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-β) 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.

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 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-β) 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.

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 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.

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.

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

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

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.

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.

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 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.

There are no ECG findings associated with POEMS syndrome.

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/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 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.

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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, skin hyperipigmentation, 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.

• 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.^[1][2]
• POEMS syndrome has been recognized by various names over the years, such as osteosclerotic myeloma, Crow-Fukase syndrome, PEP syndrome, and Takatsuki syndrome.^[1]
• In 1956, R. S. Crow published two case reports of myelomatosis with peripheral neuritis and other striking features.^[3]
• In 1977, Iwashita et al described a patient who had an osteosclerotic myeloma accompanied by sensorimotor polyneuropathy, skin hyperipigmentation, edema, hypertrichosis, gynecomastia, and white nails.^[4]
• In 1980, Bardwick et al proposed the acronym ‘POEMS’ to represent a syndrome characterized by polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes.^[5]

• Crow-Fukase syndrome^[6]
• Osteosclerotic myeloma^[7]
• PEP syndrome^[8]
• Polyneuropathy–organomegaly–endocrinopathy–M protein–skin lesions^[9]
• Shimpo syndrome^[10]
• Takatsuki syndrome^[11]

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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-β) 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.

POEMS syndrome is an acronym, where the ‘P’ stands for polyneuropathy, ‘O’ for organomegaly, ‘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.^[1]

Monoclonal Plasma Cell Proliferation

• POEMS syndrome is associated with plasma cell dyscrasia in which there is monoclonal proliferation of plasma cells. The plasma cells are involved in antibody production under physiological conditions via reorganization of immunoglobulin heavy and light chains.
• The lambda component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation.^[2]
• Bone marrow studies of patients suffering from POEMS syndrome shows lymphoid aggregates rimmed by monotypic or polytypic plasma cells.
• Diffuse infiltration of light chain restricted plasma cells leads to development of predominantly sclerotic bone lesions. This is in contrast with myeloma patients where there is a predominance of lytic bone lesions. The bony lesions are primarily restricted to the axial and proximal appendicular skeleton.^[3][4][5]
• The monoclonal gammopathy or overproduction of lambda light chain stimulates the monocyte/macrophage system to produce various proinflammatory cytokines.

Cytokine Storm

• The monoclonal plasma cell proliferation in POEMS syndrome is thought to play a major role in overproduction of numerous pro-angiogenic and pro-inflammatory cytokines.
• The hypercytokinetic state induced in patients of POEMS syndrome is thought to drive the disease process. The following cytokines are overproduced:^{_Blood_Journal-6|[6]}
  • Interleukin 1 beta (IL-1b)
  • Interleukin 6 (IL-6)^[7]
  • Interleukin 12 (IL-12)^[8]
  • Tumor necrosis factor alpha (TNF-Alpha)^[9]
  • Vascular endothelial growth factor (VEGF)^[10]

Role of Interleukin-6 , Interleukin-12 and TNF-Alpha

• Interleukin- 6 is overproduced in patients with POEMS syndrome. IL-6 is a pro-inflammatory cytokine involved in maturation of B-cells into antibody producing plasma cells, induction of acute phase reactants and thrombopoeisis.^[11][12][13] The overproduction of this cytokine may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis.^[14][15]
• Interleukin-1 beta and interleukin-6 both are also involved in increased production of VEGF in POEMS syndrome.^[16]

Upregulation of VEGF production

• VEGF is a pro-angiogenic cytokine that promotes neovascularization. It is thought to be overproduced in POEMS syndrome and can serve as a marker of disease activity in these patients.
• VEGF is expressed by osteoblasts, chondrocytes, macrophages, tumor cells (including plasma cells) and megakaryocytes.
• VEGF165 is the isoform of VEGF that is overexpressed in POEMS syndrome.
• Increased VEGF could account for the organomegaly, edema, skin hemangiomata, and possibly the occasional mesangioproliferative changes found on renal biopsy.
• Since VEGF is expressed by osteoblasts and has a role in osteoblastic differentiation, the bone condensation (sclerosis) seen in POEMS syndrome may also be partly attributed to increased circulating VEGF levels.^[17]
• 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), transforming growth factor beta (TGF-β), and fibroblast growth factor beta (FGF-β) have been implicated in mesangial cell proliferation. It has been suggested that FGF-β participates in the initiation, PDGF in the maintenance, and TGF-β (an inhibitory cytokine) in the resolution of the proliferation.^[18]

Neovascularization and Edema

• 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.
• As a result, there is accumulation of fluid in the extracellular compartment and the resultant edema seen in patients of POEMS syndrome.

Alteration of Blood-Nerve Barrier and Secondary Axonal Degenration

• Unregulated neovascularization also leads to disruption of the blood-nerve barrier in the peripheral nervous system (PNS), which subsequently results in endoneural edema. The edema compresses the nerves and eventually leads to secondary axonal degeneration.

POEMS syndrome is known to be associated with the following conditions:^[19]

• Multiple myeloma (osteosclerotic type)
• Castleman’s disease
• Plasmacytoma
• Monoclonal gammopathy of undetermined significance (MGUS).
• Pulmonary hypertension
• Restrictive lung disease
• Thrombophilia
• Cardiac amyloidosis
• Papilledema
• Necrotizing autoimmune myopathy^[20]

• POEMS syndrome is known to cause organomegaly, specially of the liver and spleen.
• A normal liver is less than 16 cm on ultrasound evaluation. Hepatomegaly may be found during physical examination or on imaging studies. Imaging is more accurate in determining liver size.^[21][22]

• POEMS syndrome is most often associated with multiple myeloma.
• On microscopic histopathological analysis, multiple myeloma is characterized by the following:^[23]

• Abundant eosinophilic cytoplasm
• Eccentrically placed nucleus
• Clock face morphology of the nucleus due to chromatin clumps around the edges
• Russell bodies which are eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions
• Dutcher bodies which are PAS stain +ve intranuclear crystalline rods

• Shown below is a series of microscopic images seen in multiple myeloma:

• 
  Bone marrow aspiration in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Bone marrow biopsy in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Bone marrow in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Bone marrow in multiple myeloma.
  (Image courtesy of Melih Aktan M.D.)
• 
  Multiple myeloma slide with intermediate magnification^[23]
• 
  Multiple myeloma slide with high magnification^[23]
• 
  Multiple myeloma slide with russell bodies^[23]

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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.

• There are no known and well established causes of POEMS syndrome.
• Some studies suggest that marked activation of the pro-inflammatory cytokines (IL-1 beta, IL-6, and TNF-alpha) play a role in the disease pathogenesis.^[1]
• Weak or even decreased (TGF beta 1) antagonistic reaction insufficient to counteract the noxious effects of cytokines can also result in this syndrome.^[1]

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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.

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, organomegaly, endocrinopathy, monoclonal plasma cell proliferation, mixed lytic/sclerotic bone lesions and skin changes. The differentials include the following:

POEMS syndrome must also be differentiated from other similar conditions which lead to multiple endocrine disorders such as autoimmune polyendocrine syndrome, Hirata syndrome, Kearns–Sayre syndrome and Wolfram syndromes.^{[73][74][75][76][77]}

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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 median survival 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 per 100,000 individuals. 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.

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 per 100,000 individuals.^[1]

The median age at presentation is 51 years.^[2]

There is no racial predilection to POEMS syndrome.^[3][4][5]

• There is no well established data regarding the gender predilection of POEMS syndrome.
• Data from Japan shows a male predilection of 2.5:1.^[6]

The majority of POEMS syndrome cases have been reported in Japan and China.^[3][4][5]

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

The most potent risk factor leading to the development of POEMS syndrome is multiple myeloma of osteosclerotic type. Other risk factors include the following:

• Castleman’s disease
• Monoclonal gammopathy of undetermined significance (MGUS)
• Plasmacytoma

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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.

• POEMS syndrome typically presents as a chronic progressive polyneuropathy with both sensory and motor disability, the motor component is usually present to a greater degree than the sensory component of the disease.^[1]
• Many patients may have coexisting multi-organ system disorders such as organomegaly (liver, spleen and lymph nodes), edema, endocrinopathy (pituitary, thyroid, adrenal glands), thrombocytosis, polycythemia, pulmonary hypertension, an M-spike (M protein or para-protein, may be IgA lambda component, IgG lambda component or light chain lambda component) and skin changes. The skin changes include angiomata, hyperpigmentation, hypertrichosis.^[2]
• The neuropathy is usually symmetrical and ascending, with either insidious or rapidly progressing onset. Sensory neuropathy precedes motor dysfunction and pin-prick and vibratory sensations are typically affected.
• The endocrinopathy is present in a majority of cases of POEMS syndrome. Almost all patients exhibiting endocrinopathy have hyperestrogenemia. The increased levels of estrogen may be the cause of hypogonadism and impotence seen in male patients. Hypogonadism, hypothyroidism, and abnormalities of the pituitary–adrenal axis are noted in order of descending frequency.^[3][4]
• POEMS syndrome may also lead to glomerular disease (membranoproliferative glomerulonephritis) eventually resulting in renal failure.
• If left untreated, patients suffering from POEMS syndrome may become wheel chair bound.

• Patients suffering from POEMS syndrome may develop the following complications:
  • Renal failure^[5]
  • Pulmonary hypertension^[6]
  • Pathological fractures (due to lytic/sclerotic bone lesions)^[7]
  • Ischemic stroke^[8]
  • Restrictive lung disease^[9]
  • Thrombocytosis^[10]
  • Arterial and venous thromboses^[11]
  • Polycythemia^[12]
  • Papilledema^[13]
  • Myocardial infarction^[14]

• The median survival of patients with POEMS syndrome is 165 months.^[15]
• 3, 5, and 10 year overall survival (OS) for patients newly diagnosed with POEMS syndrome is 87.7%, 84.1%, and 77%.^[16]
• 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.^{[16][17][18][9][19]}
• 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).^[16][20]
• Papilledema, decreased diffusing capacity of the lung for carbon monoxide (DLCO) and treatment with corticosteroids alone are also related to poor prognosis.^[21]
• 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.

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