POEMS Syndrome

From Compendium of Cancer Genome Aberrations
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Primary Author(s)*

Sohini Anand, MBBS

Tharanga Niroshini Senaratne, PhD

Cancer Category/Type

Plasma Cell Neoplasm

Cancer Sub-Classification / Subtype

Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome

Definition / Description of Disease

POEMS syndrome is a rare blood disorder which is considered to be a subtype of plasma cell neoplasm. It is a multisystem disorder and stands for Polyneuropathy, Organomegaly, Endocrinopathy/edema, Monoclonal-protein (increased levels in blood), and Skin changes. In this condition, abnormal monoclonal proteins are secreted by plasma cells leading to its clinical presentations which include nerve damage, enlargement of spleen and/or lymph nodes, endocrine involvement leading to diabetes, thyroid abnormalities and certain skin/ hair changes such as hyperpigmentation, thickening of skin, red spots and increased facial hair growth.

Synonyms / Terminology

  • [1]Crow-Fukase syndrome
  • [1]Osteosclerotic myeloma
  • [1]PEP syndrome (Polyneuropathy-endocrinopathy-plasma cell dyscrasia syndrome)
  • [1]Shimpo syndrome
  • [1]Takatsuki syndrome[2]

Epidemiology / Prevalence

Not much information can be derived regarding the incidence and prevalence of POEMS syndrome.[Epidemiology 1]. Some information can be derived from the study conducted in Japan in the year 2015. The result showed that the prevalence is 0.3 per 1,00,000 with a male: female ratio of 1.5:1.[2] The median age of occurrence is 54.[3] However, few cases have also been seen in patients in their twenties.[1] Mean survival is 13.7 years.[4]

Clinical Features

As mentioned earlier, POEMS syndrome is a rare disorder which comprises of constellation of clinical presentations with neuropathy present in almost 100% of the cases. Following are the clinical features:

  • Polyneuropathy: One of the earliest presentations or may be the only presentation. The onset is usually sub-acute with mixed (sensory-motor) distal & symmetrical involvement. This is often associated with abnormal sensations like allodynia. Sensory involvement precedes motor loss. Most patients need assistance soon after developing polyneuropathy either because of loss of function or pain.[5]
  • Organomegaly and Organ dysfunction: There are multiple organ involvement and damage leading to organ dysfunction. Most common involved organs are lymph nodes, liver, kidney and spleen. Other organs which can be affected are CNS, renal, lung which can lead to asymptomatic parenchymal thickening, decreased GFR and pulmonary HTN; respectively. [5] Furthermore, arterial vascular involvement has been noted which can lead to cerebro-vascular accidents and ischemic strokes. [5]
  • Endocrinopathy: Multiple endocrinal organs can be involved. Most common presentation noted in males are erectile dysfunction because of hypogonadism which may be because of involvement of hypothalamus, pituitary or the primary organ itself(testes).[6] Other presentations can be diabetes, hypo/hyperthyroidism or adrenal gland abnormalities.
  • Monoclonal antibodies: POEMS syndrome is typically considered to be a plasma cell abnormality where plasma cells produce excessively high paraproteins particularly light chains (lambda proteins mainly of IgA type). The unique feature of POEMS which distinguish this condition from rest of the gammopathies is that- it is found that in approximately 50% of the pre-treatment specimens have reactive lymphoid aggregates which contain a mixture of both B and T cells with a thin rim of plasma cells. Other consistent finding are atypically appearing megakaryocytes with hyperplasia. Increased platelets counts are seen in 54% of the cases.[7] PBS is usually normal. [5]
  • Skin involvement: About 68% patients diagnosed with POEMS syndrome present with skin involvement. Most common is diffuse hyperpigmentation(purplish hue), acrocyanosis, calciphylaxis, thickening of skin, papular lesions, excessive sweating; aka; hyperhidrosis. Areas most commonly involved are extensor surfaces, neck, arm pit. Nail changes such as leukonychia. Hypertrichosis has also been reported. In few cases, hemangiomas such as cherry and capillary hemangiomas has been noted.
  • Other findings- fluid accumulation in body cavities leading to peritoneal effusion, pleural effusion and ascites.
  • Papilledema
  • Polycythemia
  • Specific finding in males- gynecomastia and impotence noted in male patients.
  • Specific findings in Females- amenorrhea and galactorrhea have been reported in female patients with POEMS syndrome

Sites of Involvement

POEMS syndrome involves multiple systems of the body.

  • Peripheral nerves and spinal cord: Peripheral neuropathy is present in 100% of the cases. This is the most common manifestation of POEMS syndrome.
  • Reticuloendothelial system- Lymph node, spleen and Liver are also most frequently involved. Lymph node simulates Castleman disease. Hepatosplenomegaly is present in almost 50% of the cases.
  • Bone- Bone is involved in 95% of the POEMS patient. Bone lesions are mostly sclerotic, but occasionally can be lytic lesions surrounded by thin rim of sclerosis. "Soap bubble" appearances have also been reported.[8]
  • Skin- About 90% of the POEMS patients develop skin changes. Most commonly being skin pigmentations.
  • Kidney- Kidney damage has been reported which can alter GFR and can lead to CKD.
  • Pancreas- Diabetes type2 has been noted.[9]
  • Adrenal gland- Involvement of adrenal glands cause malfunctioning leading to Addison's disease.[9]
  • Gonads- decreased level of testosterone can lead to hypo functioning of male gonads eventually leading to hypogonadism.[9]
  • Thyroids
  • Eye

Morphologic Features

  • Bone marrow Findings- Increased monoclonal plasma cells interspersed between polyclonal plasma cells with majority of monoclonal cells resembling λ chains. Plasma cell rimming around lymphoid aggregates. Also, Platelet precursors or megakaryocytes hyperplasia have been reported. [10]
  • Nerve fiber biopsies- POEMS syndrome has predilection for peripheral nerves compared to autonomic nerve fibers. The manifestation is severe and progressive. Biopsy specimens have shown 2 specific findings including axonal degeneration and epineural blood vessels formation which can be helpful in differentiating from C IDP(Chronic Inflammatory Demyelinating Polyradiculoneuropathy). CIDP presents as endoneurial inflammation and characteristic "onion bulb appearance".[11]
  • Skin Biopsies- Cases who developed hemangioma, biopsy showed "glomeruloid pattern"; accumulation of blood vessels containing RBCs in dilated vascular space resembling renal glomeruli. Patients who presented with skin thickening showed sclerosis with dilation of blood vessels on biopsy. Livedo reticularis biopsies showed thrombosis with necrosis in arterioles.[12]
  • Bone lesions biopsy: Osteosclerotic bone lesions biopsy shows proliferation of plasma cells which stain positive for CD138.[13]


Plasma cells in BM biopsy ranges from<5% to 60%. 95% of the cases have value <5%.[14] Usually there are a combination of normal polyclonal plasma cells and monoclonal plasma cells. The monoclonal plasma cells stains positive for λ chains (IgA and IgG). [15]


  • CD138+ forms plasma cell rim around lymphoid aggregates
  • CD38+ rim around lymphoid aggregates
  • monoclonal Plasma cells stains positive for cytoplasmic λ chain immunoglobulins.
  • Bright expression of CD45 and normal expression of CD19 in polytypic CD19 (Normal finding).
  • Lymphoid aggregates were staining positive for CD20+ B cells and CD3+ T cells.


  • Diminished expression of CD45 and loss of CD19 in monotypic plasma cells. (findings in POEMS).
  • κ chain immunoglobulin stain absent.
  • JAK2V617F mutation absent
  • HHV8 staining absent

Chromosomal Rearrangements (Gene Fusions)

Characteristic Chromosomal Aberrations / Patterns

Genomic Gain/Loss/LOH

A study conducted at Peking Union Medical college Hospital from November 2011 to June 2012 showed the following chromosomal abnormalities associated with POEMS syndrome.[16]. In this study, BM plasma cells CD138+ were collected using MACS system and then FISH technique was applied.

chromosomal translocation Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence
14q32 [ t4,14( 33.3%), t11;14-(55.6%) IGHC/IGHV 45%
Chromosome Number Gain/Loss/Amp/LOH Region NAME %
13q14 loss Rb-1 25
1q12 Gain CEP-1 20

Gene Mutations (SNV/INDEL)

A study was conducted in 20 patients of POEMS syndrome. The study showed 7 gene shaving recurrent somatic gene mutations involved in POEMS syndrome. It is important to know that none of the important gene mutations involved in MM such as NRAS, KRAS, BRAF, and TP53 were found in POEMS syndrome patients.[17] Plasma Cell Neoplasms

The method used to find out the gene mutations were-

  • WES(Whole Exome Sequencing)- WES was performed in 20 patients. The mean depth in WES was 140x
  • Targeted Sequencing- TS was performed in all 20 patients. The mean depth in TS was 620x in more than 95% patients
  • Deep analysis of hot spots.
Somatic genes mutations % Type of mutations 20 MUTATIONS LOCATION
  • R559Q
  • L71R
  • A91D
  • L258P



LTB 15
  • Q51E
  • T56R
  • 163-1 G>C
EHD1 10
  • G70D
  • 71_75 del
  • 404+2 T>A
Dynamin N


  • S68N
  • D243N
  • A270V
  • V526I
cu oxidase 2/3
  • S464C
  • V565M
  • L782R
  • L397L
  • N530S
  • I682V

Other involved gene mutations were- ANK3, ATRX, BTG, CTNNB1, DNAH11, DNAH9, DST, DUSP2, EP300, EPHA7, ERBB2, HIST1H4L, IGLL5, NCKAP5, PKHD1L1, PLD1, RP1L1, RYR1, RYR3, SRCAP, USH2A, ZFHX3, and ZFHX4.

PDLIM5 4 94456293 p.V49G -3.085
SEC24B 4 109449420 p.T46M 0.387
ZFHX3 16 72958758 p.A463E -1.178
PACRG 6 163312833 p.N223S -1.098

Epigenomics (Methylation)

PDLIM 5 is considered to be a part of PDZ-LIM protein family. This protein is involved in neuronal development. PDLIM 5 binds to the inhibitors of DNA binding 2 protein leading to suppression of inhibitory activities and proliferation and/ or regeneration of nerve axons. Mutation in the genes expressing this protein lead to abnormal axon growth and degeneration. This can lead to peripheral neuropathy seen in POEMS syndrome.[18]

Genes and Main Pathways Involved


Nothing much is known about the pathophysiology of POEMS syndrome. Nevertheless, It is being presumed that various pro-inflammatory cytokines may be playing a strong role leading to multiple system involvement.[19]

  • Pro-inflammatory markers concentrations are increased leading to wide spread inflammation. Some of them are- TNF- α (Tumor Necrotic Factor), IFN-γ ( Interferon γ), IL-1β, IL-2, IL-6 (Interleukins). The cause of increased levels of cytokines are not known, but it has been hypothesized that cytokines are secreted because of stimulation by λ IGs secreted by plasma cells or by the tumor itself.
  • Decreased level of anti-inflammatory cytokines- A decreased level of TGF-β (Transforming Growth Factor β) may lead to imbalance between the pro and anti inflammatory factors resulting in disastrous clinical representation.
  • Role of VEGF- Again, it is being hypothesized that VEGF (Vascular Endothelial Growth Factor) may lead to neovascularization leading to proliferation of small blood vessels. It is important to note that disease activity correlates with VEGF levels even more than M proteins.[14]
  • λ Immunoglobulins

Diagnostic Testing Methods

Diagnosis of POEMS syndrome is extremely important because clinical features simulate other common disorder leading to misdiagnoses. In order to avoid misdiagnoses, meticulously looking into the presentations is mandatory.[7]

To start with- Detailed history taking and physical examination are important to look for constellations of clinical features mentioned above. Peripheral polyneuropathy and monoclonal plasma cells expressing λ immunoglobulins should always be present to diagnose POEMS syndrome. POEMS syndrome can be considered as one of the differential diagnoses in patients who do not respond to standard treatment of CIDP. It is also important to distinguish POEMS syndrome from other plasma cells disorders such as MGUS and multiple myeloma.

  • Biochemical tests- VEGF (Vascular Endothelial Growth Factor) levels in serum and plasma. Usual cut off level of VEGF for diagnosis of POEMS syndrome is 1920 pg/ml and 200 pg/ml. N-terminal propeptide of Type I- collagen is consider as novel blood marker for POEMS syndrome with a cutoff value of 70ng/ml. CBC to look for RBC concentrations and platelet counts. TSH, FSH, T3/T4, cortisol levels should be measured.
  • Radiological examinations- CT scan, PET scans, echocardiography should be done to look for bony lesions, organomegaly and fluid accumulations in body cavities.
  • Bone marrow biopsies- should be considered to look for presence of plasma cells in the osteosclerotic bony lesions.
  • Nerve conduction studies and nerve biopsies should be considered.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Diagnosis of POEMS syndrome requires meticulous search for clinical features and testing because of clinical simulation with other common conditions. Being one of the rare disease entities it can easily be missed by clinicians.


Management of POEMS syndrome requires multiple steps.

  1. Number one step is to determine baseline values-
  • history taking and physical examination- fundoscopy, skin examination, multiple organ assessments, neurological examinations.
  • Blood tests- CBC, hormone levels, VEGF, serum electrophoresis, quantitative immunoglobulins
  • Radiological assessments- skeletal surveys with CT/PET, organ assessments for effusion
  • Bone marrow biopsy of osteosclerotic lesions.
  • Systemic evaluation- kidneys- baseline 24 hour urine protein, urine electrophoresis, lung-PFTs, heart- Echocardiography, nerve electrophysiological studies and biopsies

2. 2nd step is to assess extent of bone marrow involvement-

SYSTEMIC THERAPY is considered in following conditions:

If iliac crest (IC) biopsy reports presence of plasma cells
If there is no plasma cells present in IC biopsy but more than 2 bony lesions are present. In disseminated lesions, systemic therapy may be needed.

Medications in systemic therapy includes- Melphalan, corticosteroids, cyclophosphamide-dexamethasone, lenalidomide-dexamethasone, proteasome inhibitors such as-Bortezomib.


If there are no plasma cells present in IC biopsy and there are less than 2 lesions present. Radiation therapy in these scenarios can be curative as well.

ASCT- Autologous stem cell transplant is considered to be 100% effective treatment.

Bevacizumab- is an anti-VEGF. It has been noted that the use of this medication has no superior effect over radiation and systemic therapy, although the main pathogenesis of POEMS syndrome is production of VEGF.

3. Supportive care - Supportive care is very important in POEMS syndrome. Physical therapy and/or occupational therapy improves short and long term complications such as contractures and improve muscle strength. Chest physiotherapy and CPAP (continuous positive airway pressure) improves lung function. Being a chronic progressive condition, physical and emotional support has a vital role in it's management.


  • VEGF
  • M spike
  • PET SCAN for FDG SUVmax (clinical improvement when there is 50% reduction)
  • DLCO
  • improvement in papilledema
  • clinical improvement in effusions

Familial Forms

Put your text here

Other Information


POEMS syndrome is a chronic progressive disorder. It can be fatal if left untreated, therefore early diagnosis and prompt treatment is crucial.[20] Median survival is 13.7 years.


  • Response to radiotherapy
  • Absence of clubbing and effusions.


  • Presence of clubbing (median survival- 2.6 years) and effusions (median survival 6.6 years)

Death usually occurs due to malnutrition or infection such as lung infection.


  • CIDP- chronic idiopathic demyelinating polyneuropathy- clinical manifestations of CIDP and POEMS are similar. However, the pathophysiology are different which can be appreciated in nerve biopsy. Both being a demyelinating conditions, can delay the diagnosis and management of POEMS syndrome because patients are usually managed for CIDP. Failure to response to management of CIDP should prompt physicians to consider possibility of POEMS syndrome.
  • AL AMYLOIDOSIS - The clinical presentations of amyloidosis may simulate POEMS syndrome such as organomegaly, nerve damage etc, but biopsy helps differentiates GB syndrome from POEMS syndrome. In former, biopsy shows amyloid fibrils accumulation where as in POEMS syndrome, neovascularization can be seen because of increased VEGF titers.
  • GUILLAINE BARRE SYNDROME- A preceding history of respiratory or genitourinary infection is present in GB syndrome. In severe form, respiratory failure can occur due to paralysis of diaphragm. GB syndrome is a self-limiting and spontaneous resolution occurs in most cases where as POEMS syndrome is a chronic progressive condition without antecedent history of diarrhea or respiratory illness.[21]
  • MGUS (MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE)- MGUS has increased levels of M protein in serum. Systemic involvement is rarely seen in MGUS. However, polyneuropathy may be seen occasionally in MGUS.

How to differentiate POEMS syndrome from Multiple myeloma (MM)?

  • Studies have shown that the POEMS syndrome patients are relatively younger than MM.[22]
  • The λ immunoglobulins in POEMS syndrome are typically IgG or IgA which is present only in small quantities. These small quantities can be easily missed by serum protein electrophoresis, therefore immunofixation electrophoresis techniques are applied to detect immunoglobulins in POEMS syndrome, unlike multiple myeloma. Also, in POEMS syndrome plasma cells in bone marrow biopsy are fewer than multiple myeloma; approximately 2%. [22] Plasma cells are present in large quantities in MM.
  • The bony lesions in POEMS syndrome are osteosclerotic type and /or mixed osteosclerosis + osteolytic giving it a "soap bubble appearance" where as in multiple myeloma it's osteolytic type. Therefore, typical symptoms of bone pain and fracture are absent in POEMS syndrome which are the presenting symptoms of multiple myeloma. Radiological studies have shown normal FDG avidity in POEMS syndrome(osteosclerotic lesions) and high FDG avidity in multiple myeloma( osteolytic lesions)[22]
  • Polyneuropathy is rarely seen in MM. It can be present with MM when associated with amyloidosis.
  • CRAB - Hypercalcemia, renal insufficiency, anemia and osteolytic bone lesions which are characteristically present in MM are rarely seen in POEMS syndrome.[23]


Plasma Cell Neoplasms with Associated Paraneoplastic Syndrome


(use "Cite" icon at top of page)

  1. 1.0 1.1 1.2 1.3 1.4 1.5 https://rarediseases.org/rare-diseases/poems-syndrome/
  2. 2.0 2.1 Suichi, Tomoki; et al. (2019-09-03). "Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey". Neurology. 93 (10): e975–e983. doi:10.1212/WNL.0000000000008062. ISSN 1526-632X. PMID 31371568.
  3. Suichi, Tomoki; et al. (2019-09-03). "Prevalence, clinical profiles, and prognosis of POEMS syndrome in Japanese nationwide survey". Neurology. 93 (10): e975–e983. doi:10.1212/WNL.0000000000008062. ISSN 1526-632X. PMID 31371568.
  4. Marinho, Flauberto Sousa; et al. (2015). "Cutaneous Manifestations in POEMS Syndrome: Case Report and Review". Case Reports in Dermatology. 7 (1): 61–69. doi:10.1159/000381302. ISSN 1662-6567. PMC 4448059. PMID 26034475.CS1 maint: PMC format (link)
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  6. Dispenzieri, Angela; et al. (2018-02). "POEMS Syndrome". Hematology/Oncology Clinics of North America. 32 (1): 119–139. doi:10.1016/j.hoc.2017.09.010. ISSN 0889-8588. Check date values in: |date= (help)
  7. 7.0 7.1 7.2 7.3 Dispenzieri, Angela (2019). "POEMS Syndrome: 2019 Update on diagnosis, risk-stratification, and management". American Journal of Hematology. 94 (7): 812–827. doi:10.1002/ajh.25495. ISSN 1096-8652.
  8. "POEMS Syndrome - an overview | ScienceDirect Topics".
  9. 9.0 9.1 9.2 "POEMS Syndrome - Hormonal and Metabolic Disorders".
  10. Dao, Linda N.; et al. (2011-06-16). "Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients". Blood. 117 (24): 6438–6444. doi:10.1182/blood-2010-11-316935. ISSN 1528-0020. PMC 3123015. PMID 21385854.
  11. Piccione, Ezequiel A.; et al. (2016-10-31). "Nerve pathologic features differentiate POEMS syndrome from CIDP". Acta Neuropathologica Communications. 4. doi:10.1186/s40478-016-0389-1. ISSN 2051-5960. PMC 5088652. PMID 27799073.
  12. Barete, Stéphane; et al. (2010-06-01). "Skin Manifestations and Vascular Endothelial Growth Factor Levels in POEMS Syndrome: Impact of Autologous Hematopoietic Stem Cell Transplantation". Archives of Dermatology. 146 (6). doi:10.1001/archdermatol.2010.100. ISSN 0003-987X.
  13. Hara, Daisuke; et al. (2017-10). "Utility of osteosclerotic lesion biopsy in diagnosis of POEMS syndrome: A case report". Medicine. 96 (41): e8188. doi:10.1097/MD.0000000000008188. ISSN 1536-5964. PMC 5662307. PMID 29019884. Check date values in: |date= (help)
  14. 14.0 14.1 Dispenzieri, Angela (2012-06-14). "How I treat POEMS syndrome". Blood. 119 (24): 5650–5658. doi:10.1182/blood-2012-03-378992. ISSN 0006-4971. PMC 3425020. PMID 22547581.CS1 maint: PMC format (link)
  15. Dao, Linda N.; et al. (2011-06-16). "Bone marrow histopathology in POEMS syndrome: a distinctive combination of plasma cell, lymphoid, and myeloid findings in 87 patients". Blood. 117 (24): 6438–6444. doi:10.1182/blood-2010-11-316935. ISSN 0006-4971. PMC 3123015. PMID 21385854.CS1 maint: PMC format (link)
  16. Kang, Wen-Ying; et al. (2013-12). "14q32 translocations and 13q14 deletions are common cytogenetic abnormalities in POEMS syndrome". European Journal of Haematology. 91 (6): 490–496. doi:10.1111/ejh.12189. Check date values in: |date= (help)
  17. Nagao, Yuhei; et al. (2019-07). "Genetic and transcriptional landscape of plasma cells in POEMS syndrome". Leukemia. 33 (7): 1723–1735. doi:10.1038/s41375-018-0348-x. ISSN 1476-5551. Check date values in: |date= (help)
  18. 18.0 18.1 Lin, Qingqing; et al. (2020-06-01). "Somatic Mutations Confer Severe Peripheral Neuropathy in POEMS Syndrome-Associated Multicentric Castleman Disease". Neuroscience Bulletin. 36 (6): 664–666. doi:10.1007/s12264-020-00481-y. ISSN 1995-8218. PMC PMC7270242 Check |pmc= value (help). PMID 32166648 Check |pmid= value (help).CS1 maint: PMC format (link)
  19. Gherardi, R. K.; et al. (1996-02-15). "Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome". Blood. 87 (4): 1458–1465. ISSN 0006-4971. PMID 8608236.
  20. "POEMS syndrome - Symptoms and causes".
  21. "Guillain-Barré syndrome". 2017-10-23.
  22. 22.0 22.1 22.2 Shi, Xiaofeng; et al. (2015-01). "Clinicopathologic Analysis of POEMS Syndrome and Related Diseases". Clinical Lymphoma Myeloma and Leukemia. 15 (1): e15–e21. doi:10.1016/j.clml.2014.04.017. ISSN 2152-2650. Check date values in: |date= (help)
  23. Nozza, Andrea (2017-09-01). "POEMS SYNDROME: AN UPDATE". Mediterranean Journal of Hematology and Infectious Diseases. 9 (1): e2017051. doi:10.4084/MJHID.2017.051. ISSN 2035-3006.


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