POEMS syndrome overview

# Overview
POEMS syndrome is a rare medical syndrome named for its main clinically recognizable features: Polyneuropathy (peripheral nerve damage), Organomegaly (abnormal enlargement of organs), Endocrinopathy (damage to hormone-producing glands)/Edema, M-protein (an abnormal antibody) and Skin abnormalities (including hyperpigmentation and hypertrichosis). In 1938, Ilya Mark Scheinker, a Russian neurologist and neuropathologist described a patient with a solitary plasmacytoma, sensorimotor polyneuropathy, and localized patches of thickened and deeply pigmented skin. In 1956, R. S. Crow published two case reports of myelomatosis with peripheral neuritis and other striking features. In 1977, Iwashita et al described a patient who had an osteosclerotic myeloma accompanied by sensorimotor polyneuropathy, skinhyperipigmentation, edema, hypertrichosis, gynecomastia, and white nails. In 1980, Bardwick et al proposed the acronym 'POEMS' to represent a syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. POEMS syndrome is a para-neoplastic syndrome characterized by multi-organ system dysfunction, monoclonal plasma cell proliferation and demyelinating inflammatory polyneuropathy. The lambda component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation. Bone marrow studies of patients suffering from POEMS syndrome shows lymphoid aggregates rimmed by monotypic or polytypic plasma cells. The monoclonal gammopathy or overproduction of lambda light chain stimulates the monocyte/macrophage system to produce various proinflammatory cytokines. such as interleukin-1, interleukin-6, interleukin-12, vascular endothelial growth factor (VEGF) and TNF-Alpha. Transforming growth factor beta (TGF-beta), an inhbitory cytokine is thought to be underproduced in patients suffering from POEMS syndrome leading to a storm of proinflammatory cytokines which drive the disease process. The overproduction of this IL-6 may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis. The mesangial proliferation and membranoproliferative glomerulonephritis (MPGN) seen in POEMS syndrome is thought to be secondary to increased production of platelet-derived growth factor(PDGF) and fibroblast growth factor beta (FGF-) have been implicated in mesangial cell proliferation. The neovascularization induced by VEGF leads to increased vascular permeability. Since the increased production of VEGF is unchecked due to the plasma cell dyscrasia, the consequence is an unregulated extravasation of intravascular fluid into the extravascular compartment. resulting in edema. POEMS syndrome is known to be associated multiple myeloma (osteosclerotic type), Castleman's disease, plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), pulmonary hypertension, restrictive lung disease, thrombophilia, cardiac amyloidosis and papilledema. There are no known and well established causes of POEMS syndrome. Marked activation of the pro-inflammatory cytokines and weak or decreased TGF beta 1 action can play a role in the disease pathogenesis. The precise incidence of POEMS syndrome is difficult to determine and we have no well established data to quote. The median age at presentation has been 51 years with the majority of the patients comprising of males. A mediansurvival of 165 months has also been recorded. The precise incidence of POEMS syndrome is difficult to determine due to the complexity of the syndrome presentation and we have no well established data regarding the incidence. Prevalence of POEMS syndrome in Japan is reported to be about 0.3/100,000. There is no racial predilection to POEMS syndrome. There is no well established data regarding the gender predilection of POEMS syndrome. Data from Japan shows a male predilection of 2.5:1. The majority of POEMS syndrome cases have been reported in Japan and China. According to the The International Myeloma Working Group, the diagnosis of POEMS syndrome may be established if both mandatory criteria, one major and one minor criteria are fulfilled. Mandatory criteria include presence of polyneuropathy and a monoclonal plasma cell proliferative disorder. Major criteria include presence of sclerotic bone lesions or mixed sclerotic/lytic lesions, presence of Castleman's disease and elevated serum VEGF levels. Minor criteria include presence of organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis and polycythemia. Patients suffering from POEMS syndrome may have variable presentation and can present a diagnostic challenge for the clinician due to non-specific symptomology. Common symptoms of POEMS syndrome include numbness, tingling and weakness affecting extremities, fatigue, generalized pain in the body, foot drop, blurred vision, peripheral edema, dyspnea and hyperpigmentation. Less common symptoms include muscle weakness, diplopia, ocular pain and ascites. Laboratory findings consistent with the diagnosis of POEMS syndrome include increased serum VEGF level, increased number of thrombocytes, increased number of erythrocytes, elevated cerebrospinal fluid (CSF) protein content, increased number of leukocytes, low levels of IgG lambda or IgA lambda M-protein in the serum, and increased number of plasma cells in the bone marrow. An x-ray may be helpful in the diagnosis of POEMS syndrome. Findings on an x-ray suggestive of POEMS syndrome include osteolytic bone lesions, pleural effusion, increased cardiac silhouette (secondary to pericardial effusion), and ascites. CT scan may be helpful in the diagnosis of POEMS syndrome. Findings on CT scan suggestive of POEMS syndrome include bone lesions, lymphadenopathy, hepatomegaly, splenomegaly, pleural effusion, pericardial effusion, and ascites. MRI may be helpful in the diagnosis of POEMS syndrome. Findings on MRI suggestive of POEMS syndrome include diffuse lumbosacral nerve root enhancement, bone lesions. Echocardiography/ultrasound may be helpful in the diagnosis of POEMS syndrome. Findings on echocardiography/ultrasound suggestive of POEMS syndrome include pericardial effusion, left ventricular hypertrophy with moderately impaired systolic function, pulmonary hypertension, seroperitoneum, and hepatosplenomegaly. CT scan may be helpful in the diagnosis of POEMS syndrome. Findings on CT scan suggestive of POEMS syndrome include bone lesions, lymphadenopathy, hepatomegaly, splenomegaly, pleural effusion, pericardial effusion, and ascites. MRI may be helpful in the diagnosis of POEMS syndrome. Findings on MRI suggestive of POEMS syndrome include diffuse lumbo-sacral nerve root enhancement and bone lesions. (18)F-FDG PET/CT is an adequate tool for evaluation, diagnosis, and monitoring of the pathology. (18)F-FDG PET/CT may be helpful in the diagnosis of POEMS syndrome. Findings suggestive of POEMS syndrome include mixed bone lesions, lymphadenopathy, hepatosplenomegaly, and serous cavity effusions. Fluorescein angiography may reveal unilateral pooling of fluid consistent with cystoid macular edema. Optical coherence tomography (OCT) may show loss of retinal nerve fiber layer thickness. Other diagnostic studies that can help in making the diagnosis of POEMS syndrome include nerve conduction study, electromyograpy, fundoscopy, serum plasma electrophoresis and immunofixation electrophoresis, visual field testing, and pulmonary function test. Patients with isolated bone lesion without bone marrow clonal plasma cells involvement can be treated with radiotherapy. Patients with a disseminated disease (more bone lesions and/or bone marrow plasmacytosis) are the candidates for systemic therapy. Systemic therapy includes corticosteroids, autologous stem cell transplantation (ASCT), induction therapy, alkylator-based therapy, thalidomide, lenalidomide, bortezomib, and bevacizumab. Surgical intervention is not recommended for the management of POEMS syndrome. There are no established measures for the primary prevention of POEMS syndrome. There are no established measures for the secondary prevention of POEMS syndrome.

# Historical Perspective
In 1938, Ilya Mark Scheinker, a Russian neurologist and neuropathologist described a patient with a solitary plasmacytoma, sensorimotor polyneuropathy, and localized patches of thickened and deeply pigmented skin. In 1956, R. S. Crow published two case reports of myelomatosis with peripheral neuritis and other striking features. In 1977, Iwashita et al described a patient who had an osteosclerotic myeloma accompanied by sensorimotor polyneuropathy, skinhyperipigmentation, edema, hypertrichosis, gynecomastia, and white nails. In 1980, Bardwick et al proposed the acronym 'POEMS' to represent a syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes.

# Pathophysiology
POEMS syndrome is an acronym, where the 'P' stands for polyneuropathy, 'O' for organomegaly (specifically of the liver and spleen), 'E' for endocrinopathy, 'M' for immunoglobulin (para-protein or M-protein) and 'S' for skin changes. POEMS syndrome is a para-neoplastic syndrome characterized by multi-organ system dysfunction, monoclonal plasma cell proliferation and demyelinating inflammatory polyneuropathy. The lambda component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation. Bone marrow studies of patients suffering from POEMS syndrome shows lymphoid aggregates rimmed by monotypic or polytypic plasma cells. The monoclonal gammopathy or overproduction of lambda light chain stimulates the monocyte/macrophage system to produce various proinflammatory cytokines. such as interleukin-1, interleukin-6, interleukin-12, vascular endothelial growth factor (VEGF) and TNF-Alpha. Transforming growth factor beta (TGF-beta), an inhbitory cytokine is thought to be underproduced in patients suffering from POEMS syndrome leading to a storm of proinflammatory cytokines which drive the disease process. The overproduction of this IL-6 may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis. The mesangial proliferation and membranoproliferative glomerulonephritis (MPGN) seen in POEMS syndrome is thought to be secondary to increased production of platelet-derived growth factor(PDGF) and fibroblast growth factor beta (FGF-) have been implicated in mesangial cell proliferation. The neovascularization induced by VEGF leads to increased vascular permeability. Since the increased production of VEGF is unchecked due to the plasma cell dyscrasia, the consequence is an unregulated extravasation of intravascular fluid into the extravascular compartment. resulting in edema. POEMS syndrome is known to be associated multiple myeloma (osteosclerotic type), Castleman's disease, plasmacytoma, monoclonal gammopathy of undetermined significance (MGUS), pulmonary hypertension, restrictive lung disease, thrombophilia, cardiac amyloidosis and papilledema. The most potent risk factor leading to the development of POEMS syndrome is multiple myeloma of osteosclerotic type.

# Causes
There are no known and well established causes of POEMS syndrome. Marked activation of the pro-inflammatory cytokines and weak or decreased TGF beta 1 action can play a role in the disease pathogenesis.

# Differential Diagnosis
The diagnosis of POEMS syndrome presents a diagnostic challenge for the physician. A thorough examination of organ systems should be attempted in order to reach a confirmed diagnosis. POEMS syndrome should be differentiated from other conditions presenting as a polyneuropathy (metabolic syndrome, vitamin B12 deficiency, Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor polyneuropathy), organomegaly with lymphadenopathy (malaria, leshmaniasis or kala-azar, infective hepatitis, chronic myelogenous leukemia, lymphoma, primary amyloidosis, Gaucher's disease), endocrinopathy (hypogonadism, hypothyroidism, hypopituitarism), monoclonal plasma cell proliferation (multiple myeloma, monoclonal gammopathy of undetermined significance, plasmacytoma), mixed lytic/sclerotic bone lesions (osteomalacia, osteogenesis imperfecta) and skin changes.

# Epidemiology and Demographics
The precise incidence of POEMS syndrome is difficult to determine and we have no well established data to quote. The median age at presentation has been 51 years with the majority of the patients comprising of males. A mediansurvival of 165 months has also been recorded. The precise incidence of POEMS syndrome is difficult to determine due to the complexity of the syndrome presentation and we have no well established data regarding the incidence. Prevalence of POEMS syndrome in Japan is reported to be about 0.3/100,000. There is no racial predilection to POEMS syndrome. There is no well established data regarding the gender predilection of POEMS syndrome. Data from Japan shows a male predilection of 2.5:1. The majority of POEMS syndrome cases have been reported in Japan and China.

# Risk Factors
The most potent risk factor leading to the development of POEMS syndrome is multiple myeloma of osteosclerotic type.

# Screening
There is insufficient evidence to recommend routine screening for POEMS syndrome.

# Natural History, Complications, and Prognosis
POEMS syndrome presents as a chronic progressive polyneuropathy. Patients may have coexisting multi-organ system disorders. The neuropathy is usually symmetrical and ascending. Endocrinopathy, present in majority of cases, involves hypogonadism, hypothyroidism, and abnormalities of the pituitary-adrenal axis. If left untreated, patients suffering from POEMS syndrome may become wheel chair bound. Complications of POEMS syndrome include renal failure, pulmonary hypertension, pathologic fractures, ischemic stroke, restrictive lung disease, polycythemia, thrombocytosis, papilledema, and myocardial infarction. 3, 5, and 10 year overall survival (OS) for patients newly diagnosed with POEMS syndrome is 87.7%, 84.1%, and 77%. Age >50 years, pulmonary hypertension, pleural effusion, and estimated glomerular filtration rate <30 ml/min/1.73 m2 were associated with inferior overall survival in the derivation cohort, with the use of multivariate Cox regression model based on randomized sample splitting of 362 patients. Low albumin (defined as<3.2 g/dl) at diagnosis and failure to achieve a complete hematologic response to first-line therapy can be independent risk factors for progression-free survival (PFS). Improvement of plasma cell dyscrasia leads to improvement or marked reduction in other abnormalities. Neuropathy, stroke, and myocardial infarction are the most common causes of death in POEMS syndrome.

# Diagnosis

## Diagnostic Study of Choice
According to the The International Myeloma Working Group, the diagnosis of POEMS syndrome may be established if both mandatory criteria, one major and one minor criteria are fulfilled. Mandatory criteria include presence of polyneuropathy and a monoclonal plasma cell proliferative disorder. Major criteria include presence of sclerotic bone lesions or mixed sclerotic/lytic lesions, presence of Castleman's disease and elevated serum VEGF levels. Minor criteria include presence of organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis and polycythemia.

## History and Symptoms
Patients suffering from POEMS syndrome may have variable presentation and can present a diagnostic challenge for the clinician due to non-specific symptomology. Common symptoms of POEMS syndrome include numbness, tingling and weakness affecting extremities, fatigue, generalized pain in the body, foot drop, blurred vision, peripheral edema, dyspnea and hyperpigmentation. Less common symptoms include muscle weakness, diplopia, ocular pain and ascites.

## Physical Examination
Common physical examination findings of POEMS syndrome include, organomegaly (hepatomegaly, splenomegaly), peripheral edema/anasarca, ascites, mixed lytic/sclerotic bone lesions, papilledema, skin hyperpigmentation and lymphadenopathy.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of POEMS syndrome include increased serum VEGF level, increased number of thrombocytes, increased number of erythrocytes, elevated cerebrospinal fluid (CSF) protein content, increased number of leukocytes, low levels of IgG lambda or IgA lambda M-protein in the serum, and increased number of plasma cells in the bone marrow.

## Electrocardiogram
There are no ECG findings associated with POEMS syndrome.

## X-ray
An x-ray may be helpful in the diagnosis of POEMS syndrome. Findings on an x-ray suggestive of POEMS syndrome include osteolytic bone lesions, pleural effusion, increased cardiac silhouette (secondary to pericardial effusion), and ascites.

## Echocardiography and Ultrasound
Echocardiography/ultrasound may be helpful in the diagnosis of POEMS syndrome. Findings suggestive of POEMS syndrome include pericardial effusion, left ventricular hypertrophy with moderately impaired systolic function, pulmonary hypertension, seroperitoneum, and hepatosplenomegaly.

## CT Scan
CT scan may be helpful in the diagnosis of POEMS syndrome. Findings on CT scan suggestive of POEMS syndrome include bone lesions, lymphadenopathy, hepatomegaly, splenomegaly, pleural effusion, pericardial effusion, and ascites.

## MRI
MRI may be helpful in the diagnosis of POEMS syndrome. Findings on MRI suggestive of POEMS syndrome include diffuse lumbo-sacral nerve root enhancement and bone lesions.

## Other Imaging Findings
(18)F-FDG PET/CT is an adequate tool for evaluation, diagnosis, and monitoring of the pathology. (18)F-FDG PET/CT may be helpful in the diagnosis of POEMS syndrome. Findings suggestive of POEMS syndrome include mixed bone lesions, lymphadenopathy, hepatosplenomegaly, and serous cavity effusions. Fluorescein angiography may reveal unilateral pooling of fluid consistent with cystoid macular edema. Optical coherence tomography (OCT) may show loss of retinal nerve fiber layer thickness.

## Other Diagnostic Studies
Other diagnostic studies that can help in making the diagnosis of POEMS syndrome include nerve conduction study, electromyograpy, fundoscopy, serum plasma electrophoresis and immunofixation electrophoresis, visual field testing, and pulmonary function test.

# Treatment

## Medical Therapy
Patients with isolated bone lesion without bone marrow clonal plasma cells involvement can be treated with radiotherapy. Patients with a disseminated disease (more bone lesions and/or bone marrow plasmacytosis) are the candidates for systemic therapy. Systemic therapy includes corticosteroids, autologous stem cell transplantation (ASCT), induction therapy, alkylator-based therapy, thalidomide, lenalidomide, bortezomib, and bevacizumab.

## Surgery
Surgical intervention is not recommended for the management of POEMS syndrome.

## Primary Prevention
There are no established measures for the primary prevention of POEMS syndrome.

## Secondary Prevention
There are no established measures for the secondary prevention of POEMS syndrome.