Elsevier

Blood Reviews

Volume 21, Issue 6, November 2007, Pages 285-299
Blood Reviews

Review
POEMS syndrome

https://doi.org/10.1016/j.blre.2007.07.004Get rights and content

Summary

POEMS syndrome is a rare paraneoplastic syndrome secondary to a plasma cell dyscrasia. Recognition of the complex of a combination of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes, papilledema, extravascular volume overload (peripheral edema, pleural effusions, ascites), sclerotic bone lesions, thrombocytosis, Castleman disease is the first step in effectively managing the disease. A rise in the blood levels of vascular endothelial growth factor is usually confirmatory. More than 95% of patients will have monoclonal lambda sclerotic plasmacytoma(s) or bone marrow infiltration. In patients with a dominant sclerotic plasmacytoma, first line therapy should include radiation to the lesion. Retrospective analysis and personal experience would dictate that systemic therapy be considered for patients with diffuse sclerotic lesions or absence of any bone lesion and for those who have not demonstrated stabilization of their disease 3 to 6 months after completing radiation therapy. For those patients with diffuse disease, systemic therapy is indicated. Useful approaches include therapy with corticosteroids, low dose alkylator therapy, and high dose chemotherapy with peripheral blood stem cell transplant. Until the pathogenesis is fully understood, these are the mainstays of treatment for patients with POEMS syndrome. The role of anti-VEGF therapies, immune modulatory drugs, and proteasome inhibitors has not yet been defined, but drugs with known high rates of treatment related neuropathy should not be considered as first line therapy.

Introduction

POEMS syndrome is a paraneoplastic disorder associated with an underlying plasma cell dyscrasia. The major clinical feature of the syndrome is a chronic progressive polyneuropathy with a predominant motor disability.1, 2 The acronym POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) captures several dominant features of the syndrome. Important traits not included in the acronym include elevated levels of vascular endothelial growth factor, sclerotic bone lesions, Castleman Disease, papilledema, peripheral edema, ascites, effusions, thrombocytosis, polycythemia, fatigue and clubbing. Other names for the syndrome include osteosclerotic myeloma, Crow-Fukase Syndrome, and Takatsuki syndrome.3, 4 Though the majority of patients have osteosclerotic myeloma, these same patients usually have only 5% bone marrow plasma cells or less (almost always monoclonal lambda), and rarely have anemia, hypercalcemia or renal insufficiency. These characteristics and the superior median survival differentiate POEMS syndrome from multiple myeloma.

Section snippets

History

Scheinker’s autopsy case in 1938 was the first report of what we now call POEMS syndrome.1, 4, 5, 6 His patient was a 39 year-old man with a solitary plasmacytoma, sensorimotor polyneuropathy, and localized patches of thickened and deeply pigmented skin on the chest.5, 7 The complexity of the interaction of plasma cell dyscrasia and peripheral neuropathy became increasingly evident in 1956 with Crow’s description of two patients with osteosclerotic plasmacytomas with neuropathy, and other

Diagnostic criteria revisited

Establishing diagnostic criteria for any syndrome is fraught with difficulty, POEMS notwithstanding. They must be broad enough to diagnose patients early to avoid cumulative morbidity, but narrow enough that patients without the syndrome are not mislabeled as having the syndrome. Soubrier et al demonstrated that prognosis was not dependent on the number of features present in these patients.20 We confirmed that in our series of 99 patients and proposed criteria, which were later criticized for

Pathogenesis

The pathogenesis of this multisystem disease is complex, but there has been some progress in our understanding. Elevations of proangiogenic 23, 25, 26, 27, 28, 29, 30, 31, 32, 33 and pro-inflammatory25, 26, 27, 32 cytokines are the hallmark of this disorder. As will be discussed, little is known about the plasma cells except that more than 95% of the time they are lambda light chain restricted. Prior hypotheses have included implication of hyperestrogenemia20 and HHV-8.34, 35, 36 The

Clinical features (Fig. 1)

The peak incidence of the POEMS syndrome is in the 5th and 6th decades of life, unlike multiple myeloma, which has a peak incidence in the 7th and 8th decades. Symptoms of peripheral neuropathy usually dominate the clinical picture.19 Symptoms begin in the feet and consist of tingling, paresthesias, and coldness. Motor involvement follows the sensory symptoms. Both are distal, symmetric, and progressive with a gradual proximal spread. Severe weakness occurs in more than one-half of patients and

Laboratory investigations

Thrombocytosis is common, and polycythemia may be seen.2, 19 Anemia and thrombocytopenia are not characteristic unless there is co-existing Castleman’s Disease. Hypercalcemia and renal insufficiency are rarely present. The size of the M-protein on electrophoresis is small (median 1.1 g/dL) and is rarely more than 3.0 g/dL. The M-protein is usually IgG or IgA and almost always of the lambda type.2, 3 Levels of serum erythropoietin are low and are inversely correlated with VEGF levels.45 Bence

Relationship to castleman disease

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 (Table 2).2, 4, 81 Between 11–30% of POEMS patients have documented Castleman disease or Castleman-like disease.4, 20 This estimate may be conservative since most

Differential diagnosis

The dominant feature of this syndrome is typically the peripheral neuropathy, and not infrequently patients are initially diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) or, less frequently, Guillan-Barre. If a monoclonal protein is detected, monoclonal gammopathy associated peripheral neuropathy and AL amyloidosis enter the differential diagnosis. The two best ways to distinguish POEMS from these entities is to measure a plasma or serum VEGF level and to determine

Prognosis

The course of POEMS syndrome is chronic and patients typically survive for more than a decade in contrast to multiple myeloma. In our experience, the median survival was 13.8 years.2 Individual reports of patients with the disease for more than 5 years are not unusual and in one French study, at least 7/15 patients were alive for more than 5 years.20 In Nakanishi’s series of 102 patients, the median survival was 33 months4 though in Takatsuki’s study of 109 patient, the authors stated that the

Therapy

There are no randomized controlled trials in patients with POEMS. Information about benefits of therapy is most typically derived retrospectively (Table 3). Given these limitations, however, there are therapies which benefit patients with POEMS syndrome, including radiation therapy,2, 7, 13, 128, 129, 130 alkylator based therapies,2, 4, 12, 70, 109, 131 and corticosteroids.2 Intensive supportive care measures must also be instituted. Single or multiple osteosclerotic lesions in a limited area

Summary points

POEMS Syndrome is a complex, but fascinating syndrome, which share elements with other diseases—most notably other plasma cell dyscrasias and Castleman’s Disease. Unraveling the elements of this paraneoplastic syndrome has the potential to provide insight into a number of other disorders. For now, the revolution in myeloma treatment provides many excellent treatment options for these patients. One of the greatest practical challenges on is making the diagnosis in a timely fashion to prevent

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    Support in part by the Robert A. Kyle Hematologic Malignancies Fund, Mayo Clinic.

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