A JH CME Information: POEMS Syndrome: 2014 update on diagnosis, risk-stratification, and management Author: Angela Dispenzieri M.D. CME Editor: Ayalew Tefferi M.D.

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䊏 Accreditation and Designation Statement: Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

䊏 Educational Objectives Upon completion of this educational activity, participants will be better able to: 1. Recognize and make diagnosis of POEMS syndrome 2. Understand best therapies for POEMS syndrome

䊏 Activity Disclosures No commercial support has been accepted related to the development or publication of this activity. Author: Angela Dispenzieri, M.D. has no conflicts of interest to disclose. CME Editor: Ayalew Tefferi, M.D. has no conflicts of interest to disclose. This activity underwent peer review in line with the standards of editorial integrity and publication ethics maintained by American Journal of Hematology. The peer reviewers have no conflicts of interest to disclose. The peer review process for American Journal of Hematology is single blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review. Conflicts of interest have been identified and resolved in accordance with Blackwell Futura Media Services’s Policy on Activity Disclosure and Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.

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C 2014 Wiley Periodicals, Inc. V

doi:10.1002/ajh.00031

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AJH Educational Material

A JH

POEMS syndrome: 2014 Update on diagnosis, risk-stratification, and management Angela Dispenzieri* Disease overview: 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 overload, and thrombocytosis. Diagnoses are often delayed because the syndrome is rare and can be mistaken for other neurologic disorders, most commonly chronic inflammatory 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 understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. The number of clinical criteria is not prognostic, but the extent of the PCD is. Those patients with an iliac crest bone marrow biopsy that does not reveal a plasma cell clone are candidates for local radiation therapy; those with a more extensive or disseminated clone will be candidates for systemic therapy. 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 3–6 months after completing radiation therapy should receive systemic therapy. Corticosteroids 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. The benefit of anti-VEGF antibodies is conflicting. Lenalidomide shows promise with manageable toxicity. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes. C 2014 Wiley Periodicals, Inc. Am. J. Hematol. 89:214–223, 2014. V

䊏 Disease Overview POEMS syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder (PCD). The acronym, which was coined by Bardwick in 1980, [1] refers to several, but not all, of the features of the syndrome: polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal PCD, and skin changes. There are three important points that relate to this memorable acronym: (1) not all of the features within the acronym are required to make the diagnosis; (2) there are other important features not included in the POEMS acronym, including papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis/erythrocytosis (P.E.S.T.), elevated VEGF levels, a predisposition towards thrombosis, and abnormal pulmonary function tests; and (3) there is a Castleman disease variant of POEMS syndrome may is associated with a clonal PCD. Other names of the POEMS syndrome that are less frequently used are osteosclerotic myeloma, Takatsuki syndrome or Crow-Fukase syndrome [2,3]. The disease was initially thought to be more common in patients of Japanese descent given the largest initial reports from Japan [2,3]. However, over the years, large series have also been reported from France, the United States, China, and India [4–8]. A national survey conducted in Japan in 2003 showed a prevalence of 0.3 per 100,000 [9]. The pathogenesis of the syndrome is not well understood. Distinctive presenting characteristics of the syndrome that differentiate POEMS syndrome from standard multiple myeloma (MM) include the following: (1) dominant symptoms have little to nothing to do with bone pain, extremes of bone marrow infiltration by plasma cells, or renal failure; (2) dominant symptoms are typically neuropathy, endocrine dysfunction, Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55906

Conflict of Interest: Research dollars from Celgene, Travel compensation from Binding Site and Celgene, and unpaid advisory board to Onyx and Millenium. *Correspondence to: Angela Dispenzieri, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55906. E-mail: [email protected] Contract grant sponsor: Robert A. Kyle Hematologic Malignancies Fund; Contract grant sponsor: Predolin Foundation; Contract grant sponsor: JABBS Foundation. Received for publication: 25 November 2013; Accepted: 26 November 2013 Am. J. Hematol. 89:214–223, 2014. Published online: in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.23644 C 2014 Wiley Periodicals, Inc. V

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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES TABLE I. Criteria for the Diagnosis of POEMS Syndromea Mandatory major criteria Other major criteria One required Minor criteria

Other symptoms and signs

1. Polyneuropathy (typically demyelinating) 2. Monoclonal plasma cell-proliferative disorder (almost always k) 3. Castleman diseasea 4. Sclerotic bone lesions 5. VEGF elevation 6. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) 7. Extravascular volume overload (edema, pleural effusion, or ascites) 8. Endocrinopathy (adrenal, thyroid,b pituitary, gonadal, parathyroid, and pancreaticb) 9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, and white nails) 10. Papilledema 11. Thrombocytosis/polycythemiac Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease, thrombotic diatheses, diarrhea, low vitamin B12 values

POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes. 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. a There is a Castleman disease variant of POEMS syndrome that occurs without evidence of a clonal PCD that is not accounted for in this table. This entity should be considered separately. b Because of the high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone is not sufficient to meet this minor criterion. c Approximately 50% of patients will have bone marrow changes that distinguish it from a typical MGUS or myeloma bone marrow [42]. Anemia and/or thrombocytopenia are distinctively unusual in this syndrome unless Castleman disease is present

and volume overload; (3) vascular endothelial growth factor (VEGF) levels are high; (4) sclerotic bone lesions are present in the majority of cases; (5) overall survival is typically superior; and (6) lambda clones predominate [10]. To date, VEGF is the cytokine that correlates best with disease activity [11–20], although it may not be the driving force of the disease based on the mixed results seen with anti-VEGF therapy [21–28]. VEGF is known to target endothelial cells, induce a rapid and reversible increase in vascular permeability, and be important in angiogenesis. It is expressed by osteoblasts, in bone tissue, macrophages, tumor cells [29] (including plasma cells) [30,31], and megakaryocytes/platelets [32]. Both IL-1b and IL-6 have been shown to stimulate VEGF production [29]. IL-12 has also been shown to correlate with disease activity [33]. Little is known about the plasma cells in POEMS syndrome except that more than 95% of the time they are lambda light chain restricted with restricted immunoglobulin light chain variable gene usage [34–36]. Translocations and deletion of chromosome 13 have been described, but hyperdiploidy is not seen [37,38].

䊏 Diagnosis The diagnosis is made based on a composite of clinical and laboratory features (Table I), and the diagnosis will be missed if it is not considered. Most notably, the constellation of neuropathy and any of the following should elicit an in depth search for POEMS syndrome: monoclonal protein (especially lambda light chain); thrombocytosis; anasarca; or papilledema. The requirements set forth in Table I are

doi:10.1002/ajh.23644

designed to retain both sensitivity 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 radiographic assessment of bones [39], measurement of VEGF [13,17,20,40,41], and careful analysis of a bone marrow biopsy [42]—can differentiate this syndrome from other conditions like chronic inflammatory polyradiculoneuropathy (CIDP), monoclonal gammopathy of undetermined significance (MGUS) neuropathy and immunoglobulin light chain amyloid neuropathy. 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 [43]. Distinguishing POEMS syndrome from a MGUS, smoldering MM (SMM), MM, or solitary plasmacytoma is important since 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 syndrome. 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 syndrome should be thoroughly evaluated to define a baseline that can be used for future assessments (Table II). A thorough review of systems and physical examination are required. Estimated frequencies of findings are shown in Table III. The variability between series is most likely a function retrospective reporting—that is, if a physician does not order a test or chart a finding, it will not be captured—and promptness of diagnosis, rather than ethnic differences [2,3,5,7,44]. The neuropathy is the dominant characteristic. The quality and extent of the neuropathy, which is peripheral, ascending, symmetrical, and affecting both sensation and motor function should be elicited [45]; in our experience, pain may be a dominant feature in about 10–15% of patients, and in one report as many as 76% of patients had hyperesthesia [9,46]. Papilledema is present in at least one-third of patients. Of the 33 patients at our institution referred for a formal ophthalmologic examination during a 10 year period, 67% had ocular signs and symptoms, the most common of which was papilledema in 52% of those examined [47]. The most common ocular symptoms reported were blurred vision in 15, diplopia in 5, and ocular pain in 3. A whole skin examination should be performed looking for hyperpigmentation, a recent out-cropping of hemangioma, hypertrichosis, dependent rubor, and acrocyanosis, white nails, sclerodermoid changes, facial atrophy, flushing, or clubbing [2,4–8,48,49]. Rarely calciphylaxis is also seen [50,51]. Respiratory complaints are usually limited given patients’ neurologic status impairing their ability to induce cardiovascular challenges. In a series of 137 POEMS syndrome patients seen at our institution between 1975 and 2003, at presentation the frequency with which patients reported dyspnea, chest pain, cough, and orthopnea, were 20, 10, 8, and 7%, respectively [52]. Patients are at increased risk for arterial and/or venous thromboses during their course, with nearly 20% of patients experiencing one of these complications [10,53]. Ten percent of patients present with a cerebrovascular event, most commonly embolic or vessel dissection and stenosis [54]. The median time between peripheral neuropathy symptom onset and the cerebrovascular event was 23 months (range 0.5–64 months). Risk factors for cerebral events included thrombocytosis and bone marrow plasmacytosis. Aberrations in the coagulation cascade have been implicated in POEMS syndrome [55]. In one report, circulating coagulation factors like fibrinopeptide A, thrombin-antithrombin complex are increased during the active phase

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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

TABLE II. Recommended Minimum Testing Test Neurologic Detailed neurologic history (numbness, pain, weakness, balance, and orthostasis) and examination (including funduscopic exam) Electrophysiologic study (nerve conduction studies) Sural nerve biopsy Organomegaly/Lymphadenopathy/Extravascular volume overload Physical exam and CT scanc documenting lymphadenopathy, organomegaly, ascites, pleural effusions, and edema Endocrinopathy History regarding menstrual and sexual function Testosterone, estradiol, fasting glucose, glycosylated hemoglobin, thyroid stimulating hormone, parathyroid hormone, prolactin, and serum cortisol Luteinizing hormone, follicle stimulating hormone, adrenocorticotropin hormone, and Cortrosyn stimulation test Hematologic Serum protein electrophoresis AND immunofixation Affected quantitative immunoglobulin Complete blood count (Hemoglobin, platelet) 24 h urine total protein, electrophoresis, and immunofixation Bone marrow aspirate and biopsy (test for kappa/lambda by IHC) VEGF Skin History and physical with attention to skin pigment, thickening and texture, body hair quantity and texture, color of distal extremities, and development of cherry angiomata Sclerotic bone lesions Skeletal radiographs and/or PET/CTc Pulmonary Function Pulmonary function tests Echocardiography to assess right ventricular systolic and pulmonary artery pressures

Baseline

Every 3 months

Yearly

X

Xa

X

X Xb

Xa

X

X

Xd

Xd

X X

X Xd

X Xd

Xb

Xd

Xd

X X X X X X

X Xb X

X X X X

X X

X

X

X

X Xb

X X X

Xd Xd

Xd Xd

a

At 6 months and then yearly. As clinically indicated. c CT bone windows are very helpful in detecting bone lesions as well as lymph nodes and organomegaly. d Only if affected. b

of illness, but other factors relating to fibrinolysis, plasminogen, a2 plasmin inhibitor plasmin complex, and FDP did not increase. On physical examination, objective evidence of the symptoms described above can be found in addition to nonbulky adenopathy, gynecomastia, darkened areolae, diminished breath sounds, hepatosplenomegaly, areflexia, and a steppage gait, commonly with a positive Romberg sign. In our experience, finger-nail clubbing is seen in about 4% of cases, but others have reported rates as high as 49% [3,52]. Laboratory findings are notable for an absence of cytopenias. In fact, nearly half of patients will have thrombocytosis or erythrocytosis [44]. 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 unprecedentedly high rate of anemia. The bone marrow biopsy reveals megakaryocyte hyperplasia and megakaryocyte clustering in 54% and 93% of cases, respectively [42]. 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. These are the patients who present at with a solitary or “multiple solitary 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 10 lb Weight loss > 10 lb Fatigue

% Affecteda 100 45–85 24–78 22–70 26–74 11–25 67–84 55–89 16–33 5–20 12–18 3–36 9–67 100 24–54 68–89 46–93 19 9–35 26–74 5–43 29–64 29–87 24–89 7–54 3–43 1–64 27–97 54–88 12–19 5–49 >15 36 37 31

a

Percentages are based on the total number of patients in the series. In both the Takasuki and Nakanishi series, only 75% of patients had a documented PCD, which defies the current definition for POEMS syndrome. Since these are among the earliest series describing the syndrome, they are included.

b

Extravascular overload most commonly manifests as peripheral edema, but pleural effusion, ascites, and pericardial effusions are common. The composition of the ascites was studied in 42 patients with POEMS syndrome. The ascitic fluid had low serum ascites albumin gradients consistent with an exudative rather than a portal hypertension process in 74% of cases [59]. Nerve conduction studies in patients with POEMS syndrome show slowing of nerve conduction that is more predominant in the intermediate 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 [9,60–63]. In contrast to CIDP, conduction block is rare [9,61,63]. 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 [63]. The nerve biopsy shows typical features of uncompacted myelin lamellae. At ultrastructural examination, there are no features of macrophage-associated demyelination, which are seen in some cases of chronic inflammatory demyelinating polyneuropathy [64–67]. In one report, the presence of hyperalgesia was closely related with a reduction in the myelinated, but not unmyelinated,

doi:10.1002/ajh.23644

fiber population [68]. In another study, ultrastuctural analysis of POEMS nerves revealed endothelial 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 endoneurial edema [69]. The authors postulate that this increased permeability could allow serum components toxic to nerves, like complement and thrombin, to induce further damage. In one study of human nerve biopsies of POEMS patients, >50% of endoneurial blood vessels had narrowed or closed lumina with thick basement membranes, strong polyclonal immunoglobulin staining in the endoneurium (consistent with bloodnerve barrier opening), and thrombin-antithrombin complexes immunohistochemically [55]. Scarlato et al. have proposed that the mechanism of peripheral neuropathy in POEMS syndrome is due to endothelial injury, indirectly 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 a recent series [70], 84% of patients had a recognized 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). Osteosclerotic lesions occur in 95% of patients, and can be confused with benign bone islands, aneurysmal bone cysts, nonossifying fibromas, and fibrous dysplasia [3,44,71,72]. 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 FDGuptake, which can be variable. The pulmonary manifestations are protean, including pulmonary hypertension, restrictive lung disease, impaired neuromuscular respiratory function, and impaired diffusion capacity of carbon monoxide, but improve with effective therapy [52,73]. In a series of 20 patients with POEMS, followed over a 10-year period, 25% manifested pulmonary hypertension [73]. In a larger series of 137 patients who were not uniformly 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 [52]. Pulmonary hypertension has been reported to occur in 27% of unselected patients with POEMS syndrome. {Li, 2013 #1287} It is more likely to occur in patients with extravascular overload. Whether the digital clubbing seen in POEMS is a reflection of underlying pulmonary hypertension and/or parenchymal disease is yet to be determined. The histologic findings of the dermis have been reported to range from non-specific to glomeruloid hemangiomata to vascular abnormalities in apparently normal dermis [74–76]. Biopsies of normal appearing skin demonstrated an extremely complex subpapillary vascular network with largely dilated and frequently anastomotic vessels [77]. 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 [78]. In our experience, at presentation, fewer than 10% of

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patients have proteinuria exceeding 0.5 g/24 hr, 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 [44]. In another series from China, 37% of patients had a creatinine clearance (CrCl) of

POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management.

POEMS syndrome is a paraneoplastic syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyradiculoneuropathy,...
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