ascites 7-54 (range 0.5-64 months). Risk factors for cerebral events included

Pleural effusion 3-43 thrombocytosis and bone marrow plasmacytosis. Aberrations in the
coagulation cascade have been implicated in POEMS syndrome.64 In
Pericardial effusion 1-64
one report, circulating coagulation factors like fibrinopeptide A,
Bone lesions 27-97
thrombin-antithrombin complex are increased during the active phase
Thrombocytosis 54-88
of illness, but other factors relating to fibrinolysis, plasminogen, a2
Polycythemia 12-19
plasmin inhibitor plasmin complex, and FDP did not increase.
Clubbing 5-49
On physical examination, objective evidence of the symptoms
Decreased DLCO >15 described above can be found in addition to non-bulky adenopathy,
Pulmonary hypertension 36 gynecomastia, darkened areolae, diminished breath sounds, hepato-
Weight loss >10 lb 37 splenomegaly, areflexia, and a steppage gait, commonly with a positive
Fatigue 31 Romberg sign. In our experience, fingernail clubbing is seen in about 4%

Abbreviations: DLCO, diffusing capacity of carbon monoxide; POEMS,
polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes.
a
In both the Takasuki and Nakanishi series, only 75% of patients had a
documented plasma cell disorder, which defies the current definition for
POEMS syndrome. As these are among the earliest series describing the
syndrome, they are included.
b
Percentages are based on the total number of patients in the series.
finding, it will not be captured—and local practices, and promptness of
2,3,5,7,50
diagnosis, rather than ethnic differences. The neuropathy is
the dominant characteristic. The quality and extent of the neuropathy,
which is peripheral, ascending, symmetrical, and affecting both sensa-
52
tion and motor function should be elicited ; in our experience, pain
of cases, but others have reported rates as high as 49%.3,61
Laboratory findings are notable for an absence of cytopenias. In
fact, half of patients will have thrombocytosis or erythrocytosis.50 In
the series of Li and colleagues, 26% of patients had anemia, which the
authors attributed to impaired renal function.7 Their series was
enriched with Castleman disease cases (25%), which may have also
contributed to this unprecedented rate of anemia.
The bone marrow biopsy reveals megakaryocyte hyperplasia and
megakaryocyte clustering in 54% and 93% of cases, respectively.41
These megakaryocyte findings are reminiscent of a myeloproliferative
disorder, but JAK2V617F mutation is uniformly absent. One-third of
patients do not have clonal plasma cells on their iliac crest biopsy.
816
These are the patients who present at with a solitary or “multiple soli-
tary plasmacytomas.” The other two-thirds of patients have clonal
plasma cells in their bone marrow, and 91% of these cases are clonal
lambda. The median percent of plasma cells observed is less than 5%.
Immunohistochemical staining is more sensitive than is six-color flow
as the former provides information on bone marrow architecture,
which is key in making the diagnosis in nearly half of cases. This find-
ing was validated in another study.33 In our study of 67 pretreatment
bone marrows biopsies from patients with POEMS syndrome, lym-
phoid aggregates were found in 49% of cases.41 Of these, there was
plasma cell rimming in all but one, and in 75% and 4% the rimming
was clonal lambda and kappa, respectively. This finding was not seen
in bone marrows from normal controls or from patients with MGUS,
MM, or amyloidosis. The only other disease that this clonal rimming
was seen was in patients with lymphoplasmacytic lymphoma. Overall,
only 8/67 (12%) of POEMS cases had normal iliac crest bone marrow
biopsies, that is, no detectable clonal plasma cells, no plasma cell
rimmed lymphoid aggregates, and no megakaryocyte hyperplasia.
Plasma and serum levels of VEGF are markedly elevated in patients
11,20,29,65
with POEMS and correlate with the activity of the dis-
ease. 13,17,20,29
The principal isoform of VEGF expressed is VEGF165. 13
VEGF levels are independent of M-protein size. 13
Increased VEGF has
been found in ascitic fluid66 and the cerebrospinal fluid.17 IL-1β, TNF-α,
and IL-6 levels are often also increased. Serum VEGF levels are 10 to
50 times higher plasma levels of VEGF,67 making it unclear which test is
preferred. In patients with POEMS, VEGF is found in both plasma
30,31,33 65
cells and platelets. The higher level observed in serum is attrib-
utable to the release of VEGF from platelets in vitro during serum
processing. Because plasma is a product of an anticoagulated sample,
DISPENZIERI
F I G U R E 1 Manifestations of
POEMS syndrome. A, Optic disc
edema. B, Skin changes including white
nails and cyanosis. C-E, Mixed lytic
osteosclerotic bone lesions on plain
radiograph (C) and CT scan (D and E).
POEMS, polyneuropathy,
organomegaly, endocrinopathy,
M-protein, skin changes [Color figure
can be viewed at
wileyonlinelibrary.com]
there is less platelet activation and therefore less platelet VEGF contrib-
uting to the plasma measurement than the serum sample. Tokashiki
et al argue that serum VEGF is the better test because it reflects the
VEGF contribution from both the serous and platelet compartments.67
However, the counter-argument is that the amount VEGF release by
platelets may vary due to collection and processing technique, making
serum measurements of VEGF less reliable.
Extravascular overload most commonly manifests as peripheral
edema, but pleural effusion, ascites, and pericardial effusions are also
common. The composition of the ascites was studied in 42 patients
with POEMS syndrome. The ascitic fluid had low serum ascites albu-
min gradients consistent with an exudative rather than a portal hyper-
tension process in 74% of cases.68
Nerve conduction studies in patients with POEMS syndrome show
slowing of nerve conduction that is more predominant in the intermedi-
ate than distal nerve segments as compared to CIDP, and there is more
severe attenuation of compound muscle action potentials in the lower
than upper limbs.9,69-72 In contrast to CIDP, conduction block is
rare.9,70,72 The conduction findings could suggest that demyelination is
predominant in the nerve trunk rather than the distal nerve terminals
and axonal loss is predominant in the lower limb nerves.9 Axonal loss is
greater in POEMS syndrome than it is in CIDP.72 The nerve biopsy
shows demyelination, often with axonal loss, and typical features of
uncompacted myelin lamellae. Large onion bulbs are typically not seen
unlike the case with CIDP.73 More inflammation is seen in CIDP nerve
biopsies. Moreover, when inflammation is observed in POEMS nerve
biopsies, it is mostly epineurial perivascular whereas in CIDP the inflam-
mation is endoneurial perivascular and epineurial perivascular. Finally,
more epineurial neovascularization is seen in POEMS biopsies than in
DISPENZIERI
those of CIDP. In one report, the presence of hyperalgesia was closely
related with a reduction in the myelinated, but not unmyelinated, fiber
population.74
At ultrastructural examination there are no features of macrophage-
associated demyelination, which are seen in some cases of CIDP75-78 In
another study, ultrastructural analysis of POEMS nerves revealed endo-
thelial cytoplasmic enlargement, opening of the tight junctions between
endothelial cells and presence of many pinocytic vesicles adjacent to
the cell membranes, all consistent with an alteration of the permeability
of endoneurial vessels.17 Arimura et al studied the direct effects of
VEGF on blood nerve barrier function using an animal model and found
that VEGF increased the microvascular permeability inducing end-
oneurial edema.79 The authors postulate that this increased permeabil-
ity could allow serum components toxic to nerves, like complement and
thrombin, to induce further damage. In one study of human nerve biop-
sies of POEMS patients, more than 50% of endoneurial blood vessels
had narrowed or closed lumina with thick basement membranes, strong
polyclonal immunoglobulin staining in the endoneurium (consistent with
blood-nerve barrier opening), and thrombin-antithrombin complexes.64
Scarlato and colleagues have proposed that the mechanism of periph-
eral neuropathy in POEMS syndrome is due to endothelial injury, indi-
rectly or directly caused by an abnormal activation of endothelial cells
by VEGF, which is overexpressed in the nerves of patients with POEMS
syndrome.17 According to these authors there may be hypertrophy and
proliferation of endothelial cells with a secondary microangiopathy,
which fuels the destructive feedback loop of reduced oxygen supply,
expression of HIF-1a, with a secondary increase in local VEGF
expression.
Endocrinopathy is a central but poorly understood feature of
POEMS. In one series,51 approximately 84% of patients had a recog-
nized endocrinopathy, with hypogonadism as the most common
endocrine abnormality, followed by thyroid abnormalities, glucose
metabolism abnormalities, and lastly by adrenal insufficiency. The
majority of patients have evidence of multiple endocrinopathies in the
four major endocrine axes (gonadal, thyroid, glucose, and adrenal).80 It is
important not to miss subclinical adrenal insufficiency, because patients
can develop adrenal crisis.
Osteosclerotic lesions occur in approximately 95% of patients, and
can be confused with benign bone islands, aneurysmal bone cysts, non-
ossifying fibromas, and fibrous dysplasia (Figure 1C-E).3,50,81,82 Some
lesions are densely sclerotic, while others are lytic with a sclerotic rim,
while still others have a mixed soap-bubble appearance. Bone windows
of CT body images are often very informative, often even more so than
FDG-uptake, which can be variable.43,44 FDG-uptake occurs in those
lesions which have a lytic component.83 The advantage of whole body
CT—even low dose like what is quickly becoming the standard in MM—
is that other features of the disease are also seen: effusions, ascites,
adenopathy, and hepatosplenomegaly.
The pulmonary manifestations are protean, including pulmonary
hypertension, restrictive lung disease, impaired neuromuscular respi-
ratory function, and impaired diffusion capacity of carbon monoxide,
but improve with effective therapy.61,84 In a series of 20 patients with
POEMS, followed over a 10-year period, 25% manifested pulmonary
817
hypertension.84 In a larger series of 137 patients who were not uni-
formly tested, nearly 10% of patients had restrictive lung disease,
reduced diffusing capacity of the lung for carbon dioxide (DLCO),
and/or pulmonary hypertension. Nearly 25% had significant chest
roentgenogram abnormalities.61 Pulmonary hypertension has been
reported to occur in 27% of unselected patients with POEMS syn-
drome.85 It is more likely to occur in patients with extravascular over-
load. Whether the digital clubbing seen in POEMS is a reflection of
underlying pulmonary hypertension and/or parenchymal disease is yet
to be determined. Impaired DLCO has been shown to be an adverse
prognostic factor another series.56
The histologic findings of the dermis have been reported to range
from nonspecific to glomeruloid hemangiomata to vascular abnormali-
ties in apparently normal dermis.86-88 Biopsies of normal appearing skin
demonstrated an extremely complex subpapillary vascular network with
largely dilated and frequently anastomotic vessels.89 Capillary loops
appeared more complex than normal, and most of them were probably
clotted.
Serum creatinine levels are normal in most cases, but serum
cystatin C, which is a surrogate marker for renal function, is high in 71%
of patients.90 In our experience, at presentation, fewer than 10% of
patients have proteinuria exceeding 0.5 g/24 hours, and only 6% have a
serum creatinine greater than or equal to 1.5 mg/dL. Four percent of
patients developed renal failure as preterminal events.50 In a series from
China, 22% of patients had a creatinine clearance (CrCl) of less than
60 mL/min/m2.7,91 In our experience, renal disease is more likely to occur
in patients who have coexisting Castleman disease. In POEMS syndrome,
the renal histologic findings are diverse with membranoproliferative fea-
tures and evidence of endothelial injury being most common.92 On both
light and electron microscopy, mesangial expansion, narrowing of capil-
lary lumina, basement membrane thickening, subendothelial deposits,
widening of the subendothelial space, swelling and vacuolization of
endothelial cells, and mesangiolysis predominate.93-99 Standard immuno-
fluorescence is negative,94,100 which differentiates it from primary
membranoproliferative glomerulitis.92 Rarely infiltration by plasma cells
nests or Castleman-like lymphoma can be seen.99
3 | RELATIONSHIP TO CASTLEMAN
DI SE A SE A ND C A ST LE M A N D I SE A SE
VARIANT OF POEMS
Castleman disease (or angiofollicular lymph node hyperplasia) is a
rare lymphoproliferative disorder which has many presentations,
ranging from an asymptomatic unifocal mass to multifocal masses
with a multitude of symptoms. The symptoms can range from simple
B-symptoms to various autoimmune phenomenon to a frank POEMS
syndrome.3,5,50,101-134 Several published cases of “interesting fea-
tures” associated with Castleman disease are likely cases of POEMS
syndrome.135-138 Multicentric Castleman disease with and without
peripheral neuropathy tend to be different; it has even been pro-
posed that the presence or absence of peripheral neuropathy should be
part of the multicentric Castleman disease classification system.139
818
Those patients with peripheral neuropathy are more likely to have
136,140-145
edema and impaired peripheral circulation, and they are
also more likely to have a monoclonal lambda protein in their
serum and/or urine.146
Between 11% and 30% of POEMS patients who have a docu-
mented clonal PCD also have documented Castleman disease or
1,3,5,7,50
Castleman-like histology. In 30 patients with POEMS syn-
drome, 19 of 32 biopsied lymph nodes showed angiofollicular hyper-
plasia typical of Castleman disease.3 In another series, 25 of
43 biopsied lymph nodes were diagnostic of Castleman disease and
84% of these had hyaline vascular type.7 Only those with peripheral
neuropathy AND a plasma cell clone should classified as classic
POEMS syndrome. Without both of these characteristics, patients can
be classified as Castleman disease variant of POEMS.
The neuropathy in Castleman disease patients tends to be more sub-
tle than that of POEMS patients with osteosclerotic myeloma and is
more often sensory. At its worst, however, it is a mixture of demyelin-
ation and axonal degeneration with normal myelin spacing on electron
microscopy,144 and abnormal capillary proliferation, similar to what is
seen in the affected lymph nodes, has been described.144 In contrast to
the osteosclerotic myeloma variant of POEMS in which VEGF is the
most consistently elevated cytokine, in Castleman disease IL-6 is the
dominant aberrantly overexpressed cytokine. Castleman disease patients
often have a brisk polyclonal hypergammaglobulinemia.
4 | RISK STRATIFICATION
To date, there are no known molecular or genetic risk factors that pre-
dict for overall survival. The course of POEMS syndrome is usually
chronic as long as patients are treated. Prior to the common use of
high-dose chemotherapy with autologous stem cell support and the
renaissance of myeloma therapies, the median survival was nearly
14 years.50,61 Overall survival has improved over time (Figure 2);
patients diagnosed before and after 2003 had 10-year survival rates
F I G U R E 2 Long term overall survival of 291 patients with POEMS
syndrome. Taken with permission from Kourelis TV, et al. (2016). Long-
term outcome of patients with POEMS syndrome: An update of the
Mayo Clinic experience. Am J Hematol. 91(6):585-589. POEMS,
polyneuropathy, organomegaly, endocrinopathy, M-protein, skin
changes
DISPENZIERI
of 55% and 79%, respectively.147 In a report from the Mayo Clinic,
favorable prognostic factors for overall survival included albumin
greater than 3.2 g/dL, attainment of a complete hematologic response
and younger age. Investigators from China have developed a risk
nomogram that includes age greater than 50, presence of a pleural
effusion, an eGFR < 30 mL/min/1.73 m2, and pulmonary hyperten-
sion.148 Other risk factors predicting for shorter overall survival that
have been previously described include fingernail clubbing, extravas-
cular volume overload—that is, effusions, edema, and ascites,50 respi-
ratory symptoms,61 pulmonary hypertension85 impaired DLCO, and
papilledema.56 The number of POEMS features does not affect sur-
vival.5,10,50 In our experience and in a report by Li and colleagues,
patients with coexisting Castleman disease may have an inferior over-
all survival as compared to patients without.7 In a series of 11 patients,
lower VEGF levels predicted for better response to therapy, with res-
olution of the skin changes, improvement of the neuropathic distur-
bances and reduction all of the features assumed to be related to
increased permeability, like papilledema and organomegaly.17
Thrombocytosis and increased bone marrow infiltration are associated
with risk for cerebrovascular accidents.63
5 | T H E R A P Y OV E R V I E W
Despite the relationship between disease response and dropping
levels of VEGF, the most experience with successful outcomes has
been associated with directing therapy at the underlying clonal PCD
rather than solely targeting VEGF with anti-VEGF antibodies. The
treatment algorithm is based on the extent of the plasma cell infiltra-
tion (Figure 3). There are those patients who do not have bone mar-
row involvement as determined by blind iliac crest sampling and those
who do have disseminated disease, that is, either bone diffuse marrow
involvement and/or more than three skeletal lesions, and the
approach to these two groups of patients differs. In general patients
have good progression-free survival (PFS) with modern therapies, with
overall 6-year PFS of more than 50% (Figure 4A). The longest PFS is
observed for those patients who achieve a hematologic complete
F I G U R E 3 Algorithm for the treatment of POEMS syndrome.
POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein,
skin changes
DISPENZIERI
F I G U R E 4 Progression-free survival (A)
among patients with POEMS
syndrome. A, Progression-free survival
of 262 patients. B, Progression-free
survival of 262 patients based on
hematologic response. C, Progression-
free survival after first relapse (n = 62).
Taken with permission from Kourelis TV,
et al. (2016). Risk factors for and
outcomes of patients with POEMS
syndrome who experience progression
after first-line treatment. Leukemia.
30(5):1079-1085. POEMS,
polyneuropathy, organomegaly, (C)
endocrinopathy, M-protein, skin changes
response (5-year PFS 88%), but even those patients who do not have
CR, 5-year PFS is 50% (Figure 4B). Among those patients who relapse,
their subsequent PFS is 39 months (Figure 4C).
6 | M A N A G E M E N T O F P O E M S SY N D RO M E
W I T H O U T D I S S E M I N A T E D BO N E M A R R O W
INVOLVMENT
In the case of patients with an isolated bone lesion without clonal
plasma cells found on iliac crest biopsy, radiation is the recommended
therapy as it is in the case of a more straightforward solitary
plasmacytoma of bone. Not only does radiation to an isolated (or even
two or three isolated) lesion(s) improve the symptoms of POEMS syn-
drome over the course of 3 to 36 months, but it can be curative. In a
series of 35 patients with POEMS syndrome treated at the Mayo clinic,
radiation was used as primary therapy.149 This resulted in a 4-year over-
all survival of 97% and a 4-year failure free survival of 52%. More than
half the “failures” occurred within 12 months of radiation. Whether
these were true failures or whether they were driven by patient and
physician anxiety over slow response is unclear in this retrospective
series. An update of this series, which now included 91 patients receiv-
147
ing radiation therapy, the 10-year overall survival was 70% and the
6-year progression-free survival was 62%.150 In a review of radiation
therapy in management of POEMS syndrome from South Korea, six
patients had radiotherapy as primary therapy—two of whom had multi-
ple lesions, but were deemed too sick for chemotherapy— and seven
patients received consolidative radiotherapy for persistent M-spike
151
and/or persistent clinical symptoms. The response rates in this series
for radiation alone were comparable to that of the Mayo series, but in
the Korean series both OS and PFS were inferior among those patients
819
(B)
who received radiation therapy alone largely due to the fact that these
patients were sicker at time of treatment.
7 | MANAGEMENT OF POEMS SYNDROME
WITH DISSEMINATED BONE MARROW
INVOLVMENT
Once there is disseminated bone marrow involvement, albeit even
with a low plasma cell percentage, radiation is not expected to be
curative. If the bone lesion (ie, plasmacytoma) is reasonably large, radi-
ation can be considered as primary therapy despite a positive iliac
crest biopsy. One approach in this type of case is to follow symptoms,
serum M-protein and blood VEGF levels over the course of 6 to
12 months after completing radiation, and then decide upon whether
systemic therapy should be added. More commonly, once there is dis-
seminated disease identified, systemic therapy is recommended with
the caveat that large bony lesions with a significant lytic component
may require adjuvant radiation therapy. Decisions about adjuvant
radiation should be made on a case by case basis, and typically not
until a minimal of 6 months after completing chemotherapy. It is
important to remember that the there is a lag between completion of
successful therapy and neurologic response, often with no discernible
improvement until 6 months after completion of therapy. Maximal
response is not seen until 2 to 3 years hence. Other features like ana-
sarca, papilledema, and even skin changes may improve sooner. Opti-
mal FDG-PET response may also lag by 6 to 12 months.
As there is a paucity published randomized clinical trials among
patients with POEMS syndrome, treatment recommendations are
based on limited trial data, case series, and anecdote. Despite the rela-
tionship between disease response and dropping levels of VEGF, the
820
TABLE 4 Activity of therapy for the treatment of POEMS
syndrome
Regimen Outcome
Radiation 50-70% of patients have significant clinical
improvement
Melphalan- 81% hematologic response rate; 100% with
dexamethasone some neurologic improvement
Corticosteroids 50% of patients have significant clinical
improvement
Cyclophosphamide- At least 50% of patients have significant
dexamethasone improvement
ASCT 100% of surviving patients have significant
clinical improvement
Thalidomide- Reported responses, but not recommended
dexamethasone as first line due to risk of neuropathy
Lenalidomide- 75-95% patients have significant clinical
dexamethasone improvement and VEGF improvement
Bortezomib Nearly 100% in combination with
cyclophosphamide and dexamethasone.
Caution regarding risk of worsening
neuropathy. Usually used after first line.
Bevacizumab No consistent benefit
Abbreviations: ASCT, autologous stem cell transplantation; POEMS,
polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes.
most experience with successful outcomes has been associated with
directing therapy at the underlying clonal PCD rather than solely
targeting VEGF with anti-VEGF antibodies. Table 4 demonstrates a
summary of observed outcomes. The treatment armamentarium is
borrowed from other PCDs, most notably MM and light chain
amyloidosis.
The most experience has been with alkylator-based therapy,
either low dose or high dose with peripheral blood stem cell trans-
plant. The first prospective clinical trial to treat POEMS syndrome
included 31 patients who were treated with 12 cycles of melphalan
and dexamethasone.152 The authors found that 81% of patients had
hematologic response, 100% had VEGF response, and 100% with at
least some improvement in neurologic status. A limitation of this study
is that follow-up was only 21 months, so long term outcomes are not
yet available. Personal experience and retrospective reports of the
use of cyclophosphamide-based therapies are also promising.
High-dose chemotherapy with peripheral blood stem cell transplant
can also be quite effective, but selection basis may confound these
reports. Case series suggest 100% of patients achieve at least some neu-
rologic improvement.18,57,92,145,153-165 Doses of melphalan ranging from
140 to 200 mg/m2 have been used, with the lower doses used for sicker
patients. In addition, tandem transplant has been applied in one patient,
but again, no information is available regarding any added value of the
second transplant.166 Anecdotally, responses are durable, but relapses
27,167,164
have been reported. In our experience with 80 patients, 6 year
147
PFS was 72% and 10-year OS was 89%.
Treatment-related morbidity and mortality can minimized by rec-
ognizing and treating an engraftment-type syndrome characterized by
fevers, rash, diarrhea, weight gain, and respiratory symptoms and
DISPENZIERI
signs that occurs anytime between days 7 and 15 post-stem cell infu-
sion.161 A starting dose of prednisone ranging between 20 and
1500 mg/day has been used. No evidence-based recommendation
can be given as to the appropriate dose, but of late we have been
using 1-2 mg/kg. The taper can typically start within 2 days and com-
pleted over 10 to 14 days. Splenomegaly was the baseline factor that
best predicted for a complicated peri-transplant course. Patients had a
higher than expected transfusion need with median numbers of plate-
let and erythrocyte transfusions being five apheresis units and six
units, respectively. They also had delayed engraftment with a median
time to neutrophil engraftment of 16 days, with only 10% engrafting
by day 13. Their times to platelets 20 × 109/L and 50 × 109/L were
14.5 and 19.5 days, respectively.
Other promising treatments include lenalidomide, thalidomide,
and bortezomib, drugs all of which can have anti-VEGF and anti-TNF
effects. Li and colleagues reported a phase II trial of 12 cycles of
lenalidomide and dexamethasone in 41 patients.168 The complete
hematologic response rate was 46%, the neurologic response rate
was 95%, and the VEGF response rate was 83%. After a median fol-
low up of 34 months, the estimated 3-year OS and PFS were 90%
and 75%, respectively. Nozza et al have reported prospective data on
18 patients (13 previously treated and 5 newly diagnosed, but not eli-
gible for autologous stem cell transplantation [ASCT]) treated with
lenalidomide and dexamethasone.169 Patient responding after six
cycles continued treatment until progression or toxicity. Endpoints
were neurological or clinical improvement. After six cycles of Rd, all
but four had improvement in their ONLS, and at 39 months of follow-
up, all patients were alive with a 3-year progression-free survival of
59%. This is consistent with other case series in which all patients
respond, but relapses appear to occur 3 to 10 months after the end of
therapy.170-172 Given the intrinsic risk patients with POEMS syn-
drome have for thrombosis, it is imperative that at least an aspirin be
used for prophylaxis. The use of low molecular weight heparin or war-
farin should be balanced against fall risk. Some authors recommend
baseline head magnetic resonance angiography prior to starting
lenalidomide and dexamethasone due to their experience with
lenalidomide-induced ischemic cerebrovascular disease in a patient
with POEMS syndrome.55
Zhao and colleagues have performed a retrospective review of
nearly 350 patients with POEMS syndrome receiving melphalan and
dexamethasone, ASCT, or lenalidomide and dexamethasone and con-
cluded that the highest response rates were seen with ASCT, followed
by lenalidomide and dexamethasone, and finally by melphalan and dexa-
methasone. Patients receiving lenalidomide and dexamethasone had
the shortest PFS and a trend for a shorted OS. It should also be noted
that those patients undergoing ASCT had the lowest risk disease.173 In
a similar vein, Bianco and colleague in a much smaller series (n = 15) sys-
tematically compared changes seen among patients receiving ASCT or
lenalidomide and dexamethasone found changes neurologic changes
and 1 and 2 years were comparable for the two therapies.174
Thalidomide in combination with dexamethasone170-172,175,176
has also shown to produce responses in terms of VEGF, peripheral
neuropathy, and extravascular volume overload, but hematologic
DISPENZIERI 821

responses have not been reported.177-180 Enthusiasm for this therapy
should be tempered by the risk of peripheral neuropathy induced by
this drug. Misawa and colleagues have reported on a 25 patient
24-week randomized double blind trial of thalidomide plus dexameth-
asone vs dexamethasone alone for patients ineligible for ASCT.181
VEGF levels dropped faster in patients treated with thalidomide,
though there were no significant differences in other endpoints
between the two groups at 24 weeks. During the 72-week open label
extension study, nerve conduction velocities increased as compared
to baseline. Fifty-four percent of the thalidomide patients had sinus
bradycardia and two-thirds had constipation. There is no mention of
worsening neuropathy in the first 24 weeks, but 23% of patients had
worsening of their sensory neuropathy in the 48-week open exten-
sion portion. Enthusiasm for this therapy should be tempered by the
risk of peripheral neuropathy induced by this drug.
Like lenalidomide and thalidomide, bortezomib also has anti-VEGF
and anti-TNF effects. Bortezomib use has been reported in approxi-
mately 50 patients.182-188 The first report is difficult to interpret as the
patient had a number of chemotherapies prior to receiving a
bortezomib, doxorubicin, and dexamethasone combination. There was
early evidence of improvement even before starting the bortezomib
regimen. The other reports as single agent, with dexamethasone, or
with dexamethasone and cyclophosphamide all showed remarkable
improvements in patients without any worsening of the peripheral neu-
ropathy. Dramatic improvement in ascites was seen in more than one
instance. Finally, the largest series was from Shanghai Changzheng
Hospital in which 20 patients with newly diagnosed POEMS syndrome
were treated with three to six cycles of cyclophosphamide, reduced
dose bortezomib, and dexamethasone.187 The overall hematologic
response rate was 76% with seven patients achieving complete hema-
tologic response; 88% had VEGF response. Ninety-five percent of
patients had a reduction of the ONLS (overall neuropathy limitation
scale) by one or more. No neurologic worsening was observed. Median
follow-up was only 11 months, though one patient switched to
lenalidomide therapy after reaching only stable disease after five cycles
of bortezomib-based therapy.
There is one report of using daratumumab in a patient with POEMS
syndrome.189 Khan et al treated a 60-year old woman 18 months after
an ASCT for progressive disease. She was given lenalidomide,
daratumumab, and dexamethasone. At 11 months, not only did she
have a complete hematologic response, but she also had neurologic
improvement. There is also a case of a patient being treated with BCMA
CAR-T who is in complete response at 10 months.190
Although an anti-VEGF strategy is appealing, the results with
bevacizumab have been mixed.22-27 Five patients who had also
received either radiation or alkylator during and/or predating the
bevacizumab had benefit,24-26,191 including three who had improve-
ment, but was then consolidated with high-dose chemotherapy with
ASCT.25,191 Three patients receiving bevacizumab died.21,22,27
Both our experience and the literature would support that single
agent IV IG or plasmapheresis is not helpful. A recent report, however,
describes reduction in serum VEGF and clinical improvement with

TABLE 5 Response criteria for POEMS syndrome

Parameter Evaluable Complete response Improvement Progressiona

Plasma VEGF 2× ULN Normalb 50% reduction from baselineb 50% increase from lowest level
c
Hematologic M-spike 0.5 g/dL , Negative serum and urine 50% reduction of M-spike 25% increase from lowest level,
1.0 g/dLd,e IFE and bone marrowb from baselinef which must be >0.5 g/dL
PET/CT At least one lesion No FDG uptake 50% reduction in 30% increase of sum of SUVmaxg
with FDG SUVmaxg sum of SUVmaxg from lowest level, which must
be at least 4 SUVmaxg OR
appearance of new
FDG avid lesion
mNIS + 7POEMS All patients … # 15% change from baseline " 15% change from lowest
(a minimum of 10 points) value (a minimum of 10 points)
Ascites/effusion/edema Present Absent Improved by one CTCAE Worsened by one CTCAE
grade from baseline grade from lowest grade
ECHO RVSP ≥40 mm Hg … <40 mm Hg
Papilledema Present Absent Worsening by one CTCAE grade
DLCO <70% predicted ≥70% predicted … Worsening by one CTCAE grade

Abbreviations: DLCO, diffusing capacity of carbon monoxide; ECHO RVSP, echocardiogram right ventricular systolic pressure; IFE, immunofixation; VEGF,
vascular endothelial growth factor.
a
Any progression event (VEGF, hematologic, or clinical) will be considered progression, assuming change is attributable to disease and not an adverse
event. To document progression, option exists for repeating value. If confirmed, progression date is first date of suspected progression.
b
For VEGF and M-spike and IFE response documentation, blood values need to be repeated for verification.
c
For very good partial response (VGPR) evaluable.
d
For PR evaluable.
e
Quantitative IgA is acceptable surrogate for M-spike for proteins migrating in the beta region.
f
VGPR is defined as no measurable monoclonal protein on serum or urine electrophoresis, but positive IFE.
g
By body weight.
822
single agent IV IG. The response was not durable, which prompted
another course of IV IG with radiation to a solitary plasmacytoma.192
Other treatments like interferon-alpha, tamoxifen, trans-retinoic acid,
ticlopidine, argatroban, and strontium-89 have been reported as hav-
10
ing activity mostly as single case reports.
8 | MANAGING SYMPTOMS OF DISEASE
Attention to supportive care is imperative. Orthotics, physical therapy,
and continuous positive airway pressure (CPAP) all play an important
role in patients' recovery. Ankle foot orthotics can increase mobility
and reduce falls. Physical therapy reduces the risk for permanent con-
tractures and leads to improved function both in the long and short
term. For those with severe neuromuscular weakness, CPAP and/or
bilevel positive airway pressure provides better oxygenation and poten-
tially reduces the risk complications associated with hypoventilation like
pulmonary infection and pulmonary hypertension. Patients should also
be screened for depression.193
9 | MONITORING RESPONSE
Patients must be followed carefully on a quarterly basis tracking the
status of deficits comparing these to baseline (Table 2).164 VEGF
responses may occur as soon as 3 months,162 but they can be delayed.
VEGF is an imperfect marker as discordance between disease activity
and response have been reported,194 so trends rather than absolute
values should direct therapeutic decisions. Serum M-protein responses
by protein electrophoresis, immunofixation electrophoresis, or serum
immunoglobulin free light chains also pose a challenge. The size of the
M-protein is typically small making standard MM response criteria
inapplicable in most cases. In addition, patients can derive very signifi-
cant clinical benefit in the absence of and M-protein response.161,195
Finally, despite the fact that the immunoglobulin free light chains are
elevated in 67% to 90% of POEMS patients, the ratio is normal in all
but 13% to 18%,90,196 making the test of limited value for patients with
POEMS syndrome.
Recommendations about how to approach organ response have
been suggested for the purposes of clinical trials as there are more than
two-dozen parameters that can be assessed in a given patient with
POEMS syndrome given the multisystem nature of the disease.164,197
Alternatively, response criteria for POEMS syndrome could be abridged
as follows: (a) hematologic response using a modified amyloid response
criteria; (b) VEGF response; (c) FDG-PET response18; (d) and a simplified
organ response, which is limited to those systems causing the most
morbidity, like peripheral neuropathy assessment, pulmonary function
testing, and extravascular overload (Table 5).
1 0 | C O N C LU D I N G R E M A R K S
In summary, POEMS syndrome is an important paraneoplastic syn-
drome associated with a clonal plasma cell neoplasm. Making the
DISPENZIERI
diagnosis can be a challenge, but a good history and physical examina-
tion followed by appropriate testing—most notably radiographic
assessment of bones, measurement of VEGF, and careful analysis of a
bone marrow biopsy—can differentiate this syndrome from other con-
ditions like CIDP, immunoglobulin light chain amyloidosis, and MGUS
neuropathy. Once the diagnosis is made, attention to supportive care
and treatments that are active in MM are essential; however, applica-
tion of neurotoxic MM therapies should be used in the context of a
clinical trial or at the time of relapsed or resistant disease.
CONFILICT OF INTEREST
Research dollars from Celgene, Millenium, Prothena, Pfizer, and
Alnylam.
OR CID
Angela Dispenzieri https://orcid.org/0000-0001-8780-9512
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How to cite this article: Dispenzieri A. POEMS Syndrome:
2019 Update on diagnosis, risk-stratification, and
management. Am J Hematol. 2019;94:812–827. https://doi.
org/10.1002/ajh.25495